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Vaccine Safety in the United States: Overview and Considerations for COVID-19 Vaccines

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Vaccine Safety in the United States: Overview
November 4, 2020January 29, 2021
and Considerations for COVID-19 Vaccines
Kavya Sekar
Widespread immunization efforts have been linked to increased life expectancy and Widespread immunization efforts have been linked to increased life expectancy and reduced
Analyst in Health Policy Analyst in Health Policy
reduced illness. U.S. vaccination programs, headed by the Centers for Disease Control illness. U.S. vaccination programs, headed by the Centers for Disease Control and Prevention

and Prevention (CDC) within the Department of Health and Human Services (HHS), (CDC) within the Department of Health and Human Services (HHS), have helped eradicate
Agata Dabrowska
Agata Bodie have helped eradicate smallpox and nearly eradicate polio globally, and eliminate smallpox and nearly eradicate polio globally, and eliminate several infectious diseases
Analyst in Health Policy Analyst in Health Policy
several infectious diseases domestically. With domestically. With the Coronavirus Disease 2019 (COVID-Coronavirus Disease 2019 (COVID- 19) pandemic 19) now causing major health and now causing major health and

economic impacts across the world, efforts economic impacts across the world, efforts arehave been underway to make safe and effective vaccines underway to make safe and effective vaccines
available quickly to help curb available quickly to help curb spread of the virus. spread of the virus.

As of the date of this report, there are two COVID-19 vaccines authorized for emergency use by the U.S. Food and Drug Administration (FDA) and recommended by the CDC. Additional vaccines may receive authorization within months. Background
Federal regulation of vaccine safety began with the Biologics Control Act of 1902, which was the first federal law to require Federal regulation of vaccine safety began with the Biologics Control Act of 1902, which was the first federal law to require
premarket review of pharmaceutical products. Since the 1902 law was enacted, federal vaccine safety activities have premarket review of pharmaceutical products. Since the 1902 law was enacted, federal vaccine safety activities have
expanded, with the aim of minimizing the possibility of adverse events following vaccination and detecting new adverse expanded, with the aim of minimizing the possibility of adverse events following vaccination and detecting new adverse
events as quickly as possible. Today, as covered in this report, federal efforts to ensure vaccine safety include the following events as quickly as possible. Today, as covered in this report, federal efforts to ensure vaccine safety include the following
activities: activities:
  Premarket requirements: Clinical trials, or testing of investigational vaccines in human Clinical trials, or testing of investigational vaccines in human subjects, and U.S. subjects, and U.S.
Food and Drug Administration (FDA)FDA licensure or authorization. licensure or authorization.
  Clinical recommendations: Recommendations for the clinical use of vaccines by the Advisory Recommendations for the clinical use of vaccines by the Advisory Committee
Committee on Immunization Practices (ACIP), and CDC clinical guidance and resources. on Immunization Practices (ACIP), and CDC clinical guidance and resources.
  Postmarket safety: Manufacturing requirements and ongoing safety monitoring Manufacturing requirements and ongoing safety monitoring of and studies of vaccines administered vaccines administered
to patients. to patients.
  Federal research on vaccine safety: Ongoing research to inform a better scientific Ongoing research to inform a better scientific understanding of understanding of
vaccine safety and comprehensive scientific reviews on the safety of vaccines in use. vaccine safety and comprehensive scientific reviews on the safety of vaccines in use.
  Vaccine injury compensation: In nonemergency circumstances, the The National Vaccine Injury National Vaccine Injury
Compensation Program (VICP) Compensation Program (VICP) provides compensation to eligible individuals found to have been injured provides compensation to eligible individuals found to have been injured
by a covered vaccine. In emergency circumstances, by a covered vaccine. In emergency circumstances, likesuch as the COVID-19 COVID-19 pandemic, a separate Countermeasures Injury , a separate Countermeasures Injury
Compensation Program (CICP) may be used. Compensation Program (CICP) may be used.
  Vaccine distribution: Programs and requirements to ensure safety controls in vaccine Programs and requirements to ensure safety controls in vaccine distribution
distribution programs, led by CDC. COVID-19 Vaccine Safety COVID-19 vaccines currently authorized for use under Emergency Use Authorization (EUA), specifically those of Pfizer-BioNTech and Moderna, have been determined to meet the safety and effectiveness standards for EUA issuance set forth in statute and by FDA in guidance. The safety and effectiveness data have been reviewed not only by FDA scientists, but also nonfederal scientists and experts of FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) and CDC’s ACIP, both of which have recommended the vaccines for use among certain age groups and populations. ACIP has also issued recommendations for priority populations to receive the initial vaccine doses while supply is limited, adopted as official CDC recommendations. Federal agencies continue to assess the safety of vaccines available under EUAs, particularly to detect long-term and rare adverse health events, as well as safety in populations excluded from the initial clinical trials (e.g., children, pregnant individuals) through various postmarket activities. Efforts and requirements are also in place to maintain safety of vaccines distributed and administered to patients. Congressional Research Service Vaccine Safety in the United States Congressional Considerations Ever since the Biologics Control Act of 1902, Congress and the federal agencies (especially programs, led by CDC.
COVID-19 Vaccine Safety Considerations
Safety considerations for COVID-19 vaccines in development are unique in many ways. FDA has never licensed a vaccine
for a coronavirus, and much remains unknown about potential safety issues related to COVID-19 vaccines. Under Operation
Warp Speed (OWS)—the Trump Administration’s major medical countermeasure development initiative—COVID-19
vaccines are under an expedited development timeline. FDA may initially make the vaccine available under an Emergency
Use Authorization (EUA) instead of its standard biologics licensing process—a first for the agency for a previously
unapproved vaccine. In light of reported concerns from the public surrounding the safety and effectiveness of COVID-19
vaccines developed on an expedited timeline, FDA officials have sought to clarify that any vaccine candidate “will be
reviewed according to the established legal and regulatory standards for medical products.” If made available within the next
several months, available safety and effectiveness data would be based on months of data collection rather than on years of
data collection typically used in vaccine development. In addition, efforts are underway with regard to (1) clinical guidance
and prioritization of individuals to receive the likely limited initial supply of COVID-19 vaccines; (2) strengthening safety
monitoring systems to collect ongoing safety surveillance data on vaccines administered to the population; and (3) preparing
for safety controls in vaccine distribution and patient administration, in addition to other activities.
Congressional Considerations
Ever since the Biologics Control Act of 1902, Congress and the Administration (especially through FDA and CDC) have FDA and CDC) have
strived to ensure the safety of vaccines in the United States—from initial development to patient administration. Congress strived to ensure the safety of vaccines in the United States—from initial development to patient administration. Congress
may consider how to best leverage existing requirements and programs to ensure that risk of harm from may consider how to best leverage existing requirements and programs to ensure that risk of harm from eventual COVID-19 vaccines is mitigated and minimized. Federal agencies, pharmaceutical and biotech companies, and others have workedCOVID-19
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Vaccine Safety in the United States

vaccines is mitigated and minimized. OWS, FDA, CDC, and others are working to expedite the availability of COVID-19 to expedite the availability of COVID-19
vaccines and to vaccines and to prepare forimplement a nationwide immunization campaign a nationwide immunization campaign. Safety has been cited as a consideration in all of these
efforts while balancing a need for safety. Congress may consider how to best provide oversight and make legislative changes to ensure a safe and successful . Congress may consider how to best provide oversight and make legislative changes to ensure a safe and successful
COVID-19 vaccination campaign. In addition, Congress may consider and evaluate the entire federal vaccine safety system COVID-19 vaccination campaign. In addition, Congress may consider and evaluate the entire federal vaccine safety system
and assess whether this system warrants any policy changes to help ensure ongoing safety of all recommended vaccines. and assess whether this system warrants any policy changes to help ensure ongoing safety of all recommended vaccines.
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Contents
Introduction ..................................................................................................................................... 1
Scope of This Report ................................................................................................................. 23
What Is a Vaccine? .................................................................................................................... 34
Federal Vaccine Safety Regulation and Programs .................................................................... 34
Vaccine Safety Basics ............................................................................................................... 56
Premarket Safety ............................................................................................................................. 78
Clinical Trials ............................................................................................................................ 78
Biologics License Application (BLA) and Licensure Requirements ........................................ 9 11
Expedited Pathways and Access to Unapproved Vaccines....................................................... 11 13
Expedited Development and Review ................................................................................. 11 13
Animal Rule ...................................................................................................................... 1214
Emergency Use Authorization (EUA) .............................................................................. 1315
Advisory Committee Consultation .......................................................................................... 1416
Clinical Recommendations ............................................................................................................ 1517
Postmarket Safety .......................................................................................................................... 1619
Manufacturing Safety .............................................................................................................. 1719
Surveillance ............................................................................................................................. 1820
Vaccine Adverse Event Reporting System (VAERS)........................................................ 1821
Vaccine Safety Datalink (VSD) ........................................................................................ 1921
Sentinel Initiative .............................................................................................................. 2022
Other Safety Monitoring Systems ..................................................................................... 2123
Clinical Assessment ................................................................................................................ 2224
Federal Research on Vaccine Safety .............................................................................................. 2224
CDC Research ......................................................................................................................... 2325
NIH Research .......................................................................................................................... 2325
FDA Research ......................................................................................................................... 2326
Other Federal Research ........................................................................................................... 2426
Challenges of Vaccine Safety Reviews ............................................................................. 2427
National Vaccine Injury Compensation ......................................................................................... 2527
Safety in Vaccine Distribution ....................................................................................................... 2628
Safety Considerations for COVID-19 Vaccines ............................................................................ 2730
Vaccine Development and Current Status ............................................................................... 28
31 Vaccine Efficacy ............................................................................................................... 33 FDA Marketing Authorization ................................................................................................ 3134
Clinical Recommendations and Prioritization ......................................................................... 3235
Safety in Vaccine Distribution ................................................................................................. 34
37 Postmarket Safety: Surveillance and Safety Monitoring ........................................................ 38 Severe Allergic Reactions ................................................. 35
................................................ 40 Injury Compensation and Patient Safety Information ............................................................. 3641
Congressional Considerations ....................................................................................................... 3741

Figures
Figure 1. NASEM-Recommended Phased Approach to COVID-19 Vaccine Allocation ............. 33
Figure 2. Graphical Presentation of Vaccine Safety Assessment for Essential Workers ............... 3637
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link to page link to page 4245 link to page 47 Vaccine Safety in the United States


Figure 2. Federal Vaccine Safety Monitoring Systems, by System and Population ...................... 40 Contacts
Author Information ........................................................................................................................ 3742

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Vaccine Safety in the United States

Introduction
Widespread immunization efforts have been linked to increased life expectancy and reduced Widespread immunization efforts have been linked to increased life expectancy and reduced
illness.1 In 1900, for every 1,000 babies born in the United States, 100 would die before their first illness.1 In 1900, for every 1,000 babies born in the United States, 100 would die before their first
birthday, often due to infectious diseases.2 One study estimated that from 1993 to 2013, routine birthday, often due to infectious diseases.2 One study estimated that from 1993 to 2013, routine
childhood immunization in the United States helped prevent 322 million illnesses, 21 million childhood immunization in the United States helped prevent 322 million illnesses, 21 million
hospitalizations, and 732,000 premature deaths.3 U.S. immunization programs, headed by the hospitalizations, and 732,000 premature deaths.3 U.S. immunization programs, headed by the
Centers for Disease Control and Prevention (CDC) within the Department of Health and Human Centers for Disease Control and Prevention (CDC) within the Department of Health and Human
Services (HHS), have helped eradicate smallpox and nearly eradicate polio globally.4 U.S. Services (HHS), have helped eradicate smallpox and nearly eradicate polio globally.4 U.S.
immunization programs have also helped eliminate measles and rubella domestically, and have immunization programs have also helped eliminate measles and rubella domestically, and have
led to substantial reductions in hospitalizations linked to pneumococcus, rotavirus, and varicella led to substantial reductions in hospitalizations linked to pneumococcus, rotavirus, and varicella
(i.e., chickenpox).5(i.e., chickenpox).5 With With the Coronavirus Disease 2019 (COVID-19) Coronavirus Disease 2019 (COVID-19) nowpandemic causing major health and causing major health and
economic impacts across the world, efforts economic impacts across the world, efforts arehave been underway to make safe and effective vaccines underway to make safe and effective vaccines
available quickly to help curb spread of the virus.available quickly to help curb spread of the virus. Currently, several COVID-19 vaccines, including those of Pfizer-BioNTech and Moderna, are available under U.S. Food and Drug Administration (FDA) Emergency Use Authorizations (EUAs).
Available evidence from thousands of scientific studies shows that currently recommended Available evidence from thousands of scientific studies shows that currently recommended
vaccines are largely safe. At a population level, widespread vaccination with recommended vaccines are largely safe. At a population level, widespread vaccination with recommended
vaccines is safer than the spread of the infectious diseases they prevent.6 Adverse health events vaccines is safer than the spread of the infectious diseases they prevent.6 Adverse health events
for which available scientific evidence shows a causal relationship with currently recommended for which available scientific evidence shows a causal relationship with currently recommended
vaccines are rare—ranging from 1 case per million doses administered (e.g., encephalitis caused vaccines are rare—ranging from 1 case per million doses administered (e.g., encephalitis caused
by the pertussis vaccine) to 333 cases per million doses (e.g., febrile seizures caused by the by the pertussis vaccine) to 333 cases per million doses (e.g., febrile seizures caused by the
measles-mumps-rubella; MMR vaccine).7 measles-mumps-rubella; MMR vaccine).7
Undervaccination linked to concerns about vaccine safety has been an issue in recent years. U.S. Undervaccination linked to concerns about vaccine safety has been an issue in recent years. U.S.
outbreaks of measles in 2019—the highest number of annual measles cases since 1992—were outbreaks of measles in 2019—the highest number of annual measles cases since 1992—were
driven in part by geographic clusters with low vaccination rates for the MMR vaccine.8 U.S.
surveys show that concerns about vaccine safety are a top reason for vaccine delays or refusals.9

1 Walter A. Orenstein and Rafi Ahmed, “Simply Put: Vaccination Saves Lives,” 1 Walter A. Orenstein and Rafi Ahmed, “Simply Put: Vaccination Saves Lives,” Proceedings of the National Academy
of Sciences
, vol. 114, no. 16 (April 10, 2017). , vol. 114, no. 16 (April 10, 2017).
2 Institute of Medicine (now National Academy of Medicine), 2 Institute of Medicine (now National Academy of Medicine), Adverse Effects of Vaccines: Evidence and Causality, ,
Washington, DC, August 25, 2011, https://www.ncbi.nlm.nih.gov/books/NBK190024/. Washington, DC, August 25, 2011, https://www.ncbi.nlm.nih.gov/books/NBK190024/.
3 Cynthia G. Whitney, Fangjun Zhou, James Singleton, et al., “Benefits from Immunization during the Vaccines for 3 Cynthia G. Whitney, Fangjun Zhou, James Singleton, et al., “Benefits from Immunization during the Vaccines for
Children Program Era—United States, 1994–2013,” Children Program Era—United States, 1994–2013,” Morbidity and Mortality Weekly Report, vol. 63, no. 16 (April 25, , vol. 63, no. 16 (April 25,
2014), pp. 352-355. 2014), pp. 352-355.
4 Eric E. Mast, Stephen L. Cochi, Olen M. Kew 4 Eric E. Mast, Stephen L. Cochi, Olen M. Kew, et al., “Fifty Years of Global Immunization at CDC, 1966-2015,” et al., “Fifty Years of Global Immunization at CDC, 1966-2015,”
Public Health Reports, vol. 132, no. 1 (Jan-Feb 2017), pp. 18-26. , vol. 132, no. 1 (Jan-Feb 2017), pp. 18-26.
5 Pneumococcus is the most common form of bacteria that causes severe pneumonia. Rotaviruses are a genus of viruses 5 Pneumococcus is the most common form of bacteria that causes severe pneumonia. Rotaviruses are a genus of viruses
that cause a large portion of severe diarrhea cases. Varicella is the scientific name for “chickenpox” disease. See that cause a large portion of severe diarrhea cases. Varicella is the scientific name for “chickenpox” disease. See
Amanda Cohn, Lance E. Rodewald, Walter A. Orenstein, et al., “Immunization in the United States,” in Amanda Cohn, Lance E. Rodewald, Walter A. Orenstein, et al., “Immunization in the United States,” in Plotkin’s
Vaccines
, ed. Stanley A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1436. , ed. Stanley A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1436.
6 Margaret A. Maglione, Courtney Gidengil, Lopamudra Das, et al. “Safety of Vaccines Used for Routine 6 Margaret A. Maglione, Courtney Gidengil, Lopamudra Das, et al. “Safety of Vaccines Used for Routine
Immunization in the United States,” Immunization in the United States,” Agency for Healthcare Research and Quality, July 2014, , July 2014,
https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/vaccine-safety_research.pdf, and Institute of Medicine (now https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/vaccine-safety_research.pdf, and Institute of Medicine (now
National Academy of Medicine), National Academy of Medicine), Adverse Effects of Vaccines: Evidence and Causality, Washington, DC, August 25, , Washington, DC, August 25,
2012, https://www.ncbi.nlm.nih.gov/books/NBK190010/#sec_0009. 2012, https://www.ncbi.nlm.nih.gov/books/NBK190010/#sec_0009.
7 Frank DeStefano, Paul A. Offit, and Allison Fisher, 7 Frank DeStefano, Paul A. Offit, and Allison Fisher, Ch. 82Ch. 82: , “Vaccine Safety,” in Vaccine Safety,” in Vaccines, ed. Stanley A. Plotkin, , ed. Stanley A. Plotkin,
Walter A. Orenstein, Paul A. OffitWalter A. Orenstein, Paul A. Offit, et. al. 67h ed. (Elsevier, 2017), pp. 1584-1600.
8 CDC, “Measles Cases and Outbreaks,” last updated August 2020, https://www.cdc.gov/measles/cases-outbreaks.html.
9 CRS Insight IN11125, Measles Outbreaks, Vaccine Hesitancy, and Federal Policy Options, and Amanda Cohn,
Lance E. Rodewald, Walter A. Orenstein, et al., “Immunization in the United States,” in Plotkin’s Vaccines, ed. Stanley
Congressional Research Service
1

Vaccine Safety in the United States
et. al. 67h ed. (Elsevier, 2017), pp. 1584-1600. Congressional Research Service 1 Vaccine Safety in the United States driven in part by geographic clusters with low vaccination rates for the MMR vaccine.8 U.S. surveys show that concerns about vaccine safety are a top reason for vaccine delays or refusals.9
From a public health perspective, vaccines for infectious diseases often work by helping provide From a public health perspective, vaccines for infectious diseases often work by helping provide
herd immunity, meaning that enough of the population has vaccine-induced immunity against the , meaning that enough of the population has vaccine-induced immunity against the
target disease to curb ongoing transmission and protect those who cannot receive vaccines (e.g., target disease to curb ongoing transmission and protect those who cannot receive vaccines (e.g.,
persons with compromised immune systems).10 Widespread vaccination can help with achieving persons with compromised immune systems).10 Widespread vaccination can help with achieving
elimination or or eradication of a given disease (see of a given disease (see text box). To effectively prevent disease spread, ). To effectively prevent disease spread,
many vaccines must be administered to a large segment of the population. Public health practice many vaccines must be administered to a large segment of the population. Public health practice
generally aims for near 100% vaccination rates among populations recommended to receive generally aims for near 100% vaccination rates among populations recommended to receive
vaccines, though the level required for herd immunity is generally lower and can vary by vaccine vaccines, though the level required for herd immunity is generally lower and can vary by vaccine
and population (75%-95% of the population).11 Nonetheless, widespread vaccination that does not and population (75%-95% of the population).11 Nonetheless, widespread vaccination that does not
meet target rates can aid in significantly curbing disease spread.12 meet target rates can aid in significantly curbing disease spread.12
Vaccines are Vaccines are generallyoften held to a higher safety held to a higher safety
Definitions: Elimination and Eradication
standard than most other medical products for standard than most other medical products for
The World Health Organization (WHO) defines The World Health Organization (WHO) defines
many reasons. For one, vaccines are often many reasons. For one, vaccines are often
disease elimination and eradication as fol ows: disease elimination and eradication as fol ows:
administered to healthy individuals to prevent administered to healthy individuals to prevent
Elimination (or interruption) of transmission:
disease; therefore, the expectation is that such disease; therefore, the expectation is that such
Reduction to zero of the incidence of infection caused Reduction to zero of the incidence of infection caused
individuals will remain healthy following individuals will remain healthy following
by a specific pathogen in a defined geographical area, by a specific pathogen in a defined geographical area,
vaccination. vaccination. Moreover, drugs administered toIn addition, vaccines are often
with minimal risk of reintroduction, as a result of with minimal risk of reintroduction, as a result of
deliberate efforts; continued actions to prevent deliberate efforts; continued actions to prevent
healthy people are expected to have fewer sideadministered to vulnerable populations,
reestablishment of transmission may be required. reestablishment of transmission may be required.
effects than drugs that treat disease, such asincluding infants and pregnant people. Also,
Eradication: Permanent reduction to zero of a Permanent reduction to zero of a
those for cancer or heart disease, mainlysince vaccines are often mandated by state and
specific pathogen, as a result of deliberate efforts, with specific pathogen, as a result of deliberate efforts, with
because the expected benefits differ. Insometimes federal law for certain groups (e.g.,
no more risk of reintroduction. no more risk of reintroduction.
addition, vaccines are often administered toschool children and military service
Source: WHO, “Generic Framework for the Control, WHO, “Generic Framework for the Control,
vulnerable populations, including infants andmembers), the government has an interest in
Elimination, and Eradication of Neglected Tropical Elimination, and Eradication of Neglected Tropical
pregnant women. Also, since vaccines areensuring that vaccines are as safe as possible. Diseases,” 2015, https://www.who.int/neglected_diseases/resources/ Because vaccines are often administered to a NTD_Generic_Framework_2015.pdf. large segment of the population, even a rare risk of adverse reactions to a vaccine could affect a sizeable number of people.13 FDA has issued EUAs for several COVID-19 vaccines, including those of Pfizer-BioNTech and Moderna, determining that they may be effective in preventing COVID-19, and that their known and potential benefits outweigh their known and potential risks.14 This is consistent with the 8 CDC, “Measles Cases and Outbreaks,” last updated August 2020, https://www.cdc.gov/measles/cases-outbreaks.html. 9 CRS Insight IN11125, Measles Outbreaks, Vaccine Hesitancy, and Federal Policy Options, and Amanda Cohn, Lance E. Rodewald, Walter A. Orenstein, et al., “Immunization in the United States,” in Plotkin’s Vaccines, ed. Stanley
Diseases,” 2015, https://www.who.int/
neglected_diseases/resources/
often mandated by state and sometimes federal
NTD_Generic_Framework_2015.pdf.
law for certain groups (e.g., school children
and military service members), the government has an interest in ensuring that vaccines are as
safe as possible. Because vaccines are often administered to a large segment of the population,
even a rare risk of adverse reactions to a vaccine could affect a sizeable number of people.13
Scope of This Report
This report provides an overview of the federal government’s role in ensuring safety of vaccines
for infectious diseases. Specifically, this report
 describes federal statutory and regulatory requirements and administrative
functions governing vaccine licensure (including pre- and post-licensure safety),
development of clinical recommendations, and vaccine injury compensation;

A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1432. A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1432.
10 Paul Fine, Ken Eames, and David L. Heymann, “‘‘Herd Immunity’’: A Rough Guide,” 10 Paul Fine, Ken Eames, and David L. Heymann, “‘‘Herd Immunity’’: A Rough Guide,” Vaccines, vol. 52 (2011). , vol. 52 (2011).
11 Ibid., and Pedro Plans-Rubió, “Evaluation of the Establishment of Herd Immunity in the Population by Means of 11 Ibid., and Pedro Plans-Rubió, “Evaluation of the Establishment of Herd Immunity in the Population by Means of
Serological Surveys and Vaccination Coverage,” Serological Surveys and Vaccination Coverage,” Human Vaccines & Immunotherapeutics. vol. 8, no. 2 (February . vol. 8, no. 2 (February
2012), pp. 184-88. 2012), pp. 184-88.
12 Paul Fine, Ken Eames, and David L. Heymann, “‘‘Herd Immunity’’: A Rough Guide,” 12 Paul Fine, Ken Eames, and David L. Heymann, “‘‘Herd Immunity’’: A Rough Guide,” Vaccines, vol. 52 (2011). , vol. 52 (2011).
13 Frank DeStefano, Paul A. Offit, and Allison Fisher, “13 Frank DeStefano, Paul A. Offit, and Allison Fisher, “Ch. 82: Vaccine Safety,” in Vaccine Safety,” in Vaccines, ed. Stanley A. Plotkin, , ed. Stanley A. Plotkin,
Walter A. Orenstein, Paul A. Offit, et al. 67h ed. (Elsevier, 2017), pp. 1584-1600, and Matthew Z. Dudley, Daniel A. Walter A. Orenstein, Paul A. Offit, et al. 67h ed. (Elsevier, 2017), pp. 1584-1600, and Matthew Z. Dudley, Daniel A.
Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in The Clinician’s Vaccine Safety Resource Guide
(Springer, (Springer, Cham, 2018). 14 FDA, Emergency Use Authorization (EUA) for an Unapproved Product- Pfizer, Inc. on behalf of Pfizer and BioNTech, December 11, 2020, https://www.fda.gov/media/144416/download; and FDA, Emergency Use Cham, 2018).
Congressional Research ServiceCongressional Research Service
2 link to page 20 link to page 35 link to page 35 Vaccine Safety in the United States statutory standard for EUA issuance (see the section “Emergency Use Authorization (EUA)”), as well as the safety and effectiveness standards set forth by FDA in guidance.15 The safety and effectiveness data have been reviewed not only by FDA scientists, but also by nonfederal scientists and experts on the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) and CDC’s Advisory Committee on Immunization Practices (ACIP). The majority of experts on these advisory committees have recommended the vaccines for emergency use among certain age groups and populations—adults 16 years of age and older for Pfizer-BioNTech’s vaccine and adults 18 years of age and older for Moderna’s vaccine.16 ACIP has also issued recommendations for priority populations to receive the initial vaccine doses while supply is limited—these recommendations have been adopted as official CDC recommendations.17 Federal agencies and vaccine manufacturers continue to assess the safety of vaccines available under EUA, particularly to detect long-term and rare adverse health events, as well as their safety in populations excluded from the initial clinical trials (e.g., pregnant individuals) through various postmarket activities, as discussed in this report. Efforts and requirements are also in place to maintain safety of vaccines distributed and administered to patients. Scope of This Report This report provides an overview of the federal government’s role in ensuring safety of vaccines for infectious diseases. Specifically, this report  describes federal statutory and regulatory requirements and administrative functions governing vaccine licensure or authorization (including pre- and post-market safety), development of clinical recommendations, and vaccine injury compensation; 2

Vaccine Safety in the United States

 summarizes ongoing federal activities related to vaccine post-  summarizes ongoing federal activities related to vaccine post-licensuremarket safety safety
(e.g., (e.g., ongoing safety monitoring and research), as well as safety assurances in ongoing safety monitoring and research), as well as safety assurances in
federal vaccine distribution programs; and federal vaccine distribution programs; and
 discusses safety considerations in the context of developing and making available  discusses safety considerations in the context of developing and making available
vaccine(s) for COVID-19 vaccine(s) for COVID-19.
, discussed in “Safety Considerations for COVID-19 Vaccines.” This report does not provide a comprehensive scientific review on the safety of existing vaccines, This report does not provide a comprehensive scientific review on the safety of existing vaccines,
nor does it specifically address vaccines for noninfectious diseases (e.g., cancer). nor does it specifically address vaccines for noninfectious diseases (e.g., cancer). A discussion of
payment and coverage for vaccines and related health care services isDiscussions of Authorization (EUA) for an Unapproved Product- ModernaTx, Inc, December 18, 2020, https://www.fda.gov/media/144673/download. 15 FDA, “Emergency Use Authorization for Vaccines to Prevent COVID-19,” Guidance for Industry, October 2020, https://www.fda.gov/media/142749/download. 16 FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC), “2020 Meeting Materials, Vaccines and Related Biological Products Advisory Committee,” https://www.fda.gov/advisory-committees/vaccines-and-related-biological-products-advisory-committee/2020-meeting-materials-vaccines-and-related-biological-products-advisory-committee; Sara E. Oliver, Julia W. Gargano, Mona Marin, et al., “The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Moderna COVID-19 Vaccine—United States, December 2020,” Morbidity and Mortality Weekly Report (MMWR), vol. 69, no. 5152 (January 1, 2021), pp. 1653-56; and Sara E. Oliver, Julia W. Gargano, Mona Marin, et al., “The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine—United States, December 2020,” Mortality and Morbidity Weekly Report, vol. 69, no. 50 (December 18, 2020), pp. 1922-24. 17 See for example, Kathleen Dooling, Mona Marin, Megan Wallace, et al., “The Advisory Committee on Immunization Practices’ Updated Interim Recommendation for Allocation of COVID-19 Vaccine—United States, December 2020,” Morbidity and Mortality Weekly Report, vol. 69, no. 5152 (January 1, 2021), pp. 1657-60. Congressional Research Service 3 Vaccine Safety in the United States payment and coverage for vaccines and related health care services, and logistical implementation of the vaccine distribution program, are outside the scope of this outside the scope of this
report. report.
What Is a Vaccine?
A vaccine is a biological preparation that contains small amounts of weak, dead, or modified A vaccine is a biological preparation that contains small amounts of weak, dead, or modified
disease-causing agents known as disease-causing agents known as antigens, which can include viruses, bacteria, fractions of these , which can include viruses, bacteria, fractions of these
agents, or the toxins they produce.agents, or the toxins they produce.18 The new messenger RNA (mRNA) vaccines instead rely on genetic material that tells the body to make a protein (the antigen).19 Once introduced to the body, the antigen elicits a response by Once introduced to the body, the antigen elicits a response by
the immune system creating antibodies and immune memory cells that prevent future infection the immune system creating antibodies and immune memory cells that prevent future infection
from the same disease. The immune response from a vaccine is similar to the immune response from the same disease. The immune response from a vaccine is similar to the immune response
from acquiring an infectious disease naturally; however, since the antigen in the vaccine is from acquiring an infectious disease naturally; however, since the antigen in the vaccine is
weakened or dead, the vaccine usually does not cause disease. In the case of vaccines made with weakened or dead, the vaccine usually does not cause disease. In the case of vaccines made with
weakened live attenuated viruses or bacteria, the vaccine may cause a form of the disease that is weakened live attenuated viruses or bacteria, the vaccine may cause a form of the disease that is
usually much milder than the actual disease. In addition, the immune response triggered by any usually much milder than the actual disease. In addition, the immune response triggered by any
vaccine may cause some symptoms in some patients.vaccine may cause some symptoms in some patients.1420
Along with the antigen, vaccines contain other ingredients such as preservatives, stabilizers, and Along with the antigen, vaccines contain other ingredients such as preservatives, stabilizers, and
adjuvants. Preservatives, like thimerosal, can help keep the vaccine free of contamination by adjuvants. Preservatives, like thimerosal, can help keep the vaccine free of contamination by
other germs (e.g., bacteria, fungi). Thimerosal is currently used only in multidose vials of other germs (e.g., bacteria, fungi). Thimerosal is currently used only in multidose vials of
vaccines, such as certain formulations of the influenza (flu) vaccine. Stabilizers, like sugar or vaccines, such as certain formulations of the influenza (flu) vaccine. Stabilizers, like sugar or
gelatin, allow the vaccine to be stored for a period of time and help keep the antigen stable. gelatin, allow the vaccine to be stored for a period of time and help keep the antigen stable.
Adjuvants, such as aluminum salts, help trigger the immune response to the vaccine, particularly Adjuvants, such as aluminum salts, help trigger the immune response to the vaccine, particularly
for vaccines made with fractions of disease-causing agents. Vaccines may also contain small for vaccines made with fractions of disease-causing agents. Vaccines may also contain small
amounts of residual material from the manufacturing process, such as egg proteins, amounts of residual material from the manufacturing process, such as egg proteins,
formaldehyde, and antibiotics.formaldehyde, and antibiotics.1521
Federal Vaccine Safety Regulation and Programs
Federal regulation of vaccine safety began with the Biologics Control Act of 1902, which was the Federal regulation of vaccine safety began with the Biologics Control Act of 1902, which was the
first federal law to require premarket review of pharmaceutical products.first federal law to require premarket review of pharmaceutical products.1622 The Biologics Control The Biologics Control
Act was enacted in response to deaths (many of them children) from tetanus contamination of Act was enacted in response to deaths (many of them children) from tetanus contamination of
smallpox vaccine and diphtheria antitoxin (a prophylaxis used for diphtheria at the time). The act smallpox vaccine and diphtheria antitoxin (a prophylaxis used for diphtheria at the time). The act

14imposed requirements on the manufacturing and labeling of biological products (“biologics”) and required inspection of manufacturing facilities before a federal license was issued for marketing the products. The Biologics Control Act was revised and recodified when the Public Health 18 CDC, “Principles of Vaccination,” in Epidemiology and Prevention of Vaccine-Preventable Diseases, ed. Jennifer Hamborsky, Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015). 19 CDC, “Understanding mRNA COVID-19 Vaccines,” December, 2020, https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html. 20 CDC, “Principles of Vaccination,” in CDC, “Principles of Vaccination,” in Epidemiology and Prevention of Vaccine-Preventable Diseases, ed. Jennifer , ed. Jennifer
Hamborsky, Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015). Hamborsky, Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015).
1521 Department of Health and Human Services (HHS), “Vaccine Ingredients,” Department of Health and Human Services (HHS), “Vaccine Ingredients,” Vaccines.gov, December 2017, December 2017,
https://www.vaccines.gov/basics/vaccine_ingredients; CDC, “What’s in Vaccines?” August 2019, https://www.vaccines.gov/basics/vaccine_ingredients; CDC, “What’s in Vaccines?” August 2019,
https://www.cdc.gov/vaccines/vac-gen/additives.htm; and the Food and Drug Administration (FDA), “Common https://www.cdc.gov/vaccines/vac-gen/additives.htm; and the Food and Drug Administration (FDA), “Common
Ingredients in U.S. Licensed Vaccines,” https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/Ingredients in U.S. Licensed Vaccines,” https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/
common-ingredients-us-licensed-vaccines. common-ingredients-us-licensed-vaccines.
1622 P.L. 57-244, enacted July 1, 1902. David M. Dudzinski, “Reflections on Historical, Scientific, and Legal Issues P.L. 57-244, enacted July 1, 1902. David M. Dudzinski, “Reflections on Historical, Scientific, and Legal Issues
Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based Therapeutics and Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based Therapeutics and
Monoclonal Antibodies,” Monoclonal Antibodies,” Food & Drug Law Journal, 2005, vol. 60, no. 2., p. 147. , 2005, vol. 60, no. 2., p. 147.
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imposed requirements on the manufacturing and labeling of biological products (“biologics”) and
required inspection of manufacturing facilities before a federal license was issued for marketing
the products. The Biologics Control Act was revised and recodified when the Public Health
Service Act (PHSA) was enacted in 1944. Biologics are now subject to regulation by the U.S. Service Act (PHSA) was enacted in 1944. Biologics are now subject to regulation by the U.S.
Food and Drug Administration (FDA) under the PHSA and the Federal Food, Drug, and Cosmetic Food and Drug Administration (FDA) under the PHSA and the Federal Food, Drug, and Cosmetic
Act (FFDCA).Act (FFDCA).1723
Since the 1902 law was enacted, federal vaccine safety activities have expanded to minimize the Since the 1902 law was enacted, federal vaccine safety activities have expanded to minimize the
possibility of adverse events following vaccination (such as by vaccine contamination) and to possibility of adverse events following vaccination (such as by vaccine contamination) and to
detect new adverse events as quickly as detect new adverse events as quickly as
possible, as discussed throughout this possible, as discussed throughout this
Federal Agencies Involved in Vaccine Safety
report. Major reforms to federal report. Major reforms to federal
Within the Department of Health and Human Services (HHS): Within the Department of Health and Human Services (HHS):
vaccine safety programs were enacted vaccine safety programs were enacted
 
FDA regulates the safety, effectiveness, and quality of FDA regulates the safety, effectiveness, and quality of
as a part of the National Childhood as a part of the National Childhood
vaccines through premarket review and postmarket vaccines through premarket review and postmarket
Vaccine Injury Act of 1986 (NCVIA; Vaccine Injury Act of 1986 (NCVIA;
requirements (e.g., adverse event reporting). requirements (e.g., adverse event reporting).
P.L. 99-660, Title III), which mandated P.L. 99-660, Title III), which mandated
 
CDC supports cross-cutting immunization programs that CDC supports cross-cutting immunization programs that
reporting of adverse events caused by reporting of adverse events caused by
include, as relevant to vaccine safety: safety monitoring, include, as relevant to vaccine safety: safety monitoring,
clinical guidance for vaccines, vaccine safety research, and clinical guidance for vaccines, vaccine safety research, and
vaccines to FDA and CDC, established vaccines to FDA and CDC, established
efforts to ensure safety in public vaccine distribution. efforts to ensure safety in public vaccine distribution.
the National Vaccine Program Office the National Vaccine Program Office
 
The National Institutes of Health (NIH) is the primary The National Institutes of Health (NIH) is the primary
(NVPO) within HHS to coordinate (NVPO) within HHS to coordinate
federal agency that supports medical and health research, federal agency that supports medical and health research,
federal vaccine efforts, granted FDA federal vaccine efforts, granted FDA
including vaccine research. including vaccine research.
mandatory recall authority for mandatory recall authority for
 
The Centers for Medicare & Medicaid Services (CMS) The Centers for Medicare & Medicaid Services (CMS)
biological products, and established the biological products, and established the
monitors vaccine safety among the Medicare population. monitors vaccine safety among the Medicare population.
National Vaccine Injury Compensation National Vaccine Injury Compensation
 
The Agency for Healthcare Research and Quality (AHRQ) The Agency for Healthcare Research and Quality (AHRQ)
Program (VICP). NCVIA was enacted Program (VICP). NCVIA was enacted
conducts vaccine safety reviews. conducts vaccine safety reviews.
after a spate of lawsuits against vaccine after a spate of lawsuits against vaccine
 
The Health Resources and Services Administration (HRSA) The Health Resources and Services Administration (HRSA)
manufacturers alleging safety issues. manufacturers alleging safety issues.
administers the VICP. administers the VICP.
The lawsuits caused several vaccine The lawsuits caused several vaccine
The Department of Veterans Affairs (VA) conducts some The Department of Veterans Affairs (VA) conducts some
manufacturers to exit the market, manufacturers to exit the market,
vaccine research and monitors vaccine safety among veterans vaccine research and monitors vaccine safety among veterans
who receive care in the VA system. who receive care in the VA system.
leading to concerns about the vaccine leading to concerns about the vaccine
supply and possible reintroduction of supply and possible reintroduction of
The Department of Defense (DOD) conducts some vaccine The Department of Defense (DOD) conducts some vaccine
research and has a database for monitoring adverse events from research and has a database for monitoring adverse events from
certain diseases. certain diseases.1824
vaccination among military service members and their families. vaccination among military service members and their families.

As covered in this report, efforts to ensure vaccine safety include several federal activities: As covered in this report, efforts to ensure vaccine safety include several federal activities:
  Premarket requirements: Clinical trials and FDA licensure or authorization. Clinical trials and FDA licensure or authorization.
Clinical recommendations: Recommendations for the safe and appropriate clinical use of vaccines by the Advisory Committee on Immunization Practices (ACIP), and CDC clinical guidance and resources.  Postmarket safety: Manufacturing requirements and ongoing safety monitoring of vaccines administered to patients.
1723 Until 1972, biologics, including vaccines, were regulated by the National Institutes of Health (NIH, or its precursors) Until 1972, biologics, including vaccines, were regulated by the National Institutes of Health (NIH, or its precursors)
under the Biologics Control Act of 1902. In 1972, regulatory responsibility over biologics was transferred from NIH to under the Biologics Control Act of 1902. In 1972, regulatory responsibility over biologics was transferred from NIH to
the U.S. Food and Drug Administration (FDA). See David M. Dudzinski, “Reflections on Historical, Scientific, and the U.S. Food and Drug Administration (FDA). See David M. Dudzinski, “Reflections on Historical, Scientific, and
Legal Issues Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based Legal Issues Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based
Therapeutics and Monoclonal Antibodies,” Therapeutics and Monoclonal Antibodies,” Food and Drug Law Journal, 2005, vol. 60, no. 2, pp. 143-260. See also , 2005, vol. 60, no. 2, pp. 143-260. See also
CRS Report R44620, CRS Report R44620, Biologics and Biosimilars: Background and Key Issues. .
1824 Geoffrey Evans, “Update on Vaccine Liability in the United States: Presentation at the National Vaccine Program Geoffrey Evans, “Update on Vaccine Liability in the United States: Presentation at the National Vaccine Program
Office on Strengthening the Supply of Routinely Recommended Vaccines in the United States, 12 February 2002,” Office on Strengthening the Supply of Routinely Recommended Vaccines in the United States, 12 February 2002,”
Clinical Infectious Diseases, vol. 42 (2006), pp. S130-7, and Nora Freeman Engstrom, “A Dose of Reality for , vol. 42 (2006), pp. S130-7, and Nora Freeman Engstrom, “A Dose of Reality for
Specialized Courts: Lessons from the VICP,” Specialized Courts: Lessons from the VICP,” University of Pennsylvania Law Review, vol. 163 (June 28, 2015), pp. , vol. 163 (June 28, 2015), pp.
1655-1658. 1655-1658.
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  Clinical recommendations: Recommendations for the safe and appropriate
clinical use of vaccines by the Advisory Committee on Immunization Practices
(ACIP), and CDC clinical guidance and resources.
Postmarket safety: Manufacturing requirements and ongoing safety monitoring
of vaccines administered to patients.
Federal research on vaccine safety: Ongoing research to inform a better Ongoing research to inform a better
scientific understanding of vaccine safety, and comprehensive scientific reviews scientific understanding of vaccine safety, and comprehensive scientific reviews
on the safety of vaccines. on the safety of vaccines.
  Vaccine injury compensation: In nonemergency circumstances, theThe VICP can VICP can
provide compensation to eligible provide compensation to eligible individuals found to have been injured by a individuals found to have been injured by a
covered vaccine. covered vaccine. In emergency circumstances, such as the COVID-19 pandemic, a separate Countermeasures Injury Compensation Program (CICP) may be used.
  Vaccine distribution: Programs and requirements to ensure safety controls in Programs and requirements to ensure safety controls in
vaccine distribution programs, led by CDC. vaccine distribution programs, led by CDC.
Vaccine Safety Basics
As defined by FDA regulations, safety is “the relative freedom from harmful effect to persons As defined by FDA regulations, safety is “the relative freedom from harmful effect to persons
affected, directly or indirectly, by a product when prudently administered, taking into affected, directly or indirectly, by a product when prudently administered, taking into
consideration the character of the product in relation to the condition of the recipient at the consideration the character of the product in relation to the condition of the recipient at the
time.”time.”1925 Vaccine safety is distinct from efficacy and effectiveness; however, it is useful to Vaccine safety is distinct from efficacy and effectiveness; however, it is useful to
consider vaccine safety in the context of efficacy and effectiveness, which are defined as follows: consider vaccine safety in the context of efficacy and effectiveness, which are defined as follows:
 Vaccine  Vaccine efficacy is defined as the reduction in disease incidence in a vaccinated is defined as the reduction in disease incidence in a vaccinated
group compared with an unvaccinated group under optimal conditions (i.e., group compared with an unvaccinated group under optimal conditions (i.e.,
healthy individuals and proper administration). healthy individuals and proper administration).
 Vaccine  Vaccine effectiveness is defined as the reduction in disease incidence in a is defined as the reduction in disease incidence in a
vaccinated group compared with an unvaccinated group under real-world vaccinated group compared with an unvaccinated group under real-world
conditions.conditions.2026
Like all pharmaceutical products, Like all pharmaceutical products, though vaccines approved or authorized for use by FDA are generally safe for the vast majority of patients, they vaccines are not 100% safe for all patients. Vaccine safety are not 100% safe for all patients. Vaccine safety
programs continually assess the benefits and risks of vaccination. Adverse events following programs continually assess the benefits and risks of vaccination. Adverse events following
vaccination can be classified in many ways:vaccination can be classified in many ways:2127
 Frequency—is the adverse event common or rare?  Frequency—is the adverse event common or rare?
 Severity—is the adverse event mild, such as minor pain or swelling, or severe,  Severity—is the adverse event mild, such as minor pain or swelling, or severe,
such as leading to hospitalization, disability, or death? such as leading to hospitalization, disability, or death?
 Causality—can a causal relationship be established with the vaccine with  Causality—can a causal relationship be established with the vaccine with
clinical, laboratory, or epidemiologic evidence? (see clinical, laboratory, or epidemiologic evidence? (see text box below) below)
 Preventability—is the adverse event intrinsic to the vaccine (e.g., provoked by the immune response caused by the vaccine), or related to faulty production or administration of the vaccine? Some adverse events following vaccination may be linked directly to the antigen in the vaccine, such as paralytic poliomyelitis (i.e., paralysis), which is rarely caused by the live oral polio 25
19 21 C.F.R. §600.3(p). 21 C.F.R. §600.3(p).
2026 Vaccine efficacy and effectiveness definitions are based on Shelly McNeil, Vaccine efficacy and effectiveness definitions are based on Shelly McNeil, Overview of Vaccine Efficacy and
Vaccine Effectiveness
, Canadian Center for Vaccinology, Presentation to the World Health Organization, , Canadian Center for Vaccinology, Presentation to the World Health Organization,
https://www.who.int/influenza_vaccines_plan/resources/Session4_VEfficacy_VEffectiveness.PDF, and Centers for https://www.who.int/influenza_vaccines_plan/resources/Session4_VEfficacy_VEffectiveness.PDF, and Centers for
Disease Control and Prevention (CDC), “How Flu Vaccine Effectiveness and Efficacy Is Measured,” 2016, Disease Control and Prevention (CDC), “How Flu Vaccine Effectiveness and Efficacy Is Measured,” 2016,
https://www.cdc.gov/flu/vaccines-work/effectivenessqa.htm. https://www.cdc.gov/flu/vaccines-work/effectivenessqa.htm.
2127 CDC, “Vaccine Safety,” in CDC, “Vaccine Safety,” in Epidemiology and Prevention of Vaccine-Preventable Diseases, ed. Jennifer Hamborsky, , ed. Jennifer Hamborsky,
Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015). Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015).
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 Preventability—is the adverse event intrinsic to the vaccine (i.e., provoked by the
immune response caused by the vaccine), or related to faulty production or
administration of the vaccine?
Some adverse events following vaccination may be linked directly to the antigen in the vaccine,
such as paralytic poliomyelitis (i.e., paralysis), which is rarely caused by the live oral polio
vaccine. Other adverse events are precipitated by the vaccine, such as febrile seizures that occur vaccine. Other adverse events are precipitated by the vaccine, such as febrile seizures that occur
following a vaccine-induced fever. Some adverse events can be linked to improper vaccine following a vaccine-induced fever. Some adverse events can be linked to improper vaccine
administration; for example, a vaccine administered too high on the arm of an adult can cause administration; for example, a vaccine administered too high on the arm of an adult can cause
deltoid bursitis (inflammation of the shoulder joint).deltoid bursitis (inflammation of the shoulder joint).2228 In the past, improper vaccine In the past, improper vaccine
manufacturing has been tied to large-scale adverse health events. In 1955, one polio vaccine manufacturing has been tied to large-scale adverse health events. In 1955, one polio vaccine
manufacturer failed to completely inactivate the poliovirus in the manufacturing process. As a manufacturer failed to completely inactivate the poliovirus in the manufacturing process. As a
result, 40,000 people developed mild polio from the vaccine, 200 became paralyzed, and 10 result, 40,000 people developed mild polio from the vaccine, 200 became paralyzed, and 10
died.died.2329
In some cases, establishing a causal connection between a vaccine and an adverse event is In some cases, establishing a causal connection between a vaccine and an adverse event is
difficult. Vaccination may difficult. Vaccination may co-occur with an adverse health event. For example, early childhood—with an adverse health event. For example, early childhood—
a time when several recommended pediatric vaccines are typically administered—coincides with a time when several recommended pediatric vaccines are typically administered—coincides with
the same period when signs and symptoms of developmental disorders, such as autism, may begin the same period when signs and symptoms of developmental disorders, such as autism, may begin
to appear.to appear.2430 Available evidence rejects a causal relationship between childhood vaccines and Available evidence rejects a causal relationship between childhood vaccines and
autism.autism.2531 To determine causality between a vaccine and a given health event, scientists and public To determine causality between a vaccine and a given health event, scientists and public
health experts evaluate many kinds of evidence, including the time period between vaccination health experts evaluate many kinds of evidence, including the time period between vaccination
and the event; the biologic plausibility that the health event was caused by vaccination; clinical or and the event; the biologic plausibility that the health event was caused by vaccination; clinical or
laboratory evidence that supports causation by the vaccine; and population-based epidemiological laboratory evidence that supports causation by the vaccine; and population-based epidemiological
analyses that assess whether vaccinated individuals are more likely to develop a certain health analyses that assess whether vaccinated individuals are more likely to develop a certain health
outcome within a certain time period following vaccination compared to outcome within a certain time period following vaccination compared to either individuals who did not individuals who did not
receive the vaccine in that time periodreceive the vaccine in that time period.26 or expected rates of the adverse health event in the population (referred to as “background rates”).32 Several of the programs covered in this report generate Several of the programs covered in this report generate
data or other evidence that can allow for causality assessments to link certain adverse events with data or other evidence that can allow for causality assessments to link certain adverse events with
vaccination (see vaccination (see text box). ).
What Is a Causality Assessment?
Immune systems are arguably among the most complex biological systems—therefore, studying vaccines and their Immune systems are arguably among the most complex biological systems—therefore, studying vaccines and their
effect on the human body can be difficult. Individual studies may provide suggestive evidence of adverse health effect on the human body can be difficult. Individual studies may provide suggestive evidence of adverse health
effects linked to vaccines. For example, an analysis of health data on a population of thousands of individuals could effects linked to vaccines. For example, an analysis of health data on a population of thousands of individuals could
find that vaccination with a certain vaccine is statistically associated with higher rates of a certain adverse health find that vaccination with a certain vaccine is statistically associated with higher rates of a certain adverse health
event that occurred fol owing vaccination. Yet, another similar event that occurred fol owing vaccination. Yet, another similar study could conduct a similar analysis among a analysis among a
different population different population andcould find no such evidence. In addition, further evidence based on the research in the find no such evidence. In addition, further evidence based on the research in the
laboratory, such as with animals or human tissue samples, might find that a certain adverse event fol owing laboratory, such as with animals or human tissue samples, might find that a certain adverse event fol owing
vaccination is or is not likely based on an understanding of biological systems. Therefore, in order to determine if vaccination is or is not likely based on an understanding of biological systems. Therefore, in order to determine if
all the available evidence favors a all the available evidence favors a causal relationship between a vaccine and a subsequent adverse health event, relationship between a vaccine and a subsequent adverse health event,
researchers wil combine evidence across many types of studies as a part of a causality assessment. Good quality systematic causality assessments usually include the fol owing attributes:  Search methods to identify all possible studies of interest within all relevant areas of research.
2228 CDC, “Vaccine Safety,” in CDC, “Vaccine Safety,” in Epidemiology and Prevention of Vaccine-Preventable Diseases, ed. Jennifer Hamborsky, , ed. Jennifer Hamborsky,
Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015). Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015).
2329 Frank Frank DestefanoDeStefano, Paul A. Offit, and Allison Fisher, “, Paul A. Offit, and Allison Fisher, “Ch. 82: Vaccine Safety,” in Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A. , ed. Stanley A.
Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1584. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1584.
2430 Frank Frank DestefanoDeStefano, Paul A. Offit, and Allison Fisher, “, Paul A. Offit, and Allison Fisher, “Ch. 82: Vaccine Safety,” in Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A. , ed. Stanley A.
Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1593. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1593.
2531 Frank DeStefano, Heather Monk Bodenstab, and Paul A. Offit, “Principal Controversies in Vaccine Safety in the Frank DeStefano, Heather Monk Bodenstab, and Paul A. Offit, “Principal Controversies in Vaccine Safety in the
United States,” United States,” Clinical Infectious Diseases, vol. 69 (August 15, 2019), pp. 726-31, vol. 69 (August 15, 2019), pp. 726-31, and Institute of Medicine (now National Academy of Medicine), Immunization Safety Review: Vaccines and Autism, 2004, Washington, DC: The National Academies Press. 32.
26 CDC, “Vaccine Safety,” in CDC, “Vaccine Safety,” in Epidemiology and Prevention of Vaccine-Preventable Diseases, ed. Jennifer Hamborsky, , ed. Jennifer Hamborsky,
Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015). Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015).
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link to page link to page 2729 link to page link to page 2124 Vaccine Safety in the United States Vaccine Safety in the United States

researchers wil combine evidence across many types of studies as a part of a causality assessment. Good quality
systematic causality assessments usually include the fol owing attributes:

Search methods to identify all possible studies of interest within all relevant areas of research.
 
A selection process to determine which studies are actually relevant and used rigorous scientific A selection process to determine which studies are actually relevant and used rigorous scientific
methods that provide quality evidence based on defined criteria. methods that provide quality evidence based on defined criteria.
 
A review process to compare evidence across studies, considering differences such as study populations, A review process to compare evidence across studies, considering differences such as study populations,
study design, and the quality of each study. study design, and the quality of each study.
 
Methods to weigh different types of evidence and combine evidence across studies in order to Methods to weigh different types of evidence and combine evidence across studies in order to
determine whether all the evidence, in total, supports or does not support a causal relationship between determine whether all the evidence, in total, supports or does not support a causal relationship between
vaccination with a specific vaccine and a subsequent adverse event, or yields inconclusive results. vaccination with a specific vaccine and a subsequent adverse event, or yields inconclusive results.
For a further discussion, see the For a further discussion, see the “Federal Research on Vaccine Safety” section. Causality assessments may also be ection. Causality assessments may also be
conducted on an ongoing basis using data and information from postmarket monitoring systems (see the conducted on an ongoing basis using data and information from postmarket monitoring systems (see the
“Postmarket Safety” section section). ).
For examples of causality assessments on the safety of vaccines, see Institute of Medicine (now National Academy For examples of causality assessments on the safety of vaccines, see Institute of Medicine (now National Academy
of Medicine, “Adverse Effects of Vaccines: Evidence and Causality,” 2012, https://www.nap.edu/catalog/13164/of Medicine, “Adverse Effects of Vaccines: Evidence and Causality,” 2012, https://www.nap.edu/catalog/13164/
adverse-effects-of-vaccines-evidence-and-causality; andadverse-effects-of-vaccines-evidence-and-causality; and Margaret A. Maglione, Courtney Gidengil, Lopamudra Das, Margaret A. Maglione, Courtney Gidengil, Lopamudra Das,
et al. “Safety of Vaccines Used for Routine Immunization in the United States,” et al. “Safety of Vaccines Used for Routine Immunization in the United States,” Agency for Healthcare Research and
Quality
, July 2014, https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/vaccine-safety_research.pdf. Also, for an , July 2014, https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/vaccine-safety_research.pdf. Also, for an
overview of causality assessments for vaccines, see Frank overview of causality assessments for vaccines, see Frank DestefanoDeStefano, Paul A. Offit, and Allison Fisher, “Ch. 82: , Paul A. Offit, and Allison Fisher, “Ch. 82:
Vaccine Safety,” in Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, , ed. Stanley A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier,
2017), p. 1589. 2017), p. 1589.
Premarket Safety
Vaccines generally follow the same clinical development and approval process as drugs and other Vaccines generally follow the same clinical development and approval process as drugs and other
biologics (i.e., therapeutics derived from living organisms).biologics (i.e., therapeutics derived from living organisms).2733 To be marketed in the United States, To be marketed in the United States,
a new vaccine must first receive licensure (i.e., approval) from FDA. Licensure is based on a a new vaccine must first receive licensure (i.e., approval) from FDA. Licensure is based on a
determination by FDA that the vaccine and the facility in which it is manufactured, processed, determination by FDA that the vaccine and the facility in which it is manufactured, processed,
packed, or held meet standards to ensure that the product is safe, pure, and potent (effective).packed, or held meet standards to ensure that the product is safe, pure, and potent (effective).2834
Except under very limited circumstances, FDA requires data from clinical trials—formally Except under very limited circumstances, FDA requires data from clinical trials—formally
designed, conducted, and analyzed studies of human subjects—to provide evidence of a vaccine’s designed, conducted, and analyzed studies of human subjects—to provide evidence of a vaccine’s
safety and effectiveness. These requirements apply to all vaccines marketed in the United States, safety and effectiveness. These requirements apply to all vaccines marketed in the United States,
regardless of whether the manufacturing facility is located domestically or in a foreign country. regardless of whether the manufacturing facility is located domestically or in a foreign country.
Clinical Trials
Vaccines are typically tested in several stages of human clinical trials. Before beginning clinical
testing, a vaccine’s sponsor must file an investigational new drug (IND) application, which is a
request for FDA authorization to administer an investigational biologic (or drug) to humans.29
The IND must include information about the proposed clinical study design, completed animal
test data, and the lead investigator’s qualifications.30 The investigator also must provide assurance

27Existing vaccines have often taken several years to develop.35 One analysis of FDA vaccine licensures between January 2010 and June 2020 found that the median time from initiation of clinical testing to FDA approval was 8.1 years.36 Clinical Trials Vaccines are typically tested in several stages of human clinical trials. Before beginning clinical testing, a vaccine’s sponsor must file an investigational new drug (IND) application, which is a 33 Biological products include vaccines, monoclonal antibodies, and cytokines, among other examples. For additional Biological products include vaccines, monoclonal antibodies, and cytokines, among other examples. For additional
information about biologics, see CRS Report R44620, information about biologics, see CRS Report R44620, Biologics and Biosimilars: Background and Key Issues. .
2834 PHSA §351(a)(2)(C) [42 U.S.C. §262(a)(2)(C)]. FDA approves drugs that are PHSA §351(a)(2)(C) [42 U.S.C. §262(a)(2)(C)]. FDA approves drugs that are safe and effective; the equivalent ; the equivalent
terminology for biologics is terminology for biologics is safe, pure, and potent. FDA has interpreted . FDA has interpreted potency to include effectiveness. See the FDA to include effectiveness. See the FDA
Guidance for Industry, Guidance for Industry, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, ,
https://www.fda.gov/media/82647/download. https://www.fda.gov/media/82647/download.
29 FFDCA §505(i) [21 U.S.C. §355(i)], PHSA §351(a)(3) [42 U.S.C. §262(a)(3)], 21 C.F.R. Part 312.
30 21 C.F.R. 312 Subpart B.
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35 R. Gordon Douglas and Vijay B. Samant, “Chapter 4: The Vaccine Industry,” in Plotkin’s Vaccines, ed. Stanley A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1593. 36 Jeremy Puthumana, Alexander C. Egilman, Audrey D. Zhang, et al., “Speed, Evidence, and Safety Characteristics of Vaccine Approvals by the U.S. Food and Drug Administration,” Journal of the American Medical Association- Internal Medicine, November 10, 2020. Congressional Research Service 8 Vaccine Safety in the United States request for FDA authorization to administer an investigational biologic (or drug) to humans.37 The IND must include information about the proposed clinical study design, completed animal test data, and the lead investigator’s qualifications.38 The investigator also must provide assurance that an Institutional Review Board (IRB) will provide initial and continuous review and approval that an Institutional Review Board (IRB) will provide initial and continuous review and approval
of each of the studies in the clinical investigation to ensure that participants are aware of the of each of the studies in the clinical investigation to ensure that participants are aware of the
drug’s investigational status, and that any risk of harm will be necessary, explained, and drug’s investigational status, and that any risk of harm will be necessary, explained, and
minimized.minimized.3139 FDA has 30 days to review an IND, after which a manufacturer may begin clinical FDA has 30 days to review an IND, after which a manufacturer may begin clinical
testing if FDA has not objected and imposed a clinical hold. testing if FDA has not objected and imposed a clinical hold.
Clinical trials for an IND may be sponsored by the drug company seeking to commercially Clinical trials for an IND may be sponsored by the drug company seeking to commercially
market the vaccine, a university or nonprofit organization, a government agency, or a market the vaccine, a university or nonprofit organization, a government agency, or a
combination or partnership of all the above. The funder(s) may differ for each stage of testing. In combination or partnership of all the above. The funder(s) may differ for each stage of testing. In
typical circumstances, the public sector (e.g., federal agencies, nonprofit organizations) generally typical circumstances, the public sector (e.g., federal agencies, nonprofit organizations) generally
finances more of the earlier stages of clinical trials, such as Phase 1 clinical trials. Later-stage finances more of the earlier stages of clinical trials, such as Phase 1 clinical trials. Later-stage
testing, such as Phase 3 clinical trials, are typically funded more so by drug companies than testing, such as Phase 3 clinical trials, are typically funded more so by drug companies than
government agencies.government agencies.3240
The sponsor of the trial is responsible for selecting qualified investigators, maintaining an The sponsor of the trial is responsible for selecting qualified investigators, maintaining an
effective IND, and ensuring proper monitoring of the investigations, including that they are effective IND, and ensuring proper monitoring of the investigations, including that they are
conducted in accordance with the IND. In certain cases, the sponsor may establish an independent conducted in accordance with the IND. In certain cases, the sponsor may establish an independent
Data and Safety Monitoring Board (DSMB) of relevant experts with no relevant financial or other Data and Safety Monitoring Board (DSMB) of relevant experts with no relevant financial or other
ties to the sponsor to oversee the investigations.ties to the sponsor to oversee the investigations.3341 The DSMB often advises the sponsor on the The DSMB often advises the sponsor on the
ongoing safety of trial subjects and the continuing validity and scientific merit of the trial. One ongoing safety of trial subjects and the continuing validity and scientific merit of the trial. One
DSMB may be responsible for overseeing multiple clinical trials. DSMB may be responsible for overseeing multiple clinical trials.
In general, vaccine clinical trials occur in three sequential phases: In general, vaccine clinical trials occur in three sequential phases:
  Phase 1 trials are the first in-human studies of a vaccine candidate, and they trials are the first in-human studies of a vaccine candidate, and they
assess safety and assess safety and immunogenicity34immunogenicity42 in a small number of volunteers. in a small number of volunteers.
  Phase 2 trials assess side effects and the dosing at which the investigational trials assess side effects and the dosing at which the investigational
vaccine may have a protective effect and may enroll hundreds of volunteers. vaccine may have a protective effect and may enroll hundreds of volunteers.
  Phase 3 trials assess effectiveness trials assess effectiveness and, continue to monitor safety and typically continue to monitor safety and typically
enroll enroll thousands of volunteers.thousands of volunteers.3543
Most clinical trials for vaccines include a control group, such as a placebo or alternative vaccine, Most clinical trials for vaccines include a control group, such as a placebo or alternative vaccine,
to compare outcomes for those who received the target vaccine compared with those who did not. to compare outcomes for those who received the target vaccine compared with those who did not.
Phase 3 clinical trial data are typically needed to fully assess the safety and effectiveness of an Phase 3 clinical trial data are typically needed to fully assess the safety and effectiveness of an
investigational vaccine. Typically, only the Phase 3 clinical trials are large enough to allow for
robust scientific evidence on the safety and effectiveness of the investigational vaccine among
different population segments (e.g., children, older adults).36 Under typical circumstances, a

31 37 FFDCA §505(i) [21 U.S.C. §355(i)], PHSA §351(a)(3) [42 U.S.C. §262(a)(3)], 21 C.F.R. Part 312. 38 21 C.F.R. 312 Subpart B. 39 21 C.F.R. §312.23(a)(1)(iv) and 21 C.F.R. Part 56. 21 C.F.R. §312.23(a)(1)(iv) and 21 C.F.R. Part 56.
3240 Stuart O. Schweitzer and Z. John Lu, “The Pharmaceutical Industry,” in Stuart O. Schweitzer and Z. John Lu, “The Pharmaceutical Industry,” in Pharmaceutical Economics and Policy:
Perspectives, Promises, and Problems
(New York, NY: Oxford University Press, 2018), pp. 37-40, and Gillian K. (New York, NY: Oxford University Press, 2018), pp. 37-40, and Gillian K.
Gresham, Stephan Erhardt, Jill L. Meinert, et al., “Characteristics and Trends of Clinical Trials Funded by the National Gresham, Stephan Erhardt, Jill L. Meinert, et al., “Characteristics and Trends of Clinical Trials Funded by the National
Institutes of Health Between 2005 and 2015,” Institutes of Health Between 2005 and 2015,” Clinical Trials, vol. 15, no. 1 (September 7, 2017), pp. 65-74. , vol. 15, no. 1 (September 7, 2017), pp. 65-74.
3341 FDA, “Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data Monitoring FDA, “Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data Monitoring
Committees,” March 2006, https://www.fda.gov/media/75398/download. Committees,” March 2006, https://www.fda.gov/media/75398/download.
3442 Immunogenicity refers to the extent to which a substance is able to stimulate an immune response. An immune refers to the extent to which a substance is able to stimulate an immune response. An immune
response to a pharmaceutical product may affect its safety and effectiveness. See Jonathan Law and Elizabeth Martin, response to a pharmaceutical product may affect its safety and effectiveness. See Jonathan Law and Elizabeth Martin,
ed., ed., Concise Medical Dictionary (Oxford University Press). (Oxford University Press).
3543 21 C.F.R. 21 C.F.R. §312.21. FDA, “Vaccine Product Approval Process,” https://www.fda.gov/vaccines-blood-biologics/312.21. FDA, “Vaccine Product Approval Process,” https://www.fda.gov/vaccines-blood-biologics/
development-approval-process-cber/vaccine-product-approval-process. development-approval-process-cber/vaccine-product-approval-process.
36 Frank Destefano, Paul A. Offit, and Allison Fisher, “Ch. 82: Congressional Research Service 9 Vaccine Safety in the United States investigational vaccine. Typically, only the Phase 3 clinical trials are large enough to allow for robust scientific evidence on the safety and effectiveness of the investigational vaccine among different population segments (e.g., younger vs. older adults).44 Under typical circumstances, a vaccine candidate moves through each phase of clinical testing upon successful completion of the prior phase. According to one analysis of vaccines licensed by FDA between January 2010 and June 2020, each vaccine was supported by a median of seven clinical trials, including two pivotal efficacy trials (e.g., late stage such as Phase 3 clinical trials). The median number of patients evaluated for each vaccine was 6,710, and the median follow-up for serious adverse events was six months. 45 Aspects specific to each vaccine and infectious disease inform vaccine development considerations, including the prevalence of the disease in the population, risk of infection, available scientific understanding of immune responses, and potential for serious adverse events linked to the vaccine and/or disease. These considerations inform clinical trial design, number of study participants, age and population groups recruited to the study, and development timelines.46 To determine efficacy, late-stage clinical trials use what are called “endpoints” to measure the clinical effect of the drug on patient outcomes (in this case, disease prevention) as compared to the control group. For vaccines, endpoints can include clinical endpoints that are a direct measure of vaccine efficacy on patient outcomes, such as laboratory-confirmed infections or disease cases with symptoms, or surrogate endpoints (also called immune response endpoints) that measure an indicator of a protective immune response, such as the presence of antibodies to the disease in the bloodstream.47 Whether a surrogate endpoint can be used to measure the efficacy of a given vaccine depends on the available scientific understanding of protective immune responses to that pathogen. While scientific understanding of protective immune responses has improved for many pathogens over the years, there are some pathogens that have been studied for decades for which scientists do not fully understand the biology of protective immune responses induced by vaccination.48 Of new vaccines licensed between January 2010 and June 2020 against pathogens for which no vaccine had been previously licensed, four out of five used clinical endpoints rather than surrogate endpoints.49 Various factors determine whether a surrogate endpoint is appropriate for use in a vaccine development program, and these decisions are made on a case-by-case basis.50 If a surrogate endpoint previously had been used to support licensure of a vaccine, it may be appropriate for use in future vaccine development programs for that same disease. A surrogate endpoint that has less evidentiary support may be more appropriate for the accelerated approval 44 Frank DeStefano, Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A. , ed. Stanley A.
Plotkin, Walter A. Orenstein, Plotkin, Walter A. Orenstein, and Paul A. Offit, Paul A. Offit, and Kathryn Edwards, 7th ed. (Elsevier, 2017), pp. 1584. 45 Jeremy Puthumana, Alexander C. Egilman, Audrey D. Zhang, et al., “Speed, Evidence, and Safety Characteristics of Vaccine Approvals by the U.S. Food and Drug Administration,” Journal of the American Medical Association- Internal Medicine, November 10, 2020. 46 Marion F. Gruber and Valerie B. Marshall, “Chapter 79: Regulation and Testing of Vaccines,” in Plotkin’s Vaccines, ed. Stanley Plotkin Walter Orenstein Paul Offit, and Kathryn M. Edwards, 7th ed., vol. 1555-6 (Elsevier, 2017). 47 Ibid. 48 Stanley A. Plotkin and Peter Gilbert, “Chapter 3: Correlates of Protection ,” in Plotkin’s Vaccines, ed. Stanley A. Plotkin, Walter A. Orenstein, Paul A. Offit, and Kathryn Edwards, 7th ed. (Elsevier, 2017), p. 39 and Stanley A. Plotkin, “Updates on Immunologic Correlates of Vaccine-Induced Protection,” Vaccine, vol. 38 (November 22, 2019). 49 Jeremy Puthumana, Alexander C. Egilman, Audrey D. Zhang, et al., “Speed, Evidence, and Safety Characteristics of Vaccine Approvals by the U.S. Food and Drug Administration,” Journal of the American Medical Association- Internal Medicine, November 10, 2020. 50 FDA, “Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure,” https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure. Congressional Research Service 10 Vaccine Safety in the United States pathway rather than traditional licensure when it is “reasonably likely to predict a clinical benefit.” 51 In other instances, relying on a surrogate endpoint for vaccine licensure may not be appropriate until more information is available about the immune response or disease.52 7th ed. (Elsevier, 2017), pp. 1584.
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vaccine candidate moves through each phase of clinical testing upon successful completion of the
prior phase.
Phase 3 clinical trials are typically longer (usually at least a year) than the other phases in order to
fully assess the safety and effectiveness of the investigational vaccine. Adequate time is often
needed to give trial participants a chance to be exposed to the target disease in the community and
to assess if infection rates vary between the vaccine recipient and control groups. In some cases, In some cases,
an experimental vaccine that showed promise in Phase 1 and Phase 2 clinical trials was found to an experimental vaccine that showed promise in Phase 1 and Phase 2 clinical trials was found to
be ineffective in Phase 3 trials. For example, an experimental vaccine for herpes simplex virus be ineffective in Phase 3 trials. For example, an experimental vaccine for herpes simplex virus
type 2 (HSV-2) showed safety and preliminary evidence of an immune response to the virus in type 2 (HSV-2) showed safety and preliminary evidence of an immune response to the virus in
Phase 2 clinical trials (i.e., HSV-2 antibodies in the bloodstream). However, during the Phase 3 Phase 2 clinical trials (i.e., HSV-2 antibodies in the bloodstream). However, during the Phase 3
clinical trials, by a year after vaccination, there was no difference in rates of acquired HSV-2 clinical trials, by a year after vaccination, there was no difference in rates of acquired HSV-2
infections between the recipient and control groups, despite vaccine recipients showing a infections between the recipient and control groups, despite vaccine recipients showing a
preliminary immune response.preliminary immune response.3753
In addition to providing insights into the effectiveness of investigational vaccines, long-term In addition to providing insights into the effectiveness of investigational vaccines, long-term
Phase 3 studies can uncover important safety data. For example, three years of safety data on the Phase 3 studies can uncover important safety data. For example, three years of safety data on the
vaccine for dengue virus produced by Sanofi Pasteur (Dengvaxia) found an issue of vaccine for dengue virus produced by Sanofi Pasteur (Dengvaxia) found an issue of antibody-
mediated enhancement
of infections,of infections, where the antibodies raised in response to vaccination could where the antibodies raised in response to vaccination could
worsen the severity of dengue for those without a prior dengue infection. Data on the vaccine worsen the severity of dengue for those without a prior dengue infection. Data on the vaccine
showed a higher rate of hospitalizations for dengue three years after vaccination in young showed a higher rate of hospitalizations for dengue three years after vaccination in young
children compared with children who were unvaccinated.children compared with children who were unvaccinated.3854
For some vaccines, Phase 3 clinical trials are very large to detect rare adverse events. For For some vaccines, Phase 3 clinical trials are very large to detect rare adverse events. For
instance, two second-generation rotavirus vaccines (RotaTeq and RotaRix) were subject to Phase instance, two second-generation rotavirus vaccines (RotaTeq and RotaRix) were subject to Phase
3 clinical trials involving over 60,000 infants in order to ascertain the risk of intussusception 3 clinical trials involving over 60,000 infants in order to ascertain the risk of intussusception
(intestinal obstruction) following vaccine administration (estimated to be about 1 in 10,000 in the (intestinal obstruction) following vaccine administration (estimated to be about 1 in 10,000 in the
first-generation vaccine).first-generation vaccine).39 However, such55 Such large trials large trials can involve higher costs and increased time to involve higher costs and increased time to
licensure. licensure.
Biologics License Application (BLA) and Licensure Requirements
After completing clinical trials, a sponsor may submit a Biologics License Application (BLA) to After completing clinical trials, a sponsor may submit a Biologics License Application (BLA) to
FDA’s Center for Biologics Evaluation and Research (CBER). A BLA is a request for permission FDA’s Center for Biologics Evaluation and Research (CBER). A BLA is a request for permission
to market the vaccine and must contain certain information, including data from nonclinical to market the vaccine and must contain certain information, including data from nonclinical
laboratory and clinical studies demonstrating that the product meets requirements of safety, laboratory and clinical studies demonstrating that the product meets requirements of safety,
purity, and potency.purity, and potency.4056 For each nonclinical laboratory study, the BLA must include either (1) a For each nonclinical laboratory study, the BLA must include either (1) a
statement that the study was conducted in compliance with FDA regulations governing Good statement that the study was conducted in compliance with FDA regulations governing Good
Laboratory Practice (GLP) for nonclinical laboratory Laboratory Practice (GLP) for nonclinical laboratory studies41studies57 or (2) if the study was not or (2) if the study was not
conducted in compliance with GLP regulations, a brief statement explaining the reason for conducted in compliance with GLP regulations, a brief statement explaining the reason for
noncompliance. In addition, for each clinical investigation involving human subjects, the BLA

37 51 FDA, “Surrogate Endpoint Resources for Drug and Biologic Development,” https://www.fda.gov/drugs/development-resources/surrogate-endpoint-resources-drug-and-biologic-development. 52 FDA, “Development and Licensure of Vaccines to Prevent COVID-19,” Guidance for Industry, June 2020, p. 18, https://www.fda.gov/media/139638/download. 53 FDA, FDA, 22 Case Studies Where Phase 2 and Phase 3 Trials had Divergent Results, January 2017. , January 2017.
3854 S.R. Hadinegoro, J.L. Arredondo-Garcia, and M.R. Capeding, et al., “Efficacy and Long-Term Safety of a Dengue S.R. Hadinegoro, J.L. Arredondo-Garcia, and M.R. Capeding, et al., “Efficacy and Long-Term Safety of a Dengue
Vaccine in Regions of Endemic Disease,” Vaccine in Regions of Endemic Disease,” The New England Journal of Medicine, vol. 373, no. 13 (September 24, , vol. 373, no. 13 (September 24,
2015). Helen Branswell, “Caution on New Dengue Vaccine: In Some Countries, Harm Outweighs Benefit,” 2015). Helen Branswell, “Caution on New Dengue Vaccine: In Some Countries, Harm Outweighs Benefit,” STAT, ,
September 1, 2016. September 1, 2016.
3955 Frank Frank DestefanoDeStefano, Paul A. Offit, and Allison Fisher, “, Paul A. Offit, and Allison Fisher, “Ch. 82: Vaccine Safety,” in Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A. , ed. Stanley A.
Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), pp. 1584. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), pp. 1584.
4056 FDA regulations at 21 C.F.R. §601.2(a) specify the required contents of a BLA. FDA regulations at 21 C.F.R. §601.2(a) specify the required contents of a BLA.
4157 21 C.F.R. Part 58 “Good Laboratory Practice for Nonclinical Laboratory Studies.” 21 C.F.R. Part 58 “Good Laboratory Practice for Nonclinical Laboratory Studies.”
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noncompliance. In addition, for each clinical investigation involving human subjects, the BLA must contain statements that each clinical investigation either was conducted in compliance with must contain statements that each clinical investigation either was conducted in compliance with
the requirements for institutional review set forth in FDA regulations,the requirements for institutional review set forth in FDA regulations,4258 or that it was not subject or that it was not subject
to such requirements and was conducted in compliance with requirements for informed consent.to such requirements and was conducted in compliance with requirements for informed consent.4359
The BLA also must contain “a full description of manufacturing methods; data establishing The BLA also must contain “a full description of manufacturing methods; data establishing
stability of the product through the dating period; sample(s) representative of the product for stability of the product through the dating period; sample(s) representative of the product for
introduction or delivery for introduction into interstate commerce; summaries of results of tests introduction or delivery for introduction into interstate commerce; summaries of results of tests
performed on the lot(s) represented by the submitted sample(s); specimens of the labels, performed on the lot(s) represented by the submitted sample(s); specimens of the labels,
enclosures, and containers;” and the address of each location involved in the manufacture of the enclosures, and containers;” and the address of each location involved in the manufacture of the
vaccine. If applicable, a BLA must contain any medication guide proposed to be used for the vaccine. If applicable, a BLA must contain any medication guide proposed to be used for the
product. Finally, the BLA must include a financial certification or disclosure statement(s) or both product. Finally, the BLA must include a financial certification or disclosure statement(s) or both
for clinical investigators. for clinical investigators.
As noted above, a vaccine manufacturer must submit proposed vaccine labeling as part of a BLA. As noted above, a vaccine manufacturer must submit proposed vaccine labeling as part of a BLA.
FDA reviews the proposed labeling to determine whether it is scientifically accurate and that it FDA reviews the proposed labeling to determine whether it is scientifically accurate and that it
conforms to regulatory requirements. As for prescription drugs and other biologics, vaccine conforms to regulatory requirements. As for prescription drugs and other biologics, vaccine
labeling must include warnings and precautions, contraindications, dosage and administration, labeling must include warnings and precautions, contraindications, dosage and administration,
storage and handling conditions, and adverse reactions, among other information.storage and handling conditions, and adverse reactions, among other information.4460 Labeling for Labeling for
vaccines must specifically contain a statement describing how suspected adverse reactions can be vaccines must specifically contain a statement describing how suspected adverse reactions can be
reported.reported.4561 In addition, the labels affixed to each container or package of a vaccine must include In addition, the labels affixed to each container or package of a vaccine must include
the name of the manufacturer, the lot number or other lot identification,the name of the manufacturer, the lot number or other lot identification,4662 and the recommended and the recommended
individual dose (for multiple dose containers), among other information.individual dose (for multiple dose containers), among other information.4763 Vaccines require Vaccines require
special processing and handling, such as refrigeration and proper storage, and information about special processing and handling, such as refrigeration and proper storage, and information about
storage temperature and other handling instructions must be on the label affixed to each package storage temperature and other handling instructions must be on the label affixed to each package
containing a vaccine.containing a vaccine.4864
FDA regulations also provide for biological product manufacturing establishment standards. Such FDA regulations also provide for biological product manufacturing establishment standards. Such
standards cover personnel, the physical establishment in which a product is manufactured, records standards cover personnel, the physical establishment in which a product is manufactured, records
maintenance, retention of samples, reporting of product deviations, and product temperature maintenance, retention of samples, reporting of product deviations, and product temperature
during shipment.during shipment.4965 Most of these requirements apply broadly to biologics, but several provisions Most of these requirements apply broadly to biologics, but several provisions
are vaccine-specific, including requirements for live vaccine work are vaccine-specific, including requirements for live vaccine work areas50areas66 and live vaccine and live vaccine
processing,processing,5167 as well as product-specific maintenance temperatures. as well as product-specific maintenance temperatures.5268 In addition, FDA In addition, FDA
regulations establish requirements for testing product potency, sterility, purity, and identity, as regulations establish requirements for testing product potency, sterility, purity, and identity, as
well as requirements for constituent materials used in licensed products, including preservatives, well as requirements for constituent materials used in licensed products, including preservatives,
diluents, and adjuvants.diluents, and adjuvants.5369 Vaccines, like other biological products, are subject to lot release Vaccines, like other biological products, are subject to lot release
requirements, which provide that “[n]o lot of any licensed product shall be released by the
manufacturer prior to the completion of tests for conformity with standards applicable to such

42 58 21 C.F.R. Part 56 “Institutional Review Boards.” 21 C.F.R. Part 56 “Institutional Review Boards.”
4359 21 C.F.R. Part 50 “Protection of Human Subjects.” 21 C.F.R. Part 50 “Protection of Human Subjects.”
4460 21 C.F.R. §§201.56 and 201.57. 21 C.F.R. §§201.56 and 201.57.
4561 21 C.F.R. §201.57(a)(11)(iii). 21 C.F.R. §201.57(a)(11)(iii).
4662 “Lot” refers to “that quantity of uniform material identified by the manufacturer as having been thoroughly mixed in “Lot” refers to “that quantity of uniform material identified by the manufacturer as having been thoroughly mixed in
a single vessel.” 21 C.F.R. § 600.3(x). a single vessel.” 21 C.F.R. § 600.3(x).
4763 21 C.F.R. §§610.60 and 610.61. 21 C.F.R. §§610.60 and 610.61.
4864 21 C.F.R. §610.61. 21 C.F.R. §610.61.
4965 21 C.F.R. Part 600. 21 C.F.R. Part 600.
5066 21 C.F.R. §600.10(c)(4). 21 C.F.R. §600.10(c)(4).
51 67 21 C.F.R. §600.11(c)(4). 21 C.F.R. §600.11(c)(4).
5268 21 C.F.R. §600.15. 21 C.F.R. §600.15.
5369 21 C.F.R. Part 610. 21 C.F.R. Part 610.
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requirements, which provide that “[n]o lot of any licensed product shall be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product.”70product.”54 FDA may require that samples of any lot of any licensed product and the protocols FDA may require that samples of any lot of any licensed product and the protocols
and applicable test results be submitted to CBER. In such case, a manufacturer may not distribute and applicable test results be submitted to CBER. In such case, a manufacturer may not distribute
a lot of a vaccine until it is released by FDA.a lot of a vaccine until it is released by FDA.5571
Expedited Pathways and Access to Unapproved Vaccines
Because clinical testing and the FDA review process typically take several years, FDA and Because clinical testing and the FDA review process typically take several years, FDA and
Congress have established mechanisms to expedite the premarket development and review Congress have established mechanisms to expedite the premarket development and review
processes for pharmaceutical products, including vaccines, coming onto the market, as well as to processes for pharmaceutical products, including vaccines, coming onto the market, as well as to
expand access to products that are still under investigation. Historically, certain FDA expedited expand access to products that are still under investigation. Historically, certain FDA expedited
pathways such as Emergency Use Authorization (EUA) have been used infrequently for vaccines. pathways such as Emergency Use Authorization (EUA) have been used infrequently for vaccines.
However, a public health emergency, such as a pandemic, may affect the risk assessment in However, a public health emergency, such as a pandemic, may affect the risk assessment in
making a vaccine available before full long-term safety data are available. making a vaccine available before full long-term safety data are available.
Expedited Development and Review
To address unmet medical needs in the treatment or prevention of serious or life-threatening To address unmet medical needs in the treatment or prevention of serious or life-threatening
diseases or conditions, FDA can expedite the development and review processes for drugs and diseases or conditions, FDA can expedite the development and review processes for drugs and
biologics, including vaccines, through four programs: biologics, including vaccines, through four programs:
 fast track product designation,  fast track product designation,
 breakthrough therapy designation,  breakthrough therapy designation,
 accelerated approval, and  accelerated approval, and
 priority review. priority review.5672
Vaccines may be designated to more than one program. Fast track product designation and Vaccines may be designated to more than one program. Fast track product designation and
breakthrough therapy are both intended to streamline the clinical development process, but the breakthrough therapy are both intended to streamline the clinical development process, but the
qualifying criteria and features of these programs differ. qualifying criteria and features of these programs differ.
To qualify for To qualify for fast track product designation, a vaccine must be intended for a serious condition, , a vaccine must be intended for a serious condition,
and nonclinical or clinical data must demonstrate its potential to address an unmet medical need.and nonclinical or clinical data must demonstrate its potential to address an unmet medical need.5773
The sponsor of a fast track-designated product is eligible for frequent interactions with the FDA The sponsor of a fast track-designated product is eligible for frequent interactions with the FDA
review team, priority review, and rolling review (in which FDA reviews portions of a BLA before review team, priority review, and rolling review (in which FDA reviews portions of a BLA before
a complete application is submitted).a complete application is submitted).5874
To qualify for To qualify for breakthrough designation, a vaccine must be intended for a serious condition, and , a vaccine must be intended for a serious condition, and
preliminary clinical evidence must indicate that it demonstrates potential substantial improvement preliminary clinical evidence must indicate that it demonstrates potential substantial improvement
on a clinically significant endpoint(s) over available therapies. Features of breakthrough therapy on a clinically significant endpoint(s) over available therapies. Features of breakthrough therapy
designation include rolling review; intensive FDA guidance on designing an efficient drug designation include rolling review; intensive FDA guidance on designing an efficient drug
development program; involvement of “senior managers and experienced review and regulatory development program; involvement of “senior managers and experienced review and regulatory
health project management staff in a proactive, collaborative, cross-disciplinary review” to health project management staff in a proactive, collaborative, cross-disciplinary review” to
expedite the development and review of a breakthrough therapy; and eligibility for other
expedited programs.

5470 21 C.F.R. §610.1. 21 C.F.R. §610.1.
5571 21 C.F.R. §610.2. 21 C.F.R. §610.2.
5672 FFDCA §506 [21 U.S.C. §356]. FDA, “Guidance for Industry Expedited Programs for Serious Conditions FFDCA §506 [21 U.S.C. §356]. FDA, “Guidance for Industry Expedited Programs for Serious ConditionsDrugs Drugs
and Biologics,” May 2014, https://www.fda.gov/media/86377/download. and Biologics,” May 2014, https://www.fda.gov/media/86377/download.
5773 FFDCA §506(b) [21 U.S.C. §356(b)]. FFDCA §506(b) [21 U.S.C. §356(b)].
5874 FFDCA §506(a) [21 U.S.C. §356(a)]. FFDCA §506(a) [21 U.S.C. §356(a)].
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expedite the development and review of a breakthrough therapy; and eligibility for other expedited programs. Interested sponsors must submit to FDA a request for fast track product designation or Interested sponsors must submit to FDA a request for fast track product designation or
breakthrough therapy designation. The request may be submitted with either the IND or any time breakthrough therapy designation. The request may be submitted with either the IND or any time
after,after,5975 as further specified in FDA guidance. as further specified in FDA guidance.6076
The The accelerated approval pathway allows a vaccine to be licensed based on its effect on a pathway allows a vaccine to be licensed based on its effect on a
surrogate endpoint (e.g., a laboratory measurement such as development of neutralizing surrogate endpoint (e.g., a laboratory measurement such as development of neutralizing
antibodies) that predicts effectiveness, or on a clinical endpoint that can be measured earlier than antibodies) that predicts effectiveness, or on a clinical endpoint that can be measured earlier than
irreversible morbidity or mortality. To qualify for accelerated approval, a vaccine must (1) be irreversible morbidity or mortality. To qualify for accelerated approval, a vaccine must (1) be
intended for a serious condition, (2) generally provide a meaningful advantage over available intended for a serious condition, (2) generally provide a meaningful advantage over available
therapies, and (3) demonstrate an effect on an endpoint that is reasonably likely to predict clinical therapies, and (3) demonstrate an effect on an endpoint that is reasonably likely to predict clinical
benefit. Postmarketing confirmatory studies generally must be completed to demonstrate actual benefit. Postmarketing confirmatory studies generally must be completed to demonstrate actual
effectiveness.effectiveness.61 Because surrogate endpoints for vaccines are often difficult to characterize, owing
to the complexity of protective immune responses, accelerated approval may not be a relevant
licensure pathway for many vaccines.62
77 A A priority review designation signifies that FDA’s goal is to take action on an application within designation signifies that FDA’s goal is to take action on an application within
6 months of its filing, compared with 10 months for standard review. A BLA may qualify for 6 months of its filing, compared with 10 months for standard review. A BLA may qualify for
priority review designation if, for example, it is for a vaccine intended for a serious condition and, priority review designation if, for example, it is for a vaccine intended for a serious condition and,
if approved, would provide a significant improvement in safety or effectiveness. A BLA also may if approved, would provide a significant improvement in safety or effectiveness. A BLA also may
qualify for priority review if submitted with a priority review voucher.qualify for priority review if submitted with a priority review voucher.6378
Animal Rule
As mentioned above, FDA typically requires substantial evidence of effectiveness from adequate As mentioned above, FDA typically requires substantial evidence of effectiveness from adequate
and well-controlled trials conducted in humans prior to licensing a vaccine. However, in certain and well-controlled trials conducted in humans prior to licensing a vaccine. However, in certain
cases, evaluating a vaccine’s efficacy or effectiveness through human trials is not possible. For cases, evaluating a vaccine’s efficacy or effectiveness through human trials is not possible. For
example, it would not be ethical to expose human subjects to lethal toxic substances in order to example, it would not be ethical to expose human subjects to lethal toxic substances in order to
test an investigational vaccine. test an investigational vaccine.
Under the Animal Rule, if human efficacy studies are not ethical, and if field trials (i.e., trials Under the Animal Rule, if human efficacy studies are not ethical, and if field trials (i.e., trials
conducted outside of the clinical setting) are not feasible, FDA may license a vaccine based on conducted outside of the clinical setting) are not feasible, FDA may license a vaccine based on
adequate and well-controlled animal efficacy studies if those studies establish that the vaccine is adequate and well-controlled animal efficacy studies if those studies establish that the vaccine is
likely to produce clinical benefit in humans.likely to produce clinical benefit in humans.6479 The Animal Rule is intended for drugs and The Animal Rule is intended for drugs and
biologics that would treat or prevent serious or life-threatening conditions caused by chemical, biologics that would treat or prevent serious or life-threatening conditions caused by chemical,
biological, radiological, or nuclear substances (e.g., nerve agents, emerging infectious pathogens, biological, radiological, or nuclear substances (e.g., nerve agents, emerging infectious pathogens,
snake venom, and industrial chemicals). For FDA to rely on evidence from animal studies to snake venom, and industrial chemicals). For FDA to rely on evidence from animal studies to
provide evidence of effectiveness, four criteria must be met: provide evidence of effectiveness, four criteria must be met:

5975 FFDCA §506(a)(2) & (b)(2) [21 U.S.C. §356(a)(2) & (b)(2)]. FFDCA §506(a)(2) & (b)(2) [21 U.S.C. §356(a)(2) & (b)(2)].
6076 FDA, “Guidance for Industry Expedited Programs for Serious Conditions FDA, “Guidance for Industry Expedited Programs for Serious ConditionsDrugs and Biologics,” May 2014, Drugs and Biologics,” May 2014,
https://www.fda.gov/media/86377/download. https://www.fda.gov/media/86377/download.
6177 FFDCA §506(c) [21 U.S.C. §356(c)]. FFDCA §506(c) [21 U.S.C. §356(c)].
62 Stanley A. Plotkin, “Updates on Immunologic Correlates of Vaccine-Induced Protection,” Vaccine, vol. 38
(November 22, 2019).
6378 Three priority review voucher programs are currently authorized in the FFDCA: (1) the tropical disease priority Three priority review voucher programs are currently authorized in the FFDCA: (1) the tropical disease priority
review program, (2) the rare pediatric disease priority review program, and (3) the material threat MCM priority review review program, (2) the rare pediatric disease priority review program, and (3) the material threat MCM priority review
voucher program. Under each of these programs, the sponsor of an NDA or BLA that meets the statutory requirements voucher program. Under each of these programs, the sponsor of an NDA or BLA that meets the statutory requirements
of the specific program is eligible to receive, upon approval, a transferable voucher, and the sponsor may either use that of the specific program is eligible to receive, upon approval, a transferable voucher, and the sponsor may either use that
voucher for the priority review of another application or sell it to another sponsor to use. voucher for the priority review of another application or sell it to another sponsor to use.
6479 21 C.F.R. §601.90 through §601.95 for biologics, including vaccines. See also FDA Guidance for Industry, “Product 21 C.F.R. §601.90 through §601.95 for biologics, including vaccines. See also FDA Guidance for Industry, “Product
Development Under the Animal Rule,” October 2015, https://www.fda.gov/media/88625/download. Development Under the Animal Rule,” October 2015, https://www.fda.gov/media/88625/download.
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There is a reasonably well-understood pathophysiological mechanism of the toxicity of the There is a reasonably well-understood pathophysiological mechanism of the toxicity of the
substance and its prevention or substantial reduction by the product; substance and its prevention or substantial reduction by the product;
The effect is demonstrated in more than one animal species expected to react with response The effect is demonstrated in more than one animal species expected to react with response
predictive for humans, unless the effect is demonstrated in a single animal species that predictive for humans, unless the effect is demonstrated in a single animal species that
represents a sufficiently well-characterized animal model for predicting the response in represents a sufficiently well-characterized animal model for predicting the response in
humans; humans;
The animal study endpoint is clearly related to the desired benefit in humans, generally the The animal study endpoint is clearly related to the desired benefit in humans, generally the
enhancement of survival or prevention of major morbidity; and enhancement of survival or prevention of major morbidity; and
The data or information on the kinetics and pharmacodynamics of the product or other The data or information on the kinetics and pharmacodynamics of the product or other
relevant data or information, in animals and humans, allows selection of an effective dose relevant data or information, in animals and humans, allows selection of an effective dose
in humans.in humans.6580
Drugs and vaccines evaluated for efficacy under the Animal Rule are evaluated for safety under Drugs and vaccines evaluated for efficacy under the Animal Rule are evaluated for safety under
the existing requirements for drugs and biologics. Postmarketing studies, such as field studies, the existing requirements for drugs and biologics. Postmarketing studies, such as field studies,
must be conducted once feasible, and the sponsor of the vaccine must prepare certain patient-must be conducted once feasible, and the sponsor of the vaccine must prepare certain patient-
specific information explaining that the approval was based on efficacy studies conducted in specific information explaining that the approval was based on efficacy studies conducted in
animals alone. FDA also may impose postmarketing restrictions on distribution of the product if animals alone. FDA also may impose postmarketing restrictions on distribution of the product if
necessary to ensure safety (e.g., restricting distribution to certain facilities or practitioners with necessary to ensure safety (e.g., restricting distribution to certain facilities or practitioners with
special training or experience).special training or experience).6681 To date, FDA has licensed one vaccine under the Animal Rule: To date, FDA has licensed one vaccine under the Animal Rule:
BioThrax (Anthrax Vaccine Adsorbed [injection]). Specifically, in 2015, the Animal Rule was BioThrax (Anthrax Vaccine Adsorbed [injection]). Specifically, in 2015, the Animal Rule was
used to approve a new use—post-exposure prophylaxis of disease—of a previously licensed used to approve a new use—post-exposure prophylaxis of disease—of a previously licensed
anthrax vaccine.anthrax vaccine.6782
Emergency Use Authorization (EUA)
In general, a vaccine may be provided to patients only if FDA has licensed its marketing under a In general, a vaccine may be provided to patients only if FDA has licensed its marketing under a
BLA or authorized its use in a clinical trial under an IND. In certain circumstances, however, BLA or authorized its use in a clinical trial under an IND. In certain circumstances, however,
FDA may allow patients to access investigational vaccines outside this framework, including FDA may allow patients to access investigational vaccines outside this framework, including
through emergency use authorization (EUA). through emergency use authorization (EUA).
FDA may enable access to an unapproved vaccine by granting an EUA, if the HHS Secretary FDA may enable access to an unapproved vaccine by granting an EUA, if the HHS Secretary
declares that circumstances exist to justify the emergency use of an unapproved product or an declares that circumstances exist to justify the emergency use of an unapproved product or an
unapproved use of an approved medical product.unapproved use of an approved medical product.6883 The HHS Secretary’s declaration must be The HHS Secretary’s declaration must be
based on one of four determinations; for example, a determination that an actual or significant based on one of four determinations; for example, a determination that an actual or significant
potential exists for a public health emergency that affects or has significant potential to affect potential exists for a public health emergency that affects or has significant potential to affect
national security or the health and security of U.S. citizens living abroad.national security or the health and security of U.S. citizens living abroad.6984 Following the HHS Following the HHS
Secretary’s declaration, FDA, in consultation with the Assistant Secretary for Preparedness and Secretary’s declaration, FDA, in consultation with the Assistant Secretary for Preparedness and
Response (ASPR), the National Institutes of Health (NIH), and CDC, may issue an EUA Response (ASPR), the National Institutes of Health (NIH), and CDC, may issue an EUA
authorizing the emergency use of a vaccine, provided that the following criteria are met: authorizing the emergency use of a vaccine, provided that the following criteria are met:

6580 21 C.F.R. §601.91. FDA Guidance for Industry, “Product Development Under the Animal Rule,” October 2015, 21 C.F.R. §601.91. FDA Guidance for Industry, “Product Development Under the Animal Rule,” October 2015,
https://www.fda.gov/media/88625/download. https://www.fda.gov/media/88625/download.
6681 21 C.F.R. §601.91. 21 C.F.R. §601.91.
6782 FDA, “CBER Regulated Biologic Animal Rule Approvals,” https://www.fda.gov/media/107839/download. FDA, FDA, “CBER Regulated Biologic Animal Rule Approvals,” https://www.fda.gov/media/107839/download. FDA,
“FDA approves vaccine for use after known or suspected anthrax exposure,” November 23, 2015, “FDA approves vaccine for use after known or suspected anthrax exposure,” November 23, 2015,
http://wayback.archive-it.org/7993/20171114165441/https://www.fda.gov/NewsEvents/Newsroom/http://wayback.archive-it.org/7993/20171114165441/https://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm474027.htm. PressAnnouncements/ucm474027.htm.
6883 FFDCA §564 [21 U.S.C. §360bbb-3]. For additional information, see CRS In Focus IF10745, FFDCA §564 [21 U.S.C. §360bbb-3]. For additional information, see CRS In Focus IF10745, Emergency Use
Authorization and FDA’s Related Authorities
. .
6984 FFDCA §564(b)(1) [21 U.S.C. §360bbb-3(b)(1)]. FFDCA §564(b)(1) [21 U.S.C. §360bbb-3(b)(1)].
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 the agent that is the subject of the EUA can cause a serious or life-threatening  the agent that is the subject of the EUA can cause a serious or life-threatening
disease or condition; disease or condition;
 based on the totality of the available scientific evidence, it is reasonable to  based on the totality of the available scientific evidence, it is reasonable to
believe that the product may be effective in diagnosing, treating, or preventing believe that the product may be effective in diagnosing, treating, or preventing
such disease or condition, and that the known and potential benefits of the such disease or condition, and that the known and potential benefits of the
product outweigh its known and potential risks; and product outweigh its known and potential risks; and
 there is no adequate, approved, or available alternative to the product.  there is no adequate, approved, or available alternative to the product.7085
The standard of evidence for an EUA is different than that for approval. EUA issuance, as noted The standard of evidence for an EUA is different than that for approval. EUA issuance, as noted
above, is based on FDA’s determination that the totality of the available scientific evidence above, is based on FDA’s determination that the totality of the available scientific evidence
suggests that a product suggests that a product may be effective in diagnosing, treating, or preventing a disease or in diagnosing, treating, or preventing a disease or
condition, and that the known and potential benefits of the product outweigh its known and condition, and that the known and potential benefits of the product outweigh its known and
potential risks. This standard of evidence is different from the one required for full FDA approval potential risks. This standard of evidence is different from the one required for full FDA approval
or licensure, which is based on or licensure, which is based on substantial evidence of effectiveness derived from adequate and of effectiveness derived from adequate and
well-controlled studies.well-controlled studies.7186
FDA must impose certain conditions as part of an EUA to the extent practicable (e.g., distributing FDA must impose certain conditions as part of an EUA to the extent practicable (e.g., distributing
certain information to health care providers and patients) and may impose additional discretionary certain information to health care providers and patients) and may impose additional discretionary
conditions where appropriate.conditions where appropriate.7287 FDA may waive or limit current good manufacturing practices FDA may waive or limit current good manufacturing practices
(e.g., storage and handling) and prescription dispensing requirements for products authorized (e.g., storage and handling) and prescription dispensing requirements for products authorized
under an EUA. In addition, FDA may establish conditions on advertisements and other under an EUA. In addition, FDA may establish conditions on advertisements and other
promotional printed matter that relates to the emergency use of a product. An EUA remains in promotional printed matter that relates to the emergency use of a product. An EUA remains in
effect for the duration of the emergency declaration made by the HHS Secretary under FFDCA effect for the duration of the emergency declaration made by the HHS Secretary under FFDCA
Section 564, unless revoked at an earlier date. Section 564, unless revoked at an earlier date.
To date, FDA has not granted anUntil December 2020, FDA had never granted EUA for an unapproved (i.e., unlicensed) vaccine. EUA for an unapproved (i.e., unlicensed) vaccine. However, in
2005, FDA had issued an EUAThe only instance of FDA issuing an EUA for a vaccine was in 2005 for the for the unapproved use of a previously licensed vaccine. of a previously licensed vaccine.73
88 However, on December 11, 2020, FDA granted EUA to the vaccine manufactured by Pfizer-BioNTech, authorizing its use for the prevention of COVID-19 in individuals 16 years of age and older. A week later, on December 18, 2020, FDA granted EUA to the vaccine manufactured by Moderna, authorizing its use for the prevention of COVID-19 in individuals 18 years of age and older. Advisory Committee Consultation
FDA consults with a federal advisory committee on various vaccine-related matters. Specifically, FDA consults with a federal advisory committee on various vaccine-related matters. Specifically,
the Vaccines and Related Biological Products Advisory Committee (VRBPAC) is made up of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) is made up of
non-FDA medical and scientific experts who inform FDA’s regulation of vaccines and related non-FDA medical and scientific experts who inform FDA’s regulation of vaccines and related
biological products. The committee “reviews and evaluates data concerning the safety, biological products. The committee “reviews and evaluates data concerning the safety,
effectiveness, and appropriate use of vaccines and related biological products” and “considers the effectiveness, and appropriate use of vaccines and related biological products” and “considers the
quality and relevance of FDA’s research program which provides scientific support for the quality and relevance of FDA’s research program which provides scientific support for the
regulation of these products and makes appropriate recommendations” to the FDA regulation of these products and makes appropriate recommendations” to the FDA
Commissioner.74 VRBPAC may, for example, meet to discuss approaches for demonstrating

7085 FFDCA §564(c) [21 U.S.C. §360bbb-3(c)]. These criteria are explained in more detail in the FDA guidance FFDCA §564(c) [21 U.S.C. §360bbb-3(c)]. These criteria are explained in more detail in the FDA guidance
Emergency Use Authorization of Medical Products and Related Authorities, January 2017, p. 7, https://www.fda.gov/Emergency Use Authorization of Medical Products and Related Authorities, January 2017, p. 7, https://www.fda.gov/
media/97321/download. media/97321/download.
7186 FFDCA §505(d) [21 U.S.C. §355(d)]. FFDCA §505(d) [21 U.S.C. §355(d)].
7287 FFDCA §564(e) [21 U.S.C. §360bbb-3(e)]. FFDCA §564(e) [21 U.S.C. §360bbb-3(e)].
7388 Authorization of Emergency Use of Anthrax Vaccine Adsorbed for Prevention of Inhalation Anthrax by Individuals Authorization of Emergency Use of Anthrax Vaccine Adsorbed for Prevention of Inhalation Anthrax by Individuals
at Heightened Risk of Exposure Due to Attack With Anthrax, 70 at Heightened Risk of Exposure Due to Attack With Anthrax, 70 Federal Register 5452, February 2, 2005. 5452, February 2, 2005.
74 Vaccines and Related Biological Products Advisory Committee, https://www.fda.gov/advisory-committees/blood-
vaccines-and-other-biologics/vaccines-and-related-biological-products-advisory-committee.
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Commissioner.89 VRBPAC may, for example, meet to discuss approaches for demonstrating effectiveness of a particular vaccine in a specific population.effectiveness of a particular vaccine in a specific population.7590 VRBPAC is subject to the VRBPAC is subject to the
requirements of the Federal Advisory Committee Act.requirements of the Federal Advisory Committee Act.7691
Clinical Recommendations
Official HHS/CDC clinical recommendations for vaccination—such as the age and population Official HHS/CDC clinical recommendations for vaccination—such as the age and population
groups recommended to receive each vaccine, as well as the number of doses and interval groups recommended to receive each vaccine, as well as the number of doses and interval
between doses—are informed by the Advisory Committee on Immunization Practices (ACIP), a between doses—are informed by the Advisory Committee on Immunization Practices (ACIP), a
federal advisory committee composed of medical and public health experts who make policy federal advisory committee composed of medical and public health experts who make policy
recommendations for the use of licensed vaccines and related agents for the control of vaccine-recommendations for the use of licensed vaccines and related agents for the control of vaccine-
preventable diseases in the civilian population of the United States.preventable diseases in the civilian population of the United States.7792 ACIP may also develop ACIP may also develop
guidance for use of unlicensed vaccines “if circumstances warrant.” guidance for use of unlicensed vaccines “if circumstances warrant.” Section 3091 of the 21st Century Cures Act (P.L. 114-255) added a requirement that ACIP make recommendations in a “timely manner, as appropriate” for vaccines that could be used in a public health emergency. ACIP was established by the ACIP was established by the
U.S. Surgeon General in 1964, under authority provided by Public Health Service Act (PHSA) U.S. Surgeon General in 1964, under authority provided by Public Health Service Act (PHSA)
Section 222.Section 222.7893 ACIP is subject to the requirements of the Federal Advisory Committee Act.94
After FDA licenses a new vaccine or licenses an existing vaccine for a new indication, ACIP After FDA licenses a new vaccine or licenses an existing vaccine for a new indication, ACIP
typically makes one of two types of clinical recommendations: typically makes one of two types of clinical recommendations:
  Full recommendation (also called “Category A”): The vaccine is recommended The vaccine is recommended for all people in an age- or for all people in an age- or
risk-based group, except for those with a risk-based group, except for those with a contraindication (i.e., a condition that (i.e., a condition that
would make the vaccine harmful, such as a condition that compromises the would make the vaccine harmful, such as a condition that compromises the
immune system). For example, ACIP has issued a full recommendation for two immune system). For example, ACIP has issued a full recommendation for two
doses of the measles-mumps-rubella (MMR) vaccine routinely for children, with doses of the measles-mumps-rubella (MMR) vaccine routinely for children, with
the first dose administered at 12-15 months and the second dose administered the first dose administered at 12-15 months and the second dose administered
before school entry at four to six years of age.before school entry at four to six years of age.7995
  Clinical Decisionmaking (also called “Category B”): The vaccine is The vaccine is recommended for certain recommended for certain
subpopulations, and its use is based on clinical decisionmaking.subpopulations, and its use is based on clinical decisionmaking.8096 For example, For example,
ACIP recommends the two Serogroup B Meningococcal vaccines for persons 10
years of age or older who have certain health conditions or are at increased risk
of exposure to the disease, as specified.81

75ACIP recommends the two Serogroup B 89 Vaccines and Related Biological Products Advisory Committee, https://www.fda.gov/advisory-committees/blood-vaccines-and-other-biologics/vaccines-and-related-biological-products-advisory-committee. 90 FDA, “2018 Meeting Materials, Vaccines and Related Biological Products Advisory Committee,” FDA, “2018 Meeting Materials, Vaccines and Related Biological Products Advisory Committee,”
https://www.fda.gov/advisory-committees/vaccines-and-related-biological-products-advisory-committee/2018-https://www.fda.gov/advisory-committees/vaccines-and-related-biological-products-advisory-committee/2018-
meeting-materials-vaccines-and-related-biological-products-advisory-committee. meeting-materials-vaccines-and-related-biological-products-advisory-committee.
7691 For additional information about the Federal Advisory Committee Act (FACA) and FACA committees, see CRS For additional information about the Federal Advisory Committee Act (FACA) and FACA committees, see CRS
Report R44253, Report R44253, Federal Advisory Committees: An Introduction and Overview. .
7792 Amanda Cohn, Lance E. Rodewald, Walter A. Orenstein, et al., “Immunization in the United States,” in Amanda Cohn, Lance E. Rodewald, Walter A. Orenstein, et al., “Immunization in the United States,” in Plotkin’s
Vaccines
, ed. Stanley A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1421. , ed. Stanley A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), p. 1421.
7893 CDC, “ACIP Charter,” June 5, 2018, https://www.cdc.gov/vaccines/acip/committee/charter.html. CDC, “ACIP Charter,” June 5, 2018, https://www.cdc.gov/vaccines/acip/committee/charter.html.
7994 For additional information about the Federal Advisory Committee Act (FACA) and FACA committees, see CRS Report R44253, Federal Advisory Committees: An Introduction and Overview. 95 Huong Q. McLean, Amy Parker Fibelkorn, Jonathan L. Temte, et al., “Prevention of Measles, Rubella, Congenital Huong Q. McLean, Amy Parker Fibelkorn, Jonathan L. Temte, et al., “Prevention of Measles, Rubella, Congenital
Rubella Syndrome, and Mumps, 2013: Summary Recommendations of the Advisory Committee on Immunization Rubella Syndrome, and Mumps, 2013: Summary Recommendations of the Advisory Committee on Immunization
Practices (ACIP),” Practices (ACIP),” Morbidity and Mortality Weekly Report (MMWR), vol. 62, no. RR04 (June 14, 2013), pp. 1-34. , vol. 62, no. RR04 (June 14, 2013), pp. 1-34.
80 96 Richard Hughes, Reed Maxim, and Alessandra Fix, “Vague Vaccine Recommendations May Be Leading to Lack of Richard Hughes, Reed Maxim, and Alessandra Fix, “Vague Vaccine Recommendations May Be Leading to Lack of
Provider Clarity, Confusion Over Coverage,” Provider Clarity, Confusion Over Coverage,” Health Affairs, May 7, 2019; and Larry K. Pickering, Walter A. , May 7, 2019; and Larry K. Pickering, Walter A.
Orenstein, and Wellington Sun, et al., “FDA Licensure of and ACIP Recommendations for Vaccines,” Orenstein, and Wellington Sun, et al., “FDA Licensure of and ACIP Recommendations for Vaccines,” Vaccine, vol. 35 , vol. 35
(2017), p. 5027–5036.
81 Monica E. Patton, David Stephens, and Kelly Moore, “Updated Recommendations for Use of MenB-FHbp
Serogroup B Meningococcal Vaccine—Advisory Committee on Immunization Practices, 2016,” Morbidity and
Mortality Weekly Report (MMWR)
, vol. 66, no. 19 (May 19, 2017), pp. 509-513.
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Congressional Research Service 17 Vaccine Safety in the United States Meningococcal vaccines for persons 10 years of age or older who have certain health conditions or are at increased risk of exposure to the disease, as specified.97
To make its vaccine recommendations, ACIP considers disease epidemiology and burden of To make its vaccine recommendations, ACIP considers disease epidemiology and burden of
disease,disease,8298 vaccine efficacy and effectiveness, the quality of evidence reviewed, economic vaccine efficacy and effectiveness, the quality of evidence reviewed, economic
analyses, and implementation issues. Recommendations made by ACIP are reviewed by the CDC analyses, and implementation issues. Recommendations made by ACIP are reviewed by the CDC
Director and, if adopted, published as official CDCDirector and, if adopted, published as official CDC/HHS recommendations. recommendations.8399 ACIP ACIP
recommendations inform which vaccines are provided through the CDC’s Vaccines for Children recommendations inform which vaccines are provided through the CDC’s Vaccines for Children
program,program,84100 as well as which vaccines must be covered by private health care insurance plans as well as which vaccines must be covered by private health care insurance plans
subject to the preventive health services requirement subject to the preventive health services requirement (PHSA §2713) as added by the Patient Protection and as added by the Patient Protection and
Affordable Care Act (ACAAffordable Care Act (ACA; P.L. 111-148, as amended).101).85
ACIP recommendations are used to establish the CDC-recommended child and adult ACIP recommendations are used to establish the CDC-recommended child and adult
immunization schedules (for children, birth to 18 years of age; for adults, 19 years of age and immunization schedules (for children, birth to 18 years of age; for adults, 19 years of age and
older), which are used by health care providers, parents, and others to understand which vaccines older), which are used by health care providers, parents, and others to understand which vaccines
should be administered at various ages. The immunization schedules distinguish between should be administered at various ages. The immunization schedules distinguish between
vaccines recommended to all people in a certain age group and vaccines recommended only for vaccines recommended to all people in a certain age group and vaccines recommended only for
certain high-risk groups. As a part of the immunization schedules, CDC also publishes a specific certain high-risk groups. As a part of the immunization schedules, CDC also publishes a specific
table of vaccine recommendations by common contraindications, such as persons with HIV, table of vaccine recommendations by common contraindications, such as persons with HIV,
immunocompromised individuals, and pregnant individuals. The table includes when immunocompromised individuals, and pregnant individuals. The table includes when
recommended vaccines should recommended vaccines should not be administered to individuals with these contraindications.be administered to individuals with these contraindications.86102
Once clinical recommendations are made, CDC develops and provides resources and training for Once clinical recommendations are made, CDC develops and provides resources and training for
health care providers on current vaccine recommendations, best practices for vaccine health care providers on current vaccine recommendations, best practices for vaccine
administration, and patient education.administration, and patient education.87103 CDC develops Vaccination Information Statements (VIS) CDC develops Vaccination Information Statements (VIS)
on the risks and benefits of vaccinations; these statements are required to be given to vaccine on the risks and benefits of vaccinations; these statements are required to be given to vaccine
recipients and their parents or legal guardians whenever vaccines recommended for routine use recipients and their parents or legal guardians whenever vaccines recommended for routine use
among children and pregnant women are administered.among children and pregnant women are administered.88104 VISs are developed by CDC in VISs are developed by CDC in
consultation with the Advisory Commission on Childhood Vaccines (ACCV; a committee of consultation with the Advisory Commission on Childhood Vaccines (ACCV; a committee of
health care professionals, attorneys, and parents of vaccine-injured children), health care health care professionals, attorneys, and parents of vaccine-injured children), health care
providers, and FDA, and are published in the providers, and FDA, and are published in the Federal Register for public comment. for public comment.89
Postmarket Safety
Although pre-licensure clinical trials and research are designed to identify common safety risks
associated with a vaccine, such trials may not identify all long-term or rare adverse effects
(similar to all pharmaceutical products). As such, vaccines may be subject to additional
postmarket study requirements, called Phase 4 studies, or other safety monitoring to provide

82105 (2017), p. 5027–5036. 97 Monica E. Patton, David Stephens, and Kelly Moore, “Updated Recommendations for Use of MenB-FHbp Serogroup B Meningococcal Vaccine—Advisory Committee on Immunization Practices, 2016,” Morbidity and Mortality Weekly Report (MMWR), vol. 66, no. 19 (May 19, 2017), pp. 509-513. 98 Burden of disease is a standardized measure for comparing the health impacts of different diseases based on Burden of disease is a standardized measure for comparing the health impacts of different diseases based on
cumulative disability, loss of full health, and premature mortality caused by each disease. See World Health cumulative disability, loss of full health, and premature mortality caused by each disease. See World Health
Organization (WHO), “About the Global Burden of Diseases (GBD) Project,” https://www.who.int/healthinfo/Organization (WHO), “About the Global Burden of Diseases (GBD) Project,” https://www.who.int/healthinfo/
global_burden_disease/about/en/. global_burden_disease/about/en/.
8399 CDC, “ACIP Charter,” June 5, 2018, https://www.cdc.gov/vaccines/acip/committee/charter.html. CDC, “ACIP Charter,” June 5, 2018, https://www.cdc.gov/vaccines/acip/committee/charter.html.
84100 Vaccines for Children is a Medicaid-financed program administered by CDC that provides vaccines at no cost to Vaccines for Children is a Medicaid-financed program administered by CDC that provides vaccines at no cost to
eligible children 18 years or younger, including those who are American Indian or Alaska Native, Medicaid-eligible, eligible children 18 years or younger, including those who are American Indian or Alaska Native, Medicaid-eligible,
uninsured, or underinsured (as defined). See https://www.cdc.gov/features/vfcprogram/index.html. uninsured, or underinsured (as defined). See https://www.cdc.gov/features/vfcprogram/index.html.
85101 ACA, P.L. 111-148, as amended, which established PHSA §2713. ACA, P.L. 111-148, as amended, which established PHSA §2713.
86102 CDC, “Immunization Schedules,” https://www.cdc.gov/vaccines/schedules/index.html. CDC, “Immunization Schedules,” https://www.cdc.gov/vaccines/schedules/index.html.
87103 CDC, “Vaccines- Healthcare Providers,” 2018, https://www.cdc.gov/vaccines/hcp/index.html. CDC, “Vaccines- Healthcare Providers,” 2018, https://www.cdc.gov/vaccines/hcp/index.html.
88104 Requirement established by the National Childhood Vaccine Injury Act, P.L. 99-660; PHSA §2126 [42 U.S.C. Requirement established by the National Childhood Vaccine Injury Act, P.L. 99-660; PHSA §2126 [42 U.S.C.
§300aa-26]. §300aa-26].
89105 P.L. 99-660; PHSA §2126 [42 U.S.C. §300aa-26]. P.L. 99-660; PHSA §2126 [42 U.S.C. §300aa-26].
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link to page link to page 3032 link to page link to page 3032 Vaccine Safety in the United States Postmarket Safety Although pre-licensure clinical trials and research are designed to identify common safety risks associated with a vaccine, such trials may not identify all long-term or rare adverse effects (similar to all pharmaceutical products). As such, vaccines may be subject to additional postmarket study requirements, called Phase 4 studies, or other safety monitoring to provide Vaccine Safety in the United States

additional information about a vaccine’s risks, benefits, and optimal use.additional information about a vaccine’s risks, benefits, and optimal use.90106 FDA may require a FDA may require a
vaccine manufacturer to conduct a postapproval study or clinical trial to assess a known serious vaccine manufacturer to conduct a postapproval study or clinical trial to assess a known serious
risk or signals of serious risk related to use of the vaccine, or to identify an unexpected serious risk or signals of serious risk related to use of the vaccine, or to identify an unexpected serious
risk when available data indicate the potential for a serious risk.risk when available data indicate the potential for a serious risk.91107 In addition, because vaccines In addition, because vaccines
require special manufacturing processes to avoid contamination, post-licensure safety programs require special manufacturing processes to avoid contamination, post-licensure safety programs
are designed to ensure safety in vaccine manufacturing. Post-licensure safety requirements and are designed to ensure safety in vaccine manufacturing. Post-licensure safety requirements and
programs are also intended to identify long-term or rare adverse health events that result from programs are also intended to identify long-term or rare adverse health events that result from
vaccination, and FDA may require vaccine manufacturers to revise vaccine product labeling if vaccination, and FDA may require vaccine manufacturers to revise vaccine product labeling if
new information becomes available after licensure.new information becomes available after licensure.92108
Manufacturing Safety
FDA continues to inspect vaccine manufacturing facilities post-licensure.FDA continues to inspect vaccine manufacturing facilities post-licensure.93109 The HHS Secretary The HHS Secretary
may authorize any HHS officer, agent, or employee to “during all reasonable hours enter and may authorize any HHS officer, agent, or employee to “during all reasonable hours enter and
inspect any establishment for the propagation or manufacture and preparation of any biological inspect any establishment for the propagation or manufacture and preparation of any biological
product [e.g., vaccine].”product [e.g., vaccine].”94110 If FDA determines that a batch, lot, or other quantity of a vaccine If FDA determines that a batch, lot, or other quantity of a vaccine
“presents an imminent or substantial hazard to the public health,” the agency must issue an order “presents an imminent or substantial hazard to the public health,” the agency must issue an order
immediately recalling the batch, lot, or other quantity of the vaccine.immediately recalling the batch, lot, or other quantity of the vaccine.95111
Manufacturers of vaccines listed in the Vaccine Injury Table (see the Manufacturers of vaccines listed in the Vaccine Injury Table (see the “National Vaccine Injury
Compensation”
section) or mandated to be state-administered must maintain records related to the section) or mandated to be state-administered must maintain records related to the
safety and quality of each batch of vaccines produced, and must report any identified public safety and quality of each batch of vaccines produced, and must report any identified public
health hazards to FDA.health hazards to FDA.96112 Specifically, vaccine manufacturers are required to maintain records Specifically, vaccine manufacturers are required to maintain records
documenting the manufacturing, processing, testing, and reworking of each batch, lot, or other documenting the manufacturing, processing, testing, and reworking of each batch, lot, or other
quantity of a vaccine, including whether any significant problems were identified during these quantity of a vaccine, including whether any significant problems were identified during these
processes, and to report if any safety test on such batch, lot, or other quantity indicates a potential processes, and to report if any safety test on such batch, lot, or other quantity indicates a potential
imminent or substantial public health hazard.imminent or substantial public health hazard.97113
In addition, In addition, vaccine manufacturersmanufacturers of licensed vaccine are required to report adverse events to FDA. This includes are required to report adverse events to FDA. This includes
the submission of 15-day alert reports and periodic safety reports. A 15-day alert report is the submission of 15-day alert reports and periodic safety reports. A 15-day alert report is
required for each serious and unexpected adverse experience and must be submitted to FDA as required for each serious and unexpected adverse experience and must be submitted to FDA as
soon as possible but no later than 15 days from initial receipt of the information by the
manufacturer.98 The manufacturer must “promptly investigate” such adverse event and submit
follow-up reports within 15 days of receiving new information or as requested by FDA. Periodic
safety reports are required for each adverse experience not reported in a 15-day alert report and
must be submitted to FDA at quarterly intervals for three years from the date of issuance of the

90 106 21 C.F.R. §312.85. See also FDA, “Vaccine Product Approval Process,” https://www.fda.gov/vaccines-blood- 21 C.F.R. §312.85. See also FDA, “Vaccine Product Approval Process,” https://www.fda.gov/vaccines-blood-
biologics/development-approval-process-cber/vaccine-product-approval-process. biologics/development-approval-process-cber/vaccine-product-approval-process.
91107 PHSA §351(a)(2)(D) [42 U.S.C. §262(a)(2)(D)] and FFDCA §505(o)(3) [21 U.S.C. §355(o)(3)]. PHSA §351(a)(2)(D) [42 U.S.C. §262(a)(2)(D)] and FFDCA §505(o)(3) [21 U.S.C. §355(o)(3)].
92108 PHSA §351(a)(2)(D) [42 U.S.C. §262(a)(2)(D)] and FFDCA §505(o)(4) [21 U.S.C. §355(o)(4)]. PHSA §351(a)(2)(D) [42 U.S.C. §262(a)(2)(D)] and FFDCA §505(o)(4) [21 U.S.C. §355(o)(4)].
93109 FDA, “Ensuring the Safety of Vaccines in the United States,” last updated July 2011, https://www.fda.gov/media/ FDA, “Ensuring the Safety of Vaccines in the United States,” last updated July 2011, https://www.fda.gov/media/
83528/download. 83528/download.
94110 PHSA §351(c) [42 U.S.C. §262(c)]. PHSA §351(c) [42 U.S.C. §262(c)].
95111 PHSA §351(d)(1) [42 U.S.C. §262(d)(1)]. PHSA §351(d)(1) [42 U.S.C. §262(d)(1)].
96112 PHSA §2128 [42 U.S.C. §300aa–28]. This authority has been delegated from the HHS Secretary to the FDA PHSA §2128 [42 U.S.C. §300aa–28]. This authority has been delegated from the HHS Secretary to the FDA
Commissioner, per the FDA Staff Manual Guide 1410.10, item 31, effective date August 26, 2016, Commissioner, per the FDA Staff Manual Guide 1410.10, item 31, effective date August 26, 2016,
https://www.fda.gov/media/81983/download. https://www.fda.gov/media/81983/download.
97113 PHSA §2128(a) [42 U.S.C. §300aa–28(a)]. PHSA §2128(a) [42 U.S.C. §300aa–28(a)].
98 21 C.F.R §600.80(c).
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link to page 30 19 Vaccine Safety in the United States soon as possible but no later than 15 days from initial receipt of the information by the manufacturer.114 The manufacturer must “promptly investigate” such adverse event and submit follow-up reports within 15 days of receiving new information or as requested by FDA. Periodic safety reports are required for each adverse experience not reported in a 15-day alert report and must be submitted to FDA at quarterly intervals for three years from the date of issuance of the Vaccine Safety in the United States

vaccine’s license, and at annual intervals thereafter. Individual case safety reports for vaccines vaccine’s license, and at annual intervals thereafter. Individual case safety reports for vaccines
submitted to FDA must include specified information about the patient who is the subject of the submitted to FDA must include specified information about the patient who is the subject of the
report (e.g., name, age, gender) and the vaccine (e.g., manufacturer, lot number).report (e.g., name, age, gender) and the vaccine (e.g., manufacturer, lot number).99115 If a vaccine If a vaccine
manufacturer fails to establish and maintain records or report adverse events, FDA can take manufacturer fails to establish and maintain records or report adverse events, FDA can take
enforcement action, including revocation of the BLA for that vaccine.enforcement action, including revocation of the BLA for that vaccine.100116 As mentioned, for a vaccine made available under EUA, FDA must impose certain conditions on use of the authorized vaccine and may impose additional discretionary conditions where necessary or appropriate to protect the public health. 117 For example, FDA can require manufacturers and vaccination providers to monitor and report adverse events associated with the emergency use of the vaccine. FDA also can impose conditions concerning recordkeeping and reporting.
Surveillance
CDC and FDA are the primary federal agencies that conduct surveillance (i.e., data monitoring) CDC and FDA are the primary federal agencies that conduct surveillance (i.e., data monitoring)
activities on the safety of administered vaccines. Other federal agencies such as the Department activities on the safety of administered vaccines. Other federal agencies such as the Department
of Defense (DOD) and the Centers for Medicare & Medicaid Services (CMS) also operate of Defense (DOD) and the Centers for Medicare & Medicaid Services (CMS) also operate
databases on vaccine safety events among their covered populations.databases on vaccine safety events among their covered populations.101118 The NVPO within the The NVPO within the
HHS Office of Infectious Disease and HIV/AIDS Policy (OIDP) is tasked with coordinating HHS Office of Infectious Disease and HIV/AIDS Policy (OIDP) is tasked with coordinating
vaccine safety monitoring across federal agencies.vaccine safety monitoring across federal agencies.102119
FDA and CDC monitor and conduct research on vaccine safety through various mechanisms. As FDA and CDC monitor and conduct research on vaccine safety through various mechanisms. As
discussed below, each of the programs or systems has strengths and limitations, but together they discussed below, each of the programs or systems has strengths and limitations, but together they
provide various ways of assessing vaccines to ensure their safety. Each of the systems allows for provide various ways of assessing vaccines to ensure their safety. Each of the systems allows for
monitoring of adverse events linked to specific lots of manufactured vaccines. This lot-specific monitoring of adverse events linked to specific lots of manufactured vaccines. This lot-specific
monitoring enables distinctions monitoring enables distinctions
between adverse events linked to between adverse events linked to
Key Terms: Passive and Active Surveillance
improper manufacturing, improper manufacturing,
Public health surveillance, or ongoing data monitoring, can be passive Public health surveillance, or ongoing data monitoring, can be passive
compared with adverse events compared with adverse events
or active or active. A A passive surveillance system relies on reports, often from relies on reports, often from
health care providers or patients. In an health care providers or patients. In an active surveillance system, data , data
linked to a particular type of
are col ected proactively—either through active analysis of electronic are col ected proactively—either through active analysis of electronic
vaccine.103
health data (such as for the monitoring systems covered here), or health data (such as for the monitoring systems covered here), or
where data are col ected directly by contacting health care where data are col ected directly by contacting health care
organizations or obtaining records. organizations or obtaining records.
Vaccine Adverse Event
Source: CDC, “Introduction to Public Health Surveillance,” CDC, “Introduction to Public Health Surveillance,”
Reporting System (VAERS)
https://www.cdc.gov/publichealth101/surveillance.html.
https://www.cdc.gov/publichealth101/surveillance.html. 114 21 C.F.R §600.80(c). 115 21 C.F.R §600.80(g). 116 21 C.F.R §600.80(l). 117 FFDCA §564(e) [21 U.S.C. §360bbb-3(e)]. 118 Matthew Z. Dudley, Daniel A. Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in The Clinician’s Vaccine Safety Resource Guide (Springer, Cham, 2018). 119 National Vaccine Advisory Committee (NVAC), White Paper on the United States Vaccine Safety System, Congressional Research Service 20 link to page 32 Vaccine Safety in the United States linked to a particular type of vaccine.120 Vaccine Adverse Event Reporting System (VAERS) VAERS, established in 1990 and VAERS, established in 1990 and
operated jointly by FDA and CDC, is a monitoring system for adverse events related to vaccines. operated jointly by FDA and CDC, is a monitoring system for adverse events related to vaccines.
Using the VAERS system, anyone, including physicians, nurses, and the general public, can Using the VAERS system, anyone, including physicians, nurses, and the general public, can
submit an online report of an adverse event following vaccination. Pursuant to PHSA Section submit an online report of an adverse event following vaccination. Pursuant to PHSA Section
2125, health care providers and vaccine manufacturers are required to report the occurrence of 2125, health care providers and vaccine manufacturers are required to report the occurrence of
any adverse event in the Vaccine Injury Table (see the any adverse event in the Vaccine Injury Table (see the “National Vaccine Injury Compensation”
section), the occurrence of a contraindicating reaction specified on the vaccine label, and other section), the occurrence of a contraindicating reaction specified on the vaccine label, and other
serious and unexpected events as required through regulations.serious and unexpected events as required through regulations.104121 Scientists at CDC and FDA Scientists at CDC and FDA
monitor VAERS reports and use the information to monitor VAERS reports and use the information to conduct further investigations on the reported cases.122conduct further investigations on the reported

99 21 C.F.R §600.80(g).
100 21 C.F.R §600.80(l).
101 Matthew Z. Dudley, Daniel A. Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in The Clinician’s
Vaccine Safety Resource Guide
(Springer, Cham, 2018).
102 National Vaccine Advisory Committee (NVAC), White Paper on the United States Vaccine Safety System,
September 2011, p. 21, https://www.hhs.gov/sites/default/files/nvpo/nvac/nvac_vswp.pdf.
103 HHS, Comprehensive Review of Federal Vaccine Safety Programs and Public Health Activities, December 2008,
https://www.hsdl.org/?abstract&did=6793; and Meghan A. Baker, Michael Nguyen, and David V. Cole, “Post-
Licensure Rapid Immunization Safety Monitoring Program (PRISM) Data Characterization,” Vaccine, vol. 31S (2013),
pp. K98-K112.
104 PHSA §2125 [42 U.S.C. §300aa-25]; 21 C.F.R. Part 600.
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cases.105 Consolidated data on reported adverse events in the VAERS system are publicly Consolidated data on reported adverse events in the VAERS system are publicly
available online.available online.106123
VAERS is a passive reporting system. Its data represent reports of adverse health events related to VAERS is a passive reporting system. Its data represent reports of adverse health events related to
vaccines, rather than validated cases. In addition, data in the system lack information on total vaccines, rather than validated cases. In addition, data in the system lack information on total
vaccines administered in the covered populations. Therefore, VAERS data are often inadequate vaccines administered in the covered populations. Therefore, VAERS data are often inadequate
for epidemiological analyses of adverse health events at a population level.for epidemiological analyses of adverse health events at a population level.107124 VAERS is useful, VAERS is useful,
however, for helping identify new and unusual clusters of cases of adverse health events linked to however, for helping identify new and unusual clusters of cases of adverse health events linked to
vaccination. VAERS also can provide some of the first postmarket safety data on newly vaccination. VAERS also can provide some of the first postmarket safety data on newly
introduced vaccines. In addition, VAERS can help identify extremely rare and unusual adverse introduced vaccines. In addition, VAERS can help identify extremely rare and unusual adverse
health events that occur following vaccination. Researchers can use VAERS reports to generate health events that occur following vaccination. Researchers can use VAERS reports to generate
hypotheses about vaccine safety and then use other sources of data (such as from the databases hypotheses about vaccine safety and then use other sources of data (such as from the databases
discussed below) and clinical evidence to assess their hypotheses.discussed below) and clinical evidence to assess their hypotheses.108125
Vaccine Safety Datalink (VSD)
VSD, established in 1990 and operated by CDC, is an active surveillance system VSD, established in 1990 and operated by CDC, is an active surveillance system that allows for
population-level scientific analyses of adverse events that follow vaccination. VSD isand a a
collaborative project for conducting studies on vaccine safety between CDC and eight integrated collaborative project for conducting studies on vaccine safety between CDC and eight integrated
health care organizations (i.e., combined payer and provider organizations) around the country. health care organizations (i.e., combined payer and provider organizations) around the country.
VSD uses electronic patient and medical records from participating sites, which allows for large-VSD uses electronic patient and medical records from participating sites, which allows for large-
scale and controlled analyses of medical events (e.g., hospitalizations, diagnoses) that occur after scale and controlled analyses of medical events (e.g., hospitalizations, diagnoses) that occur after
vaccination to identify associated risks.vaccination to identify associated risks.109126 VSD studies may supplement these records with other VSD studies may supplement these records with other
sources of information, such as patient surveys, medical charts, and pharmacy, laboratory, and sources of information, such as patient surveys, medical charts, and pharmacy, laboratory, and
radiology data, to validate vaccination data and outcomes. Health data on about 9 million people
are included annually in VSD.110
VSD allows for near real-time detection of large-scale adverse events linked to vaccination.
Researchers have developed methods to use VSD data to study the health effects of vaccines,
such as whether the measles-mumps-rubella (MMR) vaccine is associated with autism (studies
have found no such association). Among its limitations, the population represented by VSD,
while large, is not completely representative of the entire U.S. population in terms of geography,
race, socioeconomic status, and other factors, particularly because the participating organizations
are private health plans which generally over-represent people of higher socioeconomic status and

105 September 2011, p. 21, https://www.hhs.gov/sites/default/files/nvpo/nvac/nvac_vswp.pdf. 120 HHS, Comprehensive Review of Federal Vaccine Safety Programs and Public Health Activities, December 2008, https://www.hsdl.org/?abstract&did=6793; and Meghan A. Baker, Michael Nguyen, and David V. Cole, “Post-Licensure Rapid Immunization Safety Monitoring Program (PRISM) Data Characterization,” Vaccine, vol. 31S (2013), pp. K98-K112. 121 PHSA §2125 [42 U.S.C. §300aa-25]; 21 C.F.R. Part 600. 122 CDC, “Understanding the Vaccine Adverse Event Reporting System (VAERS),” https://www.cdc.gov/vaccines/hcp/ CDC, “Understanding the Vaccine Adverse Event Reporting System (VAERS),” https://www.cdc.gov/vaccines/hcp/
patient-ed/conversations/downloads/vacsafe-vaers-color-office.pdf. patient-ed/conversations/downloads/vacsafe-vaers-color-office.pdf.
106123 VAERS, “VAERS data,” https://vaers.hhs.gov/data.html. VAERS, “VAERS data,” https://vaers.hhs.gov/data.html.
107124 CDC, “Vaccine Safety Datalink (VSD),” https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/; and CDC, “Vaccine Safety Datalink (VSD),” https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/; and
Frank Frank DestefanoDeStefano, Paul A. Offit , and Allison Fisher, “Vaccine Safety,” in , Paul A. Offit , and Allison Fisher, “Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley Plotkin, , ed. Stanley Plotkin,
Walter Orenstein, Paul Offit, Kathryn M. Edwards, 7th ed. (Elsevier, 2018), pp. 1586. Walter Orenstein, Paul Offit, Kathryn M. Edwards, 7th ed. (Elsevier, 2018), pp. 1586.
108125 Frank Frank DestefanoDeStefano, Paul A. Offit, and Allison Fisher, “, Paul A. Offit, and Allison Fisher, “Ch. 82: Vaccine Safety,” in Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A. , ed. Stanley A.
Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), pp. 1586-1587. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), pp. 1586-1587.
109126 CDC, “Vaccine Safety Datalink (VSD),” https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/. CDC, “Vaccine Safety Datalink (VSD),” https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/.
110 Frank Destefano, Paul A. Offit, and Allison Fisher, “Ch. 82: Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A.
Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), pp. 1587.
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non-minority groups.111 Congressional Research Service 21 Vaccine Safety in the United States radiology data, to validate vaccination data and outcomes. Health data on about 9 million people are included annually in VSD.127 VSD allows for near real-time detection of large-scale adverse health events linked to vaccination. Researchers have developed methods to use VSD data to study the health effects of vaccines, such as whether the measles-mumps-rubella (MMR) vaccine is associated with autism (studies have found no such association). Among its limitations, the population represented by VSD, while large, is not completely representative of the entire U.S. population in terms of geography, race, socioeconomic status, and other factors, particularly because the participating organizations are private health plans which generally over-represent people of higher socioeconomic status and non-minority groups.128 In addition, VSD’s population size may not be adequate for detecting In addition, VSD’s population size may not be adequate for detecting
extremely rare adverse events linked to vaccination.extremely rare adverse events linked to vaccination.112129
Sentinel Initiative
FDA established the Sentinel Initiative in 2008, fulfilling a statutory directive to collaborate with FDA established the Sentinel Initiative in 2008, fulfilling a statutory directive to collaborate with
public, academic, and private entities to develop methods for obtaining access to disparate data public, academic, and private entities to develop methods for obtaining access to disparate data
sources and to validate means of linking and analyzing safety data from multiple sources.sources and to validate means of linking and analyzing safety data from multiple sources.113130 As As
part of the Sentinel Initiative, FDA has established two programs that address vaccines: (1) the part of the Sentinel Initiative, FDA has established two programs that address vaccines: (1) the
Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program, and (2) the Biologics Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program, and (2) the Biologics
Effectiveness and Safety (BEST) system. Effectiveness and Safety (BEST) system.
PRISM is an active surveillance program that uses electronic health records from insurance PRISM is an active surveillance program that uses electronic health records from insurance
providers and state immunization registries to monitor adverse events following vaccination. It providers and state immunization registries to monitor adverse events following vaccination. It
was established in 2009 and deployed during the H1N1 influenza pandemic.was established in 2009 and deployed during the H1N1 influenza pandemic.114131 PRISM has been PRISM has been
the largest linked database for monitoring vaccine safety in the United States, involving data on the largest linked database for monitoring vaccine safety in the United States, involving data on
over 100 million people.over 100 million people.115132 PRISM, similar to the CDC VSD program, can allow for population- PRISM, similar to the CDC VSD program, can allow for population-
level scientific analyses of adverse events following vaccination. Because of the larger population level scientific analyses of adverse events following vaccination. Because of the larger population
covered, PRISM can detect rarer adverse events than VSD and enable stratified analyses of covered, PRISM can detect rarer adverse events than VSD and enable stratified analyses of
vaccine-linked adverse events by subpopulation (e.g., by race/ethnicity).vaccine-linked adverse events by subpopulation (e.g., by race/ethnicity).116133 As of 2012, VSD As of 2012, VSD
allowed for more rapid analyses than PRISM due to data-sharing agreements between the allowed for more rapid analyses than PRISM due to data-sharing agreements between the
participating health organizations and CDC that allow for near real-time data collection.participating health organizations and CDC that allow for near real-time data collection.117
PRISM has been used to inform FDA-required postmarket labeling changes.118 For example, after
some studies found an association between risk of intussusception (i.e., intestinal blockage) and
administration of two rotavirus vaccines (RotaTeq and Rotarix), FDA launched a study in PRISM
to assess whether infants faced a similar risk.119 The PRISM study identified an increased, but

111134 127 Frank DeStefano, Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), pp. 1587. 128 CDC, “Vaccine Safety Datalink (VSD),” https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/; and CDC, “Vaccine Safety Datalink (VSD),” https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/; and
Frank Frank DestefanoDeStefano, Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in , Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley Plotkin, Walter , ed. Stanley Plotkin, Walter
Orenstein, Paul Offit, Kathryn M. Edwards, 7th ed. (Elsevier, 2018), pp. 1584-1600. Orenstein, Paul Offit, Kathryn M. Edwards, 7th ed. (Elsevier, 2018), pp. 1584-1600.
112129 Michael Nguyen, Robert Ball, Karen Midthun, et al., “The Food and Drug Administration’s Post-Licensure Rapid Michael Nguyen, Robert Ball, Karen Midthun, et al., “The Food and Drug Administration’s Post-Licensure Rapid
Immunization Safety Monitoring Program: Strengthening the Vaccine Safety Enterprise,”Immunization Safety Monitoring Program: Strengthening the Vaccine Safety Enterprise,”Pharmacoepidemiology and
Drug Safety
, vol. 21, no. S1 (2012), pp. 291-97. , vol. 21, no. S1 (2012), pp. 291-97.
113130 The Sentinel system was implemented as an “Active Post-Market Risk Identification and Analysis program” under The Sentinel system was implemented as an “Active Post-Market Risk Identification and Analysis program” under
FFDCA §505(k)(3), as amended by §905 of the FDA Amendments Act, P.L. 110-85. FFDCA §505(k)(3), as amended by §905 of the FDA Amendments Act, P.L. 110-85.
114131 PRISM is the vaccine component of FDA’s Sentinel Initiative. PRISM is the vaccine component of FDA’s Sentinel Initiative.
115132 FDA, “Advances in the Science, Surveillance, and Safety of Vaccines,” 2013, https://www.hhs.gov/vaccines/ FDA, “Advances in the Science, Surveillance, and Safety of Vaccines,” 2013, https://www.hhs.gov/vaccines/
national-vaccine-plan/annual-report-2013/goal-2/advances-in-science-surveillance-safety-of-vaccines/index.html; and national-vaccine-plan/annual-report-2013/goal-2/advances-in-science-surveillance-safety-of-vaccines/index.html; and
Matthew Z. Dudley, Daniel A. Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in Matthew Z. Dudley, Daniel A. Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in The Clinician’s
Vaccine Safety Resource Guide
(Springer, Cham, 2018). (Springer, Cham, 2018).
116133 Michael Nguyen, Robert Ball, Karen Midthun, et al., “The Food and Drug Administration’s Post-Licensure Rapid Michael Nguyen, Robert Ball, Karen Midthun, et al., “The Food and Drug Administration’s Post-Licensure Rapid
Immunization Safety Monitoring Program: Strengthening the Vaccine Safety Enterprise,” Immunization Safety Monitoring Program: Strengthening the Vaccine Safety Enterprise,” Pharmacoepidemiology and
Drug Safety
, vol. 21, no. S1 (2012), pp. 291-97. , vol. 21, no. S1 (2012), pp. 291-97.
117134 Matthew Z. Dudley, Daniel A. Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in Matthew Z. Dudley, Daniel A. Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in The Clinician’s
Vaccine Safety Resource Guide
(Springer, Cham, 2018).
118 FDA CBER, “Post-licensure Rapid Immunization Safety Monitoring (PRISM) Public Workshop,” December 7,
2016, Bethesda, MD, https://www.fda.gov/media/103876/download.
119 FDA, “RotaTeq (Rotavirus Vaccine) Questions and Answers,” https://www.fda.gov/vaccines-blood-biologics/
vaccines/rotateq-rotavirus-vaccine-questions-and-answers.
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Congressional Research Service 22 Vaccine Safety in the United States PRISM has been used to inform FDA-required postmarket labeling changes.135 For example, after some studies found an association between risk of intussusception (i.e., intestinal blockage) and administration of two rotavirus vaccines (RotaTeq and Rotarix), FDA launched a study in PRISM to assess whether infants faced a similar risk.136 The PRISM study identified an increased, but rare, risk of intussusception with RotaTeq among infants, which led to FDA-required labeling rare, risk of intussusception with RotaTeq among infants, which led to FDA-required labeling
changes for the licensed vaccine.changes for the licensed vaccine.120137
In 2017, CBER initiated the BEST system as part of Sentinel to assure the safety and In 2017, CBER initiated the BEST system as part of Sentinel to assure the safety and
effectiveness of vaccines and other biologics. It is broader than PRISM in that it also covers effectiveness of vaccines and other biologics. It is broader than PRISM in that it also covers
blood and blood products, tissue products, and other advanced therapeutic biologics.blood and blood products, tissue products, and other advanced therapeutic biologics.121138 The goal The goal
of BEST is to “leverage high-quality data, analytics and innovation to enhance surveillance, real-of BEST is to “leverage high-quality data, analytics and innovation to enhance surveillance, real-
world evidence generation, and clinical practice that benefits patients.” Like other Sentinel world evidence generation, and clinical practice that benefits patients.” Like other Sentinel
components, BEST uses electronic health record, administrative, and claims-based data for active components, BEST uses electronic health record, administrative, and claims-based data for active
surveillance and research.surveillance and research. BEST fulfills the FDAAA requirements for an active postmarket risk
and analysis system covering at least 100 million persons.122139
Other Safety Monitoring Systems
As mentioned above, federal agencies other than FDA and CDC conduct vaccine safety As mentioned above, federal agencies other than FDA and CDC conduct vaccine safety
monitoring. CMS has a database for vaccine safety among the Medicare population; the database monitoring. CMS has a database for vaccine safety among the Medicare population; the database
represents vaccines administered to persons aged 65 and older. DOD has a database for represents vaccines administered to persons aged 65 and older. DOD has a database for
monitoring adverse events from vaccination among military service members and their families, monitoring adverse events from vaccination among military service members and their families,
and the Department of Veterans Affairs (VA) has a database for veterans who receive care in the and the Department of Veterans Affairs (VA) has a database for veterans who receive care in the
VA system. In addition, the Indian Health Service (IHS) operates a database for vaccine safety VA system. In addition, the Indian Health Service (IHS) operates a database for vaccine safety
monitoring among the IHS-covered population.monitoring among the IHS-covered population.123140
Safety Monitoring Using Multiple Surveillance Systems: A Case Study
Researchers have used information from multiple vaccine safety monitoring systems to draw associations between Researchers have used information from multiple vaccine safety monitoring systems to draw associations between
vaccines and subsequent adverse health events. For example, during the 2010-2011 influenza season, VAERS vaccines and subsequent adverse health events. For example, during the 2010-2011 influenza season, VAERS
received an increased number of reports of febrile seizures fol owing vaccination with Fluzone.™ FDA then received an increased number of reports of febrile seizures fol owing vaccination with Fluzone.™ FDA then
initiated a PRISM study to investigate febrile seizures after vaccination with Fluzone™ and other trivalent initiated a PRISM study to investigate febrile seizures after vaccination with Fluzone™ and other trivalent
inactivated influenza vaccines (TIVs). The study found no statistically significant association between TIVs and
increased risk of febrile seizures.
Source:
FDA, “Update: FDA Postlicensure Rapid Immunization Safety Monitoring (PRISM) study demonstrates no
statistically significant association between Trivalent Inactivated Influenza Vaccine and Febrile Seizures in Children
during the 2010-2011 influenza season,” May 16, 2014, https://www.sentinelinitiative.org/communications/fda-
safety-communications/update-fda-postlicensure-rapid-immunization-safety.

120 Vaccine Safety Resource Guide (Springer, Cham, 2018). 135 FDA CBER, “Post-licensure Rapid Immunization Safety Monitoring (PRISM) Public Workshop,” December 7, 2016, Bethesda, MD, https://www.fda.gov/media/103876/download. 136 FDA, “RotaTeq (Rotavirus Vaccine) Questions and Answers,” https://www.fda.gov/vaccines-blood-biologics/vaccines/rotateq-rotavirus-vaccine-questions-and-answers. 137 According to FDA, “The Mini-Sentinel PRISM study is the largest study of intussusception after rotavirus vaccines According to FDA, “The Mini-Sentinel PRISM study is the largest study of intussusception after rotavirus vaccines
to date and identified an increased risk of intussusception in the 21 day time period after the first dose of RotaTeq, with to date and identified an increased risk of intussusception in the 21 day time period after the first dose of RotaTeq, with
most cases occurring in the first 7 days after vaccination. No increased risk was found after the second or third doses. most cases occurring in the first 7 days after vaccination. No increased risk was found after the second or third doses.
These findings translate into 1 to 1.5 additional cases of intussusception per 100,000 first doses of RotaTeq.” See “FDA These findings translate into 1 to 1.5 additional cases of intussusception per 100,000 first doses of RotaTeq.” See “FDA
Safety Communication: FDA Approves Required Revised Labeling for RotaTeq Based Final Study Results of a Mini-Safety Communication: FDA Approves Required Revised Labeling for RotaTeq Based Final Study Results of a Mini-
Sentinel Postlicensure Observational Study of Rotavirus Vaccines and Intussusception,” July 22, 2013, Sentinel Postlicensure Observational Study of Rotavirus Vaccines and Intussusception,” July 22, 2013,
https://www.sentinelinitiative.org/communications/fda-safety-communications/fda-safety-communication-fda-https://www.sentinelinitiative.org/communications/fda-safety-communications/fda-safety-communication-fda-
approves-required-revised. approves-required-revised.
121138 Sentinel, “Vaccines, Blood, & Biologics Assessments,” https://www.sentinelinitiative.org/assessments/vaccines- Sentinel, “Vaccines, Blood, & Biologics Assessments,” https://www.sentinelinitiative.org/assessments/vaccines-
blood-biologics. blood-biologics.
122139 FDA, “CBER Biologics Effectiveness and Safety (BEST) System,” https://www.fda.gov/vaccines-blood-biologics/ FDA, “CBER Biologics Effectiveness and Safety (BEST) System,” https://www.fda.gov/vaccines-blood-biologics/
safety-availability-biologics/cber-biologics-effectiveness-and-safety-best-system. safety-availability-biologics/cber-biologics-effectiveness-and-safety-best-system.
123140 Matthew Z. Dudley, Daniel A. Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in Matthew Z. Dudley, Daniel A. Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in The Clinician’s
Vaccine Safety Resource Guide
(Springer, Cham, 2018). (Springer, Cham, 2018).
Congressional Research Service Congressional Research Service
21 23 Vaccine Safety in the United States inactivated influenza vaccines (TIVs). The study found no statistically significant association between TIVs and increased risk of febrile seizures. Source: FDA, “Update: FDA Postlicensure Rapid Immunization Safety Monitoring (PRISM) study demonstrates no statistically significant association between Trivalent Inactivated Influenza Vaccine and Febrile Seizures in Children during the 2010-2011 influenza season,” May 16, 2014, https://www.sentinelinitiative.org/communications/fda-safety-communications/update-fda-postlicensure-rapid-immunization-safety.

Vaccine Safety in the United States

Clinical Assessment
The Clinical Immunization Safety Assessment (CISA), a CDC program established in 2001, is a The Clinical Immunization Safety Assessment (CISA), a CDC program established in 2001, is a
network of clinical scientists who conduct clinical studies (i.e., studies with patients) on vaccine network of clinical scientists who conduct clinical studies (i.e., studies with patients) on vaccine
safety. Scientists in the network can conduct studies on complex individual patient cases of safety. Scientists in the network can conduct studies on complex individual patient cases of
possible adverse health events that followed vaccination.possible adverse health events that followed vaccination.124141 Using CISA, scientists can assess the Using CISA, scientists can assess the
biological mechanisms that cause adverse health events after vaccination.biological mechanisms that cause adverse health events after vaccination.125142 In addition, CISA In addition, CISA
manages a repository of biospecimen samples from patients who experience unusual adverse manages a repository of biospecimen samples from patients who experience unusual adverse
events following vaccination.events following vaccination.126143 These samples can be systemically analyzed to inform a These samples can be systemically analyzed to inform a
mechanistic understanding of such adverse events. mechanistic understanding of such adverse events.
Federal Research on Vaccine Safety
Postmarket surveillance systems and clinical assessments provide important data and evidence on Postmarket surveillance systems and clinical assessments provide important data and evidence on
potential adverse events following vaccination. To further understand and determine whether potential adverse events following vaccination. To further understand and determine whether
vaccines cause or could plausibly cause certain adverse health events, scientists conduct various vaccines cause or could plausibly cause certain adverse health events, scientists conduct various
types of research that inform a scientific understanding of vaccine safety (separate from the types of research that inform a scientific understanding of vaccine safety (separate from the
clinical trials under an IND). Such activities are supported primarily by HHS agencies, mainly clinical trials under an IND). Such activities are supported primarily by HHS agencies, mainly
CDC and the National Institutes of Health (NIH). In addition, FDA supports regulatory research CDC and the National Institutes of Health (NIH). In addition, FDA supports regulatory research
related to methods for evaluating vaccine safety. Major areas of research related to vaccines can related to methods for evaluating vaccine safety. Major areas of research related to vaccines can
include the following:include the following:127144
  Biological research: Research often with animals, cell cultures, or biological Research often with animals, cell cultures, or biological
specimens (e.g., human tissue samples) to explore the mechanisms by which specimens (e.g., human tissue samples) to explore the mechanisms by which
vaccines act in biological systems, informing an understanding of how adverse vaccines act in biological systems, informing an understanding of how adverse
events may occur. (Also referred to as basic biomedical research). events may occur. (Also referred to as basic biomedical research).
  Epidemiological research: A form of statistical research involving health data A form of statistical research involving health data
collected among defined human populations (such as postmarket surveillance collected among defined human populations (such as postmarket surveillance
data) to explore whether statistical associations exist between vaccination and data) to explore whether statistical associations exist between vaccination and
subsequent adverse events, and any related risk factors for those events among subsequent adverse events, and any related risk factors for those events among
those populations. those populations.
Clinical research: Research with patients to understand the clinical features of
adverse health events among patients that are hypothesized to be connected to
vaccination.
Research can also explore the underlying methodologies used to assess vaccine safety
through any of these forms of research.

124141 CDC, “Clinical Immunization Safety Assessment (CISA) Project,” https://www.cdc.gov/vaccinesafety/ CDC, “Clinical Immunization Safety Assessment (CISA) Project,” https://www.cdc.gov/vaccinesafety/
ensuringsafety/monitoring/cisa/index.html. ensuringsafety/monitoring/cisa/index.html.
125142 Frank Frank DestefanoDeStefano, Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in , Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley Plotkin, , ed. Stanley Plotkin,
Walter Orenstein, Paul Offit, Kathryn M. Edwards, 7th ed. (Elsevier, 2018), pp. 1588. Walter Orenstein, Paul Offit, Kathryn M. Edwards, 7th ed. (Elsevier, 2018), pp. 1588.
126143 NVAC, NVAC, White Paper on the United States Vaccine Safety System, September 2011, p. 16, https://www.hhs.gov/sites/, September 2011, p. 16, https://www.hhs.gov/sites/
default/files/nvpo/nvac/nvac_vswp.pdf. default/files/nvpo/nvac/nvac_vswp.pdf.
127144 NVAC, NVAC, White Paper on the United States Vaccine Safety System, September 2011, p. 16, https://www.hhs.gov/sites/, September 2011, p. 16, https://www.hhs.gov/sites/
default/files/nvpo/nvac/nvac_vswp.pdf. default/files/nvpo/nvac/nvac_vswp.pdf.
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Clinical research: Research with patients to understand the clinical features of adverse health events among patients that are hypothesized to be connected to vaccination. Research can also explore the underlying methodologies used to assess vaccine safety through any of these forms of research. CDC Research
CDC conducts and supports many types of research on vaccine safety, including epidemiological CDC conducts and supports many types of research on vaccine safety, including epidemiological
and clinical studies. Many of CDC’s research publications rely on data and findings from its and clinical studies. Many of CDC’s research publications rely on data and findings from its
safety monitoring systems, as listed above, including VAERS, VSD, and CISA. CDC research safety monitoring systems, as listed above, including VAERS, VSD, and CISA. CDC research
often focuses on the use of specific vaccines in specific populations, as well as hypothesized side often focuses on the use of specific vaccines in specific populations, as well as hypothesized side
effects and adverse events potentially attributable to vaccination.effects and adverse events potentially attributable to vaccination.128145 For example, a recent CDC For example, a recent CDC
study published in 2020 explored probability-based methods of determining which vaccine or study published in 2020 explored probability-based methods of determining which vaccine or
combination of vaccines were linked to an adverse event following vaccination (in this case, a combination of vaccines were linked to an adverse event following vaccination (in this case, a
seizure) when multiple vaccines were administered at once.seizure) when multiple vaccines were administered at once.129146
NIH Research
In addition to CDC research, biological research related to immunology or infectious disease In addition to CDC research, biological research related to immunology or infectious disease
supported by NIH informs an understanding of vaccine safety. NIH tends to support more supported by NIH informs an understanding of vaccine safety. NIH tends to support more
biological research than CDC, in that NIH research focuses on the fundamental biological biological research than CDC, in that NIH research focuses on the fundamental biological
mechanisms underlying vaccine safety, as well as research methodologies for examining it. For mechanisms underlying vaccine safety, as well as research methodologies for examining it. For
the past several years, NIH, in collaboration with CDC and NVPO, has issued annual funding the past several years, NIH, in collaboration with CDC and NVPO, has issued annual funding
opportunity announcements for “Research on Vaccine Safety.” Research projects can include opportunity announcements for “Research on Vaccine Safety.” Research projects can include
scientific investigations into physiological and immunological responses to vaccines; explorations scientific investigations into physiological and immunological responses to vaccines; explorations
of how genetic variations affect responses to vaccines; investigations into risk factors for adverse of how genetic variations affect responses to vaccines; investigations into risk factors for adverse
responses to vaccination; exploration and validation of statistical methods for analyzing data on responses to vaccination; exploration and validation of statistical methods for analyzing data on
vaccine safety; and the application of genomic and molecular technologies to assess vaccine vaccine safety; and the application of genomic and molecular technologies to assess vaccine
safety.safety.130147
The National Institute of Allergy and Infectious Diseases (NIAID, which is one of 27 NIH The National Institute of Allergy and Infectious Diseases (NIAID, which is one of 27 NIH
Institutes and Centers) also supports the Human Immunology Project Consortium (HIPC), a Institutes and Centers) also supports the Human Immunology Project Consortium (HIPC), a
program established in 2010 that collects in-depth biological data over time on the immune program established in 2010 that collects in-depth biological data over time on the immune
systems of a diverse cohort of patients. The program consolidates data on the cohort into systems of a diverse cohort of patients. The program consolidates data on the cohort into
centralized databases for use by researchers.centralized databases for use by researchers.131148 Researchers are using HIPC to study certain Researchers are using HIPC to study certain
aspects of vaccine safety, such as whether a relationship exists between short-term adverse events aspects of vaccine safety, such as whether a relationship exists between short-term adverse events
caused by vaccination and long-term health effects.caused by vaccination and long-term health effects.132149 When combined with postmarket 145 When combined with postmarket
surveillance data and studies, NIH-supported research can contribute to robust evaluations on the
safety of vaccines.
FDA Research
FDA conducts regulatory science research to facilitate its evaluation of vaccine safety and
effectiveness, and to support the development of new vaccines. For example, CBER scientists
have published studies on the agency’s effort to develop and evaluate assays and animal models

128 CDC, “Vaccine Safety Publications,” https://www.cdc.gov/vaccinesafety/research/publications/index.html. CDC, “Vaccine Safety Publications,” https://www.cdc.gov/vaccinesafety/research/publications/index.html.
129146 Shirley V. Wang, Kristina Stefanini, Edwin Lewis, et al., “Determining Which of Several Simultaneously Shirley V. Wang, Kristina Stefanini, Edwin Lewis, et al., “Determining Which of Several Simultaneously
Administered Vaccines Increase Risk of an Adverse Event,” Administered Vaccines Increase Risk of an Adverse Event,” Drug Safety, vol. 43 (July 1, 2020), pp. 1057-65. , vol. 43 (July 1, 2020), pp. 1057-65.
130147 NIH, “Research to Advance Vaccine Safety (R01),” July 24, 2018, https://grants.nih.gov/grants/guide/pa-files/PA- NIH, “Research to Advance Vaccine Safety (R01),” July 24, 2018, https://grants.nih.gov/grants/guide/pa-files/PA-
18-873.html. 18-873.html.
131148 NIH, “Human Immunology Project Consortium,” https://www.immuneprofiling.org/hipc/page/showPage?pg=about. NIH, “Human Immunology Project Consortium,” https://www.immuneprofiling.org/hipc/page/showPage?pg=about.
132149 National Academy of Medicine, National Academy of Medicine, The Childhood Immunization Schedule and Safety: Stakeholder Concerns,
Scientific Evidence, and Future Studies
, Washington, DC, January 16, 2013, http://nationalacademies.org/HMD/, Washington, DC, January 16, 2013, http://nationalacademies.org/HMD/
Reports/2013/The-Childhood-Immunization-Schedule-and-Safety.aspx. Reports/2013/The-Childhood-Immunization-Schedule-and-Safety.aspx.
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link to page link to page 3032 link to page 32 Vaccine Safety in the United States surveillance data and studies, NIH-supported research can contribute to robust evaluations on the safety of vaccines. FDA Research FDA conducts regulatory science research to facilitate its evaluation of vaccine safety and effectiveness, and to support the development of new vaccines. For example, CBER scientists have published studies on the agency’s effort to develop and evaluate assays and animal models Vaccine Safety in the United States

for studying the safety and efficacy of vaccines against specific pathogens, as well as to for studying the safety and efficacy of vaccines against specific pathogens, as well as to
characterize biomarkers of vaccine safety and efficacy.characterize biomarkers of vaccine safety and efficacy.133150 In addition, FDA has studied certain In addition, FDA has studied certain
adjuvants and preservatives added to vaccines, including thimerosal and the impact of aluminum adjuvants and preservatives added to vaccines, including thimerosal and the impact of aluminum
in vaccines on infants.in vaccines on infants.134151 FDA research efforts have also focused on vaccine availability, FDA research efforts have also focused on vaccine availability,
specifically on influenza vaccine production and ensuring a sufficient supply of a safe vaccine.specifically on influenza vaccine production and ensuring a sufficient supply of a safe vaccine.135152
Other Federal Research
Other federal agencies conduct or support research related to vaccine safety. For example, the Other federal agencies conduct or support research related to vaccine safety. For example, the
NVPO has issued Funding Opportunity Announcements (FOA) for grants to support vaccine NVPO has issued Funding Opportunity Announcements (FOA) for grants to support vaccine
safety research.safety research.136153 The Agency for Healthcare Research and Quality (AHRQ) has conducted The Agency for Healthcare Research and Quality (AHRQ) has conducted
vaccine safety reviews. The Department of Defense (DOD) and the Department of Veterans vaccine safety reviews. The Department of Defense (DOD) and the Department of Veterans
Affairs (VA) also support some vaccine safety research.Affairs (VA) also support some vaccine safety research.137154
Periodically, federal agencies (particularly HHS) conduct or commission comprehensive Periodically, federal agencies (particularly HHS) conduct or commission comprehensive
scientific reviews on the safety of recommended vaccines. As described in the text box scientific reviews on the safety of recommended vaccines. As described in the text box on page 6,
(see “What Is a Causality Assessment?”), these reviews often evaluate and combine evidence from a large number of studies and a range of these reviews often evaluate and combine evidence from a large number of studies and a range of
research types to make assessments about the safety of vaccines that are as conclusive as possible. research types to make assessments about the safety of vaccines that are as conclusive as possible.
For example, in 2011, under HHS contract, the National Academy of Medicine (NAM)For example, in 2011, under HHS contract, the National Academy of Medicine (NAM)138
155 conducted a comprehensive review of the scientific evidence regarding the safety of eight conducted a comprehensive review of the scientific evidence regarding the safety of eight
pediatric vaccines. The resulting NAM report, pediatric vaccines. The resulting NAM report, Adverse Effects of Vaccines: Evidence and
Causality
, was used to inform an update of the Vaccine Injury Table for the National Vaccine , was used to inform an update of the Vaccine Injury Table for the National Vaccine
Injury Compensation Program (see the Injury Compensation Program (see the “National Vaccine Injury Compensation” section).section).139156 This This
review was subsequently updated in 2014 with additional research by AHRQ, supported by the review was subsequently updated in 2014 with additional research by AHRQ, supported by the
NVPO; AHRQ is currently in the process of updating this NVPO; AHRQ is currently in the process of updating this review.140
Challenges of Vaccine Safety Reviews
As discussed earlier, causality assessments that combine evidence across many studies allow for
researchers to assess if all the available evidence favors a causal relationship between a vaccine
and a subsequent adverse health event. In general, establishing true causal linkages between areview.157

133150 FDA, Vaccines Research, current as of August 14, 2020, https://www.fda.gov/vaccines-blood-biologics/biologics- FDA, Vaccines Research, current as of August 14, 2020, https://www.fda.gov/vaccines-blood-biologics/biologics-
research-projects/vaccines-research. research-projects/vaccines-research.
134151 L. K. Ball, R. Ball, R. D. Pratt, “An assessment of thimerosal use in childhood vaccines,” L. K. Ball, R. Ball, R. D. Pratt, “An assessment of thimerosal use in childhood vaccines,” Pediatrics, 2001, vol. 107 , 2001, vol. 107
no. 5, pp. 1147-1154. The study was required by the FDA Modernization Act (FDAMA, P.L. 105-115). FDA, “Study no. 5, pp. 1147-1154. The study was required by the FDA Modernization Act (FDAMA, P.L. 105-115). FDA, “Study
Reports Aluminum in Vaccines Poses Extremely Low Risk to Infants,” https://wayback.archive-it.org/7993/Reports Aluminum in Vaccines Poses Extremely Low Risk to Infants,” https://wayback.archive-it.org/7993/
20170405003134/https:/www.fda.gov/BiologicsBloodVaccines/ScienceResearch/ucm284520.htm. 20170405003134/https:/www.fda.gov/BiologicsBloodVaccines/ScienceResearch/ucm284520.htm.
135152 FDA, “Facilitating Influenza Virus Vaccine Production by Optimizing Vaccine Strains,” https://www.fda.gov/ FDA, “Facilitating Influenza Virus Vaccine Production by Optimizing Vaccine Strains,” https://www.fda.gov/
vaccines-blood-biologics/biologics-research-projects/facilitating-influenza-virus-vaccine-production-optimizing-vaccines-blood-biologics/biologics-research-projects/facilitating-influenza-virus-vaccine-production-optimizing-
vaccine-strains. vaccine-strains.
136153 See, for example, BetaSam.gov, “Research, Monitoring and Outcomes Definitions for Vaccine Safety,” See, for example, BetaSam.gov, “Research, Monitoring and Outcomes Definitions for Vaccine Safety,”
https://beta.sam.gov/fal/c8125303527f478981f6b7395c528788/view. https://beta.sam.gov/fal/c8125303527f478981f6b7395c528788/view.
137154 Vaccines.gov, “Vaccine Safety,” https://www.vaccines.gov/basics/safety. Vaccines.gov, “Vaccine Safety,” https://www.vaccines.gov/basics/safety.
138155 NAM was named the Institute of Medicine when the Immunization Safety Review Committee was formed. NAM was named the Institute of Medicine when the Immunization Safety Review Committee was formed.
139156 Institute of Medicine, Institute of Medicine, Adverse Effects of Vaccines: Evidence and Causality, August 25, 2011. , August 25, 2011.
140157 Margaret A. Maglione, Courtney Gidengil, Lopamudra Das, et al. “Safety of Vaccines Used for Routine Margaret A. Maglione, Courtney Gidengil, Lopamudra Das, et al. “Safety of Vaccines Used for Routine
Immunization in the United States,” Agency for Healthcare Research and Quality, July 2014,
https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/vaccine-safety_research.pdf, and AHRQ, “Safety of Vaccines
Used for Routine Immunization in the United States: Research Protocol,” April 2020,
https://effectivehealthcare.ahrq.gov/products/safety-vaccines/protocol.
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Congressional Research Service 26 Vaccine Safety in the United States Challenges of Vaccine Safety Reviews As discussed earlier, causality assessments that combine evidence across many studies allow for researchers to assess if all the available evidence favors a causal relationship between a vaccine and a subsequent adverse health event. In general, establishing true causal linkages between a vaccine and certain subsequent adverse health events can be challenging; however, researchers vaccine and certain subsequent adverse health events can be challenging; however, researchers
draw conclusions using multiple forms of evidence. The clinical trials required for vaccine draw conclusions using multiple forms of evidence. The clinical trials required for vaccine
licensure are well-controlled scientific experiments that allow researchers to draw conclusions licensure are well-controlled scientific experiments that allow researchers to draw conclusions
about the safety of products. Postmarket safety studies, on the other hand, can face a variety of about the safety of products. Postmarket safety studies, on the other hand, can face a variety of
methodological challenges. For one, the population of vaccinated individuals is often much larger methodological challenges. For one, the population of vaccinated individuals is often much larger
than and demographically different from the population of unvaccinated individuals, making it than and demographically different from the population of unvaccinated individuals, making it
difficult to draw comparisons in health outcomes between the two groups. Researchers therefore difficult to draw comparisons in health outcomes between the two groups. Researchers therefore
often rely on time intervals between vaccination and an adverse health event—assessing whether often rely on time intervals between vaccination and an adverse health event—assessing whether
a certain adverse health event is more likely to occur within a defined time interval after a certain adverse health event is more likely to occur within a defined time interval after
vaccination compared with other time periods. While this approach can work for short-term vaccination compared with other time periods. While this approach can work for short-term
health effects caused by vaccines, it can be less effective for hypothesized long-term effects of health effects caused by vaccines, it can be less effective for hypothesized long-term effects of
vaccines or adverse health events that are otherwise common in the population. Statistical vaccines or adverse health events that are otherwise common in the population. Statistical
association between vaccination and an adverse health event is often necessary but not sufficient between vaccination and an adverse health event is often necessary but not sufficient
to establish to establish causality. As discussed earlier, to make a causality assessment about whether a . As discussed earlier, to make a causality assessment about whether a
particular vaccine causes an adverse health event, experts use evidence and results from many particular vaccine causes an adverse health event, experts use evidence and results from many
scientific studies, including epidemiological evidence, clinical evidence, and biological laboratory scientific studies, including epidemiological evidence, clinical evidence, and biological laboratory
evidence, usually with methods to weigh, compare, and combine evidence across studies.evidence, usually with methods to weigh, compare, and combine evidence across studies.141158 Such Such
causality assessments may be conducted as a part of a comprehensive scientific review by federal causality assessments may be conducted as a part of a comprehensive scientific review by federal
or academic scientists, or by independent scientific advisory bodies, such as the NAM. or academic scientists, or by independent scientific advisory bodies, such as the NAM.
National Vaccine Injury Compensation
The National Vaccine Injury Compensation Program (VICP) provides compensation to The National Vaccine Injury Compensation Program (VICP) provides compensation to
individuals who file a petition and are found to have been injured by a covered vaccine. individuals who file a petition and are found to have been injured by a covered vaccine. VICP is
based in the Health Resources and Services Administration (HRSA) and was established by the
National Childhood Vaccine Injury Act of 1986 (P.L. 99-660).142Under current law, the HHS Secretary is required to promulgate VICP regulations for vaccines recommended for “routine administration” to children and pregnant women.159 Compensation can be provided for vaccines listed as a “taxable vaccine” in 26 U.S.C. §4132(a)(1).160 Anyone injured by the covered vaccines—including nonpregnant adults—can file a claim.161 VICP publishes a “Vaccine VICP publishes a “Vaccine
Injury Table” that lists vaccines covered by the program and the injuries associated with those Injury Table” that lists vaccines covered by the program and the injuries associated with those
vaccines for which claims may be filed, developedvaccines for which claims may be filed, developed in part based on the causality assessments conducted based on the causality assessments conducted
by IOMby Institute of Medicine (IOM, now called the National Academy of Immunization in the United States,” Agency for Healthcare Research and Quality, July 2014, https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/vaccine-safety_research.pdf, and AHRQ, “Safety of Vaccines Used for Routine Immunization in the United States: Research Protocol,” April 2020, https://effectivehealthcare.ahrq.gov/products/safety-vaccines/protocol. 158 Frank DeStefano, Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A. Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), pp. 1589. 159 PHSA §2114 [42 U.S.C. §300aa-14], and26 U.S.C. §4132(a)(1). 160 26 U.S.C. §9510(c). 161 U.S. Government Accountability Office, Vaccine Injury Compensation: Most Claims Took Multiple Years and Many Were Settled through Negotiation, GAO-15-142, November 21, 2014, https://www.gao.gov/products/GAO-15-142. Congressional Research Service 27 link to page 46 Vaccine Safety in the United States Medicine) and AHRQ. Claimants may submit claims for injuries that are not listed on the table, but and AHRQ. Claimants may submit claims for injuries that are not listed on the table, but
they must present evidence that the vaccine caused the injury.they must present evidence that the vaccine caused the injury.143162 VICP is funded by the Vaccine Compensation Trust Fund, which is funded by an excise tax on vaccines paid by manufacturers. Taxable vaccines included in the program are listed in 26 U.S.C. §4132(a)(1), and compensation cannot be paid from the trust fund unless the vaccine is listed as a “taxable vaccine” under that section.163 Therefore, adding a new type of vaccine to the program would generally need action by Congress. VICP was established in response to vaccine shortages that occurred after hundreds of injury lawsuits were filed against vaccine manufacturers in the 1980s, leading to halts in vaccine production and creating instability in the vaccine market. VICP is a no-fault system to compensate individuals who were injured as a result of vaccination. It serves to protect manufacturers from injury lawsuits. As of January 1, 2021, over 22,919 petitions have been filed with VICP, and 7,754 were determined to be compensable, with total compensation paid of about $4.5 billion since the program was established in 1988.164 VICP is based in the Health Resources and Services Administration (HRSA) and was established by the National Childhood Vaccine Injury Act of 1986 (P.L. 99-660).165 In addition to HHS/HRSA, VICP In addition to HHS/HRSA, VICP
involves the Department of Justice (DOJ) and the U.S. Court of Federal Claims.involves the Department of Justice (DOJ) and the U.S. Court of Federal Claims.144166 The Advisory The Advisory
Committee on Childhood Vaccines (ACCV) also provides oversight of VICP by making Committee on Childhood Vaccines (ACCV) also provides oversight of VICP by making
recommendations to the HHS Secretary, including those related to the Vaccine Injury Table. recommendations to the HHS Secretary, including those related to the Vaccine Injury Table.
ACCV is a nine-member federal advisory committee made up of health and legal representatives, ACCV is a nine-member federal advisory committee made up of health and legal representatives,
as well as parents or legal representatives of children who have been injured by vaccines.as well as parents or legal representatives of children who have been injured by vaccines.145

141 Frank Destefano, Paul A. Offit, and Allison Fisher, “Ch. 82: Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley A.
Plotkin, Walter A. Orenstein, and Paul A. Offit, 7th ed. (Elsevier, 2017), pp. 1589.
142 HRSA, “National Vaccine Injury Compensation,”167 During an emergency situation such as the COVID-19 pandemic, vaccines may be covered under a different injury compensation program—the Countermeasures Injury Compensation Program (CICP), as discussed in the “Injury Compensation and Patient Safety Information” section.168 Safety in Vaccine Distribution Managing vaccine supply and distribution requires temperature control, safety controls, and regular monitoring of expiry dates due to the limited shelf life of products.169 Given that public 162 HRSA, “National Vaccine Injury Compensation Program—Covered Vaccines,” June 2019, https://www.hrsa.gov/vaccine-compensation/ https://www.hrsa.gov/vaccine-compensation/covered-vaccines/index.html. 163 26 U.S.C. §9510(c). 164 HRSA, “Data & Statistics,” https://www.hrsa.gov/sites/default/files/hrsa/vaccine-compensation/data/data-statistics-report.pdf. 165 HRSA, “National Vaccine Injury Compensation,”index.html.
143 HRSA, “National Vaccine Injury Compensation Program—Covered Vaccines,” June 2019, https://www.hrsa.gov/ https://www.hrsa.gov/
vaccine-compensation/vaccine-compensation/covered-vaccines/index.html. index.html.
144166 HRSA, “About the National Vaccine Injury Compensation Program,” June 2019, https://www.hrsa.gov/vaccine- HRSA, “About the National Vaccine Injury Compensation Program,” June 2019, https://www.hrsa.gov/vaccine-
compensation/about/index.html. compensation/about/index.html.
145167 HHS, “Charter- Advisory Commission on Childhood Vaccines,” https://www.hrsa.gov/sites/default/files/hrsa/ HHS, “Charter- Advisory Commission on Childhood Vaccines,” https://www.hrsa.gov/sites/default/files/hrsa/
advisory-committees/vaccines/accvcharter.pdf. For the parents or legal representatives of children who have suffered a advisory-committees/vaccines/accvcharter.pdf. For the parents or legal representatives of children who have suffered a
vaccine-related injury or death, HRSA specifies that to be considered for appointment, “there must have been a finding vaccine-related injury or death, HRSA specifies that to be considered for appointment, “there must have been a finding
(i.e., a decision) by the U.S. Court of Federal Claims or a civil court that a VICP-covered vaccine caused, or was (i.e., a decision) by the U.S. Court of Federal Claims or a civil court that a VICP-covered vaccine caused, or was
presumed to have caused, the represented child’s injury or death.” From HRSA, “Advisory Commission on Vaccines: presumed to have caused, the represented child’s injury or death.” From HRSA, “Advisory Commission on Vaccines:
Frequently Asked Questions,” 2018, https://www.hrsa.gov/sites/default/files/hrsa/vaccine-compensation/job-Frequently Asked Questions,” 2018, https://www.hrsa.gov/sites/default/files/hrsa/vaccine-compensation/job-
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VICP is funded by the Vaccine Compensation Trust Fund, which is funded by an excise tax on
vaccines paid by manufacturers. VICP was established in response to vaccine shortages that
occurred after hundreds of injury lawsuits were filed against vaccine manufacturers in the 1980s,
leading to halts in vaccine production and creating instability in the vaccine market. VICP is a no-
fault system to compensate individuals who were injured as a result of vaccination. It serves to
protect manufacturers from injury lawsuits. As of October 1, 2020, over 22,272 petitions have
been filed with VICP, and 7,611 were determined to be compensable, with total compensation
paid of about $4.4 billion since the program was established in 1988.146
During an emergency situation such as the COVID-19 pandemic, vaccines may be covered under
a different injury compensation program—the Countermeasures Injury Compensation Program
(CICP), as discussed in the “Injury Compensation and Patient Safety Information” section.147
Safety in Vaccine Distribution
Managing vaccine supply and distribution requires temperature control, safety controls, and
regular monitoring of expiry dates due to the limited shelf life of products.148 Given that public
opportunities/ACCV-FAQs.pdf. 168 CRS Legal Sidebar LSB10443, The PREP Act and COVID-19: Limiting Liability for Medical Countermeasures. 169 Judith R. Kaufmann, Roger Miller, and James Cheyne, “Vaccine Supply Chains Need To Be Better Funded And Congressional Research Service 28 Vaccine Safety in the United States dollars (federal and state) pay for over 50% of vaccines (by volume) in the United States, federal dollars (federal and state) pay for over 50% of vaccines (by volume) in the United States, federal
agencies play a role in the supply and distribution of vaccines.agencies play a role in the supply and distribution of vaccines.149170 CDC, in particular, conducts CDC, in particular, conducts
activities to help improve management of the vaccine supply chain. Vaccine storage practices activities to help improve management of the vaccine supply chain. Vaccine storage practices
especially have implications for a vaccine’s potency (i.e., effectiveness).especially have implications for a vaccine’s potency (i.e., effectiveness).150171
Vaccines are distributed through a decentralized network of health care providers, health centers, Vaccines are distributed through a decentralized network of health care providers, health centers,
pharmacies, and health departments. State requirements vary regarding the types of pharmacies, and health departments. State requirements vary regarding the types of entitiesproviders that that
can be licensed or authorized to administer various vaccines. In the CDC’s Vaccines for Children can be licensed or authorized to administer various vaccines. In the CDC’s Vaccines for Children
(VFC) program, health care providers can apply to receive and provide VFC-covered vaccines (VFC) program, health care providers can apply to receive and provide VFC-covered vaccines
through state or local coordinators, who ensure that the provider meets program requirements through state or local coordinators, who ensure that the provider meets program requirements
(e.g., ability to properly store and handle vaccines).(e.g., ability to properly store and handle vaccines).151172 Any provider that is licensed or otherwise Any provider that is licensed or otherwise
authorized to administer pediatric vaccines can apply to participate in a state’s VFC program and authorized to administer pediatric vaccines can apply to participate in a state’s VFC program and
receive and administer a supply of vaccine.receive and administer a supply of vaccine.152173
Vaccine programs are expected to make vaccines widely available, while ensuring that they are Vaccine programs are expected to make vaccines widely available, while ensuring that they are
safely stored, properly administered, and used or discarded before their expiry date. However, this safely stored, properly administered, and used or discarded before their expiry date. However, this
requirement is a challenge for many vaccine programs. A 2012 HHS Inspector General report requirement is a challenge for many vaccine programs. A 2012 HHS Inspector General report
found that many VFC providers did not meet vaccine management requirements, either by found that many VFC providers did not meet vaccine management requirements, either by
exposing vaccines to improper temperatures, storing expired and nonexpired vaccines together, or exposing vaccines to improper temperatures, storing expired and nonexpired vaccines together, or
failing to maintain documentation. CDC agreed with the report recommendations and committed failing to maintain documentation. CDC agreed with the report recommendations and committed

opportunities/ACCV-FAQs.pdf.
146 HRSA, “Data & Statistics,” https://www.hrsa.gov/sites/default/files/hrsa/vaccine-compensation/data/data-statistics-
report.pdf.
147 CRS Legal Sidebar LSB10443, The PREP Act and COVID-19: Limiting Liability for Medical Countermeasures.
148 Judith R. Kaufmann, Roger Miller, and James Cheyne, “Vaccine Supply Chains Need To Be Better Funded And
to improving management among providers.174 Following the report, CDC changed VFC program requirements and issued recommendations to providers and immunization program managers.175 CDC’s immunization programs include several efforts among state and local partners to improve the vaccine supply chain and vaccine distribution:  The Vaccine Management Business Improvement Project (VMBIP) is an effort among CDC and state and local partners to improve the management of the vaccine supply chain, particularly for vaccines distributed through VFC. Since the project began in 2003, it has changed funding mechanisms, forecasting for supply needs, provider distribution, and inventory tracking among vaccine providers.176 Strengthened, Or Lives Will Be At Risk,” Strengthened, Or Lives Will Be At Risk,” Health Affairs, vol. 30, no. 6 (2011), pp. 1113-1121. , vol. 30, no. 6 (2011), pp. 1113-1121.
149170 Matthew J. Robbins and Sheldon H. Jacobson, “Analytics for Vaccine Economics and Pricing: Insights and Matthew J. Robbins and Sheldon H. Jacobson, “Analytics for Vaccine Economics and Pricing: Insights and
Observations,” Observations,” Expert Review of Vaccines, vol. 14, no. 4 (December 1, 2014), pp. 606-616. , vol. 14, no. 4 (December 1, 2014), pp. 606-616.
150171 CDC, “Vaccine Storage and Handling Toolkit,” January 2019, https://www.cdc.gov/vaccines/hcp/admin/storage/ CDC, “Vaccine Storage and Handling Toolkit,” January 2019, https://www.cdc.gov/vaccines/hcp/admin/storage/
toolkit/storage-handling-toolkit.pdf. toolkit/storage-handling-toolkit.pdf.
151172 CDC, “Why Join and How to Become a VFC Provider,” https://www.cdc.gov/vaccines/programs/vfc/providers/ CDC, “Why Join and How to Become a VFC Provider,” https://www.cdc.gov/vaccines/programs/vfc/providers/
questions/qa-join.html. questions/qa-join.html.
152173 Social Security Act §1928(c); 42 U.S.C. §1396s(c). 174 HHS Office of Inspector General, Vaccines for Children Program: Vulnerabilities in Vaccine Management, June 2012, https://oig.hhs.gov/oei/reports/oei-04-10-00430.pdf. 175 Association of Immunization Managers, AIM Statement on Vaccine Storage and Management, February 7, 2017, https://cdn.ymaws.com/www.immunizationmanagers.org/resource/resmgr/policy/AIM_Statement_on_Vaccine_Sto.pdf. 176 CDC, “Vaccine Management Business Improvement Project,” https://www.cdc.gov/vaccines/programs/vtrcks/vmbip.html. Congressional Research Service 29 link to page 39 Vaccine Safety in the United States Social Security Act §1928(c); 42 U.S.C. §1396s(c).
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to improving management among providers.153 Following the report, CDC changed VFC program
requirements and issued recommendations to providers and immunization program managers.154
CDC’s immunization programs include several efforts among state and local partners to improve
the vaccine supply chain and vaccine distribution:
 The Vaccine Management Business Improvement Project (VMBIP) is an
effort among CDC and state and local partners to improve the management of the
vaccine supply chain, particularly for vaccines distributed through VFC. Since
the project began in 2003, it has changed funding mechanisms, forecasting for
supply needs, provider distribution, and inventory tracking among vaccine
providers.155
 The  The Vaccine Tracking System (VTrckS) is an information technology platform (VTrckS) is an information technology platform
for managing the publicly funded vaccine supply chain available to CDC, state for managing the publicly funded vaccine supply chain available to CDC, state
and local health departments, and providers.and local health departments, and providers.156177
Safety Considerations for COVID-19 Vaccines
The COVID-19 vaccine development, approval, and distribution planning situation is evolving.
Readers should note the date of this publication and be aware that this report may not reflect
events or actions that occurred after that date.

Much remains unknown about potential safety issues related to COVID-19 vaccines. As of the date of this report, two COVID-19 vaccines are authorized by FDA for emergency use. FDA has determined that these vaccines may be effective in preventing COVID-19, and that their known and potential benefits outweigh their known and potential risks,178 consistent with the statutory standard for EUA issuance (see the section “FDA Marketing Authorization”) and the safety and effectiveness standards set forth by FDA in guidance.179 Ongoing programs, such as those concerning vaccine manufacturing, distribution, and clinical education, aim to ensure that vaccines are safely produced, distributed, stored, and administered. In addition, several postmarket programs continue to study and monitor vaccines in use to identify any new or rare safety risks. Any newly identified safety issues may lead to changes in vaccine labeling and clinical recommendations for use. In the event that risk of vaccination with a certain vaccine outweighs its benefits for any population, FDA may modify or revoke its EUA. FDA has
never licensed a vaccine for a coronavirus. Several COVID-19 vaccines in development use novel
vaccine technologies, some of which have never before been used in licensed FDA vaccines.157
Among the few mass emergency vaccination efforts in the past century, there have been some
unexpected safety issues. For example, in 1976, the federal government attempted a rapid mass
influenza (flu) vaccination campaign in response to a novel swine flu strain. The vaccines were
later found to lead to higher rates of Guillain-Barre Syndrome (a neurological disorder) among
those vaccinated, ending the campaign.158
U.S. vaccine development efforts have been supported and coordinated by Operation Warp Speed U.S. vaccine development efforts have been supported and coordinated by Operation Warp Speed
(OWS), the nation’s major COVID-19 vaccine, therapeutic, and diagnostic (medical (OWS), the nation’s major COVID-19 vaccine, therapeutic, and diagnostic (medical
countermeasures) countermeasures) development initiative.initiative. This report refers to this initiative as OWS, although the Biden Administration reportedly plans to retire this name and to restructure this initiative.180 OWS has chosen to support 14 potential COVID-19 OWS has chosen to support 14 potential COVID-19
vaccine candidates from a pool of 93, with the stated goal of reducing the number of candidates to vaccine candidates from a pool of 93, with the stated goal of reducing the number of candidates to
7 as additional results from clinical trials and research become available.7 as additional results from clinical trials and research become available.159181 As of October 29, 2020, OWS had announced contracts in support of six vaccines out of the eight in OWS’ portfolio.182 OWS and CDC are implementing a federally coordinated nationwide COVID-19 vaccine distribution campaign.183 177 CDC, “Vaccine Tracking System,” https://www.cdc.gov/vaccines/programs/vtrcks/index.html. 178 FDA, Emergency Use Authorization (EUA) for an Unapproved Product- Pfizer, Inc. on behalf of Pfizer and BioNTech, December 11, 2020, https://www.fda.gov/media/144416/download; and FDA, Emergency Use Authorization (EUA) for an Unapproved Product- ModernaTx, Inc, December 18, 2020, https://www.fda.gov/media/144673/download. 179 FDA, “Emergency Use Authorization for Vaccines to Prevent COVID-19,” Guidance for Industry, October 2020, https://www.fda.gov/media/142749/download. 180 White House Press Secretary Jen Psaki @jrpsaki, “OWS is the Trump team’s name for their program. We are phasing in a new structure, which will have a different name than OWS ... ” January 15, 2021, 11:44 a.m., https://twitter.com/jrpsaki/status/1350121790148902912. 181 As of October 29,

153 HHS Office of Inspector General, Vaccines for Children Program: Vulnerabilities in Vaccine Management, June
2012, https://oig.hhs.gov/oei/reports/oei-04-10-00430.pdf.
154 Association of Immunization Managers, AIM Statement on Vaccine Storage and Management, February 7, 2017,
https://cdn.ymaws.com/www.immunizationmanagers.org/resource/resmgr/policy/
AIM_Statement_on_Vaccine_Sto.pdf.
155 CDC, “Vaccine Management Business Improvement Project,” https://www.cdc.gov/vaccines/programs/vtrcks/
vmbip.html.
156 CDC, “Vaccine Tracking System,” https://www.cdc.gov/vaccines/programs/vtrcks/index.html.
157 CRS Report R46427, Development and Regulation of Medical Countermeasures for COVID-19 (Vaccines,
Diagnostics, and Treatments): Frequently Asked Questions
.
158 Lawrence O. Gostin and Lindsay F. Wiley, “Chapter 11: Public Health Emergency Preparedness: Terrorism,
Pandemics, and Disasters,” in Public Health Law: Duty, Power, Restraint (University of California Press, 2016), pp.
410-12.
159 Department of Health and Human Services (HHS), “Fact Sheet: Explaining Operation Warp Speed,” press release, Department of Health and Human Services (HHS), “Fact Sheet: Explaining Operation Warp Speed,” press release,
updated August 7, 2020, https://www.hhs.gov/about/news/2020/06/16/fact-sheet-explaining-operation-warp-updated August 7, 2020, https://www.hhs.gov/about/news/2020/06/16/fact-sheet-explaining-operation-warp-
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2020, eight investigational vaccines were supported within OWS’s portfolio.160 OWS and CDC
are planning for a federally coordinated nationwide COVID-19 vaccine distribution campaign.161
speed.html. 182 Moncef Slaoui and Matthew Hepburn, “Developing Safe and Effective Covid Vaccines—Operation Warp Speed’s Strategy and Approach,” New England Journal of Medicine, October 29, 2020. 183 Operation Warp Speed, “From the Factory to the Frontlines The Operation Warp Speed Strategy for Distributing a COVID-19 Vaccine,” https://www.hhs.gov/sites/default/files/strategy-for-distributing-covid-19-vaccine.pdf?source=email, and CDC, COVID-19 Vaccination Program: Interim Playbook for Jurisdiction Operations, September 16, 2020, https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf. Congressional Research Service 30 link to page 39 Vaccine Safety in the United States Making safe and effective COVID-19 vaccines available within a year represents an Making safe and effective COVID-19 vaccines available within a year represents an
unprecedented scientific and public health effort. The safety considerations and applicability of unprecedented scientific and public health effort. The safety considerations and applicability of
the requirements, processes, and programs described in this report the requirements, processes, and programs described in this report will likely differ when applied differ when applied
to COVID-19 vaccines in several key ways, particularly with respect to (1) vaccine development, to COVID-19 vaccines in several key ways, particularly with respect to (1) vaccine development,
(2) FDA marketing authorization, (3) clinical recommendations and prioritization, (4) (2) FDA marketing authorization, (3) clinical recommendations and prioritization, (4)
surveillance and safety monitoring, (5) injury compensation and patient safety information, and surveillance and safety monitoring, (5) injury compensation and patient safety information, and
(6) vaccine distribution. Each of these is described in more detail below. (6) vaccine distribution. Each of these is described in more detail below.
Vaccine Development and Current Status
Typically, the vaccine development and testing process is linear, with an investigational vaccine Typically, the vaccine development and testing process is linear, with an investigational vaccine
progressing through each phase of clinical testing upon completion of the prior phase. As progressing through each phase of clinical testing upon completion of the prior phase. As
mentioned above, the first stage is basic research, and if laboratory and animal test data indicate mentioned above, the first stage is basic research, and if laboratory and animal test data indicate
that a vaccine candidate appears safe and effective against a pathogen, then a first-in-human that a vaccine candidate appears safe and effective against a pathogen, then a first-in-human
Phase 1 trial generally follows. If the Phase 1 trial indicates that the vaccine is safe in humans, Phase 1 trial generally follows. If the Phase 1 trial indicates that the vaccine is safe in humans,
then Phase 2 testing commences, further examining safety and at what dosage the vaccine has an then Phase 2 testing commences, further examining safety and at what dosage the vaccine has an
effect. Finally, if those studies are successful, then a large, placebo-controlled Phase 3 trial effect. Finally, if those studies are successful, then a large, placebo-controlled Phase 3 trial
follows. This sequential process helps minimize potential health risks to study participants and follows. This sequential process helps minimize potential health risks to study participants and
financial risks to the company sponsoring the investigations. The OWS COVID-19 vaccine financial risks to the company sponsoring the investigations. The OWS COVID-19 vaccine
development process is not following this phased approach. Instead, it is conducting some of development process is not following this phased approach. Instead, it is conducting some of
these steps simultaneously to generate safety and effectiveness data in a shorter period.these steps simultaneously to generate safety and effectiveness data in a shorter period.162
Several COVID-19 vaccines are currently in Phase 3 clinical trials, and initial results are
available from several vaccines that have completed Phase 2 clinical trials.163 Federal officials
have indicated that OWS expects to have initial results from Phase 3 clinical trials in late 2020
and early 2021.164 Results from several Phase 1 and Phase 2 clinical trials of COVID-19
candidate vaccines have demonstrated short-term safety and some evidence of efficacy. Initial
safety data on vaccines supported by Moderna, Pfizer/BioNTech, AstraZeneca, and Johnson &
Johnson found no serious safety issues, although more participants who received the vaccine in
the trials experienced mild or moderate side effects (e.g., fatigue, fever) compared with the
control groups. In addition, all four vaccines show initial evidence of immunogenicity, including
antibodies (immune proteins) and other blood cells that neutralized the virus in blood samples of

speed.html.
160 Moncef Slaoui and Matthew Hepburn, “Developing Safe and Effective Covid Vaccines—Operation Warp Speed’s
Strategy and Approach,” New England Journal of Medicine, October 29, 2020.
161 Operation Warp Speed, “From the Factory to the Frontlines The Operation Warp Speed Strategy for Distributing a
COVID-19 Vaccine,” https://www.hhs.gov/sites/default/files/strategy-for-distributing-covid-19-vaccine.pdf?source=
email, and CDC, COVID-19 Vaccination Program: Interim Playbook for Jurisdiction Operations, September 16, 2020,
https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf.
162 FDA, “FDA Insight: Vaccines for COVID-19, Part 2,” July 28, 2020, https://www.fda.gov/news-events/fda-insight/
fda-insight-vaccines-covid-19-part-2.
163 STAT, “COVID-19 Drugs and Vaccine Tracker,” https://www.statnews.com/feature/coronavirus/drugs-vaccines-
tracker/.
164 Moncef Slaoui and Matthew Hepburn, “Developing Safe and Effective Covid Vaccines—Operation Warp Speed’s
Strategy and Approach,” New England Journal of Medicine, October 29, 2020.
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those who received the candidate vaccines.165 Much remains unknown about COVID-19
immunity, and these results are considered preliminary.
As covered in this report, critical data related to the safety and efficacy of vaccines are generally
collected in Phase 3 clinical trials. Given that no vaccine for a coronavirus has been previously
tested in Phase 3 clinical trials, much remains unknown about the safety issues that may arise. In
particular, experts are concerned about the potential for vaccine enhanced disease, in which
vaccination could worsen the health effects of COVID-19 infections, as seen with the dengue and
other vaccines. Animal studies of other coronavirus vaccines have found some potential for
vaccine enhanced disease, and experts recommend rigorous monitoring in clinical trials to detect
this safety issue.166 One scientific review noted that the scientific and clinical evidence with
COVID-19, thus far, provides limited evidence with respect to the issue of enhanced disease.
Along with other evidence, the authors explore evidence from treatment of COVID-19 patients
with convalescent plasma (a treatment involving antibodies) and note that distinguishing antibody
enhanced disease from worsening of symptoms is difficult, and therefore the potential for this
issue should be studied further.167
OWS reports that it is providing scientific support for COVID-19 vaccine clinical trials, in
collaboration with other federal agencies like NIH. According to a medical journal publication
authored by OWS leaders, OWS is coordinating many components of the vaccine development
process. With regard to efficacy data, “OWS will maximize the size of phase 3 trials (30,000 to
50,000 participants each) and optimize trial-site location by consulting daily epidemiologic and
disease-forecasting models to ensure the fastest path to an efficacy readout.” Phase 3 trial
endpoints have been coordinated between the trials, in collaboration with NIAID.168 NIH has
leveraged some of its existing clinical trials networks for testing certain COVID-19 vaccines
participating in Operation Warp Speed, named the COVID-19 Prevention Trials Network
(COVPN) that, among other things, works to harmonize clinical endpoints for the trials and
recruit study participants.169
All of the COVID-19 vaccines supported by OWS that are in Phase 3 clinical trials have a Data
and Safety Monitoring Board (DSMB) that independently reviews safety and effectiveness data
on the investigational vaccine to determine if the trial should continue, be modified, be
terminated, or be considered for FDA marketing authorization (see the “FDA Marketing
Authorization”
section).170 Three Phase 3 clinical trials of candidate vaccines supported by

165 Pedro M. Folegatti, Katie J.Ewer, Parvinder K. Alley, et al., “Safety and Immunogenicity of the ChAdOx1 nCoV-19
Vaccine Against SARS-CoV-2: a Preliminary Report of a Phase 1/2, Single-Blind, Randomised Controlled Trial,” The
Lancet
, July 20, 2020, and Sara Oliver, COVID-19 Vaccines: Work Group Interpretations, Advisory Committee on
Immunization Practices, August 26, 2020, https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2020-08/
COVID-07-Oliver.pdf.
166 Paul-Henri Lambert, Donna M Ambrosino, and Svein R Andersen, “Consensus Summary Report for CEPI/BC
March 12-13, 2020 Meeting: Assessment of Risk of Disease Enhancement with COVID-19 Vaccines,” Vaccine, vol. 31
(June 26, 2020), pp. 4783-4791.
167 Ann M. Arvin, Katja Fink, and Michael A. Schmid, “A Perspective on Potential Antibody-Dependent Enhancement
of SARS-CoV-2,” Nature, vol. 584 (August 20, 2020), pp. 353-363.
168 Moncef Slaoui and Matthew Hepburn, “Developing Safe and Effective Covid Vaccines—Operation Warp Speed’s
Strategy and Approach,” New England Journal of Medicine, August 26, 2020.
169 National Institutes of Health (NIH), “NIH Launches Clinical Trials Network to Test COVID-19 Vaccines and Other
Prevention Tools,” press release, July 8, 2020.
170 U.S. Congress, Senate Committee on Health, Education, Labor, and Pensions, Senate Health, Education, Labor and
Pensions Committee Holds Hearing on the Role of Vaccines in Preventing Outbreaks
, 116th Cong., 2nd sess., September
9, 2020.
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OWS—those of Moderna, AstraZeneca, and Johnson & Johnson—are overseen by a common
DSMB developed in consultation with NIH’s Accelerating COVID-19 Therapeutic Interventions
and Vaccines partnership as a part of the COVPN.171 The Pfizer/BioNTech vaccine has a separate
DSMB.172
On September 8, 2020, it was reported that AstraZeneca paused its Phase 3 clinical trial in
response to a potential safety issue; such pauses are not uncommon in any drug or biologic
development effort.173 On October 12, 2020, it was reported that Johnson & Johnson paused its
Phase 3 trial due to “an unexplained illness in a study participant” and that a DSMB has been
convened to review the case.174 As of October 23, 2020, these trials have resumed.175 In response
to calls for transparency, several vaccine developers, including Moderna, Pfizer/BioNTech,
AstraZeneca, and Johnson & Johnson, have made their Phase 3 clinical trial protocols for
COVID-19 vaccines publicly available.176
As shown in the protocols, the trials are using an event-driven design, meaning that efficacy of
the vaccines are to be evaluated once a certain number of “events” occur among the study
population—in this context, COVID-19 cases with symptoms. Once a certain number of COVID-
19 cases are detected, the DSMB is to evaluate the data and conduct a statistical analysis to
determine if the difference in cases between the vaccine recipient group and the control group
meet the FDA’s standard for effectiveness for a COVID-19 vaccine. For example, Moderna has
determined that 151 COVID-19 cases among its study population would provide enough
statistical power to determine whether the vaccine is 60% effective, with interim analyses of the
data by the DSMB planned at 35% and 70% of the total target cases. The DSMB may recommend
that the vaccine companies end the trials if interim analyses indicate safety issues or do not show
adequate evidence of effectiveness.177 Vaccine expert groups, such as the Coalition for Epidemic

171 National Institutes of Health, “Fourth Large-Scale COVID-19 Vaccine Trial Begins in the United States,” press
release, September 23, 2020, https://www.nih.gov/news-events/news-releases/fourth-large-scale-covid-19-vaccine-
trial-begins-united-states.
172 Matthew Harper, “A Layperson’s Guide to How—and When—a Covid-19 Vaccine Could be Authorized,” STAT,
September 28, 2020
173 Rebecca Robbins, Adam Feuerstein, and Helen Branswell, “AstraZeneca Covid-19 Vaccine Study Put on Hold Due
to Suspected Adverse Reaction in Participant in the U.K.,” STAT, September 8, 2020, https://www.statnews.com/2020/
09/08/astrazeneca-covid-19-vaccine-study-put-on-hold-due-to-suspected-adverse-reaction-in-participant-in-the-u-k/.
174 Matthew Herper, “Johnson & Johnson Covid-19 Vaccine Study Paused Due to Unexplained Illness in Participant,”
STAT, October 12, 2020, https://www.statnews.com/2020/10/12/johnson-johnson-covid-19-vaccine-study-paused-due-
to-unexplained-illness-in-participant/.
175 Katherine J. Wu, Carl Zimmer, and Sharon LaFraniere, et al., “Two Companies Restart Virus Trials in U.S. After
Safety Pauses,” The New York Times, October 23, 2020, https://www.nytimes.com/2020/10/23/health/covid-vaccine-
astrazeneca-johnson-and-johnson.html.
176 Pfizer, “A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine
Candidates Against COVID-19 in Healthy Individuals,” https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-09/
C4591001_Clinical_Protocol_0.pdf. Moderna, “A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-
Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in
Adults Aged 18 Years and Older,” https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf.
Janssen Vaccines & Prevention B.V.*, Clinical Protocol “A Randomized, Double-blind, Placebo-controlled Phase 3
Study to Assess the Efficacy and Safety of Ad26.COV2.S for the Prevention of SARS-CoV-2-mediated COVID-19 in
Adults Aged 18 Years and Older,” https://www.jnj.com/coronavirus/covid-19-phase-3-study-clinical-protocol.
AstraZeneca, Clinical Study Protocol, “A Phase III Randomized, Double-blind, Placebo-controlled Multicenter Study
in Adults to Determine the Safety, Efficacy, and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector
Vaccine, for the Prevention of COVID-19,” https://s3.amazonaws.com/ctr-med-7111/D8110C00001/52bec400-80f6-
4c1b-8791-0483923d0867/c8070a4e-6a9d-46f9-8c32-cece903592b9/D8110C00001_CSP-v2.pdf.
177 Moderna, “Clinical Study Protocol,” last amended August 20, 2020, https://www.modernatx.com/sites/default/files/
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Preparedness, have advocated for the event-driven approach to COVID-19 vaccine trials in order
to expedite vaccine availability without compromising scientific rigor.178 Other vaccine experts
have voiced concerns about this approach, arguing that it “may make statistical sense, but it
defies common sense.” These experts argue that the vaccines should be assessed for whether they
protect against moderate and severe forms of COVID-19 and that the trials should be fully
completed to generate adequate data.179
FDA Marketing Authorization
The development and testing process for a COVID-19 vaccine is designed to be significantly
shorter compared with the usual timeline for vaccine development. This shortened process may
make it difficult to detect potential unexpected adverse events that may not manifest right away.
Moreover, because the review process is to be shorter than the typical 6 to 10 months needed for a
Biologics License Application (BLA) review, FDA scientists would have had less time to review
the safety and effectiveness data. Although FDA uses various formal mechanisms to expedite the
development and review of medical products intended to address unmet medical need, FDA has
not yet granted Emergency Use Authorization (EUA) for a previously unapproved (i.e.,
unlicensed) vaccine. Thus, if a COVID-19 vaccine is first made available under an EUA rather
than a BLA, it will be a first for the agency.
In light of reported concerns from the public surrounding the safety and effectiveness of COVID-
19 vaccines developed184 FDA has published analyses of the Pfizer-BioNTech and Moderna Phase 3 clinical trial data, which show that these currently available vaccines, respectively, had a “favorable safety profile” and met the statutory criteria for EUA issuance. The vaccines’ safety profile was generally similar across age groups, genders, and racial and ethnic groups. FDA analyses note a risk of mild side effects associated with the vaccines (e.g., fever, fatigue). The trials did not identify serious adverse health risks associated with the vaccines, but note the need for ongoing study and data collection to identify uncommon or long-term safety events.185 Independent experts have characterized the data as strong; for example, medical experts characterized the Phase 3 trial results for the Pfizer-BioNTech vaccine as “impressive enough to hold up in any conceivable analysis.”186 Some key aspects of the Phase 3 clinical trials thus far include the following: Independent review. All of the COVID-19 vaccines supported by OWS that are in Phase 3 clinical trials have a Data and Safety Monitoring Board (DSMB) that independently reviews safety and effectiveness data on the investigational vaccine to determine if the trial should continue, be modified, be terminated, or be considered for FDA marketing authorization (see the “FDA Marketing Authorization” section).187 Members of the DSMB have no financial or other ties to the trial sponsor. Four Phase 3 clinical trials of candidate vaccines supported by OWS— 184 FDA, “FDA Insight: Vaccines for COVID-19, Part 2,” July 28, 2020, https://www.fda.gov/news-events/fda-insight/fda-insight-vaccines-covid-19-part-2. 185 FDA, Emergency Use Authorization (EUA) for an Unapproved Product Review Memorandum- Pfizer, Inc. on behalf of Pfizer and BioNTech Review Memorandum, December 11, 2020, https://www.fda.gov/media/144416/download; and FDA, Emergency Use Authorization (EUA) for an Unapproved Product Review Memorandum- ModernaTx, Inc, December 18, 2020, https://www.fda.gov/media/144673/download. 186 Eric J. Rubin and Dan L. Longo, “SARS-CoV-2 Vaccination—An Ounce (Actually, Much Less) of Prevention,” New England Journal of Medicine, vol. 383 (December 31, 2020). 187 U.S. Congress, Senate Committee on Health, Education, Labor, and Pensions, Senate Health, Education, Labor and Pensions Committee Holds Hearing on the Role of Vaccines in Preventing Outbreaks, 116th Cong., 2nd sess., September 9, 2020. Congressional Research Service 31 Vaccine Safety in the United States those of Moderna, AstraZeneca, Johnson & Johnson, and Novavax—are overseen by a common DSMB developed in consultation with NIH as a part of its COVID-19 Prevention Network.188 The Pfizer-BioNTech vaccine has a separate DSMB.189 Trial populations. The data submitted in support of EUA issuance are derived primarily from clinical trials that enrolled healthy, nonpregnant adults over the age of 18 (or age 16 for the Pfizer-BioNTech trial), as is typical in most vaccine development efforts. While pregnant individuals were excluded from the clinical trials, some became pregnant during testing and are being monitored. Clinical trials also have been initiated investigating both the Pfizer-BioNTech and Moderna vaccines in populations as young as 12 years of age.190 Safety follow-up. Per FDA’s October 2020 guidance, data from Phase 3 clinical trials submitted to the agency for EUA are to include a median safety follow-up duration of at least two months after completion of the full vaccination regimen.191 This is shorter than the median follow-up duration of six months typically used in vaccine efficacy trials. FDA officials noted in a separate commentary that the two-month follow-up is justified given the need for a vaccine to address the pandemic and based on “extensive historical experience with adverse events after vaccination.” According to FDA representatives, Adverse events considered plausibly linked to vaccination generally start within six weeks after vaccine receipt. Two months of follow-up will provide time for potential immune-mediated adverse events that began within this six-week period to be observed and evaluated.192 In the commentary, FDA acknowledges the unknowns around the new technologies used for COVID-19 vaccines and that most prior vaccine approvals have included years of follow-up data on some trial participants.193 In this circumstance, robust postmarket safety studies and data collection may therefore be especially important in detecting any new long-term safety issues linked to the vaccines. Experts have been concerned about the potential for vaccine-enhanced disease (VED), in which vaccination could worsen the health effects of COVID-19 infections, as seen with the dengue and other vaccines.194 For the vaccines currently available under EUA, clinical trials incorporated ongoing analysis to detect potential for VED and found no evidence thus far indicating VED risk. Analyses do note the need for ongoing follow-up to monitor this 188 National Institutes of Health, “Fourth Large-Scale COVID-19 Vaccine Trial Begins in the United States,” press release, September 23, 2020, https://www.nih.gov/news-events/news-releases/fourth-large-scale-covid-19-vaccine-trial-begins-united-states. 189 Matthew Harper, “A Layperson’s Guide to How—and When—a Covid-19 Vaccine Could be Authorized,” STAT, September 28, 2020, https://www.statnews.com/2020/09/28/a-laypersons-guide-to-how-and-when-a-covid-19-vaccine-could-be-authorized/. 190 NCT04649151, A Study to Evaluate the Safety, Reactogenicity, and Effectiveness of mRNA-1273 Vaccine in Adolescents 12 to <18 Years Old to Prevent COVID-19 (TeenCove), https://clinicaltrials.gov/ct2/show/NCT04649151. NCT04368728, Pfizer Study to Describe the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals, https://clinicaltrials.gov/ct2/show/NCT04368728. 191 FDA, “Emergency Use Authorization for Vaccines to Prevent COVID-19,” Guidance for Industry, October 2020, https://www.fda.gov/media/142749/download. 192 Philip R. Krause and Marion F. Gruber, “Emergency Use Authorization of Covid Vaccines—Safety and Efficacy Follow-Up Considerations,” New England Journal of Medicine, vol. 383, no. 19 (November 5, 2020). 193 Ibid. 194 Paul-Henri Lambert, Donna M Ambrosino, and Svein R Andersen, “Consensus Summary Report for CEPI/BC March 12-13, 2020 Meeting: Assessment of Risk of Disease Enhancement with COVID-19 Vaccines,” Vaccine, vol. 31 (June 26, 2020), pp. 4783-4791. Congressional Research Service 32 Vaccine Safety in the United States risk long-term.195 Both Pfizer-BioNTech and Moderna intend to follow participants for an additional two years after administration of the second vaccine dose.196 This is consistent with FDA guidance, which recommends follow-up of study participants for COVID-19 outcomes to continue as long as feasible, at least one to two years, to assess duration of protection and potential for VED.197 Vaccine Efficacy For the vaccines currently available, Phase 3 clinical trial data have found the vaccines to be efficacious at preventing confirmed symptomatic COVID-19 cases—94.5% efficacy for Moderna’s vaccine and 95.0% efficacy for Pfizer-BioNTech’s vaccine.198 Efficacy for both vaccines was similar across age, gender, and racial/ethnic groups.199 Some questions remain around effectiveness of the vaccines, including the effectiveness of the vaccines in preventing asymptomatic infections (and therefore transmission of the virus) and whether one dose is sufficient for protection against infection or if two doses are necessary. Currently, the answers to these questions are mostly unknown scientifically. Preliminary analysis on Moderna’s vaccine suggests that it may be effective against asymptomatic infections and that protection may begin after the first dose.200 No such data are available for Pfizer-BioNTech’s vaccine at this time.201 Continued clinical trials and other postmarket studies using data collected in real world settings continue to assess these questions on vaccine efficacy and effectiveness.202 In light of early distribution challenges (which are outside the scope of this report), some have proposed modifying vaccine dosing, either by altering the dose of the vaccine or the length of time between the first and second dose in order to speed up the vaccination timeline and increase 195 FDA, Emergency Use Authorization (EUA) for an Unapproved Product Review Memorandum- Pfizer, Inc. on behalf of Pfizer and BioNTech, December 11, 2020, https://www.fda.gov/media/144416/download; and FDA, Emergency Use Authorization (EUA) for an Unapproved Product Review Memorandudm- ModernaTx, Inc, December 18, 2020, https://www.fda.gov/media/144673/download. 196 Pfizer, “Pfizer and BioNTech Announce Vaccine Candidate Against COVID-19 Achieved Success in First Interim Analysis from Phase 3 Study,” November 9, 2021, https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against. Moderna, “Moderna Announces Publication of Results from the Pivotal Phase 3 Trial of the Moderna COVID-19 Vaccine in The New England Journal of Medicine,” December 31, 2020, https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-publication-results-pivotal-phase-3-trial. 197 FDA, “Development and Licensure of Vaccines to Prevent COVID-19,” Guidance for Industry, June 2020, p. 12, https://www.fda.gov/media/139638/download. 198 The clinical endpoint specifically was “incidence of COVID-19 among participants without evidence of SARS-CoV-2 infection before or during the 2-dose vaccination regimen” for the Pfizer/BioNTech vaccine, and “incidence of COVID-19 among participants without evidence of SARS-CoV-2 infection before the first dose of vaccine in the period after 14 days post-dose” for Moderna’s vaccine. 199 FDA, Emergency Use Authorization (EUA) for an Unapproved Product Review Memorandum- Pfizer, Inc. on behalf of Pfizer and BioNTech, December 11, 2020, https://www.fda.gov/media/144416/download; and FDA, Emergency Use Authorization (EUA) for an Unapproved Product Review Memorandum- ModernaTx, Inc, December 18, 2020, https://www.fda.gov/media/144673/download. 200 Moderna, “mRNA-1273 Sponsor Briefing Document Addendum,” p. 6, https://www.fda.gov/media/144453/download. 201 Matthew Herper, “Pfizer and BioNTech speed up timeline for offering Covid-19 vaccine to placebo volunteers,” STAT News, January 1, 2021, https://www.statnews.com/2021/01/01/pfizer-and-biontech-speed-up-timeline-for-offering-covid-19-to-placebo-volunteers/. 202 CDC, “Ensuring COVID-19 Vaccines Work,” https://www.cdc.gov/coronavirus/2019-ncov/vaccines/effectiveness.html. Congressional Research Service 33 Vaccine Safety in the United States the number of individuals vaccinated. FDA issued a statement that any such changes to the EUA-authorized doses and schedules would need to be supported by evidence.203 FDA Marketing Authorization Until December 2020, FDA had never before issued an EUA for a previously unlicensed vaccine. As mentioned, the level of evidence required by statute for EUA issuance is different from licensure, although both require the submission of safety and effectiveness data to FDA. This is because the EUA pathway is intended to provide a rapid review mechanism for medical products such as vaccines during emergency circumstances. For licensure under a BLA, a vaccine must be proven safe and have substantial evidence of effectiveness. For EUA issuance, substantial evidence of effectiveness is not required by statute. Rather, the totality of the available scientific evidence must indicate that the vaccine may be effective in preventing COVID-19, and that the known and potential benefits of the vaccine outweigh its known and potential risks. The statutory provisions governing EUA do not specify the type of data that must be submitted to FDA in support of an EUA and as noted in guidance, “FDA intends to assess the potential effectiveness of a possible EUA product on a case-by-case basis using a risk-benefit analysis.”204 As such, the “may be effective” standard leaves some discretion to agency scientists. In light of reported concerns from the public surrounding the safety and effectiveness of COVID-19 vaccines developed and authorized on an expedited timeline, FDA officials have sought to clarify that any on an expedited timeline, FDA officials have sought to clarify that any
vaccine candidate “will be reviewed according to the established legal and regulatory standards vaccine candidate “will be reviewed according to the established legal and regulatory standards
for medical products.”for medical products.”180205 In addition, FDA officials have indicated that the amount of safety and In addition, FDA officials have indicated that the amount of safety and
effectiveness data needed to support EUA issuance effectiveness data needed to support EUA issuance will beis similar to the data that similar to the data that would be
is appropriate for a BLA.206 FDA has noted that sponsors of the EUA-authorized vaccines are expected to continue to collect data to support eventual submission of a BLA to obtain full licensure.207 To help companies develop a vaccine to prevent COVID-19, and to increase transparency regarding the FDA’s expectations for safety and effectiveness data, the agency has issued two guidance documents. The first guidance, issued in June 2020, aims to clarify FDA’s expectations regarding the data and information necessary to support licensure under a BLA.208 The guidance notes, among other things, that with respect to effectiveness, FDA expects a COVID-19 vaccine to prevent disease or decrease disease severity in at least 50% of people who are vaccinated. On October 6, 2020, FDA issued a second guidance, which focuses on the agency’s expectations for 203 FDA, “FDA Statement on Following the Authorized Dosing Schedules for COVID-19 Vaccines,” January 4, 2021, https://www.fda.gov/news-events/press-announcements/fda-statement-following-authorized-dosing-schedules-covid-19-vaccines. 204 FDA, “Emergency Use Authorization of Medical Products and Related Authorities,” Guidance for Industry and Other Stakeholders, January 2017, p.8, https://www.fda.gov/media/97321/download. 205appropriate for a BLA.181 As mentioned above, the level of evidence required by statute for EUA
issuance is different from licensure, although both require the submission of safety and
effectiveness data to FDA. For licensure under a BLA, a vaccine would need to be proven safe
and have substantial evidence of effectiveness to receive full licensure under a BLA. In the case
that a vaccine is first made available under an EUA, substantial evidence of effectiveness would
not be required by statute. Rather, the totality of the available scientific evidence would need to
indicate that the vaccine may be effective in preventing COVID-19, and that the known and
potential benefits of the vaccine outweigh its known and potential risks.
To help companies develop a vaccine to prevent COVID-19, and to increase transparency
regarding the FDA’s expectations for safety and effectiveness data, the agency has issued two
guidance documents. The first guidance, issued in June 2020, aims to clarify FDA’s expectations

mRNA-1273-P301-Protocol.pdf.
178 Eddie Loeliger and Bob Small, Vaccine Efficacy Assessment for COVID-19, Coalition for Epidemic Preparedness
COVID-19 Clinical Working Group, May 7, 2020, https://media.tghn.org/articles/
Vaccine_Efficacy_V1.0_7_May_20.pdf.
179 Peter Doshi and Eric Topol, “These Coronavirus Trials Don’t Answer the One Question We Need to Know,” The
New York Times
, September 22, 2020.
180 Anand Shah, Peter Marks, and Jim Hahn, “Unwavering Regulatory Safeguards for COVID-19 Vaccines,” Anand Shah, Peter Marks, and Jim Hahn, “Unwavering Regulatory Safeguards for COVID-19 Vaccines,” JAMA, ,
August 2020, vol. 324, no. 10, pp. 931August 2020, vol. 324, no. 10, pp. 931-932. 932.
181206 Duke Margolis Center for Health Policy, “Safe and Effective COVID-19 Vaccination: The Path from Here,” Duke Margolis Center for Health Policy, “Safe and Effective COVID-19 Vaccination: The Path from Here,”
September 10, 2020September 10, 2020, meeting. Michael Mezher, “Marks, Hahn Confirm COVID Vaccine EUA Guidance Coming,” meeting. Michael Mezher, “Marks, Hahn Confirm COVID Vaccine EUA Guidance Coming,”
September 11, 2020, https://www.raps.org/news-and-articles/news-articles/2020/9/marks-hahn-confirm-covid-vaccine-September 11, 2020, https://www.raps.org/news-and-articles/news-articles/2020/9/marks-hahn-confirm-covid-vaccine-
eua-guidance-comi. eua-guidance-comi.
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regarding the data and information necessary to support licensure under a BLA.182 The guidance
notes, among other things, that with respect to effectiveness, FDA expects a COVID-19 vaccine
to prevent disease or decrease disease severity in at least 50% of people who are vaccinated. On
October 6, 2020, FDA issued a second guidance, which focuses on the agency’s expectations for
207 FDA, “Development and Licensure of Vaccines to Prevent COVID-19,” Guidance for Industry, June 2020, p.4, https://www.fda.gov/media/139638/download. 208 FDA, “Development and Licensure of Vaccines to Prevent COVID-19,” Guidance for Industry, June 2020, https://www.fda.gov/media/139638/download. Congressional Research Service 34 Vaccine Safety in the United States the data and information needed to support an EUA for a COVID-19 vaccine.the data and information needed to support an EUA for a COVID-19 vaccine.183209 The The
recommendations outlined in the October 2020 guidance have been characterized as more recommendations outlined in the October 2020 guidance have been characterized as more
stringent than what typically may be required for an EUA.stringent than what typically may be required for an EUA.184210 For example, the guidance indicates For example, the guidance indicates
that data from Phase 3 trials submitted to the agency should include a median follow-up duration that data from Phase 3 trials submitted to the agency should include a median follow-up duration
of at least two months after completion of the full vaccination regimen to help provide adequate of at least two months after completion of the full vaccination regimen to help provide adequate
information to assess a vaccine’s benefit-risk profile. FDA also expects clinical testing of an information to assess a vaccine’s benefit-risk profile. FDA also expects clinical testing of an
EUA-authorized vaccine to continue to support eventual licensure under a BLA. As such, the EUA-authorized vaccine to continue to support eventual licensure under a BLA. As such, the
guidance recommends that sponsors submit, as part of the EUA request, strategies that will be guidance recommends that sponsors submit, as part of the EUA request, strategies that will be
implemented to (1) address loss of follow-up information for participants who choose to implemented to (1) address loss of follow-up information for participants who choose to
withdraw from the study to receive the vaccine under an EUA, and (2) ensure that ongoing withdraw from the study to receive the vaccine under an EUA, and (2) ensure that ongoing
clinical trials of the vaccine are able to assess long-term safety and effectiveness (e.g., evaluating clinical trials of the vaccine are able to assess long-term safety and effectiveness (e.g., evaluating
for for vaccine-associated ERDVED, decreased effectiveness over time) in sufficient numbers to support , decreased effectiveness over time) in sufficient numbers to support
vaccine licensure.
The FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) met on
October 22, 2020 to discuss generally the development, authorization, and licensure of vaccines
to prevent COVID-19.185 The VRBPAC discussed, among other things, FDA’s approach to safety
and effectiveness as outlined in the agency’s guidance documents; expectations for the data that
must be submitted for licensure or EUA, including information about the manufacturing process;
and plans for postmarket surveillance, including use of existing systems such as VAERS and
BEST. FDA also is reportedly developing master protocols to guide its safety and effectiveness
oversight, to be made publicly available on its website.186 To further provide transparency, FDA
has indicated it will convene additional VRBPAC meetings to discuss specific vaccine candidates
ready for an EUA or licensure.187
Clinical Recommendations and Prioritization
ACIP has begun to weigh considerations related to COVID-19 vaccine clinical recommendations
and prioritization, and has made information available for its public meetings in June, July,
August, and September 2020. Many of these deliberations note unknowns with regard to COVID-
19 vaccines, in particular, as related to clinical trial data on the safety and efficacy of vaccines.188

182 FDA, “Development and Licensure of Vaccines to Prevent COVID-19,” Guidance for Industry, June 2020,
https://www.fda.gov/media/139638/download.
183vaccine licensure. At public meetings in December 2020, FDA’s VRBPAC considered whether the available evidence for the Pfizer-BioNTech and Moderna vaccines met FDA’s criteria for issuing an EUA. At both meetings, the majority of the committee’s membership voted that the scientific evidence for both vaccines favored the vaccines’ use—in individuals 16 years of age and older for the Pfizer-BioNTech vaccine and in individuals 18 years of age and older for Moderna’s vaccine.211 Clinical Recommendations and Prioritization ACIP has thus far issued two types of recommendations for the COVID-19 vaccines currently authorized for emergency use: (1) recommendations regarding the clinical use of each vaccine, in particular the age groups to receive each, and (2) recommendations regarding the allocation or priority groups to receive the limited vaccine supply. These recommendations have been adopted as official CDC recommendations. To date, ACIP’s clinical recommendations have followed the age groups authorized by FDA under each vaccine EUA.212 ACIP’s allocation recommendations have evolved as projected vaccine supply has changed—to date, ACIP has issued the following allocation recommendations:213  Phase 1a: health care personnel and long-term care facility residents, 209 FDA, “Emergency Use Authorization for Vaccines to Prevent COVID-19,” Guidance for Industry, October 2020, FDA, “Emergency Use Authorization for Vaccines to Prevent COVID-19,” Guidance for Industry, October 2020,
https://www.fda.gov/media/142749/download. https://www.fda.gov/media/142749/download.
184210 Michael Erman and Manas Mishra, “U.S. FDA safety guidelines likely to push COVID-19 vaccine authorization Michael Erman and Manas Mishra, “U.S. FDA safety guidelines likely to push COVID-19 vaccine authorization
past election,” October 6, 2020, past election,” October 6, 2020, Reuters. .
185 FDA, “211 FDA, “FDA Statement on Vaccines and Related Biological Products Advisory Committee Vaccines and Related Biological Products Advisory Committee October 22, 2020 Meeting Announcement,”
October 22Meeting,” press release, December 17, 2020, https://www.fda.gov/, 2020, https://www.fda.gov/advisory-committees/advisory-committee-calendar/news-events/press-announcements/fda-statement-vaccines-and-related-vaccines-and-related-
biological-products-advisory-committee-biological-products-advisory-committee-october-22-2020-meeting-announcement.
186 Kari Oakes, “FDA plans master protocols to monitor COVID vaccine safety, efficacy,” RAPS, October 22meeting-0; and FDA, “FDA Statement on Vaccines and Related Biological Products Advisory Committee Meeting,” press release, December 11, 2020, , 2020,
https://www.raps.org/news-and-articles/news-articles/2020/10/fda-plans-master-protocols-to-monitor-covid-vaccin.
187 Matthew Harper, “A Layperson’s Guide to How—and When—a Covid-19 Vaccine Could be Authorized,” STAT,
September 28, 2020. U.S. Congress, Senate Committee on Health, Education, Labor, and Pensions, COVID-19: An
Update on the Federal Response
, 116th Cong., 2nd sess., September 24, 2020, p. 35.
188 CDC ACIP, “Advisory Committee on Immunization Practices (ACIP),” August 3, 2020.
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In addition, at the direction of NIH and CDChttps://www.fda.gov/news-events/press-announcements/fda-statement-vaccines-and-related-biological-products-advisory-committee-meeting. 212 Sara E. Oliver, Julia W. Gargano, Mona Marin, et al., “The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine—United States, December 2020,” Morbidity and Mortality Weekly Report (MMWR), vol. 69, no. 50 (December 18, 2020), pp. 1922-24, and Sara E. Oliver, Julia W. Gargano, Mona Marin, et al., “The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Moderna COVID-19 Vaccine—United States, December 2020,” Mortality and Morbidity Weekly Report, vol. 69, no. 5152 (January 1, 2021). 213 Kathleen Dooling, Mona Marin, Megan Wallace, et al., “The Advisory Committee on Immunization Practices’ Updated Interim Recommendation for Allocation of COVID-19 Vaccine—United States, December 2020,” Morbidity and Mortality Weekly Report (MMWR), vol. 69, no. 5152 (December 22, 2020), https://www.cdc.gov/mmwr/volumes/69/wr/mm695152e2.htm?s_cid=mm695152e2_w. Congressional Research Service 35 link to page 42 Vaccine Safety in the United States  Phase 1b: persons aged 75 and over and nonhealth care frontline essential workers, and  Phase 1c: persons aged 65-74, persons aged 16-64 with high-risk medical conditions, and essential workers not included in Phase 1b. According to the CDC COVID-19 Vaccination Program Provider Agreement signed by all providers participating in the COVID-19 vaccination program, providers must administer COVID-19 vaccines in accordance with prioritization groups determined by appropriate public health authorities (e.g., federal, state, local).214 In general, states and other jurisdictions are setting vaccine priority groups. Many states follow ACIP-recommended phases, but some states have departed from ACIP’s recommendations.215 In early January 2021, following a slow initial vaccine rollout, then-HHS Secretary Alex Azar recommended that states expand vaccination priority groups to everyone aged 65 and older, as well as those aged 16 and older with high-risk medical conditions to avoid unused vaccine supply.216 The Biden Administration’s strategy also reiterates the recommendation to expand priority groups to those 65 and older and to frontline essential workers.217 Some media reports indicate confusion among certain states following the new recommendations and apparent contradictions with the ACIP recommendations.218 ACIP recommendations still remain the official CDC recommendations for priority groups. Prior to the issuance of ACIP’s recommendations, the National Academies of Science, Engineering, , the National Academies of Science, Engineering,
and Medicine (NASEM)and Medicine (NASEM), at the direction of NIH and CDC, set up an ad hoc committee to develop a framework for equitably set up an ad hoc committee to develop a framework for equitably
allocating COVID-19 vaccinesallocating COVID-19 vaccines, both domestically and globally. domestically and globally.189219 NASEM published its draft NASEM published its draft
framework on September 1framework on September 1, 2020, and published its final report with recommendations on October 2 and published its final report with recommendations on October 2, 2020. The framework is shown below in Figure 1.220 ACIP considered these recommendations in its deliberations; however, its Phase 1 recommendations have already differed from those proposed by NASEM, as described above. The NASEM framework assisted states with planning assumptions for the vaccine program.221 214 CDC, “CDC COVID-19 Vaccination Program Provider Requirements and Support,” December 13, 2020, https://www.cdc.gov/vaccines/covid-19/vaccination-provider-support.html. 215 Kaiser Family Foundation (KFF), “How are States Prioritizing Who Will Get the COVID-19 Vaccine First?” December 14, 2020, https://www.kff.org/policy-watch/how-are-states-prioritizing-who-will-get-the-covid-19-vaccine-first/. 216 Stephanie Ebbs, Ben Gittleson, and Luis Martinez, “Azar, Trump Administration Will no Longer Hold Back 2nd Shots, Recommend 65 and Older get COVID Vaccine,” ABC News, January 12, 2021, and Sheryl Gay Stolberg and Abby Goodnough, “States Told to Vaccinate Everyone 65 and Over as Deaths Surge,” New York Times, January 12, 2021. 217 White House, National Strategy for the COVID-19 Response and Pandemic Preparedness, January 21, 2021, p. 40, https://www.whitehouse.gov/wp-content/uploads/2021/01/National-Strategy-for-the-COVID-19-Response-and-Pandemic-Preparedness.pdf. 218 Helen Branswell, “Confusion Spreads Over System to Determine Priority Access to Covid-19 Vaccines,” STAT, July 22, 2020. 219.
The framework establishes a prioritization methodology that recommends who should be the first
to receive COVID-19 vaccines when they become available. Recommended recipients include
high-risk workers in health care facilities, first responders, older adults, people with underlying
conditions known to be associated with severe outcomes, critical risk workers (workers who are
in essential industries and are at substantially higher risk of exposure), and teachers and school
staff (see Figure 1).190
Figure 1. NASEM-Recommended Phased Approach to COVID-19 Vaccine Allocation

Source: National Academy of Sciences, Engineering, and Medicine, Framework for Equitable Allocation of COVID-19
Vaccine
, October 2, 2020.
As of September 2020, ACIP has begun to publicly weigh NASEM’s recommendations and
compare them to the recommendations from other groups, in particular, from the WHO Strategy
Advisory Group of Experts (SAGE) and from the Johns Hopkins Bloomberg School of Public
Health. ACIP is considering these recommendations in the context of its own proposed ethical
principles of (1) maximizing benefits and minimizing harm, (2) equity, (3) justice, (4) fairness,
and (5) transparency.191 In addition, ACIP has considered how to prioritize vaccine allocation

189 National Academy of Sciences, Engineering, and Medicine (NASEM), “A Framework for Equitable Allocation of National Academy of Sciences, Engineering, and Medicine (NASEM), “A Framework for Equitable Allocation of
Vaccine for the Novel Coronavirus,” https://www.nationalacademies.org/our-work/a-framework-for-equitable-Vaccine for the Novel Coronavirus,” https://www.nationalacademies.org/our-work/a-framework-for-equitable-
allocation-of-vaccine-for-the-novel-coronavirus. allocation-of-vaccine-for-the-novel-coronavirus.
190220 National Academy of Sciences, Engineering, and Medicine, National Academy of Sciences, Engineering, and Medicine, Discussion Draft of the Preliminary Framework for
Equitable Allocation of COVID-19 Vaccine
, September 1, 2020. , September 1, 2020.
191 ACIP COVID-19 Vaccines Work Group, “Overview of Vaccine Equity and Prioritization Frameworks,” September221 CDC, “COVID-19 Vaccination Program Operational Guidance,” November 5, 2020, https://www.cdc.gov/vaccines/covid-19/covid19-vaccination-guidance.html.
Congressional Research Service Congressional Research Service
33 36

Vaccine Safety in the United States Figure 1. NASEM-Recommended Phased Approach to COVID-19 Vaccine Allocation Source: National Academy of Sciences, Engineering, and Medicine, Framework for Equitable Allocation of COVID-19 Vaccine, October 2, 2020. Safety in Vaccine Distribution CDC has established requirements for vaccine management, including requirements related to storage and transportation. As announced on August 14, McKesson Corporation is to act as a central distributor for the COVID-19 vaccine campaign—the same distributor that managed the federally coordinated H1N1 influenza pandemic vaccine campaign.222 States, localities, territories, and tribes (hereinafter, jurisdictions) are to have much of the responsibility for tracking vaccines provided and for local transportation of vaccines within the jurisdiction. CDC, in collaboration with jurisdictions, is conducting trainings for newly registered providers regarding safe storage, handling, and administration of the vaccines. Providers who seek to participate in the COVID-19 vaccination program must be credentialed/licensed in the jurisdiction where vaccination takes place and sign and agree to the conditions in the CDC COVID-19 Vaccination Program Provider Agreement. The agreements includes requirements that the vaccines are stored and handled in accordance with the EUA and other CDC and manufacturer requirements.223 Jurisdictions’ immunization programs and health care providers administering COVID-19 vaccines are to be responsible for many aspects of vaccine tracking, 222 HHS, “Trump Administration Collaborates with McKesson for COVID-19 Vaccine Distribution,” press release, August 14, 2020, https://www.hhs.gov/about/news/2020/08/14/trump-administration-collaborates-mckesson-covid-19-vaccine-distribution.html, and CRS Report R40554, The 2009 Influenza Pandemic: An Overview. 223 CDC, “CDC COVID-19 Vaccination Program Provider Requirements and Support,” December 13, 2020, https://www.cdc.gov/vaccines/covid-19/vaccination-provider-support.html. Congressional Research Service 37 Vaccine Safety in the United States storage, and handling to ensure that vaccine safety and effectiveness are maintained.224 This guidance is likely to evolve as new vaccines potentially become available and as more is learned about how to best store and administer the vaccines. Vaccine Safety in the United States

within groups recommended for Phase 1 allocation, should limited vaccine supply require such
choices.192 According to media reporting, these discussions continued at a public meeting in late
October (meeting materials are not yet available on ACIP’s website).193
Both the ACIP and NASEM groups are advisory; they do not establish binding policy. Although
HHS has historically followed ACIP’s recommendations and often considers NASEM
recommendations, it is unclear whether and to what extent these recommendations will inform
HHS’s COVID-19 vaccine prioritization policies. A report to Congress from Operation Warp
Speed on September 16, 2020 noted the NASEM and ACIP roles in prioritizing eventual vaccines
but stated that final decisions about prioritization will not be made until closer to
implementation.194
Safety in Vaccine Distribution
CDC has begun to establish requirements for vaccine management, including requirements
related to storage and transportation. As announced on August 14, McKesson Corporation is to
act as a central distributor for the COVID-19 vaccine campaign—the same distributor that
managed the federally coordinated H1N1 influenza pandemic vaccine campaign.195 States,
localities, territories, and tribes (hereinafter, jurisdictions) are to have much of the responsibility
for tracking vaccines provided and for local transportation of vaccines within the jurisdiction.
COVID-19 vaccines in development have different temperature control requirements: some must COVID-19 vaccines in development have different temperature control requirements: some must
be refrigerated (2 to 8 degrees Celsius), some must be stored frozen (-15 to -25 degrees Celsius) be refrigerated (2 to 8 degrees Celsius), some must be stored frozen (-15 to -25 degrees Celsius)
and some must be kept ultra-cold (-60 to -80 degrees Celsius)and some must be kept ultra-cold (-60 to -80 degrees Celsius), such as Pfizer/BioNTech’s vaccine. CDC’s planning guidance to . CDC’s planning guidance to
jurisdictions takes these different temperature requirements into account and seeks to minimize jurisdictions takes these different temperature requirements into account and seeks to minimize
potential breaks in the cold chain during vaccine distribution. According to CDC, “certain potential breaks in the cold chain during vaccine distribution. According to CDC, “certain
COVID-19 vaccine products, such as those with ultra-cold temperature requirements, will be COVID-19 vaccine products, such as those with ultra-cold temperature requirements, will be
shipped directly from the manufacturer to the vaccination provider site,” while others will be shipped directly from the manufacturer to the vaccination provider site,” while others will be
distributed by CDC’s distributor directly to the provider sites or secondary depots for distribution distributed by CDC’s distributor directly to the provider sites or secondary depots for distribution
(e.g., chain drug store’s central distribution). (e.g., chain drug store’s central distribution). The guidance then further explains how these
CDC guidance includes detailed information about how vaccines should be stored onsite until usage.vaccines should be stored onsite until usage.196
CDC, in collaboration with jurisdictions, is planning trainings for newly registered providers
regarding safe storage, handling and administration of the vaccines. Providers who seek to
participate in the COVID-19 vaccination program must be credentialed/licensed in the
jurisdiction where vaccination takes place, and sign and agree to the conditions in the CDC
COVID-19 Vaccination Program Provider Agreement
. Jurisdictions’ immunization programs and

22, 2020, https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2020-09/COVID-06-Oliver.pdf.
192 ACIP COVID-19 Vaccines Work Group, “Phase 1 Allocation COVID-19 Vaccine: Work Group Considerations,”
September 22, 2020, https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2020-09/COVID-07-Dooling.pdf.
193 Joe Neel and Pien Huang, “Advisers To CDC Debate How COVID-19 Vaccine Should Be Rolled Out,” National
Public Radio
, October 30, 2020.
194 Operation Warp Speed, “From the Factory to the Frontlines: The Operation Warp Speed Strategy for Distributing a
COVID-19 Vaccine,” https://www.hhs.gov/sites/default/files/strategy-for-distributing-covid-19-vaccine.pdf?source=
email.
195 HHS, “Trump Administration Collaborates with McKesson for COVID-19 Vaccine Distribution,” press release,
August 14, 2020, https://www.hhs.gov/about/news/2020/08/14/trump-administration-collaborates-mckesson-covid-19-
vaccine-distribution.html, and CRS Report R40554, The 2009 Influenza Pandemic: An Overview.
196225 Postmarket Safety: Surveillance and Safety Monitoring Postmarket safety activities on vaccines in use include (1) continued clinical trials of vaccines available under EUA, (2) additional postmarket studies on the vaccines, and (3) ongoing vaccine safety monitoring, or surveillance. Given the condensed nature of the COVID-19 development programs, FDA has recommended that follow-up of study participants for COVID-19 outcomes continue as long as feasible, ideally at least one to two years, to assess duration of protection and potential for certain adverse outcomes.226 In guidance, FDA further recommends that at the time of a BLA submission for a COVID-19 vaccine, a Pharmacovigilance Plan (PVP) be submitted to address known and potential risks of the vaccine. FDA may recommend that a PVP include expedited or more frequent adverse event reporting, or the establishment of a pregnancy exposure registry to collect information on associated pregnancy and infant outcomes. Pfizer and Moderna have submitted PVPs to FDA for their EUA-authorized vaccines, which discuss plans for longer term safety follow up.227 FDA may require additional clinical studies to be conducted after eventual licensure to allow for continued evaluation of vaccine outcomes.228 As mentioned, manufacturers of BLA-licensed vaccines typically must report adverse events to FDA as soon as possible, but no later than 15 days of becoming aware of them. For EUA- 224 CDC, COVID-19 Vaccination Program: Interim Playbook for Jurisdiction Operations, October 29, 2020, https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf, pp 21-22. 225 CDC, CDC, COVID-19 Vaccination Program: Interim Playbook for Jurisdiction Operations, October 29, 2020, , October 29, 2020,
https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdfhttps://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf.
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health care providers administering COVID-19 vaccines are to be responsible for many aspects of
vaccine tracking, storage, and handling to ensure that vaccine safety and effectiveness are
maintained, as outlined in CDC’s preliminary guidance.197 This guidance is likely to evolve as
more information is available regarding the vaccines.
Surveillance and Safety Monitoring
Given the condensed nature of the COVID-19 development programs, FDA may require
additional clinical studies to be conducted post-licensure to allow for continued monitoring of
adverse events.198 In guidance, FDA further recommends that at the time of a BLA submission for
a COVID-19 vaccine, a Pharmacovigilance Plan (PVP) be submitted to address known and
potential risks of the vaccine. FDA may recommend that a PVP include expedited or more
frequent adverse event reporting or the establishment of a pregnancy exposure registry to collect
information on associated pregnancy and infant outcomes. As mentioned above, manufacturers of
BLA-licensed vaccines typically must report adverse events to FDA within 15 days of becoming
aware of them. In the event that a COVID-19 vaccine is first made available under an EUA rather
than a BLA, FDA is expected to impose, as a condition of an EUA, requirements for health care
providers and vaccine manufacturers to report and track any adverse events associated with
administration of the vaccine.199
Several federal vaccine safety databases are to be used to monitor postmarket safety for COVID-
19 vaccines. A CDC presentation from the August ACIP meeting identifies that CMS, VA, DOD,
IHS, FDA, and CDC databases will be leveraged to provide ongoing monitoring of COVID-19
vaccine safety. It was also reported that “FDA plans to develop new electronic data sources
through [electronic health record] EHR partners.”200
CDC has reported several efforts to enhance its safety monitoring systems in anticipation of the
COVID-19 vaccination program. For health care providers participating in the COVID-19
vaccination program, per the CDC , and CDC, “Vaccine Storage and Handling Toolkit,” https://www.cdc.gov/vaccines/hcp/admin/storage/toolkit/index.html. 226 FDA, “Development and Licensure of Vaccines to Prevent COVID-19,” Guidance for Industry, June 2020, p.12, https://www.fda.gov/media/139638/download. 227 FDA, “FDA Takes Key Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for First COVID-19 Vaccine,” December 11, 2020, https://www.fda.gov/news-events/press-announcements/fda-takes-key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19. FDA, “FDA Takes Additional Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for Second COVID-19 Vaccine,” December 18, 2020, https://www.fda.gov/news-events/press-announcements/fda-takes-additional-action-fight-against-covid-19-issuing-emergency-use-authorization-second-covid. 228 FDA, “Development and Licensure of Vaccines to Prevent COVID-19,” Guidance for Industry, June 2020, p. 17, https://www.fda.gov/media/139638/download. Congressional Research Service 38 link to page 45 link to page 24 Vaccine Safety in the United States authorized vaccines, FDA must impose conditions of use concerning the monitoring and reporting of adverse events. The EUAs for the Pfizer-BioNTech and Moderna vaccines include requirements for vaccination providers and vaccine manufacturers to report adverse events to VAERS and maintain certain records with respect to the authorized vaccines.229 Specifically, as noted in the EUA letters, vaccination providers and manufacturers must report (1) vaccine administration errors whether or not associated with an adverse event, (2) serious adverse events (whether or not attributed to vaccination), (3) cases of Multisystem Inflammatory Syndrome, and (4) cases of COVID-19 that result in hospitalization or death. Vaccine manufacturers must report adverse events to VAERS as soon as possible but no later than 15 calendar days from initial receipt of the information; no deadline is specified for vaccination providers. Per the CDC COVID-19 Vaccination Program Provider Agreement,,
providers are required to report adverse events following vaccination through VAERS and are providers are required to report adverse events following vaccination through VAERS and are
advised to report such events even if the providers are not sure that vaccination caused the advised to report such events even if the providers are not sure that vaccination caused the
adverse event.201 A preliminary list of “adverse events of special interest” has been developed for
monitoring attention in VAERS reports.202 As communicated to CRS, CDC is strengthening its
existing safety monitoring systems in several ways, including by adding additional clinicians to
the CISA network, by adding staff to the VAERS network, and by preparing these systems to

197 CDC, COVID-19 Vaccination Program: Interim Playbook for Jurisdiction Operations, October 29, 2020,
https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf, pp
21-22.
198 FDA, “Development and Licensure of Vaccines to Prevent COVID-19,” Guidance for Industry, June 2020, p. 17,
https://www.fda.gov/media/139638/download.
199adverse event.230 Several federal safety monitoring databases are being created, enhanced, and leveraged to collect several types of postmarket safety data on COVID-19 vaccines in use. The multiple systems are designed to allow for rapid detection and robust assessments using both passive and active surveillance methods to collect safety data among different populations. The databases include those of CMS, VA, DOD, FDA, CDC, as presented in a December 2020 ACIP meeting shown in Figure 2. CDC officials expect that some of these systems, like VAERS and v-safe (a new smartphone-based health checker for vaccine recipients), will be used more in the early stages of the vaccine program, while others will be used more at later stages, such as VSD and FDA BEST & PRISM.231 (For details about these systems, see the section “Postmarket Safety.”) 229 FDA, EUA letter to Pfizer Inc., issued December 11, 2020, and updated December 23, 2020, https://www.fda.gov/media/144412/download; and FDA, EUA letter to ModernaTX, Inc., December 18, 2020, https://www.fda.gov/media/144636/download. 230 CDC, CDC, COVID-19 Vaccination Program: Interim Playbook for Jurisdiction Operations, October 29, 2020, p. 47, , October 29, 2020, p. 47,
https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf. https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf.
200231 Tom Shimabukuro, “COVID-19 Vaccine Tom Shimabukuro, “COVID-19 Vaccine Safety Monitoring,” CDC COVID-19 Vaccine Planning Unit, Presented atPost-Authorization Safety Monitoring Update,” Presented at December 1
Advisory Committee on Immunization Practices Advisory Committee on Immunization Practices meeting, August 26, 2020(ACIP) meeting, https://www.cdc.gov/vaccines/acip/, https://www.cdc.gov/vaccines/acip/
meetings/downloads/slides-2020-meetings/downloads/slides-2020-0812/COVID-04-Shimabukuro.pdf. Congressional Research Service 39 Vaccine Safety in the United States Figure 2. Federal Vaccine Safety Monitoring Systems, by System and Population Source: Tom Shimabukuro, “COVID-19 Vaccine Post-Authorization Safety Monitoring Update,” presented at December 1 Advisory Committee on Immunization Practices (ACIP) meeting/COVID-04-Shimabukuro.pdf.
201 CDC, COVID-19 Vaccination Program: Interim Playbook for Jurisdiction Operations, October 29, 2020, p. 47,
https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf.
202 Tom Shimabukuro, “COVID-19 Vaccine Safety Monitoring,” CDC COVID-19 Vaccine Planning Unit, Presented at
Advisory Committee on Immunization Practices meeting, September 22, 2020, https://www.cdc.gov/vaccines/acip/, https://www.cdc.gov/vaccines/acip/
meetings/downloads/slides-2020-meetings/downloads/slides-2020-0912/COVID-/COVID-0304-Shimabukuro.pdf. Severe Allergic Reactions To date, concerns have focused on the issue of anaphylaxis or severe allergic reactions after receipt of mRNA-based vaccines. Based on VAERS data, CDC reported an estimate of 11.1 anaphylaxis cases per million doses of the Pfizer-BioNTech vaccine administered in late December 2020, mostly among patients with a history of allergies.232 A similar report on Moderna’s vaccine estimated 2.5 anaphylaxis cases per million doses administered in late December and early January, also mostly among patients with a history of allergies. These estimates may change as more data are collected.233 CDC has emphasized that, as of January 6, 2021, the “known and potential benefits of the current COVID-19 vaccines outweigh the known and potential risks of getting COVID-19.”234 CDC has identified certain contraindications to the mRNA vaccines, including a history of allergic reactions after receipt of mRNA vaccines or any of such vaccines’ components. For individuals with such contraindications, mRNA-based COVID-19 vaccines are not recommended. CDC currently considers history of an allergic reaction to any other vaccine as a precaution, but not a contraindication, to receiving the vaccines. CDC has also issued clinical 232 CDC COVID-19 Response Team and FDA, “Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine—United States, December 14–23, 2020,” Morbidity and Mortality Weekly Report (MMWR), January 15, 2021. 233 CDC COVID-19 Response Team and FDA, “Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Moderna COVID-19 Vaccine—United States, December 21, 2020- January 10, 2021,” Morbidity and Mortality Weekly Report (MMWR), January 22, 2021. 234 CDC, Transcript: CDC Update on COVID-19, press briefing, January 6, 2021, https://www.cdc.gov/media/releases/2021/t0106-cdc-update-covid-19.html. Congressional Research Service 40 Vaccine Safety in the United States guidance for managing potential anaphylaxis after vaccine receipt.235 These recommendations may evolve as more is learned about the potential for this adverse health event through further postmarket safety studies. Injury Compensation and Patient Safety Information Vaccine injury compensation for COVID-19 vaccines differs-Shimabukuro.pdf.
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link to page 41 link to page 41
Vaccine Safety in the United States

provide rapid analyses on COVID-19 vaccine safety data. CDC plans to implement smartphone-
based active vaccine safety monitoring of early recipients of COVID-19 vaccines, called Vaccine
Safety Assessment for Essential Workers, or v-safe.203 This process would involve text, text-to-
web survey, and email-to-web survey monitoring of healthcare workers and essential workers
who might be prioritized to receive early doses of vaccine when it becomes available (see Figure
2
).
204
Figure 2. Graphical Presentation of Vaccine Safety Assessment for Essential Workers
Presented at Advisory Committee on Immunization Practices meeting, September 22, 2020

Source: Tom Shimabukuro, “COVID-19 Vaccine Safety Monitoring,” CDC COVID-19 Vaccine Planning Unit,
Presented at Advisory Committee on Immunization Practices meeting, September 22, 2020,
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2020-09/COVID-03-Shimabukuro.pdf.
Injury Compensation and Patient Safety Information
Vaccine injury compensation for COVID-19 vaccines will likely differ from usual injury
compensation under VICP. The from usual injury compensation under VICP. HRSA has indicated that COVID-19 vaccines are covered under the Countermeasures Injury Compensation Program (CICP), not VICP.236 Use of CICP for COVID-19 vaccine injury compensation was established by the Public Readiness and Emergency Preparedness Act (PREP Act) Public Readiness and Emergency Preparedness Act (PREP Act)
declaration declaration issued on March 10, 2020, effective February 4, 2020, which established certain immunity from legal liability related to established certain immunity from legal liability related to
the “manufacture, testing, development, distribution, administration, and use” of covered the “manufacture, testing, development, distribution, administration, and use” of covered
countermeasures as part of the public health response to COVID-19.countermeasures as part of the public health response to COVID-19. 237 Vaccines are listed as among the covered countermeasures in the declaration.238 Persons who suffer serious Persons who suffer serious
injury or death from a covered countermeasure may seek compensation through the Covered injury or death from a covered countermeasure may seek compensation through the Covered
Countermeasure Process Fund as a part of the Countermeasure Process Fund as a part of the Countermeasures Injury Compensation Program
(CICP)CICP. The HHS . The HHS Secretary may transfer funds available in the Public Health and Social Services Emergency Fund (PHSSEF), as provided in several coronavirus supplemental appropriations acts, to this fund.239 Congress could take legislative action to add COVID-19 vaccines to be covered under VICP. Because COVID-19 vaccines will likely not be added to the vaccines covered under VICP (at Secretary may transfer funds available in the Public Health and Social Services

203 Tom Shimabukuro, “COVID-19 Vaccine Safety Monitoring,” CDC COVID-19 Vaccine Planning Unit, presented at
Advisory Committee on Immunization Practices meeting, September 22, 2020, https://www.cdc.gov/vaccines/acip/
meetings/downloads/slides-2020-09/COVID-03-Shimabukuro.pdf.
204 CDC communication with CRS, September 9, 2020, and CDC, COVID-19 Vaccination Program: Interim Playbook
for Jurisdiction Operations
, October 29, 2020, p. 48-49, https://www.cdc.gov/vaccines/imz-managers/downloads/
COVID-19-Vaccination-Program-Interim_Playbook.pdf.
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Emergency Fund (PHSSEF) in several coronavirus supplemental appropriations acts to this
fund.205
Because COVID-19 vaccines will likely not be added to the Vaccine Injury Table used for VICP
(at least initially), CDC is not required to develop Vaccine Information Statements (VIS) for least initially), CDC is not required to develop Vaccine Information Statements (VIS) for
COVID-19 vaccines. COVID-19 vaccines. CDC may choose to do so. Separately, if a vaccine is made available under
an EUA, FDA has stated it will make fact sheets available for vaccineFor vaccines available under EUA, the manufacturers have developed fact sheets for recipients and caregivers.240 Providers participating in the COVID-19 vaccine program are required to either give such factsheets to recipients (or their parents or recipients (or their
parents/legal guardians) legal guardians) and vaccine providers.206prior to vaccination or direct recipients to the website where the fact sheet is available.241 CDC and vaccine manufacturers CDC and vaccine manufacturers arehave also developed also
developing other educational material regarding the vaccines. other educational material regarding the vaccines.207242
Congressional Considerations
Since enactment of the Biologics Control Act of 1902, Congress and the Since enactment of the Biologics Control Act of 1902, Congress and the Administrationexecutive branch
(especially through FDA and CDC) have strived to ensure the safety of vaccines in the United (especially through FDA and CDC) have strived to ensure the safety of vaccines in the United
States—from initial development to patient administration. With the COVID-19 pandemic States—from initial development to patient administration. With the COVID-19 pandemic
causing considerable health and economic consequences, there is significant interest in causing considerable health and economic consequences, there is significant interest in
developing safe and effective vaccines to help curb transmission of the disease. Congress may safe and effective vaccines to help curb transmission of the disease. Congress may
consider how to best leverage existing requirements and programs to ensure that risk of harm consider how to best leverage existing requirements and programs to ensure that risk of harm
from eventualfrom COVID-19 vaccines is mitigated and minimized. Several efforts are underway COVID-19 vaccines is mitigated and minimized. Several efforts are underway
through OWS, FDA, through OWS, FDA, and CDC to expedite the availability of COVID-19 vaccines and to prepare
for a nationwide immunization campaign. Safety has been cited as a primary concern in all of
these efforts. Congress may consider how to best provide oversight and make legislative changes
to ensure a safe and successful COVID-19 vaccination campaign. In addition, Congress may
consider and evaluate the entire federal vaccine safety system and assess whether this system
warrants any policy changes to help ensure the safety of all recommended vaccines.

Author Information

Kavya Sekar
Agata Dabrowska
Analyst in Health Policy
Analyst in Health Policy



205 CRS Legal Sidebar LSB10443, The PREP Act and COVID-19: Limiting Liability for Medical Countermeasures.
206 CDC, COVID-19 Vaccination Program: Interim Playbook for Jurisdiction Operations, OcotberCDC, 235 CDC, “Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently Authorized in the United States,” https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html. 236 HRSA, “Frequently Asked Questions About the VICP,” https://www.hrsa.gov/vaccine-compensation/FAQ. 237 CRS Legal Sidebar LSB10443, The PREP Act and COVID-19: Limiting Liability for Medical Countermeasures. 238 HHS, “Declaration Under the Public Readiness and Emergency Preparedness Act for Medical Countermeasures Against COVID-19,” 85 Federal Register 15198, March 17, 2020. 239 CRS Legal Sidebar LSB10443, The PREP Act and COVID-19: Limiting Liability for Medical Countermeasures. 240 FDA, “Emergency Use Authorization,” accessed January 8, 2021, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization. 241 CDC, COVID-19 Vaccination Program: Interim Playbook for Jurisdiction Operations, October 29, 2020, p. 46, 29, 2020, p. 46,
https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf. https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf.
207242 Ibid Ibid., p. 23. , p. 23.
Congressional Research Service Congressional Research Service
37 41 Vaccine Safety in the United States and other agencies to monitor and ensure the safety of COVID-19 vaccines—both those available under EUA and those under development. Congress may consider how to best provide oversight and make legislative changes to ensure a safe and successful COVID-19 vaccination campaign. In addition, Congress may consider and evaluate the entire federal vaccine safety system and assess whether this system warrants any policy changes to help ensure the safety of all recommended vaccines. Author Information Kavya Sekar Agata Bodie Analyst in Health Policy Analyst in Health Policy

Vaccine Safety in the United States



Disclaimer
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Congressional Research Service Congressional Research Service
R46593 R46593 · VERSION 1 · NEW
384 · UPDATED 42