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

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

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

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

19) pandemic now causing major health and economic impacts across the world, efforts
have been underway to make safe and effective vaccines available quickly to help curb

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 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 events as quickly as possible. Today, as covered in this report, federal efforts to ensure
vaccine safety include the following activities:
 Premarket requirements: Clinical trials, or testing of investigational vaccines in human
subjects, and U.S. FDA licensure or authorization.
 Clinical recommendations: Recommendations for the 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 and studies of
vaccines administered to patients.
 Federal research on vaccine safety: Ongoing research to inform a better scientific
understanding of vaccine safety and comprehensive scientific reviews on the safety of vaccines in
use.
 Vaccine injury compensation: The National Vaccine Injury Compensation Program (VICP)
provides compensation to eligible individuals found to have been injured by a 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 vaccine
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.
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Congressional Considerations
Ever since the Biologics Control Act of 1902, Congress and the federal agencies (especially FDA and CDC) have
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
COVID-19 vaccines is mitigated and minimized. Federal agencies, pharmaceutical and biotech companies, and
others have worked to expedite the availability of COVID-19 vaccines and to implement a nationwide
immunization campaign while balancing a need for safety. 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 ongoing safety of all recommended vaccines.
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Contents
Introduction ..................................................................................................................................... 1
Scope of This Report ................................................................................................................. 3
What Is a Vaccine? .................................................................................................................... 4
Federal Vaccine Safety Regulation and Programs .................................................................... 4
Vaccine Safety Basics ............................................................................................................... 6
Premarket Safety ............................................................................................................................. 8
Clinical Trials ............................................................................................................................ 8
Biologics License Application (BLA) and Licensure Requirements ....................................... 11
Expedited Pathways and Access to Unapproved Vaccines...................................................... 13
Expedited Development and Review ................................................................................ 13
Animal Rule ...................................................................................................................... 14
Emergency Use Authorization (EUA) .............................................................................. 15
Advisory Committee Consultation .......................................................................................... 16
Clinical Recommendations ............................................................................................................ 17
Postmarket Safety .......................................................................................................................... 19
Manufacturing Safety .............................................................................................................. 19
Surveillance ............................................................................................................................. 20
Vaccine Adverse Event Reporting System (VAERS)........................................................ 21
Vaccine Safety Datalink (VSD) ........................................................................................ 21
Sentinel Initiative .............................................................................................................. 22
Other Safety Monitoring Systems ..................................................................................... 23
Clinical Assessment ................................................................................................................ 24
Federal Research on Vaccine Safety .............................................................................................. 24
CDC Research ......................................................................................................................... 25
NIH Research .......................................................................................................................... 25
FDA Research ......................................................................................................................... 26
Other Federal Research ........................................................................................................... 26
Challenges of Vaccine Safety Reviews ............................................................................. 27
National Vaccine Injury Compensation ......................................................................................... 27
Safety in Vaccine Distribution ....................................................................................................... 28
Safety Considerations for COVID-19 Vaccines ............................................................................ 30
Vaccine Development and Current Status ............................................................................... 31
Vaccine Efficacy ............................................................................................................... 33
FDA Marketing Authorization ................................................................................................ 34
Clinical Recommendations and Prioritization ......................................................................... 35
Safety in Vaccine Distribution ................................................................................................. 37
Postmarket Safety: Surveillance and Safety Monitoring ........................................................ 38
Severe Allergic Reactions ................................................................................................. 40
Injury Compensation and Patient Safety Information ............................................................. 41
Congressional Considerations ....................................................................................................... 41

Figures
Figure 1. NASEM-Recommended Phased Approach to COVID-19 Vaccine Allocation ............. 37
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Figure 2. Federal Vaccine Safety Monitoring Systems, by System and Population ...................... 40

Contacts
Author Information ........................................................................................................................ 42

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Introduction
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
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
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
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
led to substantial reductions in hospitalizations linked to pneumococcus, rotavirus, and varicella
(i.e., chickenpox).5
With the Coronavirus Disease 2019 (COVID-19) pandemic causing major health and economic
impacts across the world, efforts have been underway to make safe and effective vaccines
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
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
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
by the pertussis vaccine) to 333 cases per million doses (e.g., febrile seizures caused by the
measles-mumps-rubella; MMR vaccine).7
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

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).
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/.
3 Cynthia G. Whitney, Fangjun Zhou, James Singleton, et al., “Benefits from Immunization during the Vaccines for
Children Program Era—United States, 1994–2013,” Morbidity and Mortality Weekly Report, vol. 63, no. 16 (April 25,
2014), pp. 352-355.
4 Eric E. Mast, Stephen L. Cochi, Olen M. Kew et al., “Fifty Years of Global Immunization at CDC, 1966-2015,”
Public Health Reports, 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
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 Plotkin’s
Vaccines, 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
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 Institute of Medicine (now
National Academy of Medicine), Adverse Effects of Vaccines: Evidence and Causality, Washington, DC, August 25,
2012, https://www.ncbi.nlm.nih.gov/books/NBK190010/#sec_0009.
7 Frank DeStefano, Paul A. Offit, and Allison Fisher, Ch. 82, “Vaccine Safety,” in Vaccines, ed. Stanley A. Plotkin,
Walter A. Orenstein, Paul A. Offit et. al. 67h ed. (Elsevier, 2017), pp. 1584-1600.
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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
herd immunity, 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.,
persons with compromised immune systems).10 Widespread vaccination can help with achieving
elimination or eradication of a given disease (see text box). To effectively prevent disease spread,
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
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
meet target rates can aid in significantly curbing disease spread.12
Vaccines are often held to a higher safety
Definitions: Elimination and Eradication
standard than most other medical products for
The World Health Organization (WHO) defines
many reasons. For one, vaccines are often
disease elimination and eradication as fol ows:
administered to healthy individuals to prevent
Elimination (or interruption) of transmission:
disease; therefore, the expectation is that such
Reduction to zero of the incidence of infection caused
individuals will remain healthy following
by a specific pathogen in a defined geographical area,
vaccination. In addition, vaccines are often
with minimal risk of reintroduction, as a result of
deliberate efforts; continued actions to prevent
administered to vulnerable populations,
reestablishment of transmission may be required.
including infants and pregnant people. Also,
Eradication: Permanent reduction to zero of a
since vaccines are often mandated by state and
specific pathogen, as a result of deliberate efforts, with
sometimes federal law for certain groups (e.g.,
no more risk of reintroduction.
school children and military service
Source: WHO, “Generic Framework for the Control,
members), the government has an interest in
Elimination, and Eradication of Neglected Tropical
ensuring 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
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,” Vaccines, vol. 52 (2011).
11 Ibid., and Pedro Plans-Rubió, “Evaluation of the Establishment of Herd Immunity in the Population by Means of
Serological Surveys and Vaccination Coverage,” Human Vaccines & Immunotherapeutics. vol. 8, no. 2 (February
2012), pp. 184-88.
12 Paul Fine, Ken Eames, and David L. Heymann, “‘‘Herd Immunity’’: A Rough Guide,” Vaccines, vol. 52 (2011).
13 Frank DeStefano, Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in Vaccines, 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. Salmon,
Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in The Clinician’s Vaccine Safety Resource Guide (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
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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;
 summarizes ongoing federal activities related to vaccine post-market safety (e.g.,
ongoing safety monitoring and research), as well as safety assurances in federal
vaccine distribution programs; and
 discusses safety considerations in the context of developing and making available
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,
nor does it specifically address vaccines for noninfectious diseases (e.g., cancer). Discussions 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.
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payment and coverage for vaccines and related health care services, and logistical implementation
of the vaccine distribution program, are outside the scope of this report.
What Is a Vaccine?
A vaccine is a biological preparation that contains small amounts of weak, dead, or modified
disease-causing agents known as antigens, which can include viruses, bacteria, fractions of these
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 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 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 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 vaccine may cause some symptoms in some patients.20
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
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
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
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,
formaldehyde, and antibiotics.21
Federal Vaccine Safety Regulation and Programs
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.22 The Biologics Control
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
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

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 Epidemiology and Prevention of Vaccine-Preventable Diseases, ed. Jennifer
Hamborsky, Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015).
21 Department of Health and Human Services (HHS), “Vaccine Ingredients,” Vaccines.gov, December 2017,
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
Ingredients in U.S. Licensed Vaccines,” https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/
common-ingredients-us-licensed-vaccines.
22 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
Monoclonal Antibodies,” Food & Drug Law Journal, 2005, vol. 60, no. 2., p. 147.
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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
Act (FFDCA).23
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
detect new adverse events as quickly as
possible, as discussed throughout this
Federal Agencies Involved in Vaccine Safety
report. Major reforms to federal
Within the Department of Health and Human Services (HHS):
vaccine safety programs were enacted

FDA regulates the safety, effectiveness, and quality of
as a part of the National Childhood
vaccines through premarket review and postmarket
Vaccine Injury Act of 1986 (NCVIA;
requirements (e.g., adverse event reporting).
P.L. 99-660, Title III), which mandated

CDC supports cross-cutting immunization programs that
reporting of adverse events caused by
include, as relevant to vaccine safety: safety monitoring,
clinical guidance for vaccines, vaccine safety research, and
vaccines to FDA and CDC, established
efforts to ensure safety in public vaccine distribution.
the National Vaccine Program Office

The National Institutes of Health (NIH) is the primary
(NVPO) within HHS to coordinate
federal agency that supports medical and health research,
federal vaccine efforts, granted FDA
including vaccine research.
mandatory recall authority for

The Centers for Medicare & Medicaid Services (CMS)
biological products, and established the
monitors vaccine safety among the Medicare population.
National Vaccine Injury Compensation

The Agency for Healthcare Research and Quality (AHRQ)
Program (VICP). NCVIA was enacted
conducts vaccine safety reviews.
after a spate of lawsuits against vaccine

The Health Resources and Services Administration (HRSA)
manufacturers alleging safety issues.
administers the VICP.
The lawsuits caused several vaccine
The Department of Veterans Affairs (VA) conducts some
manufacturers to exit the market,
vaccine research and monitors vaccine safety among veterans
who receive care in the VA system.
leading to concerns about the vaccine
supply and possible reintroduction of
The Department of Defense (DOD) conducts some vaccine
research and has a database for monitoring adverse events from
certain diseases.24
vaccination among military service members and their families.
As covered in this report, efforts to
ensure vaccine safety include several federal activities:
 Premarket requirements: 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.

23 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
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
Therapeutics and Monoclonal Antibodies,” Food and Drug Law Journal, 2005, vol. 60, no. 2, pp. 143-260. See also
CRS Report R44620, Biologics and Biosimilars: Background and Key Issues.
24 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,”
Clinical Infectious Diseases, vol. 42 (2006), pp. S130-7, and Nora Freeman Engstrom, “A Dose of Reality for
Specialized Courts: Lessons from the VICP,” University of Pennsylvania Law Review, vol. 163 (June 28, 2015), pp.
1655-1658.
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 Federal research on vaccine safety: Ongoing research to inform a better
scientific understanding of vaccine safety, and comprehensive scientific reviews
on the safety of vaccines.
 Vaccine injury compensation: The VICP can provide compensation to eligible
individuals found to have been injured by a 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
vaccine distribution programs, led by CDC.
Vaccine Safety Basics
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
consideration the character of the product in relation to the condition of the recipient at the
time.”25 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:
 Vaccine efficacy is defined as the reduction in disease incidence in a vaccinated
group compared with an unvaccinated group under optimal conditions (i.e.,
healthy individuals and proper administration).
 Vaccine effectiveness is defined as the reduction in disease incidence in a
vaccinated group compared with an unvaccinated group under real-world
conditions.26
Like all pharmaceutical products, though vaccines approved or authorized for use by FDA are
generally safe for the vast majority of patients, they are not 100% safe for all patients. Vaccine
safety programs continually assess the benefits and risks of vaccination. Adverse events following
vaccination can be classified in many ways:27
 Frequency—is the adverse event common or rare?
 Severity—is the adverse event mild, such as minor pain or swelling, or severe,
such as leading to hospitalization, disability, or death?
 Causality—can a causal relationship be established with the vaccine with
clinical, laboratory, or epidemiologic evidence? (see text box 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 21 C.F.R. §600.3(p).
26 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,
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,
https://www.cdc.gov/flu/vaccines-work/effectivenessqa.htm.
27 CDC, “Vaccine Safety,” in Epidemiology and Prevention of Vaccine-Preventable Diseases, ed. Jennifer Hamborsky,
Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015).
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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
administration; for example, a vaccine administered too high on the arm of an adult can cause
deltoid bursitis (inflammation of the shoulder joint).28 In the past, improper 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
result, 40,000 people developed mild polio from the vaccine, 200 became paralyzed, and 10
died.29
In some cases, establishing a causal connection between a vaccine and an adverse event is
difficult. Vaccination may co-occur with an adverse health event. For example, early childhood—
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
to appear.30 Available evidence rejects a causal relationship between childhood vaccines and
autism.31 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
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
analyses that assess whether vaccinated individuals are more likely to develop a certain health
outcome within a certain time period following vaccination compared to either individuals who
did not receive the vaccine in that time period 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 data or other evidence that can allow for causality assessments to link certain adverse
events with vaccination (see text box).
What Is a Causality Assessment?
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
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
event that occurred fol owing vaccination. Yet, another similar analysis among a different population could 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 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 causal
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.

28 CDC, “Vaccine Safety,” in Epidemiology and Prevention of Vaccine-Preventable Diseases, ed. Jennifer Hamborsky,
Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015).
29 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), p. 1584.
30 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), p. 1593.
31 Frank DeStefano, Heather Monk Bodenstab, and Paul A. Offit, “Principal Controversies in Vaccine Safety in the
United States,” Clinical Infectious Diseases, 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 CDC, “Vaccine Safety,” in Epidemiology and Prevention of Vaccine-Preventable Diseases, ed. Jennifer Hamborsky,
Andrew Kroger, and Charles Wolfe, 13th ed. (Washington, DC: Public Health Foundation, 2015).
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
A selection process to determine which studies are actually relevant and used rigorous scientific methods
that provide quality evidence based on defined criteria.

A review process to compare evidence across studies, considering differences such as study populations,
study design, and the quality of each study.

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 vaccination
with a specific vaccine and a subsequent adverse event, or yields inconclusive results.
For a further discussion, see the “Federal Research on Vaccine Safety” section. Causality assessments may also be
conducted on an ongoing basis using data and information from postmarket monitoring systems (see the
“Postmarket Safety” section).
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/
adverse-effects-of-vaccines-evidence-and-causality; and 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. Also, for an
overview of causality assessments for vaccines, see 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), p. 1589.
Premarket Safety
Vaccines generally follow the same clinical development and approval process as drugs and other
biologics (i.e., therapeutics derived from living organisms).33 To be marketed in the United States,
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,
packed, or held meet standards to ensure that the product is safe, pure, and potent (effective).34
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
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.
Existing 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
information about biologics, see CRS Report R44620, Biologics and Biosimilars: Background and Key Issues.
34 PHSA §351(a)(2)(C) [42 U.S.C. §262(a)(2)(C)]. FDA approves drugs that are safe and effective; the equivalent
terminology for biologics is safe, pure, and potent. FDA has interpreted potency to include effectiveness. See the FDA
Guidance for Industry, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product,
https://www.fda.gov/media/82647/download.
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.
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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
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
minimized.39 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.
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
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
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
government agencies.40
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
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
ties to the sponsor to oversee the investigations.41 The DSMB often advises the sponsor on the
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.
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
assess safety and immunogenicity42 in a small number of volunteers.
 Phase 2 trials assess side effects and the dosing at which the investigational
vaccine may have a protective effect and may enroll hundreds of volunteers.
 Phase 3 trials assess effectiveness, continue to monitor safety and typically enroll
thousands of volunteers.43
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.
Phase 3 clinical trial data are typically needed to fully assess the safety and effectiveness of an

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.
40 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.
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,” Clinical Trials, vol. 15, no. 1 (September 7, 2017), pp. 65-74.
41 FDA, “Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data Monitoring
Committees,” March 2006, https://www.fda.gov/media/75398/download.
42 Immunogenicity 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,
ed., Concise Medical Dictionary (Oxford University Press).
43 21 C.F.R. §312.21. FDA, “Vaccine Product Approval Process,” https://www.fda.gov/vaccines-blood-biologics/
development-approval-process-cber/vaccine-product-approval-process.
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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 Plotkin’s Vaccines, ed. Stanley A. Plotkin,
Walter A. Orenstein, 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.
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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
In some cases, 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 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 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
preliminary immune response.53
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
vaccine for dengue virus produced by Sanofi Pasteur (Dengvaxia) found an issue of antibody-
mediated enhancement of infections, 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
showed a higher rate of hospitalizations for dengue three years after vaccination in young
children compared with children who were unvaccinated.54
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
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
first-generation vaccine).55 Such large trials can involve higher costs and increased time to
licensure.
Biologics License Application (BLA) and Licensure Requirements
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
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,
purity, and potency.56 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
Laboratory Practice (GLP) for nonclinical laboratory studies57 or (2) if the study was not
conducted in compliance with GLP regulations, a brief statement explaining the reason for

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, 22 Case Studies Where Phase 2 and Phase 3 Trials had Divergent Results, January 2017.
54 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,” The New England Journal of Medicine, vol. 373, no. 13 (September 24,
2015). Helen Branswell, “Caution on New Dengue Vaccine: In Some Countries, Harm Outweighs Benefit,” STAT,
September 1, 2016.
55 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. 1584.
56 FDA regulations at 21 C.F.R. §601.2(a) specify the required contents of a BLA.
57 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
the requirements for institutional review set forth in FDA regulations,58 or that it was not subject
to such requirements and was conducted in compliance with requirements for informed consent.59
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
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,
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
product. Finally, the BLA must include a financial certification or disclosure statement(s) or both
for clinical investigators.
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
conforms to regulatory requirements. As for prescription drugs and other biologics, vaccine
labeling must include warnings and precautions, contraindications, dosage and administration,
storage and handling conditions, and adverse reactions, among other information.60 Labeling for
vaccines must specifically contain a statement describing how suspected adverse reactions can be
reported.61 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,62 and the recommended
individual dose (for multiple dose containers), among other information.63 Vaccines require
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
containing a vaccine.64
FDA regulations also provide for biological product manufacturing establishment standards. Such
standards cover personnel, the physical establishment in which a product is manufactured, records
maintenance, retention of samples, reporting of product deviations, and product temperature
during shipment.65 Most of these requirements apply broadly to biologics, but several provisions
are vaccine-specific, including requirements for live vaccine work areas66 and live vaccine
processing,67 as well as product-specific maintenance temperatures.68 In addition, FDA
regulations establish requirements for testing product potency, sterility, purity, and identity, as
well as requirements for constituent materials used in licensed products, including preservatives,
diluents, and adjuvants.69 Vaccines, like other biological products, are subject to lot release

58 21 C.F.R. Part 56 “Institutional Review Boards.”
59 21 C.F.R. Part 50 “Protection of Human Subjects.”
60 21 C.F.R. §§201.56 and 201.57.
61 21 C.F.R. §201.57(a)(11)(iii).
62 “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).
63 21 C.F.R. §§610.60 and 610.61.
64 21 C.F.R. §610.61.
65 21 C.F.R. Part 600.
66 21 C.F.R. §600.10(c)(4).
67 21 C.F.R. §600.11(c)(4).
68 21 C.F.R. §600.15.
69 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.”70 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
a lot of a vaccine until it is released by FDA.71
Expedited Pathways and Access to Unapproved Vaccines
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
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
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
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
diseases or conditions, FDA can expedite the development and review processes for drugs and
biologics, including vaccines, through four programs:
 fast track product designation,
 breakthrough therapy designation,
 accelerated approval, and
 priority review.72
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
qualifying criteria and features of these programs differ.
To qualify for fast track product designation, a vaccine must be intended for a serious condition,
and nonclinical or clinical data must demonstrate its potential to address an unmet medical need.73
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
a complete application is submitted).74
To qualify for breakthrough designation, a vaccine must be intended for a serious condition, and
preliminary clinical evidence must indicate that it demonstrates potential substantial improvement
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
development program; involvement of “senior managers and experienced review and regulatory
health project management staff in a proactive, collaborative, cross-disciplinary review” to

70 21 C.F.R. §610.1.
71 21 C.F.R. §610.2.
72 FFDCA §506 [21 U.S.C. §356]. FDA, “Guidance for Industry Expedited Programs for Serious Conditions–Drugs
and Biologics,” May 2014, https://www.fda.gov/media/86377/download.
73 FFDCA §506(b) [21 U.S.C. §356(b)].
74 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
breakthrough therapy designation. The request may be submitted with either the IND or any time
after,75 as further specified in FDA guidance.76
The accelerated approval 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
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
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
benefit. Postmarketing confirmatory studies generally must be completed to demonstrate actual
effectiveness.77
A priority review 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
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
qualify for priority review if submitted with a priority review voucher.78
Animal Rule
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
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
test an investigational vaccine.
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
adequate and well-controlled animal efficacy studies if those studies establish that the vaccine is
likely to produce clinical benefit in humans.79 The Animal Rule is intended for drugs and
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,
snake venom, and industrial chemicals). For FDA to rely on evidence from animal studies to
provide evidence of effectiveness, four criteria must be met:

75 FFDCA §506(a)(2) & (b)(2) [21 U.S.C. §356(a)(2) & (b)(2)].
76 FDA, “Guidance for Industry Expedited Programs for Serious Conditions–Drugs and Biologics,” May 2014,
https://www.fda.gov/media/86377/download.
77 FFDCA §506(c) [21 U.S.C. §356(c)].
78 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
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
voucher for the priority review of another application or sell it to another sponsor to use.
79 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.
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There is a reasonably well-understood pathophysiological mechanism of the toxicity of the
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
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
humans;
The animal study endpoint is clearly related to the desired benefit in humans, generally the
enhancement of survival or prevention of major morbidity; and
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
in humans.80
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,
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
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
special training or experience).81 To date, FDA has licensed one vaccine under the Animal Rule:
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
anthrax vaccine.82
Emergency Use Authorization (EUA)
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,
FDA may allow patients to access investigational vaccines outside this framework, including
through emergency use authorization (EUA).
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
unapproved use of an approved medical product.83 The HHS Secretary’s declaration must be
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
national security or the health and security of U.S. citizens living abroad.84 Following the HHS
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
authorizing the emergency use of a vaccine, provided that the following criteria are met:

80 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.
81 21 C.F.R. §601.91.
82 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,
http://wayback.archive-it.org/7993/20171114165441/https://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm474027.htm.
83 FFDCA §564 [21 U.S.C. §360bbb-3]. For additional information, see CRS In Focus IF10745, Emergency Use
Authorization and FDA’s Related Authorities.
84 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
disease or condition;
 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
such disease or condition, and that the known and potential benefits of the
product outweigh its known and potential risks; and
 there is no adequate, approved, or available alternative to the product.85
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
suggests that a product may be effective in diagnosing, treating, or preventing a disease or
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
or licensure, which is based on substantial evidence of effectiveness derived from adequate and
well-controlled studies.86
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
conditions where appropriate.87 FDA may waive or limit current good manufacturing practices
(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
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
Section 564, unless revoked at an earlier date.
Until December 2020, FDA had never granted EUA for an unapproved (i.e., unlicensed) vaccine.
The only instance of FDA issuing an EUA for a vaccine was in 2005 for the unapproved use of a
previously licensed vaccine.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,
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
biological products. The committee “reviews and evaluates data concerning the safety,
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
regulation of these products and makes appropriate recommendations” to the FDA

85 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/
media/97321/download.
86 FFDCA §505(d) [21 U.S.C. §355(d)].
87 FFDCA §564(e) [21 U.S.C. §360bbb-3(e)].
88 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 Federal Register 5452, February 2, 2005.
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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.90 VRBPAC is subject to the
requirements of the Federal Advisory Committee Act.91
Clinical Recommendations
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
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
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.92 ACIP may also develop
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 U.S. Surgeon General in 1964, under authority provided by Public
Health Service Act (PHSA) Section 222.93 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
typically makes one of two types of clinical recommendations:
 Full recommendation (also called “Category A”): The vaccine is recommended
for all people in an age- or risk-based group, except for those with a
contraindication (i.e., a condition that would make the vaccine harmful, such as a
condition that compromises the immune system). For example, ACIP has issued a
full recommendation for two 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 before school entry at four to six years of age.95
 Clinical Decisionmaking (also called “Category B”): The vaccine is
recommended for certain subpopulations, and its use is based on clinical
decisionmaking.96 For example, ACIP 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,”
https://www.fda.gov/advisory-committees/vaccines-and-related-biological-products-advisory-committee/2018-
meeting-materials-vaccines-and-related-biological-products-advisory-committee.
91 For additional information about the Federal Advisory Committee Act (FACA) and FACA committees, see CRS
Report R44253, Federal Advisory Committees: An Introduction and Overview.
92 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.
93 CDC, “ACIP Charter,” June 5, 2018, https://www.cdc.gov/vaccines/acip/committee/charter.html.
94 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
Rubella Syndrome, and Mumps, 2013: Summary Recommendations of the Advisory Committee on Immunization
Practices (ACIP),” Morbidity and Mortality Weekly Report (MMWR), vol. 62, no. RR04 (June 14, 2013), pp. 1-34.
96 Richard Hughes, Reed Maxim, and Alessandra Fix, “Vague Vaccine Recommendations May Be Leading to Lack of
Provider Clarity, Confusion Over Coverage,” Health Affairs, May 7, 2019; and Larry K. Pickering, Walter A.
Orenstein, and Wellington Sun, et al., “FDA Licensure of and ACIP Recommendations for Vaccines,” Vaccine, vol. 35
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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
disease,98 vaccine efficacy and effectiveness, the quality of evidence reviewed, economic
analyses, and implementation issues. Recommendations made by ACIP are reviewed by the CDC
Director and, if adopted, published as official CDC recommendations.99 ACIP recommendations
inform which vaccines are provided through the CDC’s Vaccines for Children program,100 as well
as which vaccines must be covered by private health care insurance plans subject to the
preventive health services requirement (PHSA §2713) as added by the Patient Protection and
Affordable Care Act (ACA; P.L. 111-148, as amended).101
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
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
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
table of vaccine recommendations by common contraindications, such as persons with HIV,
immunocompromised individuals, and pregnant individuals. The table includes when
recommended vaccines should not be administered to individuals with these contraindications.102
Once clinical recommendations are made, CDC develops and provides resources and training for
health care providers on current vaccine recommendations, best practices for vaccine
administration, and patient education.103 CDC develops Vaccination Information Statements
(VIS) 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 among children and pregnant women are administered.104 VISs are developed by CDC
in consultation with the Advisory Commission on Childhood Vaccines (ACCV; a committee of
health care professionals, attorneys, and parents of vaccine-injured children), health care
providers, and FDA, and are published in the Federal Register for public comment.105

(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
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/
global_burden_disease/about/en/.
99 CDC, “ACIP Charter,” June 5, 2018, https://www.cdc.gov/vaccines/acip/committee/charter.html.
100 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,
uninsured, or underinsured (as defined). See https://www.cdc.gov/features/vfcprogram/index.html.
101 ACA, P.L. 111-148, as amended, which established PHSA §2713.
102 CDC, “Immunization Schedules,” https://www.cdc.gov/vaccines/schedules/index.html.
103 CDC, “Vaccines- Healthcare Providers,” 2018, https://www.cdc.gov/vaccines/hcp/index.html.
104 Requirement established by the National Childhood Vaccine Injury Act, P.L. 99-660; PHSA §2126 [42 U.S.C.
§300aa-26].
105 P.L. 99-660; PHSA §2126 [42 U.S.C. §300aa-26].
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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
additional information about a vaccine’s risks, benefits, and optimal use.106 FDA may require a
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 when available data indicate the potential for a serious risk.107 In addition, because vaccines
require special manufacturing processes to avoid contamination, post-licensure safety programs
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
vaccination, and FDA may require vaccine manufacturers to revise vaccine product labeling if
new information becomes available after licensure.108
Manufacturing Safety
FDA continues to inspect vaccine manufacturing facilities post-licensure.109 The HHS Secretary
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
product [e.g., vaccine].”110 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
immediately recalling the batch, lot, or other quantity of the vaccine.111
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
safety and quality of each batch of vaccines produced, and must report any identified public
health hazards to FDA.112 Specifically, vaccine manufacturers are required to maintain records
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
processes, and to report if any safety test on such batch, lot, or other quantity indicates a potential
imminent or substantial public health hazard.113
In addition, manufacturers of licensed vaccine 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 required for each serious and unexpected adverse experience and must be submitted to FDA as

106 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.
107 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)].
108 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)].
109 FDA, “Ensuring the Safety of Vaccines in the United States,” last updated July 2011, https://www.fda.gov/media/
83528/download.
110 PHSA §351(c) [42 U.S.C. §262(c)].
111 PHSA §351(d)(1) [42 U.S.C. §262(d)(1)].
112 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,
https://www.fda.gov/media/81983/download.
113 PHSA §2128(a) [42 U.S.C. §300aa–28(a)].
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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’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
report (e.g., name, age, gender) and the vaccine (e.g., manufacturer, lot number).115 If a vaccine
manufacturer fails to establish and maintain records or report adverse events, FDA can take
enforcement action, including revocation of the BLA for that vaccine.116
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)
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
databases on vaccine safety events among their covered populations.118 The NVPO within the
HHS Office of Infectious Disease and HIV/AIDS Policy (OIDP) is tasked with coordinating
vaccine safety monitoring across federal agencies.119
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
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 enables distinctions
between adverse events linked to
Key Terms: Passive and Active Surveillance
improper manufacturing,
Public health surveillance, or ongoing data monitoring, can be passive
compared with adverse events
or active. A passive surveillance system relies on reports, often from
health care providers or patients. In an active surveillance system, data
are col ected proactively—either through active analysis of electronic
health data (such as for the monitoring systems covered here), or
where data are col ected directly by contacting health care
organizations or obtaining records.
Source: CDC, “Introduction to Public Health Surveillance,”
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,
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linked to a particular type of vaccine.120
Vaccine Adverse Event Reporting System (VAERS)
VAERS, established in 1990 and 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 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 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 serious and unexpected events as required through
regulations.121 Scientists at CDC and FDA monitor VAERS reports and use the information to
conduct further investigations on the reported cases.122 Consolidated data on reported adverse
events in the VAERS system are publicly available online.123
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 administered in the covered populations. Therefore, VAERS data are often inadequate
for epidemiological analyses of adverse health events at a population level.124 VAERS is useful,
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
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
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.125
Vaccine Safety Datalink (VSD)
VSD, established in 1990 and operated by CDC, is an active surveillance system and a
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.
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
vaccination to identify associated risks.126 VSD studies may supplement these records with other
sources of information, such as patient surveys, medical charts, and pharmacy, laboratory, and

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/
patient-ed/conversations/downloads/vacsafe-vaers-color-office.pdf.
123 VAERS, “VAERS data,” https://vaers.hhs.gov/data.html.
124 CDC, “Vaccine Safety Datalink (VSD),” https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/; and
Frank DeStefano, Paul A. Offit , and Allison Fisher, “Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley Plotkin,
Walter Orenstein, Paul Offit, Kathryn M. Edwards, 7th ed. (Elsevier, 2018), pp. 1586.
125 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. 1586-1587.
126 CDC, “Vaccine Safety Datalink (VSD),” https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/.
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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 extremely rare adverse events linked to vaccination.129
Sentinel Initiative
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
sources and to validate means of linking and analyzing safety data from multiple sources.130 As
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
Effectiveness and Safety (BEST) system.
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
was established in 2009 and deployed during the H1N1 influenza pandemic.131 PRISM has been
the largest linked database for monitoring vaccine safety in the United States, involving data on
over 100 million people.132 PRISM, similar to the CDC VSD program, can allow for 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
vaccine-linked adverse events by subpopulation (e.g., by race/ethnicity).133 As of 2012, VSD
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.134

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
Frank DeStefano, Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley Plotkin,
Walter Orenstein, Paul Offit, Kathryn M. Edwards, 7th ed. (Elsevier, 2018), pp. 1584-1600.
129 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,”Pharmacoepidemiology and
Drug Safety, vol. 21, no. S1 (2012), pp. 291-97.
130 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.
131 PRISM is the vaccine component of FDA’s Sentinel Initiative.
132 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
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).
133 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,” Pharmacoepidemiology and
Drug Safety, vol. 21, no. S1 (2012), pp. 291-97.
134 Matthew Z. Dudley, Daniel A. Salmon, Neal A. Halsey, et al., “Monitoring Vaccine Safety,” in The Clinician’s
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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
changes for the licensed vaccine.137
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
blood and blood products, tissue products, and other advanced therapeutic biologics.138 The goal
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
components, BEST uses electronic health record, administrative, and claims-based data for active
surveillance and research.139
Other Safety Monitoring Systems
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
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,
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
monitoring among the IHS-covered population.140
Safety Monitoring Using Multiple Surveillance Systems: A Case Study
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
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

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
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.
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-
Sentinel Postlicensure Observational Study of Rotavirus Vaccines and Intussusception,” July 22, 2013,
https://www.sentinelinitiative.org/communications/fda-safety-communications/fda-safety-communication-fda-
approves-required-revised.
138 Sentinel, “Vaccines, Blood, & Biologics Assessments,” https://www.sentinelinitiative.org/assessments/vaccines-
blood-biologics.
139 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.
140 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).
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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.
Clinical Assessment
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
safety. Scientists in the network can conduct studies on complex individual patient cases of
possible adverse health events that followed vaccination.141 Using CISA, scientists can assess the
biological mechanisms that cause adverse health events after vaccination.142 In addition, CISA
manages a repository of biospecimen samples from patients who experience unusual adverse
events following vaccination.143 These samples can be systemically analyzed to inform a
mechanistic understanding of such adverse events.
Federal Research on Vaccine Safety
Postmarket surveillance systems and clinical assessments provide important data and evidence on
potential adverse events following vaccination. To further understand and determine whether
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
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
related to methods for evaluating vaccine safety. Major areas of research related to vaccines can
include the following:144
 Biological research: Research often with animals, cell cultures, or biological
specimens (e.g., human tissue samples) to explore the mechanisms by which
vaccines act in biological systems, informing an understanding of how adverse
events may occur. (Also referred to as basic biomedical research).
 Epidemiological research: A form of statistical research involving health data
collected among defined human populations (such as postmarket surveillance
data) to explore whether statistical associations exist between vaccination and
subsequent adverse events, and any related risk factors for those events among
those populations.

141 CDC, “Clinical Immunization Safety Assessment (CISA) Project,” https://www.cdc.gov/vaccinesafety/
ensuringsafety/monitoring/cisa/index.html.
142 Frank DeStefano, Paul A. Offit, and Allison Fisher, “Vaccine Safety,” in Plotkin’s Vaccines, ed. Stanley Plotkin,
Walter Orenstein, Paul Offit, Kathryn M. Edwards, 7th ed. (Elsevier, 2018), pp. 1588.
143 NVAC, White Paper on the United States Vaccine Safety System, September 2011, p. 16, https://www.hhs.gov/sites/
default/files/nvpo/nvac/nvac_vswp.pdf.
144 NVAC, White Paper on the United States Vaccine Safety System, September 2011, p. 16, https://www.hhs.gov/sites/
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
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
often focuses on the use of specific vaccines in specific populations, as well as hypothesized side
effects and adverse events potentially attributable to vaccination.145 For example, a recent CDC
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
seizure) when multiple vaccines were administered at once.146
NIH Research
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
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
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
scientific investigations into physiological and immunological responses to vaccines; explorations
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
vaccine safety; and the application of genomic and molecular technologies to assess vaccine
safety.147
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
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
centralized databases for use by researchers.148 Researchers are using HIPC to study certain
aspects of vaccine safety, such as whether a relationship exists between short-term adverse events
caused by vaccination and long-term health effects.149 When combined with postmarket

145 CDC, “Vaccine Safety Publications,” https://www.cdc.gov/vaccinesafety/research/publications/index.html.
146 Shirley V. Wang, Kristina Stefanini, Edwin Lewis, et al., “Determining Which of Several Simultaneously
Administered Vaccines Increase Risk of an Adverse Event,” Drug Safety, vol. 43 (July 1, 2020), pp. 1057-65.
147 NIH, “Research to Advance Vaccine Safety (R01),” July 24, 2018, https://grants.nih.gov/grants/guide/pa-files/PA-
18-873.html.
148 NIH, “Human Immunology Project Consortium,” https://www.immuneprofiling.org/hipc/page/showPage?pg=about.
149 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/
Reports/2013/The-Childhood-Immunization-Schedule-and-Safety.aspx.
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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
for studying the safety and efficacy of vaccines against specific pathogens, as well as to
characterize biomarkers of vaccine safety and efficacy.150 In addition, FDA has studied certain
adjuvants and preservatives added to vaccines, including thimerosal and the impact of aluminum
in vaccines on infants.151 FDA research efforts have also focused on vaccine availability,
specifically on influenza vaccine production and ensuring a sufficient supply of a safe vaccine.152
Other Federal Research
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
safety research.153 The Agency for Healthcare Research and Quality (AHRQ) has conducted
vaccine safety reviews. The Department of Defense (DOD) and the Department of Veterans
Affairs (VA) also support some vaccine safety research.154
Periodically, federal agencies (particularly HHS) conduct or commission comprehensive
scientific reviews on the safety of recommended vaccines. As described in the text box (see
“What Is a Causality Assessment?”), 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. For example, in 2011, under HHS contract, the
National Academy of Medicine (NAM)155 conducted a comprehensive review of the scientific
evidence regarding the safety of eight 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 Injury Compensation Program (see the “National Vaccine Injury
Compensation” section).156 This review was subsequently updated in 2014 with additional
research by AHRQ, supported by the NVPO; AHRQ is currently in the process of updating this
review.157

150 FDA, Vaccines Research, current as of August 14, 2020, https://www.fda.gov/vaccines-blood-biologics/biologics-
research-projects/vaccines-research.
151 L. K. Ball, R. Ball, R. D. Pratt, “An assessment of thimerosal use in childhood vaccines,” Pediatrics, 2001, vol. 107
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/
20170405003134/https:/www.fda.gov/BiologicsBloodVaccines/ScienceResearch/ucm284520.htm.
152 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-
vaccine-strains.
153 See, for example, BetaSam.gov, “Research, Monitoring and Outcomes Definitions for Vaccine Safety,”
https://beta.sam.gov/fal/c8125303527f478981f6b7395c528788/view.
154 Vaccines.gov, “Vaccine Safety,” https://www.vaccines.gov/basics/safety.
155 NAM was named the Institute of Medicine when the Immunization Safety Review Committee was formed.
156 Institute of Medicine, Adverse Effects of Vaccines: Evidence and Causality, August 25, 2011.
157 Margaret A. Maglione, Courtney Gidengil, Lopamudra Das, et al. “Safety of Vaccines Used for Routine
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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
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
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
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
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
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
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
to establish causality. 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
scientific studies, including epidemiological evidence, clinical evidence, and biological laboratory
evidence, usually with methods to weigh, compare, and combine evidence across studies.158 Such
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.
National Vaccine Injury Compensation
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. Under
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 Injury Table” that lists vaccines covered by the program and the injuries associated with
those vaccines for which claims may be filed, developed in part based on the causality
assessments conducted by 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.
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Medicine) 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.162
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 involves the Department of Justice (DOJ) and the U.S. Court of Federal
Claims.166 The Advisory 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. 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.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/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,” https://www.hrsa.gov/vaccine-compensation/index.html.
166 HRSA, “About the National Vaccine Injury Compensation Program,” June 2019, https://www.hrsa.gov/vaccine-
compensation/about/index.html.
167 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
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
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-
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
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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.170 CDC, in particular, conducts
activities to help improve management of the vaccine supply chain. Vaccine storage practices
especially have implications for a vaccine’s potency (i.e., effectiveness).171
Vaccines are distributed through a decentralized network of health care providers, health centers,
pharmacies, and health departments. State requirements vary regarding the types of providers that
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
through state or local coordinators, who ensure that the provider meets program requirements
(e.g., ability to properly store and handle vaccines).172 Any provider that is licensed or otherwise
authorized to administer pediatric vaccines can apply to participate in a state’s VFC program and
receive and administer a supply of vaccine.173
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
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
exposing vaccines to improper temperatures, storing expired and nonexpired vaccines together, or
failing to maintain documentation. CDC agreed with the report recommendations and committed
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,” Health Affairs, vol. 30, no. 6 (2011), pp. 1113-1121.
170 Matthew J. Robbins and Sheldon H. Jacobson, “Analytics for Vaccine Economics and Pricing: Insights and
Observations,” Expert Review of Vaccines, vol. 14, no. 4 (December 1, 2014), pp. 606-616.
171 CDC, “Vaccine Storage and Handling Toolkit,” January 2019, https://www.cdc.gov/vaccines/hcp/admin/storage/
toolkit/storage-handling-toolkit.pdf.
172 CDC, “Why Join and How to Become a VFC Provider,” https://www.cdc.gov/vaccines/programs/vfc/providers/
questions/qa-join.html.
173 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.
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 The Vaccine Tracking System (VTrckS) is an information technology platform
for managing the publicly funded vaccine supply chain available to CDC, state
and local health departments, and providers.177
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.
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.
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
countermeasures) 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 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.181 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 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-
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.
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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
the requirements, processes, and programs described in this report differ when applied 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)
surveillance and safety monitoring, (5) injury compensation and patient safety information, and
(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
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
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,
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
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
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.184
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.
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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.
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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.
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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 vaccine candidate “will be reviewed according to the established legal and
regulatory standards for medical products.”205 In addition, FDA officials have indicated that the
amount of safety and effectiveness data needed to support EUA issuance is similar to the data that
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.
205 Anand Shah, Peter Marks, and Jim Hahn, “Unwavering Regulatory Safeguards for COVID-19 Vaccines,” JAMA,
August 2020, vol. 324, no. 10, pp. 931-932.
206 Duke Margolis Center for Health Policy, “Safe and Effective COVID-19 Vaccination: The Path from Here,”
September 10, 2020, 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-
eua-guidance-comi.
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.
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the data and information needed to support an EUA for a COVID-19 vaccine.209 The
recommendations outlined in the October 2020 guidance have been characterized as more
stringent than what typically may be required for an EUA.210 For example, the guidance indicates
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
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
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
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
for VED, decreased effectiveness over time) in sufficient numbers to support vaccine 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,
https://www.fda.gov/media/142749/download.
210 Michael Erman and Manas Mishra, “U.S. FDA safety guidelines likely to push COVID-19 vaccine authorization
past election,” October 6, 2020, Reuters.
211 FDA, “FDA Statement on Vaccines and Related Biological Products Advisory Committee Meeting,” press release,
December 17, 2020, https://www.fda.gov/news-events/press-announcements/fda-statement-vaccines-and-related-
biological-products-advisory-committee-meeting-0; and FDA, “FDA Statement on Vaccines and Related Biological
Products Advisory Committee Meeting,” press release, December 11, 2020, https://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.
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 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, and Medicine (NASEM), at the direction of NIH and CDC, set up an ad hoc
committee to develop a framework for equitably allocating COVID-19 vaccines domestically and
globally.219 NASEM published its draft framework on September 1, 2020, 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 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-
allocation-of-vaccine-for-the-novel-coronavirus.
220 National Academy of Sciences, Engineering, and Medicine, Discussion Draft of the Preliminary Framework for
Equitable Allocation of COVID-19 Vaccine, September 1, 2020.
221 CDC, “COVID-19 Vaccination Program Operational Guidance,” November 5, 2020, https://www.cdc.gov/vaccines/
covid-19/covid19-vaccination-guidance.html.
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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.
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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.
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)
and some must be kept ultra-cold (-60 to -80 degrees Celsius), such as Pfizer/BioNTech’s
vaccine. CDC’s planning guidance to 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 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 distributed by CDC’s distributor directly to the provider sites
or secondary depots for distribution (e.g., chain drug store’s central distribution). CDC guidance
includes detailed information about how vaccines should be stored onsite until usage.225
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, 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, 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.
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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 advised to report such events even if the
providers are not sure that vaccination caused the adverse 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, 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.
231 Tom Shimabukuro, “COVID-19 Vaccine Post-Authorization Safety Monitoring Update,” Presented at December 1
Advisory Committee on Immunization Practices (ACIP) meeting, https://www.cdc.gov/vaccines/acip/meetings/
downloads/slides-2020-12/COVID-04-Shimabukuro.pdf.
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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, https://www.cdc.gov/vaccines/acip/
meetings/downloads/slides-2020-12/COVID-04-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.
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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 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) declaration effective February 4, 2020, which established certain
immunity from legal liability related to the “manufacture, testing, development, distribution,
administration, and use” of covered 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 injury or death from a covered countermeasure may seek
compensation through the Covered Countermeasure Process Fund as a part of the CICP. 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
least initially), CDC is not required to develop Vaccine Information Statements (VIS) for
COVID-19 vaccines. For 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 legal guardians) prior
to vaccination or direct recipients to the website where the fact sheet is available.241 CDC and
vaccine manufacturers have also developed other educational material regarding the vaccines.242
Congressional Considerations
Since enactment of the Biologics Control Act of 1902, Congress and the executive branch
(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
causing considerable health and economic consequences, there is significant interest in 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 from COVID-19
vaccines is mitigated and minimized. Several efforts are underway through OWS, FDA, CDC,

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,
https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf.
242 Ibid., p. 23.
Congressional Research Service

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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

Disclaimer
This document was prepared by the Congressional Research Service (CRS). CRS serves as nonpartisan
shared staff to congressional committees and Members of Congress. It operates solely at the behest of and
under the direction of Congress. Information in a CRS Report should not be relied upon for purposes other
than public understanding of information that has been provided by CRS to Members of Congress in
connection with CRS’s institutional role. CRS Reports, as a work of the United States Government, are not
subject to copyright protection in the United States. Any CRS Report may be reproduced and distributed in
its entirety without permission from CRS. However, as a CRS Report may include copyrighted images or
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copy or otherwise use copyrighted material.

Congressional Research Service
R46593 · VERSION 4 · UPDATED
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