mRNA Technologies: A Primer
mRNA Technologies: A Primer
May 24, 2022
Decades of research on messenger RNA (mRNA) and related technologies enabled the rapid
development of the Pfizer/BioNTech and Moderna Coronavirus Disease 2019 (COVID-19)
Marcy E. Gallo
vaccines. Some experts believe that this success portends a revolution in medicine that will bring
Analyst in Science and
better pandemic preparedness and new treatments for disease. This rapid progress may present
Technology Policy
questions for congressional consideration. For example, what is the appropriate role for the
federal government in supporting and coordinating mRNA-related research and development
Frank Gottron
(R&D)?
Specialist in Science and
Technology Policy
Messenger RNA is a biological molecule whose central role in cellular protein production makes
it an attractive target for a host of medical treatments and vaccines. The COVID-19 mRNA
vaccines represent the first Food and Drug Administration-approved uses of mRNA-based
technology. Vaccines against Human Immunodeficiency Virus (HIV), rabies, and influenza and
treatments for cancer and certain rare diseases are in clinical trials. At the same time, mRNA research and the development of
other, more-wide ranging, uses of this technology face challenges, including potential undesired immune responses to
repeated treatments, complications with targeting the appropriate tissue, and the need to protect the mRNA from premature
degradation. The federal government, largely through the National Institutes of Health (NIH) and the Defense Advanced
Research Projects Agency (DARPA), has invested billions of dollars in R&D of mRNA and related technologies.
Despite the research challenges facing further commercial applications, several groups project mRNA-related revenue to
increase by a compound annual growth rate of between 10% and 90% over the next 5 to 10 years. Consistent with these
growth projections, private investments are being made by and in companies of varying size and technology maturity that are
conducting mRNA R&D.
The potential future benefits of mRNA technology and the lessons learned during past R&D on this technology raise some
possible issues for Congress:
In addition to funding the foundational basic research that led to this technology, the federal government
shifted its support during the COVID-19 pandemic to include activities generally left to the private sector,
such as late-stage clinical trials and research, product development, and manufacturing. The appropriate
role of the federal government in late-stage R&D is not a new issue; however, the pandemic would mark an
inflection point if Congress were to continue increased support for such activities.
The difficulty faced by some researchers in obtaining funding for what, in retrospect, were crucial
fundamental studies raises questions about whether NIH’s committee-based peer review process adequately
funds “high-risk, high-reward” projects. Support for high-risk, high-reward research is considered an
important element in developing breakthrough technologies that address societal challenges, including
health-related challenges, and in maintaining the economic competitiveness of the United States. Congress
may have already taken steps to address this through the $1 billion it appropriated for FY2022 to establish
the Advanced Research Projects Agency for Health (ARPA-H) in the Department of Health and Human
Services (HHS). ARPA-H is modeled after DARPA in its approach to funding high-risk, high-reward
research.
Apart from directly setting the level of support for mRNA technology R&D, Congress may consider
options such as facilitating coordination of this research or providing for a technological research plan.
If the U.S. seeks to maintain its global leadership role in the life sciences broadly, and in mRNA
technologies specifically, then Congress would likely face consideration of how to ensure the
implementation of robust federal policies, which may include increased federal R&D funding; an effective
regulatory environment; a well-trained and adequate life sciences workforce; and public and private sector
coordination.
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Contents
Introduction ..................................................................................................................................... 1
What Is mRNA? ........................................................................................................................ 1
mRNA-based Medicine ................................................................................................................... 2
Potential Future Uses ................................................................................................................ 3
Other mRNA-Based Vaccines ............................................................................................. 3
Cancer Treatments .............................................................................................................. 4
Rare Diseases ...................................................................................................................... 5
Research Challenges ................................................................................................................. 5
Federal Support, Market Projections, and Private Investment ........................................................ 6
Federal Support ......................................................................................................................... 6
Market Projections and Private Investment .............................................................................. 7
Potential Considerations for Congress ............................................................................................ 8
Role of the Federal Government ............................................................................................... 8
Coordination of Federal Research ............................................................................................. 9
U.S. Competitiveness .................................................................................................................... 10
Figures
Figure 1. The Role of mRNA in Protein Production ....................................................................... 1
Figure 2. Select mRNA Research Milestones ................................................................................. 3
Contacts
Author Information ......................................................................................................................... 11
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mRNA Technologies: A Primer
Introduction
The unprecedented development speed of the Pfizer/BioNTech and Moderna Coronavirus Disease
2019 (COVID-19) vaccines highlight just one application of emerging technologies based on
messenger RNA (mRNA), which have many promising uses and benefits. In addition to enabling
rapid vaccine development for emerging infectious diseases, these technologies may soon have
wider application in preventing and treating other diseases. This report discusses what mRNA is
and why it has so many potential uses; how the federal government and private companies
developed these technologies; federal and other investments in research and development (R&D)
related to these technologies; future potential uses; and congressional considerations raised by
these technologies.
What Is mRNA?
Ribonucleic acid (RNA) is a macromolecule found in all living cells. Cells use RNA for many
functions, including in protein production. A particular type of RNA, messenger RNA (mRNA),
is so named because it conveys protein-encoding information stored in the cell’s DNA
(deoxyribonucleic acid) to the protein production machinery of the cell. (See Figure 1.) Enzymes
called RNA polymerases “transcribe” the DNA sequence into an mRNA sequence. Then
ribosomes produce specific proteins by linking amino acids in the order directed by the mRNA
sequence, a process known as “translation.”
Figure 1. The Role of mRNA in Protein Production
Source: CRS.
Notes: In correspondence to a DNA sequence, the RNA polymerase enzyme links RNA bases together to form
an mRNA sequence. The mRNA disengages from the DNA strand and travels to a ribosome, which in
correspondence to the mRNA sequence, links amino acids together to form a protein.
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mRNA-based Medicine
Because of its central role in protein production, mRNA is an attractive target for manipulating
the proteins a cell makes without having to alter the cell’s DNA. Adding the appropriate mRNA
to a cell can cause it to make a specified protein. This can be useful in treating and preventing
many diseases. To develop the ability to do this, scientists had to work for decades to overcome
many technical hurdles before realizing the promise of mRNA technology through its first
successful commercial applications, the Pfizer/BioNTech and Moderna COVID-19 vaccines. (See
Figure 2.)
Since the discovery of mRNA in the 1960s, researchers have expanded their understanding of
how it works and its potential role in the treatment and prevention of human disease. Early
research focused on understanding the structure and function of mRNA and its metabolism in
cells. In the late 1960s and early 1970s, scientists were able to produce proteins from mRNA
isolated in the laboratory. In 1984, scientists synthesized mRNA in the laboratory for the first
time. In the early 1990s, scientists reported the first successful uses of mRNA in rodents as a
treatment and as a vaccine. For example, in 1992, scientists caused rats to produce a hormone by
injecting the appropriate mRNA. In 2005, scientists were able to overcome one of the major
hurdles preventing the widespread use of mRNA as a therapeutic—the triggering of an immune
response. This was achieved by modifying the synthetically produced mRNA. The first human
clinical trials for mRNA-based vaccines began in 2014 (rabies) and 2015 (influenza).
The first Food and Drug Administration (FDA)-
approved human uses for mRNA were the 2021
Lipid Nanoparticles
approvals of the COVID-19 vaccines by
Lipid nanoparticles are small bubbles of fat
Pfizer/BioNTech and Moderna. Their success relied on
that can be used to encapsulate mRNA. This
encapsulation can help protect the mRNA
breakthroughs in protecting mRNA from degradation
from degradation before it reaches the
and in using precisely formulated lipid nanoparticles
targeted cel s. Precisely control ing the types
(see text box, “Lipid Nanoparticles”). In contrast to
of lipids and other chemicals used to
other vaccines that rely on injecting premade
produce the nanoparticles can maximize the
amount of mRNA delivered to the targeted
antigens—substances that cause the body to formulate
cells and thus increase the chance that the
an immune response—mRNA-based vaccines cause
cell wil produce the desired protein. Both
cells to make the antigens themselves. In the case of
successful mRNA-based COVID-19 vaccines
the COVID-19 vaccines, the delivered mRNA encodes
relied on precisely formulated lipid
for a modified spike protein on the surface of the
nanoparticles.
SARS-CoV-2 virus (which causes COVID-19). In
other words, the COVID-19 mRNA vaccines cause a person’s cells to make one modified viral
protein, which can trigger an immune response to protect against future exposures to the virus.
One of the most promising aspects of mRNA-based medicine is the relative ease of creating the
mRNA. In particular, it is relatively easy to produce at commercial scale and has the potential to
increase the adaptability of medical interventions, especially of vaccines. Producers of mRNA-
based vaccines can more easily modify their vaccines to account for antigen drift—genetic
changes in a virus that produce a new strain—than traditional vaccine producers. For example, if
new strains of SARS-CoV-2 virus arise that are vaccine resistant because of changes to the spike
protein, mRNA vaccine manufacturers can adjust their mRNA and begin producing an updated
vaccine more quickly than manufacturers of other types of vaccines.
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Figure 2. Select mRNA Research Milestones
Source: CRS, modified from Elie Dolgin, “The Tangled History of mRNA Vaccines,” Nature, vol. 597
(September 16, 2021), p. 323; and Ugur Sahin, Katalin Kariko, and Ozlem Tureci, “mRNA-Based Therapeutics-
Developing a New Class of Drugs,” Nature Reviews Drug Discovery, vol. 13 (October 2014), pp. 760-761.
Potential Future Uses
While scientists have long recognized the potential of RNA-based therapeutics, the rapid
development of mRNA-based COVID-19 vaccines has renewed interest and increased investment
in such technologies. Future mRNA technologies include new mRNA-based vaccines (both
prophylactic/preventative and therapeutic vaccines), as well as non-vaccine therapies. The
following sections provide illustrative examples of the potential uses of mRNA technologies
currently being explored, in addition to outlining some challenges associated with their
development.
Other mRNA-Based Vaccines
As do COVID-19 vaccines, other mRNA-based vaccines seek to trigger a prophylactic or
protective response to a known virus (e.g., Zika, shingles, influenza) through the use of synthetic
mRNA. The synthetic mRNA serves as the template for the production of viral proteins that
activate the body’s immune system and the production of antibodies. As long as the vaccine
induces a sufficient immune response, when a person is subsequently exposed to the targeted
virus then the antibodies will recognize it and help the immune system identify and eliminate the
virus before it can cause illness (or severe illness).
Human Immunodeficiency Virus (HIV)
In January 2022, the International AIDS Vaccine Initiative (IAVI) and Moderna began a Phase I
clinical trial for an mRNA-based HIV vaccine.1 HIV is a fast-evolving virus that has been
difficult to target effectively because of the number and diversity of HIV strains. Many scientists
consider stimulating the production of broadly neutralizing antibodies as the key to developing an
1 Clinical trials are typically divided into three sequential categories or phases. Phase I tests safety and dosage. Phase II
tests effectiveness and side effects. Phase III tests effectiveness and adverse effects in a larger population. For more
information, see CRS Infographic IG10013, The Pharmaceutical Drug Development Process, by Agata Bodie and
Kavya Sekar.
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effective HIV vaccine. The production of broadly neutralizing antibodies will likely involve
sequential vaccinations, and the use of an mRNA-based vaccine platform has the potential to
reduce development times dramatically for such vaccines. According to IAVI and Moderna, the
purpose of the trial is to determine whether the mRNA vaccine platform can safely and
effectively generate a specific immune response (i.e., a rare class of B cells) that is considered the
first step in the process of inducing broadly neutralizing antibodies to HIV.2
Rabies
In January 2020, CureVac reported positive results associated with a Phase I clinical trial for an
mRNA-based rabies vaccine.3 Specifically, all 53 study participants produced antibodies at a level
above the threshold recommended by the World Health Organization (WHO). According to the
WHO, most cases of rabies occur in Africa and Asia, with 40% of cases occurring in children
under the age of 15. The WHO and others are seeking to achieve zero human deaths from dog-
transmitted rabies bites by 2030.4
Influenza
Several companies, including Pfizer, Moderna, CureVac, and Sanofi, are in the process of
developing mRNA-based influenza vaccines. Given the burden of seasonal flu, such companies
were already focused on creating new influenza vaccines before the COVID-19 pandemic.5 Many
see the potentially shorter development time and flexibility associated with mRNA-based vaccine
platforms as being advantageous in addressing the flu, which is caused by four different types of
influenza viruses (A, B, C, and D) with many strains that are constantly changing.6 Current
influenza vaccines—based on inactivated viruses or recombinant proteins—are generally 40% to
60% effective in preventing infection; it remains to be seen whether mRNA-based flu vaccines
would have greater efficacy.7
Cancer Treatments
In general, the primary difference in the use of mRNA-based vaccines for cancer compared to
infectious disease (e.g., COVID-19, influenza) is that they are therapeutic vaccines, meaning the
goal is treatment, not prophylaxis. That is, the synthetic mRNA triggers the immune system to
identify and attack cancer cells that already exist in the patient, rather than teaching the immune
2 IAVI, “IAVI and Moderna Launch Trial of HIV Vaccine Antigens Delivered through mRNA Technology,” press
release, January 27, 2022, https://www.iavi.org/news-resources/press-releases/2022/iavi-and-moderna-launch-trial-of-
mrna-hiv-vaccine-antigens.
3 CureVac, “CureVac Announces Positive Results in Low Dose—1 µg—Rabies Vaccine Clinical Phase 1 Study,” press
release, January 7, 2020, https://www.curevac.com/en/2020/01/07/curevac-announces-positive-results-in-low-dose-1-
%C2%B5g-rabies-vaccine-clinical-phase-1-study/.
4 World Health Organization, Rabies Vaccines: WHO Position Paper, April 2018, https://apps.who.int/iris/bitstream/
handle/10665/272372/WER9316-201-219.pdf.
5 The U.S. Centers for Disease Control and Prevention (CDC) estimates that seasonal flu resulted in 9 million to 41
million illnesses, 140,000 to 710,000 hospitalizations, and 12,000 to 52,000 deaths annually between 2010 and 2020.
According to the CDC, “it uses the estimates of the burden of flu in the population and the impact of flu vaccination to
inform policy and communications related to flu.” (CDC, “Disease Burden of Flu,” https://www.cdc.gov/flu/about/
burden/index.html)
6 Elie Dolgin, “mRNA Flu Shots Move into Trials,” Nature Reviews, vol. 20, November 2021, pp. 801-803.
7 Derek Lowe, “Moderna’s mRNA Flu Vaccine,” December 10, 2021, at https://www.science.org/content/blog-post/
moderna-s-mrna-flu-vaccine.
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system to identify and attack a virus that a patient may later be exposed to. Several
biopharmaceutical companies are pursuing the development of mRNA-based cancer treatments
for a variety of different cancers. For example, BioNTech is developing cancer treatments that
target common molecules associated with cancer cells across patients with a particular type of
cancer, in addition to developing treatments that identify and target cancer mutations that are
unique and specific to a patient (i.e., personalized cancer treatments). Both treatments would help
the patient’s immune system identify and attack cancer cells by providing synthetic mRNA as a
template for the production of antibodies. BioNTech is conducting clinical trials on its broader or
more generalized mRNA-based cancer vaccines for advanced melanoma, prostate cancer, head
and neck cancer, and ovarian cancer. It is conducting clinical trials on its personalized cancer
vaccines for colon cancer, solid tumors, and melanoma.8
Rare Diseases
Messenger RNA technologies also have the potential to treat patients with rare genetic diseases or
other disorders associated with missing or dysfunctional proteins. Similar to the potential uses
described above, synthetic mRNA introduced into a patient’s body would serve as a template for
the production of the missing or dysfunctional protein that is the cause of the rare disease or
disorder. For example, Arcturus Therapeutics is in the process of initiating a Phase Ib clinical trial
to use mRNA to treat Ornithine Transcarbamylase (OTC) Deficiency. OTC is a liver enzyme that
removes ammonia from the body; if ammonia accumulates it can cause diminished cognitive
ability, seizures, coma, and death. The clinical trial seeks to determine the safety and tolerability
of the mRNA treatment, which has the goal of increasing OTC levels in study participants.9 In
another example, Moderna is initiating a Phase I/II clinical trial to treat elevated levels of
methylmalonic acid which are caused by a deficiency or defect in one of the enzymes responsible
for breaking down the acid. High levels of methylmalonic acid can cause drowsiness, coma, and
seizures, among other long-term consequences. The clinical trial seeks to determine the safety of
the mRNA treatment, which has the goal of increasing the amount of enzymes that break down
methylmalonic acid in study participants.10
Research Challenges
While mRNA technologies may have the potential to revolutionize medicine, challenges remain
in unlocking their full potential.11 In particular, the use of mRNA technologies to treat chronic or
genetic diseases would typically require repeated doses to replace a missing or defective protein
over a patient’s lifetime as the mRNA is degraded over time. Repeated dosing could trigger the
body’s immune response and lead to adverse reactions and side effects. There is also a possibility
that the effectiveness of a treatment could wane over time. In addition, there is a need to improve
8 Derek Thompson, “Maybe the Coronavirus Was Lower-Hanging Fruit,” The Atlantic, October 18, 2021,
https://www.theatlantic.com/ideas/archive/2021/10/mrna-vaccines-cure-cancer-biontech/620383/; Kaitlin Sullivan,
Reynolds Lewis, and Akshay Syal, “Could mRNA Vaccines Be the Next Frontier of Cancer Treatment?,” NBC News,
https://www.nbcnews.com/health/cancer/mrna-vaccines-frontier-cancer-treatment-rcna8886; BioNTech, “Pipeline,” at
https://biontech.de/science/pipeline; and BioNTech, “Platforms,” at https://biontech.de/science/platforms.
9 “Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects with Ornithine Transcarbamylase
Deficiency,” NCT04442347, https://clinicaltrials.gov/ct2/show/NCT04442347.
10 “A Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of mRNA-3705 in Participants with Isolated
Methylmalonic Acidemia,” NCT04899310, https://clinicaltrials.gov/ct2/show/NCT04899310.
11 See, for example, Mary Bates, “The mRNA Revolution Is Coming,” IEEE Pulse, November/December 2021,
https://www.embs.org/pulse/articles/the-mrna-revolution-is-coming/; and Kelly Servick, “Messenger RNA Gave Us a
COVID-19 Vaccine. Will It Treat Diseases, Too?,” Science, December 16, 2020, https://www.science.org/content/
article/messenger-rna-gave-us-covid-19-vaccine-will-it-treat-diseases-too.
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mRNA Technologies: A Primer
methods for delivering mRNA drugs or therapeutics to targeted cells or tissues to enable effective
treatment. Finally, the stability of mRNA remains an issue. It requires special cold-chain storage
and handling before use. Additionally, once injected, it is actively degraded by the body, but will
need to persist long enough to have the desired effect. The success of the mRNA-based COVID-
19 vaccines reflects the ability of the research community to overcome these challenges, but they
remain key issues if mRNA technologies are to be expanded beyond their use in vaccine
development.
Federal Support, Market Projections, and Private
Investment
This section discusses federal support for mRNA R&D and related activities (e.g., manufacturing
facilities), recent projections made by market research firms, and selected private investments
related to mRNA technologies.
Federal Support
The success of the mRNA-based COVID-19 vaccines relied on decades of federally supported
research and development on mRNA and lipid nanoparticles, primarily through the National
Institutes of Health and the Defense Advanced Research Projects Agency.
Although NIH—the primary federal agency charged with performing and supporting biomedical
research—has not reported the amount it invested in this development, a group of university
researchers has estimated that between 2000 and 2019 NIH directed approximately $950 million
towards mRNA vaccines and $500 million towards lipid nanoparticles.12
DARPA also contributed to the development of these technologies. Between 2011 and 2020,
DARPA invested approximately $400 million through the Autonomous Diagnostics to Enable
Prevention and Therapeutics (ADEPT) program and the Pandemic Prevention Platform (P3)
program.13 The objective of the ADEPT program was to support “individual troop readiness and
total force health protection by developing technologies to rapidly identify and respond to threats
posed by natural and engineered diseases and toxins,” including “novel methods for rapidly
manufacturing new types of vaccines.”14 In 2011, through the ADEPT program, DARPA started
investing in the development of nucleic acid vaccines.15 The P3 program, an outgrowth of the
ADEPT program, “focuses on rapid discovery, characterization, production, testing, and delivery
of efficacious DNA- and RNA-encoded medical countermeasures,” including vaccines.16
During the COVID-19 pandemic, the Biomedical Advanced Research and Development
Authority (BARDA), an office in the Department of Health and Human Services (HHS),
provided Moderna with approximately $1.4 billion for nonclinical and clinical research to
12 Anthony E. Kiszewski, Ekaterina Galkina Cleary, and Matthew J. Jackson, et al., “NIH Funding for Vaccine
Readiness Before the COVID-19 Pandemic,” Vaccine, vol. 39 (2021), pp. 2458-2466.
13 CRS calculations based on DARPA budget documents. The $400 million figure represents the total amount for the
ADEPT and P3 programs, of which an unspecified portion went to non-mRNA related development.
14 DARPA, “Autonomous Diagnostics to Enable Prevention and Therapeutics (ADEPT),” https://www.darpa.mil/
program/autonomous-diagnostics-to-enable-prevention-and-therapeutics.
15 DARPA, “COVID-19,” https://www.darpa.mil/work-with-us/covid-19.
16 DARPA, “Pandemic Prevention Platform (P3),” https://www.darpa.mil/program/pandemic-prevention-platform.
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develop an mRNA COVID-19 vaccine and to expand manufacturing facilities through Operation
Warp Speed.17
Market Projections and Private Investment
A few market research firms have published market projections for mRNA-based vaccines and
therapeutics. Although estimates vary widely due to different underlying assumptions, these firms
generally predict robust growth for the mRNA vaccine and therapeutic global market.
In August 2020, India-based IMARC estimated that the global market for mRNA
vaccines and therapeutics would grow at a compound annual growth rate
(CAGR) of 10.5%, from $9.41 billion in 2021 to $15.49 billion in 2026.18
In October 2021, Ireland-based Research and Markets estimated that the global
market for mRNA therapeutics would increase from $46.7 billion in 2021 to
$101.3 billion in 2026, a CAGR of 16.8%.19
In 2021, U.S.-based BIS Research estimated that the global market for COVID-
19 mRNA vaccines and therapeutics would decrease from $51.65 billion in 2021
to $28.92 billion in 2025, a CAGR of -13.5%. However, for non-COVID-19
mRNA vaccines and therapeutics, BIS Research estimated that the global market
would increase from $0.05 billion in 2026 to $1.69 billion in 2031, a CAGR of
95.5%.20
Private investments are a commonly used metric for assessing the economic potential of a
technology. Investments are being made by and in companies of varying size and technology
maturity that are conducting mRNA R&D. In addition to numerous mergers and acquisitions,
these companies are engaging in a wide range of collaborations and partnerships. Below are
several examples of investments in, acquisitions of, and partnerships with mRNA technology
firms:
Sanofi, a biopharmaceutical company headquartered in Paris, France, acquired
Bio Translate, a clinical-stage mRNA therapeutics company based in Lexington,
MA, for $3.2 billion in August 2021.21
AbCellara, a biotech company headquartered in Vancouver, Canada, and
Moderna, an mRNA vaccine and therapeutics company headquartered in
Cambridge, MA, announced a multi-year research collaboration in September
17 CRS calculations based on public award announcements. See “BARDA’s Expanding COVID-19 Medical
Countermeasure Portfolio,” at https://www.medicalcountermeasures.gov/app/barda/coronavirus/COVID19.aspx.
Pfizer/BioNTech, the other successful mRNA vaccine developer, did not receive U.S. government funds to conduct
R&D.
18 IMARC, “Global mRNA Vaccines and Therapeutics Market to Reach US$ 15.49 Billion by 2026, Spurred by
Increasing Investments in Biotechnology,” August 31, 2020, https://www.imarcgroup.com/global-mrna-vaccines-
therapeutics-market.
19 Research and Markets, “Outlook on the mRNA Global Market and Therapeutics to 2026,” October 6, 2021,
https://www.globenewswire.com/news-release/2021/10/06/2309400/28124/en/Outlook-on-the-mRNA-Global-Market-
and-Therapeutics-to-2026.html.
20 BIS Research, “Global mRNA Vaccines and Therapeutics Market,” 2021, https://bisresearch.com/industry-report/
mrna-vaccines-therapeutics-market.html.
21 Sanofi, “Sanofi to Acquire Translate Bio; Advances Deployment of mRNA Technology Across Vaccines and
Therapeutics Development,” August 31, 2021, https://www.sanofi.com/en/media-room/press-releases/2021/2021-08-
03-07-00-00-2273307.
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2021 that will use “AbCellera’s AI-powered technology to search and analyze
natural immune responses to identify therapeutic antibodies against up to six
targets selected by Moderna.”22
Strand Therapeutics, an mRNA therapeutics startup based in Cambridge, MA,
raised $52 million in June 2021 to advance the development of its mRNA
platform for cancer immunotherapies and enter into clinical trials.23
Abogen Biosciences, a China-based biotech company, raised over $700 million
in August 2021 to support clinical trials on its mRNA-based COVID-19 vaccine
and the development of other mRNA-based vaccines and treatments.24
Potential Considerations for Congress
The following sections address selected areas that Congress might consider in determining
whether and how to support the advancement of mRNA technologies.
Role of the Federal Government
There is general agreement that the federal government’s role in supporting basic research and the
creation of foundational knowledge was important for the subsequent development of mRNA
technologies. Some experts have noted, however, that in response to the COVID-19 pandemic the
federal government shifted its support to activities generally left to the private sector, including
late-stage clinical trials and research, product development, and manufacturing.25 This shift has
caused some to raise a number of questions about what, if any, changes may be appropriate
regarding federal support for biomedical research and innovation, including advancements in
mRNA technologies, beyond the context of the COVID-19 pandemic. The appropriate role of the
federal government in late-stage R&D is not a new issue; however, the pandemic would mark an
inflection point if Congress were to continue increased support for such activities.
Beyond the degree to which the federal government should provide late-stage research and
innovation funding for mRNA and other biomedical technologies, questions have been raised
regarding traditional funding mechanisms. For example, a number of articles have been written
about how Dr. Katalin Karikó—whose pioneering work on mRNA helped form the foundation for
the mRNA-based COVID-19 vaccines—was unable to get her research funded by NIH.26 NIH
22 AbCellera, “AbCellera Announces Collaboration with Moderna to Discover Therapeutic Antibodies for mRNA
Medicines,” September 15, 2021, https://www.abcellera.com/news/abcellera-collaboration-moderna.
23 Strand Therapeutics, “Strand Therapeutics Raises $52M in Oversubscribed Series A Round,” June 23, 2021,
https://www.businesswire.com/news/home/20210623005302/en/Strand-Therapeutics-Raises-52M-in-Oversubscribed-
Series-A-Round.
24 Nick Paul Taylor, “China’s Abogen Raises $700M Series C for mRNA Trials, Catapulting Itself into the Big
Leagues,” August 20, 2021, https://www.fiercebiotech.com/biotech/china-s-abogen-raises-700m-series-c-for-mrna-
trials-catapulting-itself-into-big-leagues.
25 Bhaven N. Sampat and Kenneth C. Shadlen, “The COVID-19 Innovation System,” Health Affairs, vol. 40, no. 3
(February 4, 2021), https://www.healthaffairs.org/doi/full/10.1377/hlthaff.2020.02097#B21.
26 See, for example, Damian Garde and Jonathan Saltzman, “The Story of mRNA: How a Once-Dismissed Idea
Became a Leading Technology in the COVID Vaccine Race,” STATNews, November 10, 2020,
https://www.statnews.com/2020/11/10/the-story-of-mrna-how-a-once-dismissed-idea-became-a-leading-technology-in-
the-covid-vaccine-race/; and Carolyn Y. Johnson, “Vaccine Vanguard: A One-Way Ticket. A Cash-Stuffed Teddy
Bear. A Dream Decades in the Making,” Washington Post, October 1, 2021, https://www.washingtonpost.com/health/
2021/10/01/katalin-kariko-covid-vaccines/.
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funds most of its research through the scientific peer review process—a committee-based review
process to evaluate scientific, investigator-driven research proposals for funding.27 Some analysts
suggest that this investigator-driven and consensus-based process may not adequately fund “high-
risk, high-reward” projects,28 a term often associated with projects that have high potential for
meeting fundamental scientific or technological challenges and that involve a high degree of
novelty and/or multidisciplinary approaches.29 Support for high-risk, high-reward research is
widely considered an important element in developing breakthrough technologies that address
societal challenges, including health-related challenges, and in maintaining the economic
competitiveness of the United States.30
Through FY2022 appropriations, Congress provided $1 billion to HHS to establish the Advanced
Research Projects Agency for Health (ARPA-H).31 Some view ARPA-H as a necessary response
to concerns about the risk aversion of traditional funding mechanisms, as well as a way to
accelerate the development of biomedical technologies.32 According to a concept paper issued by
the Biden Administration, one of the potential projects that ARPA-H could pursue is the
development of mRNA-based vaccines that would prevent most cancers.33 President Biden’s
FY2023 budget request proposes $5 billion for ARPA-H in an NIH account, with funding
available until September 30, 2025.34 Congress could consider how to define the mission of
ARPA-H and the activities it would support, in addition to providing funding for the agency, if it
seeks to use this approach to advance the development of mRNA technologies.
Coordination of Federal Research
According to an Organization for Economic Cooperation and Development (OECD) workshop,
Priority Setting and Coordination of Research Agendas: Lessons Learned from COVID 19:
Priority setting, steering and coordination of research efforts has been a major challenge.
From the policy perspective, different parts of government have different priorities and
different requirements for scientific evidence and research. In the absence of effective
27 See “Peer Review Process for Extramural Funding” in CRS Report R41705, The National Institutes of Health (NIH):
Background and Congressional Issues, by Judith A. Johnson and Kavya Sekar.
28 Chiara Franzoni, Paula Stephan, and Reinhilde Veugelers, “Funding Risky Research,” National Bureau of Economic
Research Working Paper, June 2021; Mikko Packalen and Jay Bhattacharya, “NIH Funding and the Pursuit of Edge
Science,” Proceedings of the National Academy of Sciences, vol. 117, no. 22 (June 2, 2020), pp. 12011-12016; and
Pierre Azoulay, Erica Fuchs, and Anna Goldstein, “Funding Breakthrough Research: Promises and Challenges of the
‘ARPA Model,’” National Bureau of Economic Research, June 2018.
29 For a discussion of definitions of “high-risk, high-reward research,” see pp. 11-13 of Organization for Economic
Cooperation and Development (OECD), Effective Policies to Foster High-Risk/High-Reward Research, OECD
Science, Technology, and Industry Policy Papers, No. 112, May 2021, https://read.oecd.org/10.1787/06913b3b-en?
format=pdf.
30 Organization for Economic Cooperation and Development (OECD), Effective Policies to Foster High-Risk/High-
Reward Research, OECD Science, Technology, and Industry Policy Papers, No. 112, May 2021, https://read.oecd.org/
10.1787/06913b3b-en?format=pdf.
31 For more on ARPA-H see, CRS Report R47074, Advanced Research Projects Agency for Health (ARPA-H):
Congressional Action and Selected Policy Issues, by Kavya Sekar and Marcy E. Gallo.
32 For example, see Suzanne Wright Foundation, “HARPA: Health Advanced Research Projects
Agency,” https://www.harpa.org/; and Bhaven N. Sampat and Robert Cook-Deegan, “An ARPA for Health
Research?,” Milbank Quarterly, https://www.milbank.org/quarterly/opinions/an-arpa-for-health-research/.
33 White House, Advanced Research Project Agency for Health (ARPA-H): Concept
Paper, https://www.whitehouse.gov/wp-content/uploads/2021/06/ARPA-H-Concept-Paper.pdf.
34 NIH, Congressional Justification: FY2023, March 28, 2022, p. 33, https://officeofbudget.od.nih.gov/pdfs/FY23/br/
Overview%20of%20FY%202023%20Presidents%20Budget.pdf.
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mRNA Technologies: A Primer
cross-government (and cross-agency) coordination, this can lead to fragmentation and/or
duplication of research efforts, with insufficient attention being given to some areas (such
as PHSMs [public health and social measures]).35
Advancement of mRNA technologies, including the development of mRNA-based vaccines in
response to future pandemics, might benefit from the development of a research roadmap, a
federal standing committee, or a process for coordination and communication. In 2020, NIH
created the “Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-
private partnership to develop a coordinated research strategy for prioritizing and speeding
development of the most promising [COVID-19] treatments and vaccines.”36 ACTIV is
coordinated by the Foundation for the National Institutes of Health and includes NIH, BARDA,
FDA, the Centers for Disease Control and Prevention, the Department of Defense, the
Department of Veterans Affairs, the European Medicines Agency, and representatives from
academia, philanthropic organizations, and biopharmaceutical companies.37 Congress could
consider modifying ACTIV or creating a similar mechanism for post-COVID-19 research
coordination. An assessment by the Office of Science and Technology Policy, the Government
Accountability Office, or the National Academies of Science, Engineering, and Medicine might
also be helpful in suggesting strategies for increased and enhanced coordination of mRNA R&D.
After past disease outbreaks, such as Ebola and Zika, federal funding for related research
declined. A similar decline in research funding for mRNA technologies after the COVID-19
pandemic subsides, some argue, might stunt the projected growth in this field. Continued and
enhanced cross-agency coordination and evaluation of federal R&D efforts associated with
mRNA technologies and their potential in future pandemics might also help to address such
concerns.
U.S. Competitiveness
While the United States remains the global leader in the life sciences, concerns about future
leadership abound. According to the Information Technology and Innovation Foundation,
During the last few decades, other nations have come to realize the importance of the [life
sciences] sector to their economies and have therefore increasingly tried to win a larger
share of global life-sciences activity. These efforts have been marginally successful, in part
because U.S. policy has been less than fully adequate. The competitive threat is important
because if the United States’ advantage of having a strong ecosystem gets eroded beyond
a certain point, it will be extremely difficult to regain.38
As indicated above, many expect mRNA technologies to play a prominent role in the future of the
pharmaceutical industry and medicine. If the United States seeks to maintain its leadership role in
the life sciences broadly, and in mRNA technologies, specifically, then Congress may consider
options to ensure the implementation of robust federal policies, which may include increased
35 OECD Global Science Forum, Workshop on “Priority Setting and Coordination of Research Agendas: Lessons
Learned from COVID-19,” Workshop Summary, January 20, 2022, https://one.oecd.org/document/DSTI/STP/
GSF(2021)21/FINAL/en/pdf.
36 NIH, “Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV),” https://www.nih.gov/research-
training/medical-research-initiatives/activ.
37 Foundation for the National Institutes of Health, “About ACTIV,” https://www.fnih.org/our-programs/activ/about.
38 Joe Kennedy, How to Ensure That America’s Life-Sciences Sector Remains Globally Competitive, Information
Technology and Innovation Foundation, Washington, DC, March 2018 (Revised July 2020), p. 1, https://www2.itif.org/
2018-life-sciences-globally-competitive.pdf.
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federal R&D funding; an effective regulatory environment; a well-trained and adequate life
sciences workforce; and public and private sector coordination.
Author Information
Marcy E. Gallo
Frank Gottron
Analyst in Science and Technology Policy
Specialist in Science and Technology 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
material from a third party, you may need to obtain the permission of the copyright holder if you wish to
copy or otherwise use copyrighted material.
Congressional Research Service
R47112 · VERSION 1 · NEW
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May 24, 2022
Decades of research on messenger RNA (mRNA) and related technologies enabled the rapid
development of the Pfizer/BioNTech and Moderna Coronavirus Disease 2019 (COVID-19)
Marcy E. Gallo
vaccines. Some experts believe that this success portends a revolution in medicine that will bring
Analyst in Science and
better pandemic preparedness and new treatments for disease. This rapid progress may present
Technology Policy
questions for congressional consideration. For example, what is the appropriate role for the
federal government in supporting and coordinating mRNA-related research and development
Frank Gottron
(R&D)?
Specialist in Science and
Technology Policy
Messenger RNA is a biological molecule whose central role in cellular protein production makes
it an attractive target for a host of medical treatments and vaccines. The COVID-19 mRNA
vaccines represent the first Food and Drug Administration-approved uses of mRNA-based
technology. Vaccines against Human Immunodeficiency Virus (HIV), rabies, and influenza and
treatments for cancer and certain rare diseases are in clinical trials. At the same time, mRNA research and the development of
other, more-wide ranging, uses of this technology face challenges, including potential undesired immune responses to
repeated treatments, complications with targeting the appropriate tissue, and the need to protect the mRNA from premature
degradation. The federal government, largely through the National Institutes of Health (NIH) and the Defense Advanced
Research Projects Agency (DARPA), has invested billions of dollars in R&D of mRNA and related technologies.
Despite the research challenges facing further commercial applications, several groups project mRNA-related revenue to
increase by a compound annual growth rate of between 10% and 90% over the next 5 to 10 years. Consistent with these
growth projections, private investments are being made by and in companies of varying size and technology maturity that are
conducting mRNA R&D.
The potential future benefits of mRNA technology and the lessons learned during past R&D on this technology raise some
possible issues for Congress:
In addition to funding the foundational basic research that led to this technology, the federal government
shifted its support during the COVID-19 pandemic to include activities generally left to the private sector,
such as late-stage clinical trials and research, product development, and manufacturing. The appropriate
role of the federal government in late-stage R&D is not a new issue; however, the pandemic would mark an
inflection point if Congress were to continue increased support for such activities.
The difficulty faced by some researchers in obtaining funding for what, in retrospect, were crucial
fundamental studies raises questions about whether NIH’s committee-based peer review process adequately
funds “high-risk, high-reward” projects. Support for high-risk, high-reward research is considered an
important element in developing breakthrough technologies that address societal challenges, including
health-related challenges, and in maintaining the economic competitiveness of the United States. Congress
may have already taken steps to address this through the $1 billion it appropriated for FY2022 to establish
the Advanced Research Projects Agency for Health (ARPA-H) in the Department of Health and Human
Services (HHS). ARPA-H is modeled after DARPA in its approach to funding high-risk, high-reward
research.
Apart from directly setting the level of support for mRNA technology R&D, Congress may consider
options such as facilitating coordination of this research or providing for a technological research plan.
If the U.S. seeks to maintain its global leadership role in the life sciences broadly, and in mRNA
technologies specifically, then Congress would likely face consideration of how to ensure the
implementation of robust federal policies, which may include increased federal R&D funding; an effective
regulatory environment; a well-trained and adequate life sciences workforce; and public and private sector
coordination.
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link to page 4 link to page 4 link to page 5 link to page 6 link to page 6 link to page 7 link to page 8 link to page 8 link to page 9 link to page 9 link to page 10 link to page 11 link to page 11 link to page 12 link to page 13 link to page 4 link to page 6 link to page 14 mRNA Technologies: A Primer
Contents
Introduction ..................................................................................................................................... 1
What Is mRNA? ........................................................................................................................ 1
mRNA-based Medicine ................................................................................................................... 2
Potential Future Uses ................................................................................................................ 3
Other mRNA-Based Vaccines ............................................................................................. 3
Cancer Treatments .............................................................................................................. 4
Rare Diseases ...................................................................................................................... 5
Research Challenges ................................................................................................................. 5
Federal Support, Market Projections, and Private Investment ........................................................ 6
Federal Support ......................................................................................................................... 6
Market Projections and Private Investment .............................................................................. 7
Potential Considerations for Congress ............................................................................................ 8
Role of the Federal Government ............................................................................................... 8
Coordination of Federal Research ............................................................................................. 9
U.S. Competitiveness .................................................................................................................... 10
Figures
Figure 1. The Role of mRNA in Protein Production ....................................................................... 1
Figure 2. Select mRNA Research Milestones ................................................................................. 3
Contacts
Author Information ......................................................................................................................... 11
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mRNA Technologies: A Primer
Introduction
The unprecedented development speed of the Pfizer/BioNTech and Moderna Coronavirus Disease
2019 (COVID-19) vaccines highlight just one application of emerging technologies based on
messenger RNA (mRNA), which have many promising uses and benefits. In addition to enabling
rapid vaccine development for emerging infectious diseases, these technologies may soon have
wider application in preventing and treating other diseases. This report discusses what mRNA is
and why it has so many potential uses; how the federal government and private companies
developed these technologies; federal and other investments in research and development (R&D)
related to these technologies; future potential uses; and congressional considerations raised by
these technologies.
What Is mRNA?
Ribonucleic acid (RNA) is a macromolecule found in all living cells. Cells use RNA for many
functions, including in protein production. A particular type of RNA, messenger RNA (mRNA),
is so named because it conveys protein-encoding information stored in the cell’s DNA
(deoxyribonucleic acid) to the protein production machinery of the cell. (See Figure 1.) Enzymes
called RNA polymerases “transcribe” the DNA sequence into an mRNA sequence. Then
ribosomes produce specific proteins by linking amino acids in the order directed by the mRNA
sequence, a process known as “translation.”
Figure 1. The Role of mRNA in Protein Production
Source: CRS.
Notes: In correspondence to a DNA sequence, the RNA polymerase enzyme links RNA bases together to form
an mRNA sequence. The mRNA disengages from the DNA strand and travels to a ribosome, which in
correspondence to the mRNA sequence, links amino acids together to form a protein.
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mRNA-based Medicine
Because of its central role in protein production, mRNA is an attractive target for manipulating
the proteins a cell makes without having to alter the cell’s DNA. Adding the appropriate mRNA
to a cell can cause it to make a specified protein. This can be useful in treating and preventing
many diseases. To develop the ability to do this, scientists had to work for decades to overcome
many technical hurdles before realizing the promise of mRNA technology through its first
successful commercial applications, the Pfizer/BioNTech and Moderna COVID-19 vaccines. (See
Figure 2.)
Since the discovery of mRNA in the 1960s, researchers have expanded their understanding of
how it works and its potential role in the treatment and prevention of human disease. Early
research focused on understanding the structure and function of mRNA and its metabolism in
cells. In the late 1960s and early 1970s, scientists were able to produce proteins from mRNA
isolated in the laboratory. In 1984, scientists synthesized mRNA in the laboratory for the first
time. In the early 1990s, scientists reported the first successful uses of mRNA in rodents as a
treatment and as a vaccine. For example, in 1992, scientists caused rats to produce a hormone by
injecting the appropriate mRNA. In 2005, scientists were able to overcome one of the major
hurdles preventing the widespread use of mRNA as a therapeutic—the triggering of an immune
response. This was achieved by modifying the synthetically produced mRNA. The first human
clinical trials for mRNA-based vaccines began in 2014 (rabies) and 2015 (influenza).
The first Food and Drug Administration (FDA)-
approved human uses for mRNA were the 2021
Lipid Nanoparticles
approvals of the COVID-19 vaccines by
Lipid nanoparticles are small bubbles of fat
Pfizer/BioNTech and Moderna. Their success relied on
that can be used to encapsulate mRNA. This
encapsulation can help protect the mRNA
breakthroughs in protecting mRNA from degradation
from degradation before it reaches the
and in using precisely formulated lipid nanoparticles
targeted cel s. Precisely control ing the types
(see text box, “Lipid Nanoparticles”). In contrast to
of lipids and other chemicals used to
other vaccines that rely on injecting premade
produce the nanoparticles can maximize the
amount of mRNA delivered to the targeted
antigens—substances that cause the body to formulate
cells and thus increase the chance that the
an immune response—mRNA-based vaccines cause
cell wil produce the desired protein. Both
cells to make the antigens themselves. In the case of
successful mRNA-based COVID-19 vaccines
the COVID-19 vaccines, the delivered mRNA encodes
relied on precisely formulated lipid
for a modified spike protein on the surface of the
nanoparticles.
SARS-CoV-2 virus (which causes COVID-19). In
other words, the COVID-19 mRNA vaccines cause a person’s cells to make one modified viral
protein, which can trigger an immune response to protect against future exposures to the virus.
One of the most promising aspects of mRNA-based medicine is the relative ease of creating the
mRNA. In particular, it is relatively easy to produce at commercial scale and has the potential to
increase the adaptability of medical interventions, especially of vaccines. Producers of mRNA-
based vaccines can more easily modify their vaccines to account for antigen drift—genetic
changes in a virus that produce a new strain—than traditional vaccine producers. For example, if
new strains of SARS-CoV-2 virus arise that are vaccine resistant because of changes to the spike
protein, mRNA vaccine manufacturers can adjust their mRNA and begin producing an updated
vaccine more quickly than manufacturers of other types of vaccines.
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Figure 2. Select mRNA Research Milestones
Source: CRS, modified from Elie Dolgin, “The Tangled History of mRNA Vaccines,” Nature, vol. 597
(September 16, 2021), p. 323; and Ugur Sahin, Katalin Kariko, and Ozlem Tureci, “mRNA-Based Therapeutics-
Developing a New Class of Drugs,” Nature Reviews Drug Discovery, vol. 13 (October 2014), pp. 760-761.
Potential Future Uses
While scientists have long recognized the potential of RNA-based therapeutics, the rapid
development of mRNA-based COVID-19 vaccines has renewed interest and increased investment
in such technologies. Future mRNA technologies include new mRNA-based vaccines (both
prophylactic/preventative and therapeutic vaccines), as well as non-vaccine therapies. The
following sections provide illustrative examples of the potential uses of mRNA technologies
currently being explored, in addition to outlining some challenges associated with their
development.
Other mRNA-Based Vaccines
As do COVID-19 vaccines, other mRNA-based vaccines seek to trigger a prophylactic or
protective response to a known virus (e.g., Zika, shingles, influenza) through the use of synthetic
mRNA. The synthetic mRNA serves as the template for the production of viral proteins that
activate the body’s immune system and the production of antibodies. As long as the vaccine
induces a sufficient immune response, when a person is subsequently exposed to the targeted
virus then the antibodies will recognize it and help the immune system identify and eliminate the
virus before it can cause illness (or severe illness).
Human Immunodeficiency Virus (HIV)
In January 2022, the International AIDS Vaccine Initiative (IAVI) and Moderna began a Phase I
clinical trial for an mRNA-based HIV vaccine.1 HIV is a fast-evolving virus that has been
difficult to target effectively because of the number and diversity of HIV strains. Many scientists
consider stimulating the production of broadly neutralizing antibodies as the key to developing an
1 Clinical trials are typically divided into three sequential categories or phases. Phase I tests safety and dosage. Phase II
tests effectiveness and side effects. Phase III tests effectiveness and adverse effects in a larger population. For more
information, see CRS Infographic IG10013, The Pharmaceutical Drug Development Process, by Agata Bodie and
Kavya Sekar.
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effective HIV vaccine. The production of broadly neutralizing antibodies will likely involve
sequential vaccinations, and the use of an mRNA-based vaccine platform has the potential to
reduce development times dramatically for such vaccines. According to IAVI and Moderna, the
purpose of the trial is to determine whether the mRNA vaccine platform can safely and
effectively generate a specific immune response (i.e., a rare class of B cells) that is considered the
first step in the process of inducing broadly neutralizing antibodies to HIV.2
Rabies
In January 2020, CureVac reported positive results associated with a Phase I clinical trial for an
mRNA-based rabies vaccine.3 Specifically, all 53 study participants produced antibodies at a level
above the threshold recommended by the World Health Organization (WHO). According to the
WHO, most cases of rabies occur in Africa and Asia, with 40% of cases occurring in children
under the age of 15. The WHO and others are seeking to achieve zero human deaths from dog-
transmitted rabies bites by 2030.4
Influenza
Several companies, including Pfizer, Moderna, CureVac, and Sanofi, are in the process of
developing mRNA-based influenza vaccines. Given the burden of seasonal flu, such companies
were already focused on creating new influenza vaccines before the COVID-19 pandemic.5 Many
see the potentially shorter development time and flexibility associated with mRNA-based vaccine
platforms as being advantageous in addressing the flu, which is caused by four different types of
influenza viruses (A, B, C, and D) with many strains that are constantly changing.6 Current
influenza vaccines—based on inactivated viruses or recombinant proteins—are generally 40% to
60% effective in preventing infection; it remains to be seen whether mRNA-based flu vaccines
would have greater efficacy.7
Cancer Treatments
In general, the primary difference in the use of mRNA-based vaccines for cancer compared to
infectious disease (e.g., COVID-19, influenza) is that they are therapeutic vaccines, meaning the
goal is treatment, not prophylaxis. That is, the synthetic mRNA triggers the immune system to
identify and attack cancer cells that already exist in the patient, rather than teaching the immune
2 IAVI, “IAVI and Moderna Launch Trial of HIV Vaccine Antigens Delivered through mRNA Technology,” press
release, January 27, 2022, https://www.iavi.org/news-resources/press-releases/2022/iavi-and-moderna-launch-trial-of-
mrna-hiv-vaccine-antigens.
3 CureVac, “CureVac Announces Positive Results in Low Dose—1 µg—Rabies Vaccine Clinical Phase 1 Study,” press
release, January 7, 2020, https://www.curevac.com/en/2020/01/07/curevac-announces-positive-results-in-low-dose-1-
%C2%B5g-rabies-vaccine-clinical-phase-1-study/.
4 World Health Organization, Rabies Vaccines: WHO Position Paper, April 2018, https://apps.who.int/iris/bitstream/
handle/10665/272372/WER9316-201-219.pdf.
5 The U.S. Centers for Disease Control and Prevention (CDC) estimates that seasonal flu resulted in 9 million to 41
million illnesses, 140,000 to 710,000 hospitalizations, and 12,000 to 52,000 deaths annually between 2010 and 2020.
According to the CDC, “it uses the estimates of the burden of flu in the population and the impact of flu vaccination to
inform policy and communications related to flu.” (CDC, “Disease Burden of Flu,” https://www.cdc.gov/flu/about/
burden/index.html)
6 Elie Dolgin, “mRNA Flu Shots Move into Trials,” Nature Reviews, vol. 20, November 2021, pp. 801-803.
7 Derek Lowe, “Moderna’s mRNA Flu Vaccine,” December 10, 2021, at https://www.science.org/content/blog-post/
moderna-s-mrna-flu-vaccine.
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system to identify and attack a virus that a patient may later be exposed to. Several
biopharmaceutical companies are pursuing the development of mRNA-based cancer treatments
for a variety of different cancers. For example, BioNTech is developing cancer treatments that
target common molecules associated with cancer cells across patients with a particular type of
cancer, in addition to developing treatments that identify and target cancer mutations that are
unique and specific to a patient (i.e., personalized cancer treatments). Both treatments would help
the patient’s immune system identify and attack cancer cells by providing synthetic mRNA as a
template for the production of antibodies. BioNTech is conducting clinical trials on its broader or
more generalized mRNA-based cancer vaccines for advanced melanoma, prostate cancer, head
and neck cancer, and ovarian cancer. It is conducting clinical trials on its personalized cancer
vaccines for colon cancer, solid tumors, and melanoma.8
Rare Diseases
Messenger RNA technologies also have the potential to treat patients with rare genetic diseases or
other disorders associated with missing or dysfunctional proteins. Similar to the potential uses
described above, synthetic mRNA introduced into a patient’s body would serve as a template for
the production of the missing or dysfunctional protein that is the cause of the rare disease or
disorder. For example, Arcturus Therapeutics is in the process of initiating a Phase Ib clinical trial
to use mRNA to treat Ornithine Transcarbamylase (OTC) Deficiency. OTC is a liver enzyme that
removes ammonia from the body; if ammonia accumulates it can cause diminished cognitive
ability, seizures, coma, and death. The clinical trial seeks to determine the safety and tolerability
of the mRNA treatment, which has the goal of increasing OTC levels in study participants.9 In
another example, Moderna is initiating a Phase I/II clinical trial to treat elevated levels of
methylmalonic acid which are caused by a deficiency or defect in one of the enzymes responsible
for breaking down the acid. High levels of methylmalonic acid can cause drowsiness, coma, and
seizures, among other long-term consequences. The clinical trial seeks to determine the safety of
the mRNA treatment, which has the goal of increasing the amount of enzymes that break down
methylmalonic acid in study participants.10
Research Challenges
While mRNA technologies may have the potential to revolutionize medicine, challenges remain
in unlocking their full potential.11 In particular, the use of mRNA technologies to treat chronic or
genetic diseases would typically require repeated doses to replace a missing or defective protein
over a patient’s lifetime as the mRNA is degraded over time. Repeated dosing could trigger the
body’s immune response and lead to adverse reactions and side effects. There is also a possibility
that the effectiveness of a treatment could wane over time. In addition, there is a need to improve
8 Derek Thompson, “Maybe the Coronavirus Was Lower-Hanging Fruit,” The Atlantic, October 18, 2021,
https://www.theatlantic.com/ideas/archive/2021/10/mrna-vaccines-cure-cancer-biontech/620383/; Kaitlin Sullivan,
Reynolds Lewis, and Akshay Syal, “Could mRNA Vaccines Be the Next Frontier of Cancer Treatment?,” NBC News,
https://www.nbcnews.com/health/cancer/mrna-vaccines-frontier-cancer-treatment-rcna8886; BioNTech, “Pipeline,” at
https://biontech.de/science/pipeline; and BioNTech, “Platforms,” at https://biontech.de/science/platforms.
9 “Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects with Ornithine Transcarbamylase
Deficiency,” NCT04442347, https://clinicaltrials.gov/ct2/show/NCT04442347.
10 “A Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of mRNA-3705 in Participants with Isolated
Methylmalonic Acidemia,” NCT04899310, https://clinicaltrials.gov/ct2/show/NCT04899310.
11 See, for example, Mary Bates, “The mRNA Revolution Is Coming,” IEEE Pulse, November/December 2021,
https://www.embs.org/pulse/articles/the-mrna-revolution-is-coming/; and Kelly Servick, “Messenger RNA Gave Us a
COVID-19 Vaccine. Will It Treat Diseases, Too?,” Science, December 16, 2020, https://www.science.org/content/
article/messenger-rna-gave-us-covid-19-vaccine-will-it-treat-diseases-too.
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methods for delivering mRNA drugs or therapeutics to targeted cells or tissues to enable effective
treatment. Finally, the stability of mRNA remains an issue. It requires special cold-chain storage
and handling before use. Additionally, once injected, it is actively degraded by the body, but will
need to persist long enough to have the desired effect. The success of the mRNA-based COVID-
19 vaccines reflects the ability of the research community to overcome these challenges, but they
remain key issues if mRNA technologies are to be expanded beyond their use in vaccine
development.
Federal Support, Market Projections, and Private
Investment
This section discusses federal support for mRNA R&D and related activities (e.g., manufacturing
facilities), recent projections made by market research firms, and selected private investments
related to mRNA technologies.
Federal Support
The success of the mRNA-based COVID-19 vaccines relied on decades of federally supported
research and development on mRNA and lipid nanoparticles, primarily through the National
Institutes of Health and the Defense Advanced Research Projects Agency.
Although NIH—the primary federal agency charged with performing and supporting biomedical
research—has not reported the amount it invested in this development, a group of university
researchers has estimated that between 2000 and 2019 NIH directed approximately $950 million
towards mRNA vaccines and $500 million towards lipid nanoparticles.12
DARPA also contributed to the development of these technologies. Between 2011 and 2020,
DARPA invested approximately $400 million through the Autonomous Diagnostics to Enable
Prevention and Therapeutics (ADEPT) program and the Pandemic Prevention Platform (P3)
program.13 The objective of the ADEPT program was to support “individual troop readiness and
total force health protection by developing technologies to rapidly identify and respond to threats
posed by natural and engineered diseases and toxins,” including “novel methods for rapidly
manufacturing new types of vaccines.”14 In 2011, through the ADEPT program, DARPA started
investing in the development of nucleic acid vaccines.15 The P3 program, an outgrowth of the
ADEPT program, “focuses on rapid discovery, characterization, production, testing, and delivery
of efficacious DNA- and RNA-encoded medical countermeasures,” including vaccines.16
During the COVID-19 pandemic, the Biomedical Advanced Research and Development
Authority (BARDA), an office in the Department of Health and Human Services (HHS),
provided Moderna with approximately $1.4 billion for nonclinical and clinical research to
12 Anthony E. Kiszewski, Ekaterina Galkina Cleary, and Matthew J. Jackson, et al., “NIH Funding for Vaccine
Readiness Before the COVID-19 Pandemic,” Vaccine, vol. 39 (2021), pp. 2458-2466.
13 CRS calculations based on DARPA budget documents. The $400 million figure represents the total amount for the
ADEPT and P3 programs, of which an unspecified portion went to non-mRNA related development.
14 DARPA, “Autonomous Diagnostics to Enable Prevention and Therapeutics (ADEPT),” https://www.darpa.mil/
program/autonomous-diagnostics-to-enable-prevention-and-therapeutics.
15 DARPA, “COVID-19,” https://www.darpa.mil/work-with-us/covid-19.
16 DARPA, “Pandemic Prevention Platform (P3),” https://www.darpa.mil/program/pandemic-prevention-platform.
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develop an mRNA COVID-19 vaccine and to expand manufacturing facilities through Operation
Warp Speed.17
Market Projections and Private Investment
A few market research firms have published market projections for mRNA-based vaccines and
therapeutics. Although estimates vary widely due to different underlying assumptions, these firms
generally predict robust growth for the mRNA vaccine and therapeutic global market.
In August 2020, India-based IMARC estimated that the global market for mRNA
vaccines and therapeutics would grow at a compound annual growth rate
(CAGR) of 10.5%, from $9.41 billion in 2021 to $15.49 billion in 2026.18
In October 2021, Ireland-based Research and Markets estimated that the global
market for mRNA therapeutics would increase from $46.7 billion in 2021 to
$101.3 billion in 2026, a CAGR of 16.8%.19
In 2021, U.S.-based BIS Research estimated that the global market for COVID-
19 mRNA vaccines and therapeutics would decrease from $51.65 billion in 2021
to $28.92 billion in 2025, a CAGR of -13.5%. However, for non-COVID-19
mRNA vaccines and therapeutics, BIS Research estimated that the global market
would increase from $0.05 billion in 2026 to $1.69 billion in 2031, a CAGR of
95.5%.20
Private investments are a commonly used metric for assessing the economic potential of a
technology. Investments are being made by and in companies of varying size and technology
maturity that are conducting mRNA R&D. In addition to numerous mergers and acquisitions,
these companies are engaging in a wide range of collaborations and partnerships. Below are
several examples of investments in, acquisitions of, and partnerships with mRNA technology
firms:
Sanofi, a biopharmaceutical company headquartered in Paris, France, acquired
Bio Translate, a clinical-stage mRNA therapeutics company based in Lexington,
MA, for $3.2 billion in August 2021.21
AbCellara, a biotech company headquartered in Vancouver, Canada, and
Moderna, an mRNA vaccine and therapeutics company headquartered in
Cambridge, MA, announced a multi-year research collaboration in September
17 CRS calculations based on public award announcements. See “BARDA’s Expanding COVID-19 Medical
Countermeasure Portfolio,” at https://www.medicalcountermeasures.gov/app/barda/coronavirus/COVID19.aspx.
Pfizer/BioNTech, the other successful mRNA vaccine developer, did not receive U.S. government funds to conduct
R&D.
18 IMARC, “Global mRNA Vaccines and Therapeutics Market to Reach US$ 15.49 Billion by 2026, Spurred by
Increasing Investments in Biotechnology,” August 31, 2020, https://www.imarcgroup.com/global-mrna-vaccines-
therapeutics-market.
19 Research and Markets, “Outlook on the mRNA Global Market and Therapeutics to 2026,” October 6, 2021,
https://www.globenewswire.com/news-release/2021/10/06/2309400/28124/en/Outlook-on-the-mRNA-Global-Market-
and-Therapeutics-to-2026.html.
20 BIS Research, “Global mRNA Vaccines and Therapeutics Market,” 2021, https://bisresearch.com/industry-report/
mrna-vaccines-therapeutics-market.html.
21 Sanofi, “Sanofi to Acquire Translate Bio; Advances Deployment of mRNA Technology Across Vaccines and
Therapeutics Development,” August 31, 2021, https://www.sanofi.com/en/media-room/press-releases/2021/2021-08-
03-07-00-00-2273307.
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2021 that will use “AbCellera’s AI-powered technology to search and analyze
natural immune responses to identify therapeutic antibodies against up to six
targets selected by Moderna.”22
Strand Therapeutics, an mRNA therapeutics startup based in Cambridge, MA,
raised $52 million in June 2021 to advance the development of its mRNA
platform for cancer immunotherapies and enter into clinical trials.23
Abogen Biosciences, a China-based biotech company, raised over $700 million
in August 2021 to support clinical trials on its mRNA-based COVID-19 vaccine
and the development of other mRNA-based vaccines and treatments.24
Potential Considerations for Congress
The following sections address selected areas that Congress might consider in determining
whether and how to support the advancement of mRNA technologies.
Role of the Federal Government
There is general agreement that the federal government’s role in supporting basic research and the
creation of foundational knowledge was important for the subsequent development of mRNA
technologies. Some experts have noted, however, that in response to the COVID-19 pandemic the
federal government shifted its support to activities generally left to the private sector, including
late-stage clinical trials and research, product development, and manufacturing.25 This shift has
caused some to raise a number of questions about what, if any, changes may be appropriate
regarding federal support for biomedical research and innovation, including advancements in
mRNA technologies, beyond the context of the COVID-19 pandemic. The appropriate role of the
federal government in late-stage R&D is not a new issue; however, the pandemic would mark an
inflection point if Congress were to continue increased support for such activities.
Beyond the degree to which the federal government should provide late-stage research and
innovation funding for mRNA and other biomedical technologies, questions have been raised
regarding traditional funding mechanisms. For example, a number of articles have been written
about how Dr. Katalin Karikó—whose pioneering work on mRNA helped form the foundation for
the mRNA-based COVID-19 vaccines—was unable to get her research funded by NIH.26 NIH
22 AbCellera, “AbCellera Announces Collaboration with Moderna to Discover Therapeutic Antibodies for mRNA
Medicines,” September 15, 2021, https://www.abcellera.com/news/abcellera-collaboration-moderna.
23 Strand Therapeutics, “Strand Therapeutics Raises $52M in Oversubscribed Series A Round,” June 23, 2021,
https://www.businesswire.com/news/home/20210623005302/en/Strand-Therapeutics-Raises-52M-in-Oversubscribed-
Series-A-Round.
24 Nick Paul Taylor, “China’s Abogen Raises $700M Series C for mRNA Trials, Catapulting Itself into the Big
Leagues,” August 20, 2021, https://www.fiercebiotech.com/biotech/china-s-abogen-raises-700m-series-c-for-mrna-
trials-catapulting-itself-into-big-leagues.
25 Bhaven N. Sampat and Kenneth C. Shadlen, “The COVID-19 Innovation System,” Health Affairs, vol. 40, no. 3
(February 4, 2021), https://www.healthaffairs.org/doi/full/10.1377/hlthaff.2020.02097#B21.
26 See, for example, Damian Garde and Jonathan Saltzman, “The Story of mRNA: How a Once-Dismissed Idea
Became a Leading Technology in the COVID Vaccine Race,” STATNews, November 10, 2020,
https://www.statnews.com/2020/11/10/the-story-of-mrna-how-a-once-dismissed-idea-became-a-leading-technology-in-
the-covid-vaccine-race/; and Carolyn Y. Johnson, “Vaccine Vanguard: A One-Way Ticket. A Cash-Stuffed Teddy
Bear. A Dream Decades in the Making,” Washington Post, October 1, 2021, https://www.washingtonpost.com/health/
2021/10/01/katalin-kariko-covid-vaccines/.
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funds most of its research through the scientific peer review process—a committee-based review
process to evaluate scientific, investigator-driven research proposals for funding.27 Some analysts
suggest that this investigator-driven and consensus-based process may not adequately fund “high-
risk, high-reward” projects,28 a term often associated with projects that have high potential for
meeting fundamental scientific or technological challenges and that involve a high degree of
novelty and/or multidisciplinary approaches.29 Support for high-risk, high-reward research is
widely considered an important element in developing breakthrough technologies that address
societal challenges, including health-related challenges, and in maintaining the economic
competitiveness of the United States.30
Through FY2022 appropriations, Congress provided $1 billion to HHS to establish the Advanced
Research Projects Agency for Health (ARPA-H).31 Some view ARPA-H as a necessary response
to concerns about the risk aversion of traditional funding mechanisms, as well as a way to
accelerate the development of biomedical technologies.32 According to a concept paper issued by
the Biden Administration, one of the potential projects that ARPA-H could pursue is the
development of mRNA-based vaccines that would prevent most cancers.33 President Biden’s
FY2023 budget request proposes $5 billion for ARPA-H in an NIH account, with funding
available until September 30, 2025.34 Congress could consider how to define the mission of
ARPA-H and the activities it would support, in addition to providing funding for the agency, if it
seeks to use this approach to advance the development of mRNA technologies.
Coordination of Federal Research
According to an Organization for Economic Cooperation and Development (OECD) workshop,
Priority Setting and Coordination of Research Agendas: Lessons Learned from COVID 19:
Priority setting, steering and coordination of research efforts has been a major challenge.
From the policy perspective, different parts of government have different priorities and
different requirements for scientific evidence and research. In the absence of effective
27 See “Peer Review Process for Extramural Funding” in CRS Report R41705, The National Institutes of Health (NIH):
Background and Congressional Issues, by Judith A. Johnson and Kavya Sekar.
28 Chiara Franzoni, Paula Stephan, and Reinhilde Veugelers, “Funding Risky Research,” National Bureau of Economic
Research Working Paper, June 2021; Mikko Packalen and Jay Bhattacharya, “NIH Funding and the Pursuit of Edge
Science,” Proceedings of the National Academy of Sciences, vol. 117, no. 22 (June 2, 2020), pp. 12011-12016; and
Pierre Azoulay, Erica Fuchs, and Anna Goldstein, “Funding Breakthrough Research: Promises and Challenges of the
‘ARPA Model,’” National Bureau of Economic Research, June 2018.
29 For a discussion of definitions of “high-risk, high-reward research,” see pp. 11-13 of Organization for Economic
Cooperation and Development (OECD), Effective Policies to Foster High-Risk/High-Reward Research, OECD
Science, Technology, and Industry Policy Papers, No. 112, May 2021, https://read.oecd.org/10.1787/06913b3b-en?
format=pdf.
30 Organization for Economic Cooperation and Development (OECD), Effective Policies to Foster High-Risk/High-
Reward Research, OECD Science, Technology, and Industry Policy Papers, No. 112, May 2021, https://read.oecd.org/
10.1787/06913b3b-en?format=pdf.
31 For more on ARPA-H see, CRS Report R47074, Advanced Research Projects Agency for Health (ARPA-H):
Congressional Action and Selected Policy Issues, by Kavya Sekar and Marcy E. Gallo.
32 For example, see Suzanne Wright Foundation, “HARPA: Health Advanced Research Projects
Agency,” https://www.harpa.org/; and Bhaven N. Sampat and Robert Cook-Deegan, “An ARPA for Health
Research?,” Milbank Quarterly, https://www.milbank.org/quarterly/opinions/an-arpa-for-health-research/.
33 White House, Advanced Research Project Agency for Health (ARPA-H): Concept
Paper, https://www.whitehouse.gov/wp-content/uploads/2021/06/ARPA-H-Concept-Paper.pdf.
34 NIH, Congressional Justification: FY2023, March 28, 2022, p. 33, https://officeofbudget.od.nih.gov/pdfs/FY23/br/
Overview%20of%20FY%202023%20Presidents%20Budget.pdf.
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cross-government (and cross-agency) coordination, this can lead to fragmentation and/or
duplication of research efforts, with insufficient attention being given to some areas (such
as PHSMs [public health and social measures]).35
Advancement of mRNA technologies, including the development of mRNA-based vaccines in
response to future pandemics, might benefit from the development of a research roadmap, a
federal standing committee, or a process for coordination and communication. In 2020, NIH
created the “Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-
private partnership to develop a coordinated research strategy for prioritizing and speeding
development of the most promising [COVID-19] treatments and vaccines.”36 ACTIV is
coordinated by the Foundation for the National Institutes of Health and includes NIH, BARDA,
FDA, the Centers for Disease Control and Prevention, the Department of Defense, the
Department of Veterans Affairs, the European Medicines Agency, and representatives from
academia, philanthropic organizations, and biopharmaceutical companies.37 Congress could
consider modifying ACTIV or creating a similar mechanism for post-COVID-19 research
coordination. An assessment by the Office of Science and Technology Policy, the Government
Accountability Office, or the National Academies of Science, Engineering, and Medicine might
also be helpful in suggesting strategies for increased and enhanced coordination of mRNA R&D.
After past disease outbreaks, such as Ebola and Zika, federal funding for related research
declined. A similar decline in research funding for mRNA technologies after the COVID-19
pandemic subsides, some argue, might stunt the projected growth in this field. Continued and
enhanced cross-agency coordination and evaluation of federal R&D efforts associated with
mRNA technologies and their potential in future pandemics might also help to address such
concerns.
U.S. Competitiveness
While the United States remains the global leader in the life sciences, concerns about future
leadership abound. According to the Information Technology and Innovation Foundation,
During the last few decades, other nations have come to realize the importance of the [life
sciences] sector to their economies and have therefore increasingly tried to win a larger
share of global life-sciences activity. These efforts have been marginally successful, in part
because U.S. policy has been less than fully adequate. The competitive threat is important
because if the United States’ advantage of having a strong ecosystem gets eroded beyond
a certain point, it will be extremely difficult to regain.38
As indicated above, many expect mRNA technologies to play a prominent role in the future of the
pharmaceutical industry and medicine. If the United States seeks to maintain its leadership role in
the life sciences broadly, and in mRNA technologies, specifically, then Congress may consider
options to ensure the implementation of robust federal policies, which may include increased
35 OECD Global Science Forum, Workshop on “Priority Setting and Coordination of Research Agendas: Lessons
Learned from COVID-19,” Workshop Summary, January 20, 2022, https://one.oecd.org/document/DSTI/STP/
GSF(2021)21/FINAL/en/pdf.
36 NIH, “Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV),” https://www.nih.gov/research-
training/medical-research-initiatives/activ.
37 Foundation for the National Institutes of Health, “About ACTIV,” https://www.fnih.org/our-programs/activ/about.
38 Joe Kennedy, How to Ensure That America’s Life-Sciences Sector Remains Globally Competitive, Information
Technology and Innovation Foundation, Washington, DC, March 2018 (Revised July 2020), p. 1, https://www2.itif.org/
2018-life-sciences-globally-competitive.pdf.
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federal R&D funding; an effective regulatory environment; a well-trained and adequate life
sciences workforce; and public and private sector coordination.
Author Information
Marcy E. Gallo
Frank Gottron
Analyst in Science and Technology Policy
Specialist in Science and Technology Policy
Disclaimer
This document was prepared by the Congressional Research Service (CRS). CRS serves as nonpartisan
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under the direction of Congress. Information in a CRS Report should not be relied upon for purposes other
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