Capabilities and Challenges for Addressing Infectious Diseases (GAO-22-104371)
Summary
A GAO technology assessment report to congressional committees, GAO-22-104371, dated November 2021, on vaccine development capabilities and challenges for addressing infectious diseases. It discusses technologies, approaches and challenges in four areas: research and development, testing, manufacturing, and the economic factors that affect vaccine investment. GAO states that reverse vaccinology and next-generation platforms, combined with existing research, helped researchers develop some COVID-19 vaccines more quickly and effectively. For the assessment GAO searched the literature, interviewed stakeholders and experts, and convened a 3-day meeting of 22 experts with assistance from the National Academies of Sciences, Engineering, and Medicine.
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United States Government Accountability Office
Report to Congressional Committees
November 2021 TECHNOLOGY ASSESSMENT
Vaccine Development
Capabilities and Challenges for Addressing
Infectious Diseases
GAO-22-104371
The cover image displays a stylized representation of vaccine research and development in a scientific lab, testing
vaccines using artificial intelligence on a computer, manufacturing vaccines and placing them storage containers, an
individual receiving vaccination by injection, and financial resources necessary to incentivize the development and
manufacturing of vaccines.
Cover sources (photos): pickup/stock.adobe.com (top left); Mike Mareen/stock.adobe.com (top middle);
Gorodenkoff/stock.adobe.com (bottom middle); Pormezz/stock.adobe.com (top right); Robert
Kneschke/stock.adobe.com (bottom right). | GAO-22-104371
TECHNOLOGY ASSESSMENT
Highlights of GAO-22-104371, a report to
congressional committees Vaccine Development
November 2021 Capabilities and Challenges for Addressing
Infectious Diseases
Why GAO did this study What GAO found
The CARES Act included a provision Vaccines protect people from disease by preparing the body to respond to an
for GAO to report on its ongoing infection. Vaccinations are a key part of individual and community health, but
monitoring and oversight efforts
related to the COVID-19 pandemic. vaccine development remains complex and costly. Innovative technologies and
This report discusses technologies, approaches, such as those identified in this report, may enhance the nation’s ability
approaches, and associated to respond to infectious diseases. For example, reverse vaccinology and next-
challenges for vaccine (1) research generation platforms—combined with existing research—helped researchers
and development, (2) testing, and (3) develop some COVID-19 vaccines more quickly and effectively.
manufacturing, as well as (4) the
economic factors that affect vaccine
investment.
GAO conducted literature searches
including scholarly articles and
government reports relevant to these
four areas. GAO interviewed
stakeholders and experts with a
diverse set of perspectives on the
science, administration, and
economics of vaccine development.
GAO also convened a 3-day meeting
of 22 experts with expertise in at
least one area related to our four
objectives with assistance from the
National Academies of Sciences,
Engineering, and Medicine. GAO
received technical comments on a
draft of this report from 1 federal
agency and 9 participants at its expert However, key challenges may hinder the adoption of these innovative technologies
meeting, which it incorporated as and approaches. Some promising technologies face issues and challenges such as
appropriate. inherent technical limitations and high cost. For example, organ chips may facilitate
GAO is identifying policy options in testing, but they are not yet able to replicate many of the complex functions of the
this report. human immune system. Similarly, single-use systems may increase the flexibility of
vaccine manufacturing facilities, but may require extensive testing to ensure that
they do not negatively affect the resulting vaccine. Further, economic challenges
may hinder vaccine development. Experts attribute underinvestment in vaccines to
market failures (i.e., market interactions that fall short of what would have been
socially beneficial). For example, vaccines benefit those who are vaccinated, and, to
some degree, those who are not. This additional benefit is not captured in the price,
which reduces return on vaccine investment.
View GAO-22-104371. For more information,
contact Karen L. Howard at (202) 512-6888
or, howardk@gao.gov.
United States Government Accountability Office
GAO identified 9 policy options that may help address challenges hindering the adoption of vaccine development technologies and
approaches or economic challenges. These policy options involve possible new actions by policymakers, who may include Congress,
federal agencies, state and local governments, academic and research institutions, and industry. See below for details for some of
the policy options and relevant opportunities and considerations.
Selected Policy Options to Address Challenges in Vaccine Development
Opportunities Considerations
Prioritize infectious disease pathogens • Prioritizing pathogens with pandemic • As new threats are identified,
(report page 21) potential could improve strategic vaccine priorities may change, which may
Policymakers could collaborate across R&D decision-making and help focus cause uncertainty for vaccine
sectors (e.g., government, academia, resources on developing and adopting key developers.
researchers, industry, and nonprofit technologies and approaches that most • Policymakers may have different
organizations) to prioritize infectious disease effectively address those pathogens. priorities based on their respective
pathogens with pandemic potential for • Appropriately matching the technologies and missions.
vaccine R&D. approaches to the prioritized potential • There may be disagreements as to
For example, policymakers could develop a pandemic pathogens then leveraging which key technologies should be
working group to prioritize pathogens with technologies may help address certain prioritized and used, resulting in
pandemic potential and work more closely technical limitations and cost. the need for policymakers to weigh
with international organizations to prioritize • With greater leadership and strategic the potential advantages and
vaccine development as well as develop partnerships, policymakers could more disadvantages associated with
monoclonal antibodies. quickly address threats to the U.S. various options.
population.
Improve preparedness (report page 21) • This early development could provide a • The lack of certainty of the
Policymakers could provide support for coordinated foundation that can be commercial market and
public-private partnerships to strategically mobilized in an emergency. Such an approach government funding for vaccines
address potential pandemic pathogens could speed vaccine development as well as against pathogens with pandemic
identified as priorities. These partnerships potentially reduce risk for vaccine potential may be too risky for the
could, for example, develop and test researchers and developers concerning private sector to undertake.
vaccine candidates that may provide questions of safety, efficacy, and
protection from pathogens with pandemic manufacturability.
potential.
Further support development of data • Integrating researchers’ needs into the • Expanding access to patient heath
standards (report page 32) standards development process could better data requires attention to ensure
Policymakers could further support ensure the necessary data are available. privacy.
coordinated efforts to obtain the views of • Access to high-quality data in a standardized • Developing and implementing
all stakeholders and to develop standards format may allow streamlined patient standardized data formats and IT
for health data and their use in clinical recruitment for clinical trials. infrastructure is time-consuming
trials. and costly.
Improve preparedness (report page 41) • Manufacturing, testing, and stockpiling • May require new resources or
Policymakers could provide support vaccines could be mobilized in an reallocation of resources from
for public/private partnerships to emergency and more rapidly mitigate other efforts.
strategically develop manufacturing future pandemics. • There may be a risk that the
capacity to respond to surge • By leveraging strategic partnerships, vaccines manufactured, tested,
requirements. To maintain this policymakers could take steps to increase the and stockpiled against prioritized
capacity, partnerships could availability of vaccines to more quickly pathogen classes miss certain
manufacture prototype vaccine address threats to the U.S. population. pandemic pathogens.
candidates against high-priority • The stockpiled vaccines would
pathogens. need to be regularly replenished
prior to expiration.
Evaluate factors that inhibit vaccine • A clear understanding of the range of • Collaboration between
investment and mechanisms to increase it factors discouraging vaccine investment policymakers and other
(report page 54) would provide the basis for effectively stakeholders to obtain all
Policymakers could collaborate across addressing those factors. relevant viewpoints can be time-
sectors, such as government, academia, consuming and it may be hard to
and industry, to conduct a systematic reach a consensus.
evaluation of factors that inhibit
developers from investing in new vaccines.
Source: GAO. | GAO-22-104371
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Table of Contents
Introduction ........................................................................................................................ 1
1 Background ...................................................................................................................... 5
1.1 How vaccines work ............................................................................................................ 5
1.2 Vaccine development ........................................................................................................ 6
2 Technologies and Approaches for Vaccine R&D .............................................................. 9
2.1 Factors Affecting Vaccine R&D .......................................................................................... 9
2.2 Technologies and approaches for vaccine R&D .............................................................. 11
2.3 Challenges affecting the adoption of R&D technologies and approaches ......................15
2.4 Infectious disease prioritization ...................................................................................... 18
2.5 Policy options that may help address challenges related to vaccine R&D ......................20
3 Technologies and Approaches for Vaccine Testing ....................................................... 22
3.1 Factors affecting vaccine testing ..................................................................................... 22
3.2 Technologies and approaches that may enhance vaccine testing .................................. 23
3.3 Challenges affecting the adoption of vaccine testing technologies
and approaches ............................................................................................................ 26
3.4 Policy options that may help address challenges related to vaccine testing ..................31
4 Technologies and approaches for vaccine manufacturing ............................................ 33
4.1 Factors affecting vaccine manufacturing......................................................................... 33
4.2 Technologies and approaches for vaccine manufacturing .............................................. 34
4.3 Challenges affecting the adoption of vaccine manufacturing technologies ...................37
4.4 Challenges affecting scaling up manufacturing to meet surges in demand ....................39
4.5 Policy options that may help address challenges related to vaccine
manufacturing .............................................................................................................. 40
5 Economics of vaccine development and the role of incentives .................................... 43
5.1 Market failures and other challenges result in fewer vaccines ....................................... 44
5.2 Mechanisms to incentivize vaccine development ........................................................... 48
5.3 Policy options that may help address economic challenges to vaccine
development ................................................................................................................ 53
Vaccine Development GAO-22-104371 i
6 Agency and Expert Comments ....................................................................................... 55
Appendix I: Objectives, Scope, and Methodology ............................................................ 57
Appendix II: Research and Development Technologies and Approaches ........................ 60
Appendix III: Testing Technologies and Approaches ........................................................ 65
Appendix IV: Manufacturing Technologies and Approaches ........................................... 71
Appendix V: Expert Participation ...................................................................................... 73
Appendix VI: GAO Contact and Staff Acknowledgments.................................................. 75
Vaccine Development GAO-22-104371 ii
Abbreviations
AI artificial intelligence
BARDA Biomedical Advanced Research and Development Authority
CDC Centers for Disease Control and Prevention
COVID-19 Coronavirus Disease 2019
DOD Department of Defense
EHR electronic health record
EUA emergency use authorization
FDA Food and Drug Administration
HHS Department of Health and Human Services
MERS middle east respiratory syndrome
ML machine learning
mRNA messenger RNA
NIAID National Institute of Allergy and Infectious Diseases
NIH National Institutes of Health
R&D research and development
SARS severe acute respiratory syndrome
WHO World Health Organization
Vaccine Development GAO-22-104371 iii
441 G St. N.W.
Washington, DC 20548
Introduction
November 16, 2021
Congressional Committees
Vaccinations are an important tool for individual and public health, and have saved millions of
lives. For example, between 1900 and 1980, smallpox killed approximately 300 million people
and disfigured millions more. However, by 1980, a successful vaccination campaign eliminated
smallpox worldwide. Similarly, in 1988, at the onset of a global campaign to end polio, there
were 350,000 polio cases worldwide. According to the World Health Organization (WHO), the
number of polio cases has since declined by over 99 percent worldwide.
Infectious diseases carry a high price tag for society. According to the World Bank, the economic
losses from six major outbreaks of highly fatal infectious diseases that occurred between 1997
and 2009 amounted to at least $80 billion globally. 1 According to the National Foundation for
Infectious Diseases, in the U.S., an average influenza illness can last up to 15 days, typically
resulting in 5 or 6 missed work or school days. Adults who contract hepatitis A lose an average
of one month of work. Further, when people are not vaccinated, they may be vulnerable to
serious infections, such as human papillomavirus and hepatitis B (both can cause cancer), which
have significant personal and economic burdens.
Providing the public with safe and effective vaccines is also crucial to mitigating global
pandemics. The Coronavirus Disease 2019 (COVID-19) pandemic has highlighted the devastating
impact new infectious diseases can have. As of November 1, 2021, the Centers for Disease
Control and Prevention (CDC) reported that over 745,000 people in the U.S. had died of COVID-
19. An October 2020 study estimated the total economic cost of the at more than $16 trillion, or
approximately 90 percent of the annual U.S. gross domestic product. 2 In December 2020, the
U.S. took an important step to protect the public against COVID-19, as the first COVID-19
vaccines—developed in a shorter time than any previous vaccine—were authorized for
1
The infectious diseases included in this study were Nipah Virus (Malaysia), West Nile Fever (U.S.), severe acute respiratory
syndrome (Asia, Canada, other), highly pathogenic avian Influenza (Asia, Europe), bovine spongiform encephalopathy (U.S., U.K.),
Rift Valley Fever (Tanzania, Kenya, Somalia). See World Bank People, Pathogens and our Planet: The Economics of One Health. 2012,
Washington, DC. https://openknowledge.worldbank.org/handle/10986/11892.
2
D.M. Cutler and L. Summers “The COVID-19 Pandemic and the $16 Trillion Virus,” Journal of the American Medical Association, Oct.
20, 2020.
Vaccine Development GAO-21-104622 1
emergency use and administered. 3 As of November 2021, three COVID-19 vaccines were
available in the United States. One vaccine was licensed by the Food and Drug Administration
(FDA) for individuals 16 and older, and was also available for individuals aged 5-15 years under
an emergency use authorization (EUA). 4 Since implementation of the COVID-19 vaccine program
in December of 2020, the number of new daily cases has declined. 5 For example, the number of
COVID-19 cases in the U.S. reached a high of over 290,000 new daily cases on January 8, 2021,
but declined to about 75,000 new daily cases as of November 2, 2021. 6
While the National Institutes of Health (NIH) conducts and supports research that contributes to
relevant technological advances, vaccine development overall continues to be a difficult,
complex, and costly endeavor, and from an investment standpoint remains highly risky for those
who pursue it. Economists we spoke to stated that the benefits that vaccines provide are not
necessarily commensurate with the return on investment from developing or manufacturing
them and vaccine development from discovery to licensure can cost billions of dollars and can
take over 10 years to complete. 7 Vaccine developers face numerous technical challenges related
to the biological complexity of some infectious diseases and the maturity of new vaccine
technologies. Other challenges include long development time frames, high rates of clinical trial
failure, and the lack of incentives to invest in vaccines.
Given the public health consequences of infectious disease, policymakers have a vital interest in
developing and maintaining modern, flexible, rapid, and robust vaccine development and
manufacturing capabilities. 8 These capabilities will allow for better response to endemic levels
of infectious disease, as well as better preparation for potential future epidemics and
3
The Secretary of Health and Human Services (HHS) may declare that circumstances, prescribed by statute, justify the emergency
use of certain medical products, such as vaccines. Once a declaration of an emergency has been made, the Food and Drug
Administration (FDA) may temporarily allow use of unlicensed vaccines through an emergency use authorization (EUA). For FDA to
issue an EUA for a vaccine, it must be reasonable to believe that the vaccine may be effective and that the known and potential
benefits of the vaccine outweigh the known and potential risks, among other statutory criteria. See 21 U.S.C. § 360bbb-3. See also
HHS, FDA, Center for Biologics Evaluation and Research, Emergency Use Authorization for Vaccines to Prevent COVID-19, Guidance
for Industry, (Washington, D.C.: May 2021).
4
FDA licenses biological products, such as vaccines, through review and approval of a biologics license application. See 42 U.S.C. §
262. FDA guidance indicates that licensure is the goal for COVID-19 vaccines, including those that first receive an EUA.
5
COVID-19 vaccine implementation involves the prioritization, allocation, distribution, and administration of vaccine doses.
6
For more information on the accelerated COVID-19 vaccine development process, see GAO, COVID-19: Efforts to Increase Vaccine
Availability and Perspectives on Initial Implementation, GAO-21-443, (Washington, D.C.: April 14, 2021), GAO, Operation Warp
Speed: Accelerated COVID-19 Vaccine Development Status and Efforts to Address Manufacturing Challenges, GAO-21-319,
(Washington, D.C.: Feb. 11, 2021), and GAO, COVID-19: Federal Efforts Accelerate Vaccine and Therapeutic Development, but More
Transparency Needed on Emergency Use Authorizations, GAO-21-207 (Washington, D.C.: Nov. 17, 2020). GAO has also produced an
interactive dashboard that integrates multiple data sources to visualize the status of vaccine development, which may be found at
https://ows.gaoinnovations.gov/
7
D. Gouglas et al., "Estimating the Cost of Vaccine Development Against Epidemic Infectious Diseases: a Cost Minimisation Study."
The Lancet Global Health, vol. 6, no. 12 (2018): pp. e1386-e1396.
8
Policymakers is a broad term including, for example, Congress, federal agencies, state and local governments, academic and
research institutions, and industry.
Vaccine Development GAO-22-104371 2
pandemics. 9 This urgent need comes at a time marked by rapid growth in basic scientific
understanding—in areas such as genomics and structural biology that are supporting a new era
in vaccine development—as well as ongoing challenges.
The CARES Act includes a provision for GAO to report on its ongoing monitoring and oversight
efforts related to the COVID-19 pandemic. 10 This technology assessment is part of our body of
work in response to the CARES Act and describes various technologies and approaches
applicable to developing vaccines for infectious diseases. Specifically, in this technology
assessment, we describe
• technologies and approaches for vaccine research and development (R&D) and
challenges that affect their use,
• technologies and approaches for vaccine testing and challenges that affect their use,
• technologies and approaches for vaccine manufacturing and challenges that affect their
use, and
• economic factors that affect vaccine investment and preparedness for future
pandemics.
To address our all of our objectives, we conducted literature searches including scholarly articles
and government reports describing current and emerging technologies and approaches for
vaccine R&D, testing, and manufacturing. 11 We used the results of our literature review to
address our objectives as well as identify experts to interview and invite to participate in our
expert meeting. Additionally, we interviewed stakeholders and experts with a diverse set of
perspectives on the science, administration, and economics of vaccine development. To address
all of our objectives, we held an expert meeting from January 25-28, 2021. This meeting was
held in collaboration with the National Academies of Sciences, Engineering, and Medicine, and
was divided into six sessions on technologies and approaches for vaccine: (1) research and
development; (2) manufacturing, (3) preclinical and clinical trials, (4) pathogen scenarios, (5)
economics factors, and (6) lessons learned.
9
Endemic refers to the constant presence or usual prevalence of disease in a population within a geographic area. An epidemic
refers to an increase, often sudden, in the number of cases of a disease above what is normally expected in a population and area. A
pandemic refers to an epidemic that has spread over several countries or continents, usually affecting a large number of people.
10
Pub. L. No. 116-136, § 19010, 134 Stat. 281, 579-81 (2020). We regularly issue government-wide reports on the federal response
to the COVID-19 pandemic. For our 8th comprehensive report on the ongoing federal pandemic response, see GAO, COVID-19:
Additional Actions Needed to Improve Accountability and Program Effectiveness of Federal Response, GAO-22-105051, (Washington,
D.C.: Oct. 27, 2021). Our next government-wide report will be issued in January 2022 and can be found on GAO’s website at
https://www.gao.gov/coronavirus.
11
For purposes of this report, vaccine testing refers to preclinical studies, clinical trials, and post-marketing surveillance studies.
Vaccine Development GAO-22-104371 3
Based on the information we obtained, we developed a series of policy options intended to
represent possible options that policymakers can take to address a policy objective. Consistent
with our quality assurance framework, we provided the relevant agencies and experts with a
draft of our report and solicited their feedback, which we incorporated as appropriate. See
appendix I for additional information on our scope and methodology.
We conducted our work from June 2020 through November 2021 in accordance with all sections
of GAO’s Quality Assurance Framework that are relevant to technology assessments. The
framework requires that we plan and perform the engagement to obtain sufficient and
appropriate evidence to meet our stated objectives and to discuss any limitations to our work.
We believe the information and data obtained, and the analysis conducted, provide a
reasonable basis for any findings and conclusions in this product.
Vaccine Development GAO-22-104371 4
1 Background
1.1 How vaccines work and in some cases prevent future infections
(see fig. 1). The immune system also
Vaccines protect people from disease by produces specific cells—such as T-
triggering the immune system to produce lymphocytes—that assist in neutralizing
antibodies that will fight a pathogen pathogens in a process known as cell-
attacking the body. A pathogen is a mediated immunity. When the human body
bacterium, virus, or other microorganism is exposed to an antigen for the first time, it
that can cause disease. Preparing the takes time for the immune system to
immune system through vaccination allows respond and produce antibodies specific to
the body to respond more quickly if that that antigen. During that period of time, the
pathogen infects the individual in the individual is susceptible to becoming ill
future. from the disease caused by the pathogen.
Once antigen-specific antibodies are
During an infection, the immune system produced, they work with the rest of the
responds to specific parts of a pathogen immune system to destroy the pathogen.
called antigens by producing antibodies—
proteins that help bind to and neutralize Vaccines mimic this natural process by
specific pathogens—to fight the pathogen introducing antigens without necessarily
introducing the disease-causing pathogen
Vaccine Development GAO-22-104371 5
itself; for example, vaccines can use a against Mycobacterium leprae—a
weakened or inactive pathogen, a bacterium that causes leprosy in humans.
microorganism that is closely related to the
pathogen but does not cause disease in 1.2 Vaccine development
humans, or a molecule derived from the
pathogen. 12 Vaccines may include a variety The traditional process for developing a
of ingredients such as stabilizers, adjuvants, new vaccine is well established and tends to
and preservatives to enhance the be sequential (see fig. 2), although stages
effectiveness of the vaccine or offer other sometimes overlap. 15 The purpose of this
benefits. 13 sequential approach is, in part, to reduce
financial risk because each stage is costly—
Once an immune response has been with later stages being especially costly—
generated, if the person is exposed later to and each stage improves the understanding
the pathogen, their immune system will of whether the next stage might be
‘remember’ seeing that pathogen and successful. However, one expert told us
respond more quickly, increasing their that this is not guaranteed. At any stage,
chances of fighting off the infection. 14 the process can be terminated for a variety
Additionally, vaccines that protect against of reasons, including detection of adverse
one pathogen may also protect against events, such as serious side effects or if the
similar pathogens. Vaccines may also evidence suggests that the vaccine is
reduce the spread of infectious disease, unlikely to be protective.
which can convey some level of protection
to those who are not vaccinated. For
example, the bacille Calmette–Guérin
vaccine, which contains weakened
Mycobacterium bovis—a bacterium that
causes tuberculosis in cattle—is used to
protect humans from Mycobacterium
tuberculosis—a bacterium that causes
tuberculosis in humans. Further, this
vaccine may also provide some protection
12 14
For example, the smallpox vaccine uses a related poxvirus, Vaccine effectiveness varies for each vaccine. For
the vaccinia virus, which is unlikely to cause significant example, according to CDC, the effectiveness of seasonal
disease in healthy human recipients, but elicits an immune influenza vaccines ranges from between 40 percent to 60
response that is protective for smallpox. percent during seasons when influenza vaccine viruses are
13 similar to circulating influenza viruses, while a two–dose
Stabilizers are substances such as amino acids and other course of the measles, mumps, and rubella vaccine is 97
substances that help the antigen maintain its effectiveness percent effective at preventing measles.
during storage. Adjuvants are compounds such as aluminum
15
salts that help to enhance the immune response. We have previously reported on the traditional vaccine
Preservatives are chemical substances that help to protect development timeline compared to a potential timeline for
against bacterial and fungal growth during storage. COVID-19 vaccine development. See GAO-21-319.
(https://www.fda.gov/vaccines-blood-biologics/safety-
availability-biologics/common-ingredients-us-licensed-
vaccines).
Vaccine Development GAO-22-104371 6
Note: The steps shown in the timeline are not drawn to scale, and the specific development steps for a given vaccine
may vary. For example, the federal government accelerated this process for the development of a COVID-19 vaccine
under the HHS-DOD COVID-19 Countermeasures Acceleration Group (formerly known as Operation Warp Speed) by
overlapping certain phases to speed up the process so the vaccines could be used as quickly as possible to control the
pandemic. No trial phases were skipped.
In this report, we use the term “efficacy” to refer to the results of adequate and controlled clinical trial studies that
evaluate clinical disease endpoints, and “effectiveness” to refer to the results of studies carried out under field
conditions. For regulatory purposes, FDA determines whether a vaccine is safe and effective, and effectiveness is
generally based on the results of adequate and well controlled studies evaluating a clinical disease endpoint (efficacy
studies) or a well-accepted immune endpoint (effectiveness studies).
Vaccine Development GAO-22-104371 7
Chapters 2 through 4 of this report discuss report discusses economic challenges that
technologies and approaches to enhance may result in fewer vaccines being
overall response to endemic infectious developed and tools to incentivize
diseases, as well as improve capabilities to additional vaccine investment to enhance
respond to potential future epidemics or overall response to endemic infectious
pandemics. Specifically, chapter 2 discusses disease, as well as improve capabilities to
the vaccine R&D stage; chapter 3 focuses respond to potential future epidemics and
on vaccine testing, including preclinical pandemics.
testing, clinical trials, and post-marketing
surveillance; and chapter 4 discusses
vaccine manufacturing. Chapter 5 of this
Vaccine Development GAO-22-104371 8
2 Technologies and Approaches for Vaccine R&D
Technologies and approaches for vaccine R&D 2.1 Factors Affecting Vaccine R&D
may help researchers, developers, or other
scientists better identify and characterize Key factors in conducting vaccine R&D are:
pathogens and their antigens—the
components of the pathogen that stimulate • Identifying and characterizing a
an immune response—and determine how pathogen’s key antigens and the immune
the human immune system responds to system response
pathogens. This improved understanding may
also result in more efficient generation of safe • Applying knowledge about antigens and
and effective vaccines and other biological immune responses to rapidly develop
products, such as monoclonal antibodies. 16 vaccines or other biological products that
However, the use of some technologies may safely and effectively stimulate or
be affected by their inherent technical complement an immune response
limitations, complexity, and high cost. • Considering the various routes of
Further, while policymakers—which include delivery, including alternative routes such
Congress, federal agencies, state and local as dermal or oral, that may help maximize
governments, academic and research vaccination rates
institutions, and industry—have supported
vaccine R&D for many infectious diseases, it is Identifying antigens that stimulate a
not clear the extent to which they have protective immune response has,
prioritized specific potential pandemic traditionally, been a slow process done largely
pathogens for vaccine R&D. 17 This lack of through trial-and-error testing. Any given
clarity raises questions about whether vaccine pathogen may have thousands of potential
R&D efforts, and the technologies needed to antigens, and the human immune system
support those efforts, enhance the includes many different types of cells with
capabilities to best respond to endemic levels different functions, not all of which are fully
of infectious disease and potential future understood. To identify the antigens that
epidemics and pandemics. most effectively stimulate a protective
response in the human immune system,
researchers typically select and test potential
16 Respiratory Syndrome (MERS) contributed to the successful
Biological products, which include a wide range of
products—including vaccines, blood and blood components, development of vaccines for COVID-19. However, we note that
allergenics, somatic cells, gene therapy, and tissues, among no commercial vaccines for SARS or MERS exist. This was partly
other things—are derived from living sources such as humans, attributed to lack of continued investments in a vaccine for
animals, and microorganisms. See 42 U.S.C. § 262(i)(1) and 21 SARS, for which cases ceased to be reported, and for MERS,
C.F.R. § 600.3(h) (2020). which resulted in relatively few and geographically isolated
cases. One expert who had developed a SARS vaccine
17
NIH conducts and supports basic, translational, and applied candidate stated that had that vaccine been able to proceed
clinical research that contributes to technological advances through phase 1 clinical trials and stockpiled, it could have
relevant for vaccine development. For example, NIH officials been beneficial for COVID-19 and accelerated vaccine
noted the National Institute of Allergy and Infectious Diseases’ development.
(NIAID) role in funding research on SARS and Middle East
Vaccine Development GAO-22-104371 9
antigens one or a few at a time. Researchers Finally, administering vaccines by injection
then run laboratory tests or conduct animal using a needle and syringe—the traditional
studies to see if any of the antigens they method of delivering vaccines—may affect,
selected produces a protective immune for example, some individuals’ willingness to
response. (See text box for one example of get a vaccination due to a fear of needles.
how antigens were identified.) Additionally, the need for trained personnel
and the costs and potential scarcity of
It is also difficult to quickly develop vaccines vaccination supplies (e.g., vials, syringes, and
that safely and effectively stimulate an needles), particularly during pandemics, can
immune response. There are many reasons make administration of vaccines using
for this, but two key factors are the time traditional injections difficult.
needed to produce antigens and a lack of
adaptability. First, traditional vaccine Coronavirus research
development often requires the growth of
In the case of COVID-19, identifying and characterizing the
pathogens or the use of other cells, such as spike protein antigen was the result of decades of previous
bacteria, yeast, or insect cells, containing the research dating back to human coronavirus research begun
in the 1960s, the Severe Acute Respiratory Syndrome (SARS)
antigen(s) of interest from the pathogen. Viral epidemic in 2003-2005, and the Middle Eastern Respiratory
pathogens can be grown in eggs or other Syndrome (MERS) outbreak of 2012. If earlier research on
SARS and MERS had not been funded, development of a
cells—known as cell cultures. These methods COVID-19 vaccine may have taken significantly longer.
can take months to years to develop. Second, Source: GAO analysis of information from literature and an expert meeting. |
traditional methods of vaccine development GAO-22-104371
may be not highly adaptable for multiple
pathogens or diverse antigens. This may limit
the ability to quickly develop vaccines when
new pathogens emerge or change a vaccine
when variants arise. 18
18
A variant is a new form of the same pathogen that arises
from distinct changes—also known as mutations—in the
genetic sequence of the pathogen.
Vaccine Development GAO-22-104371 10
2.2 Technologies and approaches for identified four technologies and approaches
vaccine R&D that may improve vaccine R&D (see table 1).
Appendix II provides additional information
Drawing on information from experts, on these technologies and approaches.
stakeholders, and related literature, we
Table 1: Selected technologies and approaches for vaccine research and development (R&D)
Name Description
Omics Omics refers to the combined analyses of DNA (genomics and epigenomics), RNA
(transcriptomics), proteins (proteomics), other small molecules (metabolomics), and other
biological components. In vaccine R&D, omics is meant to improve the understanding of
pathogens and host immune responses.
Reverse Reverse vaccinology uses computer-based analytics to assess a pathogen’s genetic code and
vaccinology identify potential antigens. Reverse vaccinology allows researchers to identify potential
vaccine antigen candidates without the need to grow the pathogens and develop vaccines
that were previously difficult or impossible to make.
Next-generation Next-generation vaccine platforms incorporate the genetic information that codes for a
vaccine platforms pathogen’s antigen into a delivery vehicle. A delivery vehicle can be another virus (viral
vector), a microparticle, or a lipid nanoparticle. The delivery vehicle protects the genetic
information until it is administered into an individual, where the immune response is
triggered. The platform may also be able to be used in a plug-and-play fashion to pair a
delivery vehicle with different genetic sequences to create new or updated vaccines. Vaccine
platforms may have uniform, predictable characteristics, such as safety effects; however,
each antigen in a specific platform will have different immune response characteristics.a
Routes of Traditional vaccinations are delivered by injection either under the skin (subcutaneous) or
vaccination into muscle (intramuscular). The identification and use of nontraditional vaccine delivery
routes, such as dermal (skin) and mucosal (oral, nasal) may offer the potential for better
immune responses, increased public acceptance, and lower dosages.
Source: GAO. | GAO-22-104371
aAccording to National Institutes of Health (NIH), vaccine platform technologies are approaches, delivery systems, and
other tools that serve as the basis for delivering those vaccine antigen designs and for the development of candidate
vaccines. Vaccine prototype design is the research and development that results in a candidate antigen design as the
basis of a vaccine.
Vaccine Development GAO-22-104371 11
The technologies and approaches we biological molecules. Then, researchers can
identified can be applied at different stages of apply computer simulations to predict more
vaccine R&D. For example, in early quickly which of the potential antigens may
exploration and research, omics and reverse stimulate an immune response and which
vaccinology can help researchers to more modifications to the antigens may enhance
rapidly identify antigens and how they the immune response. As a result,
stimulate an immune response. For later researchers can more quickly begin testing
stages of vaccine R&D, genetic code for the those antigens that are most likely to work.
identified antigens can be quickly (See text box for an example of how reverse
incorporated into delivery vehicles, such as vaccinology has been used.)
lipid nanoparticles or viral vectors,
accelerating vaccine testing (see fig. 3).
Omics and reverse vaccinology aid in the early
exploration process by helping researchers to
more quickly identify antigens that stimulate
a protective immune response by analyzing
the pathogen’s DNA, RNA, proteins, or other
Vaccine Development GAO-22-104371 12
Reverse vaccinology and the COVID-19 vaccine of a vaccine. Specifically, next-generation
platforms can help speed development,
Researchers used reverse vaccinology to accelerate
development of some COVID-19 vaccines. When the genetic particularly when new pathogens emerge,
code of SARS-CoV-2—the virus that causes COVID-19— because they rely on the pathogen’s genetic
became available, researchers quickly identified it as a
coronavirus similar to the Severe Acute Respiratory information that codes for antigens. This
Syndrome (SARS) coronavirus. According to the National eliminates the need to grow the pathogen or
Institutes of Health (NIH), this enabled researchers to use
information gained from prior National Institute of Allergy
purify antigens. These platforms are also
and Infectious Diseases (NIAID)-funded studies, among highly adaptable to multiple pathogens,
others, that used reverse vaccinology and protein structure
allowing the development of many different
analysis to characterize the SARS and Middle East
Respiratory Syndrome (MERS) spike protein antigens and vaccines to address a diverse range of
their human cell receptors. This then helped researchers pathogens on a single platform. They also
more quickly identify, assess, and stabilize the spike protein
from SARS-CoV-2, which, in turn, allowed for the quick have the potential to be used to develop
development of potential COVID-19 messenger RNA (mRNA) universal vaccines which protect against
vaccine candidates, according to NIH. Researchers were able
to test mRNA vaccines in a phase 1 clinical trial within 90
multiple pathogens from the same or closely
days of the SARS-CoV-2 genetic code release. In comparison, related families. However, next-generation
the vaccine candidates for MERS and SARS reached clinical
trials within about 22 months and 25 months, respectively,
platforms may not be practical for certain
after their outbreaks. Dengue, Chikungunya, and Zika pathogens or developing countries, according
vaccine candidates took even longer to reach clinical trials: to one expert we spoke to.
approximately 52 years, 19 years, and 9 years, respectively,
after declaration of major outbreaks. According to Food and
Drug Administration (FDA) officials, other differences, Three nontraditional routes of vaccination—
including the nature of the pathogens and funding levels,
also contributed to the extended development timeframes. dermal, nasal, and oral—are an important
Source: GAO analysis of literature. | GAO-22-104371 consideration in vaccine development. Using
nontraditional routes of vaccination can
reduce or eliminate the pain that some
Omics can also help researchers characterize people associate with injections, potentially
the human immune system by allowing increasing vaccination rates or reducing the
researchers to understand which cells provide need for trained personnel and certain
protection. Omics analysis of the immune supplies.
system may also enable researchers to
predict how individuals may react to vaccines
• Dermal delivery. Delivering vaccines
and could allow for tailored vaccines for
through the skin can produce strong
certain populations. 19
immune responses at much lower doses
than intramuscular and subcutaneous
Next-generation vaccine platforms, such as vaccines, making it a good route for
nucleic acid (e.g., mRNA and DNA) and viral vaccination. Microneedles, which can be
vector platforms, also aid in the development
19
For example, researchers used omics analysis to characterize
the differences in the immune system to the hepatitis B vaccine
in two groups of older adults, one that quickly produces high
levels of antibodies and another that does not produce any
response. The results of these studies may enable researchers
to better predict vaccination outcomes—whether a strong,
weak, or no immune response occurs—in individuals and help
researchers increase vaccine effectiveness.
Vaccine Development GAO-22-104371 13
nearly pain-free, are small structures today include those for polio, rotavirus,
designed to pierce the skin and deliver and cholera. 22
vaccines in the epidermis or dermis
layers. 20 FDA has licensed one influenza Additionally, experts we spoke with
vaccine that uses dermal delivery. emphasized that monoclonal antibodies are
• Nasal delivery. Nasal vaccines can induce emerging as a potential approach to
immunity even at distant sites of the preventing infections. Monoclonal antibodies
body. The antigens are taken up by cells are laboratory-produced antibodies that act
in the nasal cavity, stimulating a potent to mimic the immune system's ability to fight
antibody in the respiratory tract that off pathogens. They are not vaccines and
prevents the pathogen from entering the have traditionally been used as treatments for
body. The antigens also stimulate the individuals that are already infected.
body’s overall immune response, which However, many of the same types of
may increase the general effectiveness of technologies—for example, omics and
the vaccine. There are FDA-licensed nasal delivery platforms—used for vaccine
vaccines for seasonal influenza; however, development could also be used for
in the past, one was less effective than an monoclonal antibodies. Unlike vaccines,
injected vaccine. 21 which can stimulate an individual’s immune
system to produce protective antibodies for
• Oral delivery. The intestine contains 70 to years, monoclonal antibodies may provide
80 percent of all antibody-producing cells shorter protection against infectious diseases,
in the body. Oral vaccination—delivered usually for weeks to months. If able to be
in a pill or liquid form—can induce a developed and used early in a pandemic,
broad protective immune response in the monoclonal antibodies may potentially
body (including the intestine), which can provide some initial benefit. It is for this
be difficult to achieve using injections reason that we include monoclonal antibodies
with needles and syringes. However, oral as an approach that could be considered
vaccines must be formulated to protect alongside traditional vaccine R&D. Appendix II
against degradation in the provides additional information on
gastrointestinal tract, while still monoclonal antibodies. (See text box for
stimulating an effective immune examples of COVID-19 monoclonal
response. Examples of oral vaccines in use antibodies).
20 specific vaccine for the 2016-2017 and 2017-2018 influenza
The epidermis is the outermost layer of skin, which provides
a waterproof barrier and contributes to skin tone. The dermis seasons. For more information on the flu mist nasal vaccine,
lies just beneath the epidermis and contains tough connective see https://www.fda.gov/vaccines-blood-
tissue, hair follicles, and sweat glands. biologics/vaccines/fda-information-regarding-flumist-
quadrivalent-vaccine.
21
After the 2009 H1N1 influenza pandemic, several U.S. studies 22
Oral poliovirus vaccine is no longer used in the U.S., but it is
among 2 through 17-year-olds found that the live attenuated
influenza vaccine administered intranasally was as effective used in other countries. The U.S. no longer uses the oral
against influenza B viruses and influenza A (H3N2) viruses as poliovirus vaccine due to the risk of vaccine-derived poliovirus
the traditional injectable vaccine, but it was less effective than disease in certain individuals. However, other oral vaccines
the injectable vaccines against the 2009 pandemic H1N1 have been shown to be safe when not contraindicated.
viruses. These data led CDC to recommend against use of this
Vaccine Development GAO-22-104371 14
COVID-19 monoclonal antibodies 2.3.1 Inherent technological limitations
During the COVID-19 pandemic, the Food and Drug
Administration (FDA) issued four emergency use The extent to which the following
authorizations (EUA) for monoclonal antibodies to treat
technologies and approaches are adopted
COVID-19. Two of these four treatments consist of a
mixture of two monoclonal antibodies, while the may depend on their technological limits.
remaining two treatments each consist of a single
monoclonal antibody. Additionally, researchers are
investigating using monoclonal antibodies to protect • Omics and reverse vaccinology. Reverse
against COVID-19 before someone is infected or for vaccinology cannot predict some
individuals with compromised immune systems. For
example, one developer recently published clinical trial antigens—such as sugar-based
data showing that a mixture of two monoclonal (polysaccharides) or fat-based (lipids and
antibodies reduced the risk of people developing any
COVID-19 symptoms by 77 percent.
glycolipids) antigens found in bacteria and
Source: GAO analysis of literature. | GAO-22-104371
parasites—so more traditional
approaches are used. Also, individual
immune system responses among people
2.3 Challenges affecting the adoption vary widely, which may limit the ability to
of R&D technologies and approaches identify common immune responses to
antigens even with the use of omics.
Drawing on information from experts, • Next-generation vaccine platforms. To
stakeholders, and related literature, we ensure the effectiveness of next-
identified three key challenges affecting the generation vaccine platforms, vaccine
adoption of technologies and approaches for researchers need to carefully consider the
vaccine R&D: selected genetic sequences from
pathogens that code for antigens. If they
• Inherent technological limitations do not, the result can be ineffective
• Complex, costly instruments vaccine candidates. For example, while
the first two mRNA COVID-19 vaccines
• The need for highly trained personnel
authorized for emergency use were highly
effective at preventing disease, a
different mRNA vaccine candidate was
not as efficacious in clinical trials. 23
Vaccine researchers stated that this was
23
In this report, we use the term efficacy to refer to the results
of adequate and controlled clinical trial studies that evaluate
clinical disease endpoints, and effectiveness to refer to the
results of studies carried out under field conditions. For
regulatory purposes, FDA determines whether a vaccine is safe
and effective, and effectiveness is generally based on the
results of adequate and well controlled studies evaluating a
clinical disease endpoint (efficacy studies) or a well-accepted
immune endpoint (effectiveness studies). For more information
on the mRNA vaccine candidate that was not as efficacious in
clinical trials, see CureVac, CureVac Provides Update on Phase
2b/3 Trial of First-Generation COVID-19 Vaccine Candidate,
CVnCoV (Tübingen, Germany / Boston, USA, June 16, 2021).
Vaccine Development GAO-22-104371 15
partly due to the fact that this vaccine that are administered via nontraditional
candidate lacked key structural routes may also require investment in
modifications to the mRNA that were manufacturing capability to
made in the first two mRNA vaccines. accommodate new delivery mechanisms.
For example, while various vaccines may
The cold storage requirements for some be able to be delivered via dermal
vaccines being developed using next- patches, concerns about costs and mass
generation vaccine platforms are also a production have been raised.
challenge because they require
specialized shipping containers and • Monoclonal antibodies. Monoclonal
laboratory refrigerators and freezers not antibodies differ from vaccines in several
readily available at all health care ways. For example, they are made of
facilities. Vaccines become less effective proteins that can degrade over time, do
or completely ineffective if stored at the not stimulate the human immune system
incorrect temperature. While most the same way that vaccines do, and do
vaccines require refrigerated storage at not provide the long-term protection that
between 2 and 8°C, some mRNA vaccines vaccines may provide. Also, monoclonal
require storage in freezers at ultra-low antibodies have traditionally been
temperatures as cold as -80°C. 24 administered intravenously at a medical
Challenges associated with cold storage facility. However, modifications to specific
requirements and scaling up the parts of these proteins can extend the
production of vaccines developed using period of protection and may allow for
next-generation platforms may affect the delivery by intramuscular or
ability to use vaccines worldwide. One subcutaneous injection rather than
expert we spoke with noted that these intravenously. Monoclonal antibodies
challenges largely impact low and middle
have traditionally been developed for use
income countries.
as therapeutics against non-infectious
• Routes of vaccination. Nontraditional diseases such as various cancers and
routes of vaccination require researchers autoimmune diseases. Careful
to ensure that the antigen remains assessment, development, and evaluation
capable of producing the required of safety and effectiveness are important
immune response. Some antigens may for monoclonal antibodies as for vaccines.
not be amenable to administration by More than 100 monoclonal antibodies
nontraditional routes. For example, oral have been licensed for use by FDA, but
vaccines must be developed in such a way
that the formulation can survive the harsh
gastrointestinal environment. Vaccines
24
Some vaccines that require freezer storage, such as the two
COVID-19 mRNA vaccines authorized for emergency use in the
U.S., can be safely stored for a limited time between 2°C and
8°C. See https://www.fda.gov/news-events/press-
announcements/fda-brief-fda-authorizes-longer-time-
refrigerator-storage-thawed-pfizer-biontech-covid-19-vaccine.
Vaccine Development GAO-22-104371 16
only seven are indicated to treat or manufacturing may decrease production
prevent infectious diseases. 25 costs.
2.3.2 Complex, costly instruments These potentially high costs and complexity
may be exacerbated by the lack of defined or
The extent to which the following profitable markets, such as vaccines for
technologies and approaches are adopted pathogens with pandemic potential or that
may also depend on their complexity and primarily affect developing countries. These
cost. economic challenges may inhibit new vaccine
development. 26
• Omics and reverse vaccinology. The high
cost of omics-based instruments, such as 2.3.3 The need for highly trained
massively parallel sequencing instruments personnel
and their reagents, and the complexity of
the resulting data may prevent use by The extent to which the following
some researchers. technologies and approaches are adopted
• Routes of vaccination. Developing may also depend on a highly-trained
vaccines for different routes of workforce to operate the complex
vaccination may be expensive due to instruments and processes.
complex technologies used in formulation
development, according to one expert we • Omics and reverse vaccinology. Because
spoke to. the instruments and techniques, such as
massively parallel sequencing instruments
• Monoclonal antibodies. Traditionally, and bioinformatics tools, needed for
development and manufacturing of omics analyses are complex, highly-
monoclonal antibodies has been complex, trained personnel may also be needed.
expensive, and time consuming. However,
new techniques for easier identification, • Monoclonal antibodies. The complexity
selection, and optimization of monoclonal of the technology and approaches for
antibodies have reduced the complexity monoclonal antibody development and
and time for development from years to manufacturing require a specialized
weeks. Further, improvements in workforce. For example, a manufacturing
run may require up to two weeks with as
many as 10 distinct steps.
25 26
The seven licensed monoclonal antibodies indicated to treat For additional discussion of economics issues that inhibit
or prevent infectious disease include those for Ebola virus, HIV, vaccine development see Chapter 5.
Clostridium difficile, Bacillus anthracis (the organism that
causes anthrax), and respiratory syncytial virus. FDA has also
issued four EUAs for monoclonal antibodies to treat COVID-19.
Two of these four treatments consist of a mixture of two
monoclonal antibodies, while the remaining two treatments
each consist of a single monoclonal antibody. Most licensed
monoclonal antibodies are used as therapeutics for cancer and
other non-infectious diseases, such as rheumatoid arthritis.
Vaccine Development GAO-22-104371 17
• Next-Generation Vaccine Platforms. The and Human Services (HHS) also noted that
complexity of platform technologies NIAID publishes a list of priority pathogens. 30
requires a highly skilled workforce, However, this list also does not explicitly
according to an expert we spoke to. For prioritize specific potential pandemic
example, for platform technologies, pathogens that researchers should consider
execution of the biological processes is developing vaccines against, and—as noted
important for consistency of on the website—it appears the content has
manufactured doses. not been reviewed since July 2018. As a
result, we have not found evidence that a list
2.4 Infectious disease prioritization which prioritizes specific potential pandemic
pathogens for vaccine development exists.
The federal government supports R&D for
infectious disease vaccine development, While infectious disease prioritization cannot
which is guided, in part, by the Department of address potential pandemic pathogens yet to
Health and Human Services’ Vaccines be identified, a strategy for vaccine
National Strategic Plan 2021–2025, among development against families of known
other strategies. 27 This plan provides a pathogens with pandemic potential could
strategy to promote vaccine R&D and other
areas for the U.S. vaccine and immunization
enterprise. Further, the Public Health
Emergency Medical Countermeasures
Enterprise, which makes recommendations to
the Secretary of Health and Human Services,
has a list of high-priority biological threats. 28
While this list includes emerging infectious
diseases, it does not identify which diseases
or disease families have pandemic potential—
with the exception of pandemic influenza—
for researchers to target development of
vaccines against. 29 The Department of Health
27 may be included if Public Health Emergency Medical
NIAID has supported and conducted research for vaccines
against viral, bacterial, fungal, and parasitic diseases. The Countermeasures Enterprise leadership determines they have
National Health Security Strategy 2019-2022 “provides a vision the potential to affect national health security.
for strengthening our nation’s ability to prevent, detect, assess, 29
Some of the functions of the Public Health Emergency
prepare for, mitigate, respond to, and recover from 21st Medical Countermeasures Enterprise have been paused since
century health security threats.” The National Influenza 2018-2020, and only minimal operations have occurred. We
Vaccine Modernization Strategy 2020-2030 outlines a vision for previously reported on recent efforts to restructure the Public
the U.S. influenza vaccine enterprise to reduce the impact of Health Emergency Medical Countermeasures Enterprise. See
seasonal and pandemic influenza viruses. GAO, COVID-19: Continued Attention Needed to Enhance
28 Federal Preparedness, Response, Service Delivery, and Program
The 2017-2018 Public Health Emergency Medical
Countermeasures Enterprise Strategy lists high-priority threats. Integrity, GAO-21-551 (Washington, D.C.: July 19, 2021).
The Public Health Emergency Medical Countermeasures 30
This list is available at
Enterprise also developed a risk assessment framework to https://www.niaid.nih.gov/research/emerging-infectious-
assess whether specific emerging pathogens should be diseases-pathogens.
included on the list of high-priority threats. These pathogens
Vaccine Development GAO-22-104371 18
help with preparedness. 31 As discussed Other countries and international entities,
earlier, the speed of COVID-19 vaccine such as the United Kingdom, the WHO, and
development was unprecedented. Had it not the Coalition for Epidemic Preparedness
been for two previous coronavirus Innovations, have lists that prioritize
outbreaks— Severe Acute Respiratory pandemic potential pathogens. 32 These lists
Syndrome (SARS) and Middle East Respiratory assist vaccine researchers and developers in
Syndrome (MERS)—and NIH investments in prioritizing their vaccine R&D efforts. (See
coronavirus research, along with investments text box for one approach to prioritization.)
in new vaccine platform technologies, the
development of a COVID-19 vaccine would NIH officials noted that potential pandemic
have taken significantly longer. pathogen prioritization for vaccine
development may stifle innovation. HHS
officials also noted that such prioritization
Prioritization of infectious disease would not fully address pathogens that are
Experts told us that one way of prioritizing infectious yet to be identified or pathogens that emerge
disease could be to use a “stock index fund” approach
whereby policymakers select a group of about 100 unexpectedly. 33 However, any prioritized list
infectious diseases and work toward making incremental of pandemic potential infectious diseases or
progress on each infectious disease. The experts stated
that the rapid development of a vaccine for COVID-19 was
disease families used to guide or direct
largely the result of incremental progress that had been vaccine R&D efforts could be updated
made on developing vaccines for Severe Acute
Respiratory Syndrome (SARS) and Middle East Respiratory
Syndrome (MERS). Using an index fund approach could
provide a similar foundation for the development of new
vaccines to respond to future epidemics and pandemics.
One basis for selecting diseases to include in the “fund”
could be by pathogen family so as to leverage progress on
one pathogen to others. For example, families of viruses
include paramyxoviridae, which include the Nipah virus;
orthomyxoviridae, which include influenza viruses; and
coronaviridae, which include SARS-CoV-2 that causes
COVID-19.
Source: GAO analysis of information from scientific literature and an expert
meeting. | GAO-22-104371
31 32
According to researchers from the Johns Hopkins University The Coalition for Epidemic Preparedness Innovations is a
Center for Health Security, of the 24 families of viruses capable global partnership launched in 2017 to develop vaccines to
of infecting humans, six families have characteristics that will stop future epidemics. Its mission is to accelerate the
likely result in one of them being the source of the next development of vaccines against emerging infectious diseases
pandemic. Those characteristics include no existing immunity and enable equitable access to these vaccines during
in the world’s population, respiratory transmission, outbreaks. According to the HHS, NIAID’s public list of priority
transmissible by infected people who have no symptoms, and pathogens includes some of the same pathogens that have
the lack of any existing, effective therapeutics or vaccines. Such been prioritized by the WHO and the Coalition for Epidemic
pathogens constitute a global catastrophic biological risk, Preparedness Innovations.
according to Johns Hopkins University Center for Health 33
Security researchers. The researchers also noted that RNA As previously noted, the Coalition for Epidemic Preparedness
viruses merit special concern because of their higher tendency Innovations and the WHO have prioritized pathogen lists for
to mutate, and they recommended that vaccines against vaccine development that include pathogens that have yet to
viruses with these characteristics be pursued due to their be identified—termed disease “X.” Johns Hopkins University’s
higher probability to produce global catastrophic biological risk Center for Health Security states that disease X includes those
events. viral families that are likely to cause future catastrophic
outbreaks.
Vaccine Development GAO-22-104371 19
periodically to include newly identified
threats. 34
2.5 Policy options that may help
address challenges related to vaccine
R&D
We identified two policy options that may
help address challenges related to the
adoption of vaccine R&D technologies and
approaches. We define policymakers in this
report as a broad term including, for example,
Congress, federal agencies, state and local
governments, academic and research
institutions, and industry.
34
The Department of Homeland Security, in coordination with
CDC, the Department of Defense (DOD), and the U.S.
Department of Agriculture, has created a tiered list of
biological terrorism agents that is regularly updated. As part of
this effort, these entities conduct a biological threat risk
assessment every two years to address shifting priorities or
newly identified threats. This bi-annual risk assessment assists
in prioritizing R&D of basic biological threat agent research,
biosurveillance methods, and the development of
countermeasures. This methodology could be likewise used to
regularly update a prioritized list of potential pandemic
pathogens.
Vaccine Development GAO-22-104371 20
Policy options that may help address challenges with developing vaccines for
infectious diseases
Policy option Opportunities Considerations
Prioritize infectious disease pathogens Prioritizing pathogens with As new threats are identified,
Policymakers could collaborate across pandemic potential could improve priorities may change, which may
sectors (e.g., government, academia, strategic vaccine R&D decision- cause uncertainty for vaccine
researchers, industry, and nonprofit making and help focus resources developers.
organizations) to prioritize infectious on developing and adopting key Policymakers may have different
disease pathogens with pandemic technologies and approaches that priorities based on their respective
potential for vaccine R&D. most effectively address those missions; for example, private sector
pathogens. priorities may differ from
For example, policymakers could
develop a working group to prioritize Appropriately matching the government priorities.
pathogens with pandemic potential technologies and approaches to There may be disagreements as to
and work more closely with the prioritized potential pandemic which key technologies should be
international organizations to prioritize pathogen, then leveraging prioritized and used, resulting in the
vaccine development as well as technologies and expertise held by need for policymakers to weigh the
develop monoclonal antibodies as various entities—such as potential advantages and
prophylactics and therapeutics. The government, private sector, and disadvantages associated with
working group could also periodically academic laboratories—may help various options.
revisit the prioritized list and update as address certain technological
appropriate to ensure newly identified limitations and costs.
threats are addressed. This could help With greater leadership and
address the challenges we identified strategic partnerships,
related to appropriately prioritizing policymakers could take steps to
potential pandemic pathogen vaccine increase preparedness to more
R&D efforts and the technologies and quickly address threats to the U.S.
approaches needed to support those population.
efforts, address technological
limitations, and focus the use of costly
instruments and personnel.
Improve preparedness This early development of vaccine The lack of certainty of the
Policymakers could provide funding and candidates and monoclonal commercial market and government
other support for public/private antibodies could provide a procurement for vaccines against
partnerships to strategically address coordinated foundation that can pathogens with pandemic potential
potential pandemic pathogens be mobilized in an emergency. may be too risky for the private
identified as priorities. Such an approach could speed sector to undertake.
vaccine development as well as
These partnerships could, for example, potentially reduce risk for vaccine
develop and test vaccine candidates researchers and developers
and monoclonal antibodies that may concerning questions of safety,
provide protection from high impact efficacy, and manufacturability.
pathogens and pathogens with Assessing the likelihood of
pandemic potential. Leveraging outbreaks from known pathogens,
relationships with the private sector and developing vaccines through
may allow for sharing of highly trained at least phase 1 clinical trials may
personnel and costs of the complex make it easier to more rapidly
instruments that are critical parts of mitigate future pandemics.
the pandemic preparedness
infrastructure.
Source: GAO. | GAO-22-104371
Vaccine Development GAO-22-104371 21
3 Technologies and Approaches for Vaccine Testing
Innovative technologies and approaches demonstrate that a product produces the
may enhance vaccine testing, which desired result (57 percent of failures are for
includes preclinical studies, clinical trials, this reason); failure to demonstrate that the
and post-marketing surveillance studies, product is safe (17 percent); failure to
allowing vaccine developers to more quickly address business challenges, such as
or effectively test for vaccine safety, keeping costs within budget (22 percent);
identify and recruit clinical trial participants, and failure due to unknown reasons (5
and analyze clinical trial data. However, percent). 37
challenges, including technological
maturity, patient privacy, developing data Developers may also struggle to enroll
standards, and the need for stakeholder enough participants. According to a 2015
collaboration, may affect widespread study, 19 percent of all initiated phase 2
adoption. and 3 intervention clinical trials in the
National Library of Medicine clinical trial
3.1 Factors affecting vaccine testing registry either failed to enroll enough
participants or completed with less than 85
percent of their expected enrollment, thus
Numerous factors affect developers’ ability
reducing the sample size from that planned
to test vaccines, including obtaining animals
at trial initiation. 38 For randomized control
needed for preclinical studies, recruiting a
trials (i.e., those that include both a
sufficient number of participants for clinical
treatment group and a control group, the
trials, and managing costs for this portion of typical approach for vaccines), one study
development. The mean cost of developing from the United Kingdom found that 56
a vaccine from preclinical studies through percent of trials between 2004 and 2016
early clinical safety and efficacy testing achieved the target number of
(phase 2a) is $31 million to $68 million. 35 participants. 39
Further, according to research, about 67
percent of vaccine clinical trials are
estimated to fail. 36 Clinical trials may fail for
several reasons including failure to
35 38
D. Gouglas et al., "Estimating the Cost of Vaccine B. Carlisle et al., “Unsuccessful Trial Accrual and Human
Development Against Epidemic Infectious Diseases: A Cost Subjects Protections: An Empirical Analysis of Recently
Minimisation Study." The Lancet Global Health, vol. 6, no. 12 Closed Trials.” Clin Trials, vol. 12, no. 1 (2015): pp. 77-83.
(2018): pp. e1386-e1396. 39
S. J. Walters et al., “Recruitment and Retention of
36
C. Wong et al., “Estimation of Clinical Trial Success Rates Participants in Randomised Controlled Trials: A Review of
and Related Parameters.” Biostatistics, vol. 20, no. 2 (2019): Trials Funded and Published by the United Kingdom Health
pp. 273-286. Technology Assessment Programme,” BMJ Open, vol.7, no.3
37 (2017).
These statistics are drawn from a study of trials for new
drugs, therapeutic biologics, and vaccines. T. Hwang et al.,
“Failure of Investigational Drugs in Late-Stage Clinical
Development and Publication of Trial Results,” JAMA Intern
Med, vol. 176, no. 12 (2016): pp. 1826-1833.
Vaccine Development GAO-22-104371 22
3.2 Technologies and approaches of vaccine testing. For example, in the
that may enhance vaccine testing preclinical phase organ chips may be used
to determine whether vaccine ingredients
Drawing on information from experts, have any toxic effects on human cells,
stakeholders, and the scientific literature, which may complement the information
we identified six technologies and gleaned from testing in animals or reduce
approaches that may improve vaccine the need for such testing. Artificial
testing and provide additional methods for intelligence (AI) and machine learning (ML)
assessing data gathered during clinical trials may be used for a number of purposes. For
(see table 2). See appendix III for additional example, AI and ML could be used during
information on technologies and each phase to predict toxicity in preclinical
approaches related to vaccine testing. studies, identify suitable participants for
clinical trials, and track long-term side
effects during post-marketing surveillance
The technologies and approaches we
studies (see fig. 4), among other things. 40
identified can be applied at different phases
Table 2: Selected technologies and approaches for vaccine testing
Name Description
Organ chips Populated with cells and used in preclinical studies, organ chips mimic the function
of human organs and can be used to study the effect of a vaccine candidate.
Artificial intelligence (AI) AI and ML systems can analyze large amounts of data gathered during preclinical
and machine learning (ML) studies and clinical trials.
Electronic health records An EHR is a digital record of a patient's medical information that can be used to
(EHR) support trials for patient recruitment, clinical data analysis, and post-trial follow-
up.
Common control groups A common control group allows multiple groups of participants in preclinical
studies or clinical trials to be compared with a single control group, reducing the
number of participants needed or enabling comparison among vaccine candidates.
Standardized assays Standardized assays are standardized tests or investigative procedures that can
potentially be used by different vaccine developers to determine the immune
response induced by a vaccine candidate. For example, standardized assays could
measure the presence of antibodies in clinical trial participants who have received
different vaccines candidates.
Virtual clinical trials and Virtual clinical trials, also referred to as decentralized trials, extend the reach of
wearable devices clinical investigations to where patients live and work. Data for virtual trials can be
collected remotely via wearable digital health technologies including watches,
bracelets, patches, textiles, and clothing.
Source: GAO. | GAO-22-104371
40
Post-marketing surveillance studies, also referred to as
phase 4 clinical trials, may be required after licensure to
obtain additional information on the product’s benefits,
risks, and optimal use.
Vaccine Development GAO-22-104371 23
The technologies and approaches we
identified may help address factors that affect
clinical trials by enabling developers to better
collect and analyze safety and efficacy data
for various vaccine candidates and more
successfully recruit and retain clinical trial
participants, among other things (see fig. 5).
Vaccine Development GAO-22-104371 24
Vaccine Development GAO-22-104371 25
3.3 Challenges affecting the adoption NIH, organ chips replicate the innate
of vaccine testing technologies and immune response, but the ability to
approaches replicate the adaptive immune response
is still being developed. 41 While organ
chips can be used for some aspects of
Based on information from experts,
toxicity testing, further maturity may be
stakeholders, and the scientific literature, we
needed to demonstrate that they do not
identified four challenges affecting the
produce false negative results.
adoption of technologies and approaches for
vaccine testing: • Virtual trials and wearable devices. To
conduct fully virtual trials, many
• Limited technological maturity organizations will need to develop new
technical capabilities. For example, they
• Difficulty protecting patient data
will need to integrate wearable
• Ongoing data standards development technologies and develop ways to capture
• Limited stakeholder collaboration and and analyze potentially large volumes of
agreement on common approaches to data. Many wearable devices are in early
testing development and will need to
demonstrate analytical and clinical
validation to support data submitted for
These challenges may affect vaccine
vaccine licensure.
developers, researchers who conduct clinical
trials, and patients who participate.
3.3.2 Challenges protecting patient data
3.3.1 Limited technological maturity
When patients consent to allow data from
their health records and other sources to be
The extent to which the following
made available for use in trials, more people
technologies and approaches are adopted will
gain access to this information, and the
depend on their technological maturity or
challenge of protecting data privacy
ability to demonstrate validity.
increases. 42 Researchers conducting clinical
trials must adhere to federal privacy laws and
• Organ chips. Organ chips are not yet
regulations, such as the Health Insurance
mature enough to replicate many of the
Portability and Accountability Act Privacy Rule
complex functions and responses of the
and other relevant requirements. 43
human immune system, limiting their
applicability. Specifically, according to
41 health information may be used or disclosed for research
The innate immune system is the body’s first line of defense
against germs entering the body. It consists of protection purposes. Researchers may obtain an individual authorization
offered by the skin, mucous membranes, immune system cells, from the patient that meets the requirements set out in the
and proteins. The adaptive immune system responds if the Privacy Rule or they may seek an institutional review board or
innate immune system is not able to destroy the germs. It is privacy board waiver of the Privacy Rule’s authorization
made up of T-lymphocytes, B-lymphocytes, and antibodies. requirement. 45 C.F.R. §§ 164.508, 164.512(i)(1)(i).
43
42
The Health Insurance Portability and Accountability Act A HIPAA-covered entity may also “de-identify” patient data
Privacy Rule establishes the conditions under which protected in accordance with the Privacy Rule prior to sharing it for
research purposes. 45 C.F.R. §§ 164.502(d), 164.514. This is
Vaccine Development GAO-22-104371 26
Technologies and approaches directly Technology and the Centers for Medicare &
affected by the need to protect patient data Medicaid Services issued final rules that
include: require data exchange and data element
standards for use in EHRs in order to promote
• Electronic health records (EHR). EHRs interoperability—generally defined as the
contain a wealth of sensitive information ability of a system to exchange electronic
including patients’ social security health information with, and use electronic
numbers, addresses, and health health information from other systems,
diagnoses. without special effort on the part of the
user. 44 This includes the use of technical
• AI and ML. AI and ML systems that are
standards for transmitting EHR data and
deployed in clinical settings contribute to
vocabulary standards for the content of EHR
privacy risks, and there are concerns that
data. 45
the use of increasingly sophisticated
computer techniques could make it easier
HHS has identified the need for securely
to re-identify data from patient records
available electronic health information since
and other sources.
2015, and has stated that it expects improved
• Virtual trials and wearable devices. interoperability to benefit researchers.
Virtual trials collect data outside the Specifically, due to a lack of data standards
traditional clinical care setting. There is a and interoperability in the past, researchers
need for security in the transmission of have been hindered in their ability to use
data. Researchers must maintain EHRs for research including clinical trials. The
protections in accordance with the new rules may help address the following
Privacy Rule. challenges to the use of EHRs in clinical trials:
3.3.3 Ongoing data standards • Lack of consistency in health record data.
development For some kinds of clinical data, standards
either have not been previously
In 2020, the HHS Office of the National developed or have not been universally
Coordinator for Health Information adopted. This inconsistency has hindered
typically done by removing data fields such as names, social other things, that health plans in Medicare Advantage,
security numbers, account numbers, and full faced Medicaid, the Children’s Health Insurance Program, and the
photographs. However, studies have shown that even properly federal exchanges make certain data available to patients
de-identified data may retain some risk of re-identification. through an application programming interface.
44 45
21st Century Cures Act: Interoperability, Information Key requirements of the Office of the National Coordinator
Blocking, and the Office of the National Coordinator for Health for Health Information Technology and the Centers for
Information Technology Health IT Certification Program, 85 Medicare & Medicaid Services rules are (1) the adoption of the
Fed. Reg. 25,642 (May 1, 2020). Interoperability and Patient Health Level 7 (HL7®) Fast Healthcare Interoperability
Access Final Rule, and 85 Fed. Reg. 25,510 (May 1, 2020). The Resources application programming interface standard, which
Office of the National Coordinator for Health Information enables health information technology systems and
Technology’s final rule establishes new rules to prevent applications to receive and exchange information from EHRs
“information blocking” practices by healthcare providers, and (2) adoption of the United States Core Data for
developers of certified health information technology, and Interoperability standard, which is a common set of data
other entities as required by the 21st Century Cures Act. Pub. L. elements, organized by data classes, that use a standardized
No. 114-255, § 4004, 130 Stat. 1034, 1176 (2016). The Centers content and format.
for Medicare & Medicaid Services’ final rule requires, among
Vaccine Development GAO-22-104371 27
the ability to use criteria to identify guidance collaboratively and that even with
eligible patients and analyze data from data standards in place, it will be difficult for
EHRs. researchers to use EHR data in clinical trials
without additional guidance. If efforts to
• Lack of EHR interoperability. EHR data
develop standards and advance
have in the past been based on different
interoperability do not continue to
data standards that cannot be exchanged
incorporate the specific needs of the research
easily. A lack of widely adopted data
and clinical trial communities, researchers
standards has hindered the exchange of
may be unable to optimize the potential for
data between EHRs and electronic data
electronic health data to be used in clinical
capture systems, which researchers use
trials.
to collect and manage clinical trial data. 46
While improved interoperability is expected
3.3.4 Limited stakeholder collaboration
to benefit researchers who use EHRs, new and agreement on common approaches
data standards may affect how researchers to vaccine testing
are able to use data. The Office of the
National Coordinator for Health Information Using common approaches, such as
Technology stated that while standardized standardized assays and common control
data elements successfully gather general groups, allows for direct comparisons among
structured information, these data are limited multiple vaccine candidates. However,
and often insufficient for clinical trials, which vaccine developers traditionally test their
require data that can answer specific research vaccines candidates using their own assays
questions. It also stated that researchers may and recruit their own participants for clinical
need to supplement these data from sources trials because companies tend to operate
outside the EHR, such as genomic data, but independently. Also, the tasks involved to
these data are not currently available using develop assays and plan trials are often
the adopted standard. Additionally, data closely integrated, and the timing of clinical
standards are still being developed, which trials for different vaccines would need to
may affect the availability of data elements align in order to use a common control group.
for research, including for clinical trials. 47 Using developer-specific approaches to
vaccine testing makes it more difficult to
Expanding and implementing standards for compare data from clinical trials of more than
electronic health data requires cooperation one vaccine candidate and determine the
between health care providers, government, relative efficacy of each. While experts said it
and industry. Industry representatives told us is important for different kinds of vaccines to
there’s a need to develop implementation be developed during a pandemic, they also
46 Interoperability standard and it adopts eight types of clinical
Food and Drug Administration, Use of Electronic Health
Record Data in Clinical Investigations (Silver Spring, Md.: July notes as standard data elements. Version 2 of the United
2018). States Core Data for Interoperability standard was released in
July 2021 and it includes only five data elements within the
47
For example, the Office of the National Coordinator for clinical notes data class: consultation note, discharge summary
Health Information Technology’s final rule states that clinical note, history & physical, procedure note, and progress note.
notes would be included within the United States Core Data for
Vaccine Development GAO-22-104371 28
said it is important to be able to directly work such as the difficult process of
compare the results to better understand the developing assays, or by tying government
potential differences in protection provided funding for vaccine development to the use of
by each vaccine candidate. Stakeholders, master protocols. One expert told us that
including vaccine developers and government expanding inventories of available assays for
decision-makers, would need to collaborate pathogens and families of pathogens could
to use standardized assays and common expedite the development and testing of new
control groups in order to benefit from the vaccine candidates. Another expert told us
advantages they may provide. that developing standardized assays to
measure cellular response to vaccine
According to experts we met with, it may be candidates could streamline the evaluation of
feasible and advantageous to use vaccine efficacy during clinical trials.
standardized assays and common control
groups in some scenarios. For example, when According to NIH officials, however,
government invests in developing a vaccine, it developing meaningful master protocols for
has an opportunity to work with industry using standardized assays and common
stakeholders to design clinical trials that control groups in advance of a pandemic
include these features. Experts said master outbreak from a novel pathogen would be
protocols, also known as common protocols challenging. According to officials, the
(a common set of processes that govern a set development of assays can require substantial
of studies), could be developed that include investment of time and resources to ensure
the use of standardized assays and common their safety, validity, and reproducibility, and
control groups that vaccine developers could this would likely need to be done for each
agree to follow in vaccine testing. 48 The individual pathogen. Furthermore, officials
protocols would ideally be developed prior to said adopting common control groups across
the onset of a pandemic event, according to multiple vaccine developers’ vaccine trials
experts, but the approach might also be also requires care, particularly if there are
possible in an emergency. differences in the doses required or the
timing of when different vaccine companies
The master protocol approach has been used are ready to begin clinical trials. NIH officials
previously with therapeutics, including for said there may be ways to address these
COVID-19, but HHS officials told us COVID-19 challenges, however. They said NIH’s Rapid
vaccine developers maintained control over Acceleration of Diagnostics program is an
their own trial protocols. However, it may be example of early-stage government
possible to incentivize developers to agree to investment to jump-start diagnostic
master protocols by completing formative development when a new infectious agent
48
FDA guidance defines a master protocol as a protocol
designed with multiple sub-studies, which may have different
objectives and involve coordinated efforts to evaluate one or
more investigational drugs in one or more disease subtypes
within the overall trial structure. FDA, COVID-19: Master
Protocols Evaluating Drugs and Biological Products for
Treatment or Prevention (Silver Spring, Md.: May 2021).
Vaccine Development GAO-22-104371 29
threatens public health, and NIH’s clinical trial Harmonized protocols for COVID-19 vaccine
evaluating mixed COVID-19 vaccine schedules candidates
serves as a model for addressing these The National Institutes of Health (NIH)-led Accelerating
challenges. COVID-19 Therapeutic Interventions and Vaccines is a
public-private partnership that was formed to speed
development of the most promising treatments and
One expert stated that even if standardized vaccines for COVID-19 by coordinating activities by federal
agencies, vaccine developers, and other stakeholders. The
assays are not ready at the start of a clinical partnership advised on protocol designs to harmonize the
trial, once the assays are available they can be approach to phase 3 clinical trials for COVID-19 vaccines
used on stored samples from trials. The conducted through the National Institute of Allergy and
Infectious Diseases’ (NIAID) COVID-19 Prevention
expert said that this approach could be part Network. 50
of the protocols and could help in making
Features of the harmonized protocols included:
comparisons across vaccine candidates.
• Standardized assays. Standardized assays were
Furthermore, according to the expert, when
developed collaboratively and were used to evaluate
the federal government is contributing the efficacy of COVID-19 vaccine candidates in phase
funding it could also encourage companies to 3 clinical trials.
share biological samples and establish • Shared data and safety monitoring board. Clinical
trials were overseen by a single shared independent
common definitions of infection and disease, data safety monitoring board, established by NIAID.
which would help improve the ability to
• Separate control groups. Phase 3 clinical trials for
compare results across vaccine candidates. COVID-19 vaccine candidates maintained separate
control groups for each vaccine trial.
As part of the response to the COVID-19 According to NIH, clinical trials of COVID-19 vaccines
conducted through NIAID’s COVID-19 Prevention Network
pandemic, NIH’s Accelerating COVID-19 used these standardized assays. The Accelerating COVID-
Therapeutic Interventions and Vaccines 19 Therapeutic Interventions and Vaccines partnership
partnership initiative used some common coordinated efforts helped address challenges related to
enrolling enough participants for trials and interpreting
protocols, including standardized assays, to and comparing trial results.
guide phase 3 clinical trials of certain COVID- Source: GAO analysis of information from scientific literature and an expert
19 vaccines (see text box for an example of meeting. | GAO-22-104371
how harmonized protocols have been used). 49
Experts said that the Accelerating COVID-19
Therapeutic Interventions and Vaccines
partnership could provide a model for using
master protocols for vaccine clinical trials.
Following this approach, stakeholders could
collaborate to develop protocols and could
follow the protocols to advance vaccine
candidates to phase 1 clinical trials. Once a
49 Operation Warp Speed), the European Medicines Agency, and
The Accelerating COVID-19 Therapeutic Interventions and
Vaccines public-private partnership is coordinated by the representatives from academia, philanthropic organizations,
Foundation for the National Institutes of Health and brings and numerous biopharmaceutical companies.
together NIH, the Biomedical Advanced Research and 50
According to NIH, the harmonized approach was intended to
Development Authority (BARDA), CDC, FDA, DOD, the guide vaccine developers. However, developers still designed
Department of Veterans Affairs, the HHS-DOD COVID-19 their own specific clinical trial protocols.
Countermeasures Acceleration Group (formerly known as
Vaccine Development GAO-22-104371 30
pandemic event occurs, the protocols could 3.4 Policy options that may help
be modified as necessary, according to address challenges related to vaccine
experts. Such protocols could also guide testing
phase 3 clinical trials as was done for COVID-
19 vaccine candidates.
We identified two policy options that may
help address challenges related to the
Although the Accelerating COVID-19
adoption of testing technologies and
Therapeutic Interventions and Vaccines
approaches. As mentioned previously,
partnership did not use common control
policymakers include Congress, federal
groups—and they may not be applicable in
agencies, state and local governments,
every scenario—experts told us that doing so
academic and research institutions, and
has the potential to improve trial recruitment
industry.
and might enable adaptive designs that could
speed up clinical trials involving multiple
vaccine candidates. 51 Along with the adoption
of data standards, which may improve the
readiness of EHRs for use in clinical trials,
these potentially allow for more efficient
means to enhance the response to endemic
levels of infectious disease as well as better
respond to potential future epidemics and
pandemics.
51
FDA defines an adaptive design as a clinical trial design that
allows for prospectively planned modifications to one or more
aspects of the design based on accumulating data from
subjects in the trial. FDA, Adaptive Designs for Clinical Trials of
Drugs and Biologics (Silver Spring, Md.: Nov. 2019).
Vaccine Development GAO-22-104371 31
Policy options that may help address challenges related to vaccine testing
Policy option Opportunities Considerations
Further support • Integrating researchers’ needs into • Expanding access to patient heath data
development of data the standards development process requires attention to ensure privacy. If
standards could better ensure the necessary patient data have been de-identified,
Policymakers could data are available. combining data from multiple sources
further support • Data standards could more easily may make it easier to re-identify.
coordinated efforts to allow researchers to combine • Data from different sources, such as
obtain the views of all different data sets, enabling better wearable devices and clinical notes, may
stakeholders and to transmission of data for analysis in vary in quality and reliability, making it
develop standards for trials. difficult to use them in combination.
health data and their • Interoperable systems may eliminate • Developing and implementing
use in clinical trials. the manual transcription of data, standardized data formats and IT
This support could help reducing data entry errors. infrastructure is time-consuming and
address the challenge • Access to high-quality data in a costly.
we identified related to standardized format may allow • Disparities in access to health care,
ongoing data standards streamlined patient recruitment for particularly among some population
development. clinical trials. groups, may limit the pool of patient
• Improving standards may facilitate records available for research.
identification of differences in
clinical trial efficacy across
population subgroups (e.g.,
differences by age, race, and gender)
by broadening the pool of patient
records available for research.
Study feasibility of • Trial logistics could be streamlined, • Vaccine developers may be unwilling to
using common control and cost-sharing could produce give up control of designing trials and
groups and savings. use of proprietary assays, and may resist
standardized assays • Meeting recruitment goals could be having head-to-head comparisons with
Policymakers could faster, which can be important other vaccine candidates.
study the feasibility of during pandemics. • If not agreed to in advance, stakeholder
collaborating with • Trial participants are more likely to coordination, infrastructure
industry for use of receive a vaccine candidate, which requirements, and complex trial design
standardized assays may boost recruitment. elements could make the start-up time
and common control • Incorporating adaptive trial designs for a master protocol longer than that of
groups during in planned protocols may lessen a single-purpose trial.
pandemic and non- regulatory review requirements • Determining the timing and predicting
pandemic scenarios. when modifications need to be the required funding level could be
This option could help made. difficult if new vaccine candidates will be
address the challenge • A head-to-head comparison of added to a trial design on an ongoing
we identified related to vaccine candidates, enabled by basis.
limited stakeholder following master protocols, improves • Developing assays requires significant
collaboration and understanding of efficacy. The effort. Harmonizing results across
agreement on common master protocol approach may also vaccine candidates, as was done for
approaches to testing. facilitate the implementation of COVID-19 phase 3 clinical trials, may be
clinical research across successive more achievable than requiring
outbreaks of a disease since developers to use a standardized
protocols will already be in place. method to measure immune response.
Source: GAO. | GAO-22-104371
Vaccine Development GAO-22-104371 32
4 Technologies and approaches for vaccine manufacturing
Certain technologies and approaches for • An inability to rapidly scale up
vaccine manufacturing may have the manufacturing to meet surges in new
potential to enhance the U.S.’s ability to vaccine demand
address infectious diseases and prepare for
• An inability to use available capacity to
future epidemics and pandemics. These
manufacture new vaccines without
technologies and approaches may allow for
impacting the manufacture of other
an increase in manufacturing flexibility—the
licensed vaccines
ability to quickly switch from manufacturing
one vaccine to another—and an increase in Vaccine manufacturing is traditionally
manufacturing productivity. However, inflexible, with many manufacturers
challenges such as technical limitations, producing single vaccines products in
costs, and the need for highly trained centrally located, dedicated facilities. As a
personnel affect vaccine manufacturers’ result, new vaccines cannot be easily
ability to adopt new technologies and incorporated into existing facilities, and
approaches. Further, private manufacturers different vaccines cannot be manufactured
may be reluctant to establish and maintain simultaneously, in quick succession, or
costly excess manufacturing capacity to closer to the geographic point of need.
address surges in vaccine demand during Further, centrally located, dedicated
pandemics. The federal government has product manufacturing facilities can be a
attempted to address these issues; single point of failure—a risk that can
however, challenges remain. negatively impact vaccine supply.
4.1 Factors affecting vaccine Besides influenza vaccine manufacturing,
manufacturing the U.S. lacks the infrastructure—known as
surge capacity—needed to quickly scale up
the manufacture of new vaccines to address
Factors that affect vaccine manufacturing
outbreaks, including pandemics. The lack of
include: 52
surge capacity is caused partially by the
reluctance of vaccine manufacturers in the
• A lack of flexibility to rapidly switch
private sector to invest in the high cost of
manufacturing lines from one vaccine
maintaining excess, idle capacity in
to another
anticipation of unknown future vaccine
52
As noted in GAO-21-207, vaccine manufacturing supply
chains may be strained by disruptions caused by the COVID-
19 pandemic, including changes in the labor market,
increases or decreases in the demand for certain goods, or
export restrictions implemented by some countries. For
example, obtaining manufacturing materials, such as
disposable reactor bags, reagents, and certain chemicals,
may be a challenge. Further, the supply of materials used in
fill-finish manufacturing, such as glass vials and pre-filled
syringes, may be limited.
Vaccine Development GAO-22-104371 33
needs. As a result, U.S. manufacturing maintaining operational readiness. Further,
capacity is generally focused on meeting in congressional testimony, a
market demand for vaccines listed on the representative from another center noted
child and adolescent immunization the challenge of maintaining operational
schedule (e.g., measles, mumps, rubella, readiness. 56 These centers’ facilities also
and polio) and those on the adult needed retrofitting, such as equipment and
immunization schedule for which profitable facility upgrades, to be able to sufficiently
markets exist (e.g., shingles and and timely manufacture the vaccines
pneumonia). 53 needed to respond to the COVID-19
pandemic.
To increase U.S. surge capacity, the
Biomedical Advanced Research and 4.2 Technologies and approaches
Development Authority (BARDA), within for vaccine manufacturing
HHS’s Office of the Assistant Secretary for
Preparedness and Response, established Drawing on information from experts,
three Centers for Innovation in Advanced stakeholders, and the scientific literature,
Development and Manufacturing in June we identified five selected technologies and
2012. 54 Among other capabilities, these approaches that may improve vaccine
centers were designed to provide technical manufacturing—collectively known as
assistance and to support additional surge bioprocess intensification (see table 3).
capacity that would be capable of delivering These selected technologies and
finished doses of pandemic vaccine within approaches are not necessarily new: some
12 weeks of the declaration of a have been used for years in other
pandemic. 55 However, as noted by industries, including chemical and
representatives from these centers that we pharmaceutical manufacturing, and some
spoke with, these facilities had difficulties in have already been applied in vaccine
53 55
The child and adolescent immunization schedule includes While the 12-week goal is specific to an influenza
recommended vaccines for children from birth through age pandemic, the capacity and capabilities developed for
18. The adult immunization schedule includes pandemic influenza preparedness could enable HHS to
recommended vaccines for ages 19 years and older. respond more effectively to other emerging infectious
54 diseases. HHS’s Office of the Assistant Secretary for
Created as public-private partnerships, the three Centers Preparedness and Response’s goal is to provide 600 million
for Innovation in Advanced Development and Manufacturing doses of pandemic vaccine for the U.S. within 6 months or
were established to address influenza pandemic vaccine less after a pandemic is declared.
availability, which fell short in 2009 because of an outdated
56
egg-based manufacturing process and bottlenecks in the fill- Transcript from “Examining Emergent Biosolutions’ Failure
finish step. The term fill-finish refers to the process of filling to Protect Public Health and Public Funds Hearing Before the
sterile containers with vaccine and finishing the process of Select Subcommittee On The Coronavirus Crisis of the
packaging filled containers for distribution. To address the Committee on Oversight and Reform House of
fill-finish bottlenecks, the federal government established Representatives One Hundred Seventeenth Congress First
the Fill Finish Manufacturing Network, a group of pre- Session May 19, 2021”.
qualified facilities that fill and finish vaccines for
manufacturers in a public health emergency. See GAO,
“National Preparedness: HHS Has Funded Flexible
Manufacturing Activities for Medical Countermeasures, but
It Is Too Soon to Assess Their Effect,” GAO-14-329
(Washington, D.C.: March 31, 2014).
Vaccine Development GAO-22-104371 34
manufacturing processes. These manage surge demand, and potentially
technologies and approaches may help distributing manufacturing closer to points
vaccine manufacturers increase flexibility of need. See appendix IV for additional
and capacity by allowing for rapid switching information on technologies and
between different vaccines within the same approaches related to vaccine
facility, increasing productivity to help manufacturing.
Table 3: Selected technologies and approaches for vaccine manufacturing
Name Description
Single-use systems Single-use systems refer to bioprocessing equipment that is designed to be used once
and then discarded. Such equipment is generally composed of sealed, pre-sterilized,
plastic components.
Modular These systems divide the manufacturing process into smaller functional building blocks
bioprocessing known as modules, suites, or pods that can stand alone or be incorporated into an
systems existing facility. For example, new modules can be added to quickly expand capacity or
switched to rapidly change processes, according to an expert we spoke to.
Cell-free synthesis Biological enzymes—proteins that cause biochemical reactions—are used to generate
antigens, which are then combined with other materials to create vaccines.
Process This approach improves the cells and growth ingredients—known as medium—and other
optimization processing steps. According to an expert we interviewed, this technology may increase
productivity and allow manufactures to get more out of the same equipment or facility.
Continuous These systems use automated, high-throughput, small-footprint production and
manufacturing purification equipment to manufacture vaccines. In contrast to existing batch processing
systems methods, which use separate tanks for each step in the process, continuous
manufacturing allows all steps of vaccine production to continue without interruption as
the materials flow through the system.
Source: GAO. | GAO-22-104371
The technologies and approaches we
identified can be applied at different stages
of vaccine manufacturing. For example,
modular bioprocessing systems may replace
fixed, inflexible infrastructure, potentially
allowing for rapid switching between
vaccines, scale up, and customization.
Process optimization can enable vaccine
manufacturers to increase antigen yields
and use smaller production volumes
through, for example, the use of specific cell
lines and growth ingredients (see fig. 6).
Vaccine Development GAO-22-104371 35
Single-use systems may help vaccine Modular bioprocessing systems may also
manufacturers increase the flexibility of help vaccine manufacturers increase the
their vaccine manufacturing facilities. For flexibility of their facilities. For example, a
example, manufacturers can replace vaccine facility’s fixed infrastructure, such
traditional stainless-steel vessels—known as rooms and areas dedicated to specific
as bioreactors—that are used to grow the bioprocessing steps, can be replaced with
cells that produce antigens with disposable modular components. These modular
plastic bioreactor bags. Single-use systems components can allow manufacturers to
eliminate the need for cleaning and rapidly switch from manufacturing one
sterilizing fixed equipment between vaccine vaccine to another, scale up manufacturing,
manufacturing runs—also known as or add a new facility in a new location more
batches—resulting in shorter turn-around quickly, according to an expert we spoke to.
times and increased efficiency. Since they Modular bioprocessing systems also allow
are discarded after each use, single-use vaccine manufacturers to continuously
systems may also reduce the potential for customize and reconfigure their equipment
contamination caused by inadequate to accommodate new vaccines or processes
cleaning or sterilization. more quickly—changes that are
Vaccine Development GAO-22-104371 36
traditionally difficult and costly. This ability growth medium. Antigen productivity can
to customize bioprocesses could allow be increased by growing cells at higher
vaccine manufacturers to establish smaller densities. 58 High-cell density can be
vaccine manufacturing facilities at sites achieved by selecting for or artificially
closer to infectious disease outbreaks. modifying cells that grow to high densities
or by changing how the cells are grown. For
For some vaccines, cell-free synthesis may example, cells that freely grow in liquid
eliminate the need to grow living cells to medium—called suspension cultures,
produce the antigen of interest, potentially typically result in higher cell densities and
resulting in smaller, more distributed antigen yields than cells that have been
facilities, and faster manufacture of new adapted to grow attached to a surface,
vaccines in existing facilities. Cell-free called adherent cultures.
synthesis combines purified biological
molecules to produce antigens, which are Continuous manufacturing systems may
then purified and formulated into also increase vaccine yields through
vaccines. 57 Additionally, while the first step automated, continuous antigen production
in mRNA vaccine manufacturing involves and purification. Continuous manufacturing
traditional growth of cells to generate a key systems may run for weeks or even months,
component—DNA—needed to make the reducing, for example, the requirement to
vaccine, the subsequent step to start new cell cultures for antigen
manufacture the mRNA uses cell-free production, stoppages between production
synthesis. The flexibility of cell-free and purification steps, and the potential for
synthesis reduces the single point of failure contamination. For example, one
risk that may be associated with centrally manufacturer we spoke with has tested its
located, dedicated product facilities. closed-production systems with continuous
Further, cell-free synthesis may allow for downstream processing technology to
the simultaneous manufacture of different produce vaccines for clinical trials. 59
vaccine antigens within the same facility,
which cannot be done in most existing 4.3 Challenges affecting the
facilities. adoption of vaccine manufacturing
technologies
Process optimization allows manufacturers
to increase antigen yields through, for
Drawing on information from experts,
example, the use of cells specifically
stakeholders, and the scientific literature,
developed to increase antigen productivity, we identified three key challenges that
known as optimized cell lines, matched with
specific growth ingredients, known as
57 59
Cell-free synthesis uses a number of purified biological A closed-production system uses equipment designed and
molecules, including enzymes and nucleic acids. operated in such a way that the product is not exposed to
58 the room environment. Materials may be introduced to a
Cell density describes the number of cells in a specific closed system, but exposure of the product to the room
volume of growth medium. environment must be avoided.
Vaccine Development GAO-22-104371 37
affect the adoption of technologies for • Continuous manufacturing. Continuous
vaccine manufacturing: manufacturing cannot be used for all
types of vaccines. For example, vaccines
• Inherent technological limitations produced in eggs, such as most
seasonal influenza vaccines, cannot use
• High costs and the need for highly
continuous manufacturing processes.
trained personnel
Additionally, continuous manufacturing
• Business risk processes cannot be used for some
vaccines because the biochemical
4.3.1 Inherent technological limitations processes by which cells produce the
antigens are not well defined and the
The extent to which some technologies and ability to control the production process
approaches are adopted for vaccine is limited.
manufacturing will depend on their
technological limits. Changing from batch to continuous
manufacturing also presents challenges
because depending on the
• Single-use systems. Some of the plastic
circumstances, vaccine companies also
materials used in single-use systems
may be required to seek and obtain FDA
may leach unwanted substances into
approval of manufacturing changes
the process, and disposable bioreactor prior to vaccine distribution to ensure
bags may leak. 60 Also, limitations in the safety and effectiveness of the
disposable bioreactor scale require vaccine have not been adversely
scale out versus scale up, according to affected. 61
an expert we spoke to. Further, there
are concerns about the environmental 4.3.2 High costs and the need for highly
impact of the waste plastic materials trained personnel
used in single-use systems after
disposal.
The extent to which some technologies and
• Cell-free synthesis. Cell-free systems approaches are adopted will also depend on
may be unable to synthesize some their cost and need for specialized
proteins, such as sugar-based personnel. For example, these technologies
(polysaccharide) antigens, or to require upfront capital expenditures by
produce properly folded or modified manufacturers that may be prohibitively
proteins. expensive. Further, manufacturers may be
reluctant to replace equipment for which
60 61
Because these leachable substances may be present, A sponsor may be required to seek and obtain FDA
manufacturers perform extensive testing to ensure that approval of certain changes to an existing biologics license
single-use systems do not negatively impact the vaccine and application to ensure the safety and effectiveness of the
so that batches do not need to be discarded, according to an biologic has not been adversely affected. This may include
expert we spoke to. changes to the product, production process, quality
controls, equipment, facilities, or responsible personnel. See
21 C.F.R. § 601.12 (2020).
Vaccine Development GAO-22-104371 38
they have already made significant capital a new vaccine manufacturing technology
expenditures. and how that could affect its financial
viability. According to a National Academies
• Single-use and modular bioprocessing of Sciences, Engineering, and Medicine
systems. Modular bioprocessing report that was sponsored by FDA, if
systems may involve significant capital introducing an innovative technology might
expenditures to implement. However, result in additional activities, costs, and
once implemented, single-use and time to support product approval, it often
modular bioprocessing systems may makes business sense for a manufacturer to
reduce operational costs and increase use more conventional technology for the
efficiencies that offset upfront product. 63 Furthermore, different
expenses. Further, building an requirements in other countries pose
integrated modular facility requires additional challenges to manufactures that
more skill and expertise, including aspire to market a product internationally.
technical construction and qualified, While the National Academies of Sciences,
experienced personnel to get a facility Engineering, and Medicine report focused
fully operational. on pharmaceutical manufacturing, one
expert we spoke to said the same principles
• Continuous bioprocessing. The costs
apply to manufacturing for vaccines.
involved in developing new
infrastructure and adding new
equipment and automation for 4.4 Challenges affecting scaling up
continuous processing may discourage manufacturing to meet surges in
the use of this technology. Further, the demand
skill set and capabilities required to
design, develop, validate, and operate a Two key challenges impact the ability to
continuous flow process are different meet surges in vaccine demand, including
from those required for conventional surges caused by epidemics or global
batch processing. 62 pandemics. The first is the capability of
private sector manufacturers to meet new
4.3.3 Business risk demand without negatively impacting their
ability to manufacture other licensed
The extent to which some technologies and vaccines. The second is the ability of the
approaches are adopted may also depend federal government to ensure that
on how manufacturers perceive the manufacturing capacity to respond to
business risk. Manufacturers may face pandemics is available and operational.
uncertainty in how regulators will evaluate
62 63
Baxendale, I. R., R.D. Braatz, B. K.Hodnett, K. F. Jensen, M. National Academies of Sciences, Engineering, and
D. Johnson, P. Sharratt, J-P. Sherlock, and A. J. Florence, Medicine, Innovations in Pharmaceutical Manufacturing on
“Achieving Continuous Manufacturing: Technologies and the Horizon, Consensus Study Report Highlights, National
Approaches for Synthesis, Workup, and Isolation of Drug Academies Press (2021).
Substance,” Journal of Pharmaceutical Sciences, vol. 104, no.
3, (2015): 781-791.
Vaccine Development GAO-22-104371 39
According to experts we spoke with, vaccine at the Maryland center appeared to be
manufacturers cannot fully address novel due, in part, to inadequately trained
threats from different categories of personnel. Similarly, the Texas center
pathogens because they do not create found it challenging to fill open mid-
excess, unused capacity for emergency and upper-management positions
events, and using existing infrastructure to during COVID-19 vaccine ramp up.
manufacture pandemic vaccines could
• Technologies and approaches that
negatively impact the production of current
enhance flexibility or increase
vaccines for diseases such as measles,
productivity are not supported. For
mumps, and rubella.
example, facility retrofitting and
technology transfer of new
The federal government has attempted to manufacturing processes for COVID-19
address private sector capacity gaps by vaccines required for the Texas and
establishing manufacturing capacity and Maryland centers were done during the
flexibility across a range of vaccine pandemic rather than in advance.
platforms to respond to infectious disease
outbreaks. However, these attempts have
4.5 Policy options that may help
not created adequate capacity to address
real-world pandemic manufacturing address challenges related to
needs. 64 For example, the Centers for vaccine manufacturing
Innovation in Advanced Development and
Manufacturing have not been effectively We identified two options for policymakers
maintained, updated, or made that may help address challenges related to
operationally ready to meet the new the adoption of technologies and the
COVID-19 vaccine surge in manufacturing improvement of vaccine manufacturing
during the pandemic as noted by capacity and operational readiness. As
representatives from one center we spoke mentioned previously, policymakers include
with and in congressional testimony. 65 Two Congress, federal agencies, state and local
key barriers inhibit scaling up governments, academic and research
manufacturing to meet such surges in institutions, and industry.
demand.
• Sufficiently trained personnel are
limited. For example, the COVID-19
vaccine cross contamination problems
64 65
While the approximately 10.5 months it took to develop a Transcript from “Examining Emergent Biosolutions’ Failure
COVID-19 vaccine was unprecedented, innovations and new to Protect Public Health and Public Funds Hearing Before the
approaches could accelerate vaccine development and Select Subcommittee On The Coronavirus Crisis of the
manufacture in the future. For example, the Coalition for Committee on Oversight and Reform House of
Epidemic Preparedness Innovations has an aspirational Representatives One Hundred Seventeenth Congress First
goal—“a moon-shot”—to make vaccines available in 100 Session May 19, 2021.”
days after determination of the pathogen’s genetic
sequence.
Vaccine Development GAO-22-104371 40
Policy options that may help address challenges related to vaccine manufacturing
Policy option Opportunities Considerations
Assess vaccine manufacturing Determining U.S. vaccine Vaccine manufacturing capacity
capacity and operational readiness manufacturing capacity and requirements may change based on
operational readiness and routinely the specific infectious disease and
Policymakers could routinely assess
pressure testing it can help identify vaccine platforms being pressure
U.S. manufacturing capacity and
gaps as well as key technologies and tested.
operational readiness.
approaches to address them.
For example manufacturing
capabilities could be pressure tested
to determine the nation’s overall
capability to manufacture current
vaccines and meet pandemic surge
demands.a
This could help address the
challenges identified related to
meeting new demands without
negatively impacting manufacturers’
ability to produce current vaccines.
Improve preparedness Manufacturing, testing and May require new resources or
Policymakers could provide support stockpiling vaccine candidates could reallocation of resources from other
and coordination for public-private be mobilized in an emergency and efforts.
partnerships to strategically develop more rapidly mitigate future There may be a risk that the vaccines
manufacturing capacity to respond pandemics. manufactured, tested, and stockpiled
to surge requirements. By leveraging strategic partnerships, against prioritized pathogen classes
To maintain this capacity, policymakers could take steps to miss certain pandemic pathogens.
partnerships could manufacture increase the availability of vaccines The stockpiled vaccines would need
prototype vaccine candidates against to more quickly address threats to to be regularly replenished prior to
high-priority pathogens.b For the U.S. population. expiration.
example, manufacturing, testing
through phase 1-2 clinical trials, and
stockpiling prototype vaccine
candidates against prioritized classes
of pathogens could decrease the
amount of time needed to validate
and scale up manufacturing
processes if a pathogen from those
classes does emerge.c
This could help address the
challenges identified related to the
ability of the federal government to
ensure that the manufacturing
capacity to respond to pandemics is
available and operational.
Source: GAO. | GAO-22-104371
aOperational readiness includes having available, well maintained equipment and facilities as well as enough trained
personnel. Further, operational readiness includes maintaining “warm” manufacturing capabilities—for example, by
Vaccine Development GAO-22-104371 41
operating at least one shift daily—so that equipment remains operational and personnel retain manufacturing
competency.
bAs described in chapter 2, if able to be developed and manufactured early in a pandemic, monoclonal antibody
candidates may also provide some initial benefit.
cOne expert estimated the cost to produce and test a vaccine through phase 2 clinical trials would be approximately
$50 million, with one-third of that cost required for manufacturing the vaccine.
Vaccine Development GAO-22-104371 42
5 Economics of vaccine development and the role of incentives
Vaccines confer significant public health including funding for clinical trials, and
and economic benefits. However, offering a financial incentive for the
economists we spoke with stated that the successful development of vaccines for
benefits that vaccines provide are not COVID-19. However, it is unclear whether
necessarily commensurate with the return policymakers have systematically examined
on investment from developing or how various tools can be used to incentivize
manufacturing them. Experts attribute the vaccine investment. 67
low rate of vaccine investment to market
failures (i.e., market interactions that fall As discussed earlier, vaccines have far-
short of what would have been socially reaching, positive effects on public health.
beneficial), challenging markets for some In addition to health benefits, such as
vaccines, high costs, and risks of reducing death and preventing infectious
development. Experts also stated that diseases and certain types of cancer,
uncertainty as to whether a vaccine, once vaccines also produce economic and social
developed, would be recommended for benefits. For example, a July 2020 report
universal use—for example, for all children found that vaccination enhances economic
as opposed to a subset of individuals with growth due to improved health as well as
certain risk factors—is an additional risk and productivity gains from better physical and
negatively affects incentives to develop cognitive performance. 68
them as it reduces the number of people
recommended to be vaccinated. 66 Vaccines also produce social benefits
Policymakers have a number of including improving equity in healthcare,
mechanisms to encourage investment in increased life expectancy, and
vaccine development. Some of these strengthening healthcare resources (see fig.
mechanisms have been used by HHS and 7). The July 2020 report also found that
the Department of Defense (DOD), when infrastructure is developed to
66 capabilities will not have to be developed rapidly or all at
One expert stated that vaccine entrants who enter a
market first will have a larger market share. A 2014 report once in response to a pandemic event. Similarly, having
from McKinsey & Company found that first-to-market vaccine candidates under development for pathogens
entrants into drug markets had a 6 percent market share similar to a potential future pandemic pathogen may further
advantage over later entrants. See M. Cha and F. Yu, reduce development costs as well as the overall price for
“Pharma’s First To Market Advantage,” McKinsey & vaccines. According to one economist we spoke to,
Company, Sept. 2014. investment undertaken at a more measured pace can be
cheaper because it does not stretch scarce (and thus
67
Several entities have reported on large profits earned by expensive) inputs. The economist noted that procuring
pharmaceutical companies for COVID-19 vaccines. vaccines under less urgency facilitates entry of multiple
Economists we spoke to stated that, from a benefit-to-cost competitors and allows a competitive tender process to be
perspective, it makes sense for policymakers to invest organized that favors low prices over speed.
significant funds in vaccine development, manufacturing 68
C.M., Rodrigues and S.A., Plotkin, “Impact of Vaccines:
capacity, and supply chain development to respond to an
active pandemic to meet immediate needs and reduce loss Health, Economic and Social Perspectives”, Frontiers in
of life. However, investing in vaccine technologies and Microbiology, vol. 11, article 1526 (2020): 1-15
manufacturing capacity in preparation for future pandemics
has the potential to reduce costs for vaccines because these
Vaccine Development GAO-22-104371 43
administer vaccines, it provides a basis for of what would have been socially beneficial.
the provision of other health and social care In the case of vaccines, market failures lead
services, particularly improving maternal to vaccine developers producing fewer
and infant mortality in developing regions. vaccines than what would have most
Although making projections about the benefited society, resulting in less
economic and social benefit of vaccines is protection from infectious diseases. Other
complex, a 2005 economic article reported challenges that contribute to low vaccine
that current childhood vaccinations against investment include markets that offer no or
tetanus, polio, measles, mumps, rubella, negative returns on investment, as well as
hepatitis B, and others, when considered the high cost and low probability of success
together, create significant economic and in developing vaccines.
social benefits. 69
5.1.1 Positive externalities
5.1 Market failures and other
challenges result in fewer vaccines We focused on two specific market failures
for vaccine development. 70 The first has to
Market failures occur when interactions in do with the nature of vaccines. Vaccines
the market lead to outcomes that fall short offer protection to those who are
69 “Overcoming Economic Barriers to the Optimal Use of
Current childhood vaccines against diphtheria, tetanus,
pertussis, Hib, polio, measles, mumps, rubella, and hepatitis Vaccines,” Health Affairs, vol. 24, no. 3 (2005): 667.
B, when considered together, were estimated to have a 70
Other market failures may also explain underinvestment
benefit cost ration of more than five to one for direct costs in vaccines. For example, vaccine research is a “public good”
and seventeen to one for societal costs. T.A. Lieu, et al., as the benefits of scientific and technological advances can
extend to others, regardless of who is making the
Vaccine Development GAO-22-104371 44
vaccinated as well as providing some level products based on this additional benefit
of protection to those who are not by and, as a result, are not rewarded for
reducing the spread of infectious disease preventing the spread of the disease.
(see fig. 8). In economics, this situation is Consequently, developers tend to
known as a positive externality. Because underinvest in vaccines, even though
this protection is inherent to all vaccines, society would benefit from having more
developers are unable to price their vaccines available.
Note: This figure is not intended to demonstrate vaccination levels commensurate with herd immunity. For more
information on herd immunity, see GAO-20-646SP.
investment, without reducing anyone else’s access to the developers being limited in how much they can charge when
advances. Researchers and developers cannot fully capture a pandemic arises. In this situation, the price is not set by
the financial benefits of this research and tend to invest less the market but by government purchases, and governments
than what the social value of this knowledge is, leading to a can limit prices, which means that the developers’ expected
situation where government action can improve upon revenue is low.
market outcomes. Similarly, one economist we spoke to
stated that there is a market failure associated with
Vaccine Development GAO-22-104371 45
5.1.2 Imperfect information high, only workers in the industry would
choose to get vaccinated, leaving others
The second type of market failure is caused unprotected. If a significant portion of the
by the inability of developers to fully market—in this case, workers not in the
account for the disease risk in the price of industry—chose not to purchase the
the product because of imperfect vaccine because of its price, then the
information. Vaccine developers have little developer would have less incentive to
information on how likely a particular produce the vaccine.
healthy person is to contract the disease or
seek vaccination to avoid becoming sick. 5.1.3 Challenging markets due to
However, when an individual contracts the uncertain demand
disease, the developer knows that the
individual is likely to seek treatment. 71 Some markets offer little, no, or negative
Developers can use this information to returns on investment, presenting
charge much higher prices for therapeutics challenges to vaccine developers. Such
than vaccines. As a result, the return on markets include vaccines that are
investment from vaccines is commonly developed for infectious diseases that occur
lower than that of therapeutics. With price only in developing countries, are considered
incentives skewed away from vaccines and low priority, or may result in future
toward therapeutics, vaccines make up only pandemics but are not currently an issue. 73
about 1.5 percent of global pharmaceutical Experts told us that because of low returns
sales. 72 or uncertainty in these markets, developers
have little financial incentive to invest in
In an example of a disease where workers such vaccines.
employed in an industry may be at higher
risk of being infected than workers not in Experts stated that infectious diseases that
that industry, workers in that industry who primarily affect developing countries which
are at higher risk would be willing to pay a have little ability to pay for vaccines provide
higher price for a vaccine. Workers not in little incentive for investment. For example,
that industry who are less likely to become a May 2020 study estimated that the rate of
infected would not be willing to pay as investment return on a portfolio of vaccines
much. However, all workers could become for nine infectious diseases identified by the
infected and suffer adverse health Coalition for Epidemic Preparedness
consequences. If the vaccine’s price was too Innovations as high priority, many of which
71 72
The developer may have some information about the T.A. Lieu, et al., “Overcoming Economic Barriers.” 675.
probability distribution of a particular infectious disease in 73
the population. However, an individual’s likelihood of NIAID officials stated that it conducts research to develop
contracting the disease depends on many other factors vaccine candidates that is not subject to the same market
including the individual’s behavior and the availability and challenges that private sector developer’s face.
use of preventive measures, which are unknown to vaccine
developers. In the case of therapeutics, the developer can
indirectly observe who has contracted the disease by
observing who seeks treatment for it.
Vaccine Development GAO-22-104371 46
affect developing countries, was negative told us that Epstein-Barr virus, which can
61 percent, implying that the private sector cause mononucleosis rarely results in
is unlikely to address this need without death, and therefore is considered a low
public-sector intervention. 74 In these priority for vaccine development. 76 Another
instances, international organizations, such expert stated that companies would be
as the Coalition for Epidemic Preparedness more encouraged to develop a vaccine for a
Innovations and philanthropic entities such larger or more defined population, such as
as the Bill and Melinda Gates Foundation children or people over the age of 65. For
fund research in these infectious diseases. 75 example, CDC recommends that all
(See textbox for an example of a challenging individuals 50 years or older should receive
market). the vaccine for shingles.
Challenging Market for Group A Streptococcus Vaccines for pathogens that may cause
Vaccine future pandemics but are not currently a
Group A Streptococcus causes, among other things, strep significant issue also face uncertain market
throat, scarlet fever, and rheumatic fever. Currently, there demand. Because developers receive no
is no vaccine, even though about 500,000 people
worldwide die due to Group A Streptococcus infections return on their investment unless a
annually, including between 1,100 and 1,600 deaths in the pandemic occurs, there is little incentive to
U.S. The pathogen is one of the top 10 causes of death
from infectious diseases worldwide and is considered
invest in these vaccines. Further, even if a
endemic in lower income areas of the globe. While NIAID pandemic event does occur, the demand for
supports research to develop a vaccine with several a vaccine may still be uncertain. If an
candidates in various phases of development, one expert
told us that to produce a Group A Streptococcus vaccine outbreak quickly dissipates, the market for
at a price that could be purchased in lower income the vaccine may be limited because
countries (less than $2 per dose), a business case analysis
anticipated that total sales would be between $200 individuals may not seek a vaccine and
million and $300 million annually, which is not sufficient governments may be unlikely to purchase
to incentivize developers to invest in such a vaccine.
it. For example, a May 2020 report found
Source: GAO analysis of information from literature and an expert
meeting. | GAO-22-104371 that the SARS and Zika epidemics ended
before vaccine development was complete,
and federal funding agencies reallocated
Further, infectious diseases that are
funds that had been committed to vaccine
considered lower priority can have limited
development for these diseases, leaving
market potential. For example, one expert
manufacturers with financial losses and
74 76
The study estimated a rate of return for a portfolio of 141 According to CDC, Epstein-Barr virus is one of the most
trial vaccines to address infectious diseases from the common human viruses in the world. It spreads primarily
Coalition for Epidemic Preparedness Innovations’ Priority through saliva. Epstein-Barr virus can cause infectious
Pathogen List including: Chikungunya, MERS, SARS, Marburg, mononucleosis, also called mono, and other illnesses. Most
Rift Valley Fever, Lassa, Nipah, Crimean-Congo hemorrhagic people will get infected with Epstein-Barr virus in their
Fever, and Zika virus. See J. Vu et al., “Financing Vaccines for lifetime and will not have any symptoms. Mono caused by
Global Health Security,” National Bureau of Economic Epstein-Barr virus is most common among teens and adults.
Research, May 2020. Other infections sometimes go along with mononucleosis,
75 which may need to be treated with antibiotics. NIH noted
The Bill and Melinda Gates Foundation is a philanthropic that its researchers have developed vaccine candidates for
organization that funds global health efforts. A priority area Epstein-Barr virus. For more information see
for the Gates Foundation is to develop effective and https://www.cdc.gov/epstein-barr/index.html.
affordable vaccines, medicines, and other health tools.
Vaccine Development GAO-22-104371 47
setting back other vaccine development effectively reduced the number of people
programs. 77 The article also found that, who would be receiving the vaccine and,
even with successful development and therefore, the return on investment. 79
licensure, commercial markets still may not
sustain multiple vaccines for which 5.1.4 High development costs and low
relatively few doses may need to be probability of success
manufactured. One expert said that the
potentially low number of doses to be Two additional challenges further
manufactured increases the uncertainty of contribute to the low return on investment:
the potential return on investment and high costs and low probability of success. 80
therefore risk for vaccine developers, which
creates an even lower incentive to develop • High costs. According to a 2018 study,
a vaccine during any subsequent infectious vaccine development from discovery to
disease outbreak and hinders preparation licensure can cost billions of dollars and
for future pandemics. can take over 10 years to complete. 81
Another expert told us that vaccines placed • Low probability of success. The same
on vaccine schedules—the lists of vaccines study found that on average, vaccine
recommended for children and adults in the candidates have a 94 percent chance of
U.S.—and recommended for universal use failure.
generally have large markets and are often
covered by insurance. However, the lack of 5.2 Mechanisms to incentivize
assurance that a vaccine would be vaccine development
considered for inclusion on the vaccine
schedule can also hinder investment. For Several mechanisms can potentially be used
example, experts told us that, following to incentivize additional investment in
review by the CDC’s Advisory Committee on vaccines. These mechanisms either
Immunization Practices, a vaccine for subsidize some portion of the development
meningitis B was not recommended for process or provide rewards for successful
universal use. 78 This recommendation development. Given the market failure
77 that adolescents between the ages of 16 and 23 consult with
See N. Lurie, et al., “Developing COVID-19 Vaccines at
Pandemic Speed,” The New England Journal of Medicine, their clinician to determine whether they should receive the
vol. 382, no. 21 (2020): 1969 vaccine.
80
78
CDC’s Advisory Committee on Immunization Practices is One economist we spoke to stated that some factors
comprised of medical and public health experts who make impair how lucrative a market is, but they aren’t market
recommendations on the use of vaccines in the civilian failures if they don’t generate a wedge between a firm’s
population of the U.S. Its recommendations serve as public commercial incentives and social benefits. Factors, such as
health guidance for safe use of vaccines and other related high cost and low probability of success are not market
products. If adopted by the CDC Director, CDC’s Advisory failures, but they may serve to amplify them.
Committee on Immunization Practices’ recommendations 81
D. Gouglas et al., "Estimating the Cost of Vaccine
are published as official HHS/CDC recommendations in the Development Against Epidemic Infectious Diseases: a Cost
Morbidity and Mortality Weekly Report. Minimisation Study," The Lancet Global Health, vol. 6, no. 12
79 (2018): pp. e1386-e1396.
According to CDC, in 2019, there were about 371 total
cases of meningococcal disease reported. CDC recommends
Vaccine Development GAO-22-104371 48
associated with vaccines, it is unlikely Policymaker interventions can be broadly
private investments will sufficiently support classified into push and pull incentives (see
the development of all socially beneficial table 4). Push incentives subsidize the costs
vaccines. Policymakers could fill this gap by of developing a product or general research
taking actions to incentivize investment in in vaccines by providing funding for grants
new vaccines to better address infectious to academic institutions, tax credits for
disease; improve overall societal, health, R&D, and low or no cost manufacturing.
and economic outcomes; and prepare for Pull incentives increase revenue once a
future pandemics. To do so, policymakers vaccine receives authorization or licensure.
need a combination of tools to incentivize This can be done, for example, by
investment. HHS has leveraged some guaranteeing to purchase a certain quantity
mechanisms to incentivize vaccine or promising a cash prize for successful
investment, most recently to respond to the authorization or licensure. Other examples
COVID-19 pandemic. of pull incentives include patent extensions
and priority review vouchers (which can be
5.2.1 Incentives for vaccine investment sold for revenue or used for faster review
on a future drug or biologic application).
We identified several mechanisms with the
potential to incentivize vaccine investment.
According to experts, policymakers need
access to a wide range of mechanisms,
because different mechanisms are better
for some infectious disease scenarios than
for others.
Vaccine Development GAO-22-104371 49
Table 4: Potential mechanisms to incentivize vaccine development
Mechanism Definition Opportunities Challenges
Grants (push) Financial assistance • Support basic research that • Do not guarantee development
that may cover some cannot be incentivized with of a product
or all of the costs pull funding
associated with
vaccine R&D
Tax incentives Reductions in tax • Support basic research that • Do not guarantee development
(push) liabilities to defray cannot be incentivized with of a product
some of the costs of pull funding • Can be very costly
R&D
• Beneficial only if the developer
has a tax liability
Advanced Agreements to • Product can be stockpiled • Can be expensive, especially if
purchase purchase vaccines in for future use or used to several products are incentivized
commitments the future, after they vaccinate people
(pull) are fully developed immediately, or both
• In many cases, paid only if
a product is developed and
receives emergency use
authorization or licensure
• Developers can be
incentivized to select the
most promising products
Subsidizing Allowing excess • Developers can be • May be expensive to maintain
manufacturing manufacturing incentivized to take facilities for manufacturing
capacity capacity to be used to vaccines to clinical trials • May not ensure sufficient
(push) manufacture vaccines due to lower capacity to respond to all
for clinical trials at manufacturing costs potential infectious diseases
low or no cost • Excess capacity can be used scenarios
to respond to future
infectious disease
outbreaks
Prizes (pull) Reward for receiving • Product can be stockpiled • Do not reduce the cost of R&D
authorization or for future use, used to • Would have to be sufficiently
licensure of a vaccine vaccinate people large to induce investment
product immediately, or both
• In many cases, paid only if
a product is developed and
receives emergency use
authorization or licensure
Patent An extension on a • Greater protection from • Patents can result in higher
extensions patent that exceeds competition and a longer prices, making the vaccine too
(pull) the usual time limits period to benefit from expensive for some patients or
higher prices may governments
encourage greater
innovation
Priority review Award for the • Potential for additional • The financial reward—that is, the
voucher (pull) development of drugs revenue could provide an amount of revenue earned from
and biologics, incentive to develop sale of a priority review
Vaccine Development GAO-22-104371 50
including vaccines, for vaccines for tropical voucher—could decline if more
tropical diseases, rare diseases, rare pediatric vouchers are awarded and
pediatric diseases, diseases, and medical available for sale
and material threat countermeasures
medical
countermeasures,
which can be sold or
redeemed for faster
review of a future
application.
Source: GAO. | GAO-22-104371
Experts we spoke to stated that different administered to a large number of people,
incentives work better for developing such as the entire population of a country.
vaccines for some infectious diseases than However, when a vaccine will be used by a
for others. For example, push incentives smaller number of people, such as during a
such as grants, may be beneficial because regional epidemic, the number of doses of
they can encourage the use of a particular the vaccine to be purchased may not be
technology, such as certain vaccine enough of an incentive. In these instances,
platforms. However, grants do not a prize may be more appropriate. One
necessarily result in the development of a benefit of pull incentives is that, in many
vaccine. Tax incentives may be useful in cases, developers are only paid if a vaccine
incentivizing research into a particular area, is eventually produced and is authorized for
but they do not work for developers emergency use or licensed.
without tax liability. Similarly, offering
unused manufacturing capacity, public or Pull funding is intended to supplement, not
private, for no or low cost to vaccine replace, push funding. For example, pull
developers to produce vaccine candidates incentives may not incentivize sufficient at-
for clinical trials can encourage developers risk manufacturing capacity for developers,
to proceed with testing of candidates that leading to fewer vaccines than would have
they might not have been able to been beneficial from society’s perspective.
otherwise. This mechanism also has the A combination of pull and push funding may
benefit of keeping manufacturing capacity be needed to assure sufficient vaccine
“warm” (i.e., available and ready to be supply can be manufactured. Additionally, a
used) and personnel at these facilities combination of push and pull incentives
trained so they can quickly respond to may allow for program costs to be lower
potential pandemics. One expert told us than with pull incentives alone, while
that the cost to move a vaccine candidate avoiding some of the inefficiency created by
through phase 2 clinical trials is about $50 push incentives.
million, with one third of that cost spent on
manufacturing vaccines in support of the Experts we spoke to stated that the best
trials. mechanisms to incentivize vaccine
investment would:
Pull incentives also have opportunities and
challenges. Advanced market commitments
are most beneficial when a vaccine will be
Vaccine Development GAO-22-104371 51
• Reward the development of new priority review voucher programs, FDA can
vaccines award a voucher upon approval of the
application. 83 These vouchers may be
• Keep prices low and thus allow vaccines
redeemed with submission of a future
to be accessible to as many people as
application, shortening FDA’s targeted
possible
review time from the standard 10-month
• Incentivize several pharmaceutical review to 6 months. 84 The vouchers may
companies to produce vaccines by also be sold or transferred to another
allowing benefits from incentives to be company, which may then choose to use it
available to all pharmaceutical or similarly sell or transfer it.
companies, not just some
• Be simple A partnership between HHS and DOD was
established in May 2020 to accelerate the
• Be transparent to operate
development, manufacturing, and
• Develop a capacity that allows for distribution of COVID-19 vaccines. 85 This
better responses to endemic infectious was accomplished through the award of
diseases as well as prepare for potential contracts and other transaction agreements
future epidemics or pandemics to six vaccine companies for different types
of activities, including clinical development
5.2.2 Federal use of vaccine incentives and manufacturing activities or the
purchase of COVID-19 vaccine doses. These
Some HHS programs have incentivized the awards were made, according to HHS and
development of vaccines. For example, the DOD officials, in anticipation that some of
priority review voucher programs are the vaccine candidates would subsequently
intended to encourage development of receive authorization or licensure. By
drugs or biologics for tropical diseases, rare providing significant up-front funding to
pediatric diseases, and material threat several of the companies, the government
medical countermeasures. 82 If an took on some financial risk, which enabled
application meets the criteria for one of the these companies to accelerate vaccine
development and production. 86 As of
82 applications within 10 months and 90 percent of priority
See 21 U.S.C. §§ 360n (tropical diseases), 360ff (rare
pediatric diseases), and 360bbb-4a (material threat medical applications within 6 months of receipt. For original biologics
countermeasures). Material threat medical and new drugs that contain a new molecular entity, FDA’s
countermeasures are drugs and biologics used to prevent or goal is to review and act on 90 percent of standard
treat harm from any chemical, biological, radiological, and applications within 10 months following a 60-day filing
nuclear agent identified as a material threat. period (a total of 12 months from receipt). Priority review
reduces this time to 6 months following the filing period (a
83
From 2009 through 2019, FDA awarded 31 priority review total of 8 months from receipt).
vouchers to drug sponsors. Of those, available data indicate 85
This partnership was formerly known as Operation Warp
that 17 were subsequently sold to another drug sponsor,
providing revenue to the sponsor selling the priority review Speed, but since May 2021 it is has been called the HHS-
voucher. See GAO, Drug Development, FDA’s Priority Review DOD COVID-19 Countermeasures Acceleration Group.
Voucher Programs, GAO-20-251 (Washington, D.C.: Jan. 31. 86
See, COVID-19: Efforts to Increase Vaccine Availability and
2020). Perspectives on Implementation, GAO-21-443, (Washington,
84 D.C.: Apr. 14. 2021).
For new drugs that do not contain a new molecular entity,
FDA’s goal is to review and act on 90 percent of standard
Vaccine Development GAO-22-104371 52
October 2021, three COVID-19 vaccines that 5.3 Policy options that may help
participated in the federal partnership were address economic challenges to
available in the U.S. vaccine development
While HHS has used some mechanisms
We identified three policy options for
intended to incentivize development, it is
policymakers that may help address
not clear that it has examined how or under
economic challenges with incentivizing
what circumstances different incentives can
vaccine development. As mentioned
be most effective. In June 2021, BARDA
previously, policymakers include Congress,
officials told us that they were not aware of
federal agencies, state and local
any HHS effort to examine market
governments, academic and research
incentives for vaccines.
institutions, and industry.
Further, experts we spoke with expressed
Policymakers could conduct a systematic
concern that, if policymakers do not have
assessment of the various mechanisms to
the authority to implement appropriate
incentivize vaccine development to
incentives, they will be limited in their
determine which incentives could work best
ability to help facilitate investment in new
for infectious diseases identified as high
vaccines. If officials lack the authority to use
priority, as discussed in chapter 2.
different mechanisms, it may result in
Policymakers could also examine the
reduced preparation for future pandemics
authorities necessary to use these
and weakened efforts to address infectious
mechanisms and, to the extent that
disease.
agencies lack such authority, take steps to
obtain or provide it.
Vaccine Development GAO-22-104371 53
Policy options that may help address economic challenges related to vaccine
development
Policy option Opportunities Considerations
Evaluate factors that discourage vaccine A clear understanding of the Collaboration between policymakers
investment range of factors discouraging and other stakeholders to obtain all
vaccine investment would relevant viewpoints can be time-
Policymakers could collaborate across
provide the basis for consuming and it may be hard to
sectors, such as government, academia and
effectively addressing those reach a consensus.
industry, to conduct a systematic evaluation
factors.
of factors that discourage developers from
investing in new vaccines.
This could help address the challenges we
identified related to market failures,
challenging markets, high costs, and low
probability of success.
Evaluate mechanisms for increasing vaccine Economic and societal costs Evidence on some mechanisms for
investment from infectious diseases incentivizing vaccine investment may
could be reduced. not be available or sufficient to make
Policymakers could consider conducting a
determinations on the effectiveness
systematic evaluation of the effectiveness of
of some mechanisms.
different mechanisms to incentivize vaccine
investment and determine what
circumstances or time frames may make
some mechanisms more or less useful.
For example, policymakers could evaluate
the effectiveness of mechanisms used to
incentivize COVID-19 vaccine development.
This could help identify when mechanisms
to incentivize vaccine development is likely
to be most successful.
Evaluate authority Identifying and addressing Granting additional authority may
any gaps in authority could not result in increased use of these
Policymakers could consider determining allow policymakers to more mechanisms to address economic
whether HHS, DOD, or other relevant effectively address the challenges.
agencies have the authority to use these economic challenges to Even if incentives are used more
mechanisms to incentivize vaccine vaccine development. widely, additional vaccines may not
development. For any identified gaps in be produced due to technical and
authority, policymakers could consider other challenges.
seeking or providing such authority.
Expanded use of incentives is likely
to require more resources or a
This could help address the challenges we
shifting of resources from other
identified related to incentivizing vaccine
areas.
development.
Source: GAO. | GAO-22-104371
Vaccine Development GAO-22-104371 54
6 Agency and Expert Comments
We provided a draft of this product to DOD and HHS for review. DOD concurred without
comment with the draft report provided by GAO. HHS provided technical comments on the draft
report, which we incorporated as appropriate. Nine participants from our expert meeting also
reviewed a draft of this product; we incorporated their technical comments as appropriate.
We are sending copies of this report to the appropriate congressional committees and other
interested parties. In addition, the report is available at no charge on the GAO website at
https://www.gao.gov.
If you or your staff have any questions about this report, please contact me at (202) 512-6888 or
howardk@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs
may be found on the last page of this report. GAO staff who made key contributions to this
report are listed in appendix VI.
Karen L. Howard, PhD
Director,
Science, Technology Assessment, and Analytics
Vaccine Development GAO-22-104371 55
List of Congressional Addressees
The Honorable Patrick Leahy The Honorable Frank Pallone, Jr.
Chairman Chairman
The Honorable Richard Shelby The Honorable Cathy McMorris Rodgers
Vice Chairman Republican Leader
Committee on Appropriations Committee on Energy and Commerce
United States Senate House of Representatives
The Honorable Ron Wyden The Honorable Bennie G. Thompson
Chairman Chairman
The Honorable Mike Crapo The Honorable John Katko
Ranking Member Ranking Member
Committee on Finance Committee on Homeland Security
United States Senate House of Representatives
The Honorable Patty Murray The Honorable Carolyn B. Maloney
Chair Chairwoman
The Honorable Richard Burr The Honorable James Comer
Ranking Member Ranking Member
Committee on Health, Education, Labor, Committee on Oversight and Reform
and Pensions House of Representatives
United States Senate
The Honorable Richard Neal
The Honorable Gary C. Peters Chairman
Chairman The Honorable Kevin Brady
The Honorable Rob Portman Republican Leader
Ranking Member Committee on Ways and Means
Committee on Homeland Security and House of Representatives
Governmental Affairs
United States Senate
The Honorable Rosa L. DeLauro
Chair
The Honorable Kay Granger
Ranking Member
Committee on Appropriations
House of Representatives
Vaccine Development GAO-22-104371 56
Appendix I: Objectives, Scope, and Methodology
Objectives Limitations to scope
This report identifies and discusses:
We focused our assessment on U.S. vaccine
development. However, with pandemics
1. technologies and approaches for vaccine
posing a global threat, the policy options we
research and development (R&D) and
identified include actions U.S. policymakers
challenges that affect their use,
can take alongside international partners. The
2. technologies and approaches for vaccine technologies and approaches to vaccine
testing and challenges that affect their development, testing, and manufacturing
use, discussed in this report are not an exhaustive
3. technologies and approaches for vaccine list of all possible methods. We selected
manufacturing and challenges that affect technologies and approaches we identified as
their use, and most promising from our review of the
literature and from discussions with
4. economic factors that affect vaccine
stakeholders. We do not discuss technologies
investment and preparedness for future
and approaches related to how vaccines are
pandemics
distributed after they have been
manufactured, as that was not within our
Scope and methodology
scope. The list of mechanisms for incentivizing
vaccine investment are also not exhaustive of
To address the first three of our objectives,
all possible methods.
we assessed available and developing
technologies and approaches that vaccine
Literature search
developers could use for R&D, testing, and
manufacturing of vaccines. For the fourth
objective, we assessed available and potential In the course of our work we conducted
mechanisms for incentivizing vaccine literature searches with ProQuest using
development. To do so, we reviewed search terms including “vaccine technology,”
scientific literature describing current and “clinical trials,” “vaccine manufacturing,” and
developing tools; interviewed experts from “vaccine economics,” among a wide selection
government, academia, the nonprofit sector, of keywords relevant to vaccine research and
and the research industry; and collaborated development. We conducted a broad search
with the National Academies of Sciences, of materials published within the last 7 years,
Engineering, and Medicine to convene a 3-day including scholarly articles and government
expert meeting to discuss the objective reports. We used the results of our literature
topics. review to address our objectives as well as
identify experts to interview and to
participate in our expert meeting.
Vaccine Development GAO-22-104371 57
Interviews Expert meeting
We interviewed stakeholders and experts To address all of our objectives, we held an
with a diverse set of perspectives on the expert meeting from January 25-28, 2021.
science, administration, and economics of This meeting was held in collaboration with
vaccine development. the National Academies of Sciences,
Engineering, and Medicine and was divided
To address technologies, and approaches for into six sessions, each moderated by two or
vaccine R&D, we discussed developments in three representatives from GAO. 87 The topics
vaccine platforms and ways researchers can of each session were: (1) Technologies and
identify and characterize pathogens and Approaches for Research and Development,
antigens. To address vaccine testing we (2) Technologies and Approaches for Vaccine
discussed the design and purpose of Manufacturing, (3) Technologies and
preclinical testing, clinical trials, and ways Approaches for Preclinical Studies and Clinical
vaccine testing could be conducted more Trials, (4) Pathogen Scenarios, (5) Economic
efficiently and effectively. For manufacturing, Factors that Impact Vaccine Investment, (6)
we discussed emerging vaccine Lessons Learned and Next Steps.
manufacturing technologies and
infrastructure approaches to support greater Meeting participants were selected if they
flexibility, productivity, and capacity. To had expertise either broadly or specifically in
address the economic landscape of vaccine at least one area related to our four
development, we discussed the market for objectives. We provided the National
vaccines as compared to other Academies of Sciences, Engineering, and
pharmaceutical products, the development Medicine with descriptions of the expertise
costs and time requirements of vaccines needed by expert meeting participants. From
relevant to other products, how these factors this information, the National Academies
influence the choices made by provided an initial list of experts to potentially
pharmaceutical companies in deciding participate in the expert meeting. We
whether to develop vaccines, and reviewed the list and provided an additional
government efforts to encourage vaccine list of experts based on our review of the
development. For all relevant objectives, we literature. In addition to evaluating experts on
spoke with stakeholders about key issues the basis of their expertise, we evaluated
affecting the adoption of the technologies them for any conflicts of interest. A conflict of
and approaches we identified. interest was considered to be any current
financial or other interest, such as an
organizational position, that might conflict
87
This meeting of experts was planned and convened with the
assistance of the National Academies of Sciences, Engineering,
and Medicine to better ensure that a breadth of expertise was
brought to bear in its preparation. However all final decisions
regarding meeting substance and expert participation were
made by GAO.
Vaccine Development GAO-22-104371 58
with the service of an individual because it Based on the goal of improving U.S. vaccine
could (1) impair objectivity or (2) create an development capabilities, we decided on an
unfair competitive advantage for any person objective designed to identify options that
or organization. Of the 22 experts, some were could help improve capabilities for developing
affiliated with companies, government, or vaccines more effectively and efficiently,
research-funding entities. We took these including during emergencies. We limited
affiliations into consideration as potential policy options to those that fit the objective
conflicts of interest when conducting our and fell within the report scope.
analysis and preparing our report. We
determined that these experts’ relationships To develop the policy options, we compiled a
did not account for any inappropriate biases list of possible options (19 in total) over the
in our reporting. We did not suggest policy course of our work based on our review of
options that we have reason to believe will the scientific and economic literature,
improperly promote or adversely affect any interviews with experts, and our vaccine
company. The comments of these experts development expert meeting. We analyzed
generally represented the views of the these options and removed ideas that were
experts themselves and not the agency, either redundant, not feasible to implement,
university, or company with which they were or did not fit into the overall scope of our
affiliated, and are not generalizable to the work. We then analyzed each policy option by
views of others in the field. Appendix V identifying potential benefits and
provides additional information on the considerations of implementing them. The
meeting participants. policy options and analyses were supported
by documentary and testimonial evidence.
Policy options
We conducted our work from June 2020 to
November 2021 in accordance with all
Based on our research, we developed a series
sections of GAO’s Quality Assurance
of policy options. Policy options are not
Framework that are relevant to technology
formal recommendations for federal
assessments. The framework requires that we
agencies, or matters for congressional
plan and perform the engagement to obtain
consideration, but they are intended to
sufficient and appropriate evidence to meet
represent possible options policymakers can
our stated objectives and to discuss any
take to address a policy objective. 88 For each
limitations to our work. We believe that the
policy option we discussed potential
information and data obtained, and the
opportunities and considerations. These are
analysis conducted, provide a reasonable
not listed in any particular order within each
basis for any findings and conclusions in this
chapter, nor are they inclusive of all possible
product.
policy options.
88
Policymakers is a broad term including, for example,
Congress, federal agencies, state and local governments,
academic and research institutions, and industry.
Vaccine Development GAO-22-104371 59
Appendix II: Research and Development Technologies and
Approaches
We identified four technologies and approaches that may improve vaccine research and
development (R&D). This appendix provides three summaries of these technologies and
approaches. Additionally, this appendix provides a summary of monoclonal antibodies, which
are emerging as an important approach to preventing infectious disease.
These summaries are based on documents we reviewed and interviews we conducted.
Specifically, we reviewed scientific literature describing current and developing tools,
interviewed experts from government, academia, the nonprofit sector, and industry, and
collaborated with the National Academies of Sciences, Engineering, and Medicine to convene
a 3-day expert meeting to discuss these technologies and approaches. Each summary includes
information on what the technology or approach is, its maturity, and how it works.
Vaccine Development GAO-22-104371 60
Omics and
Reverse Vaccinology
By integrating information from multiple fields of biology—collectively known as omics and including fields such as genomics and
proteomics— researchers can better understand how pathogens cause illness and how different people respond to immunization. Reverse
vaccinology applies omics approaches to identify potential vaccine candidates more effectively and shorten development time. In the
future, such approaches could lead to a new generation of vaccines that are safer, generate a stronger immune response, and perhaps can
even be personalized for vulnerable populations.
What is it? How mature is it?
Omics refers to the combined study of multiple areas of biology Individually, these omics fields are not new. However, recent
whose names end with “omics.” The omics commonly used in advances in technology have allowed for integrated analyses
vaccine development include genomics, transcriptomics, that apply a combination of omics across large datasets,
proteomics, and metabolomics (table 1). resulting in much faster development of vaccines, including
those for COVID-19 (10 months to develop) and Ebola virus (5
Table 1: Some omic fields used in vaccine development years).
Field Description
How does it work?
Genomics is the study of the genome—the complete
set of genetic instructions to create an organism. Within a cell, information generally flows from the genome
Studying the genome is the first step in reverse (DNA) to proteins and metabolites via RNA. Researchers can use
Genomics
vaccinology and allows researchers to understand omics and reverse vaccinology to identify antigens faster and
what information exists and, therefore, what could compare antigens to identify similarities across different types
happen inside microbial organisms or human cells.
of pathogens. Using omics, researchers can also better
Transcriptomics is the study of RNA. RNA carries understand human immune responses, including how specific
genetic instructions on what proteins should be populations would likely respond to a particular vaccine. Figure
made by the cells. Studying RNA allows researchers 1 shows how they were used for COVID-19.
to understand what genetic information is being
Transcriptomics used and, therefore, what appears to be happening Figure 1: Researchers used omics and reverse vaccinology to
inside microbial organisms or human cells.
develop COVID-19 vaccines and prioritize vaccine recipients
Proteomics is the study of the proteins made within more quickly and effectively.
a microbial organism or human cell. Proteins play
leading roles in cellular structure, facilitating
metabolic reactions, and responding to stimuli,
Proteomics among other things. Studying proteins allows
researchers to more directly observe cellular
processes.
Metabolomics is the study of small molecules,
commonly known as metabolites, made within a
microbial organism or human cell. Metabolites can
Metabolomics be found in biological samples, such as saliva, blood,
and urine. Studying metabolites allows researchers
to understand what is or has happened within a
microbial organism or human cell.
Source: GAO analysis and fizzgig/ logos2012/stock.adobe.com. | GAO-22-104371
Reverse vaccinology analyzes a pathogen’s genome to identify
the individual genes that are most likely to provide instructions
for proteins that stimulate an immune response (antigens). This
approach differs from traditional methods where the first step
is to grow pathogens in a lab and characterize multiple antigens
over many iterations.
Source: Design Cells/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 61
Next-Generation Vaccine
Platforms
Next-generation platforms allow vaccines to be developed based on the pathogen’s genetic information, instead of first growing the
pathogen (e.g., a virus) in the lab. As a result, next-generation platforms are highly adaptable, and can potentially accelerate vaccine
development.
What is it? licensed for certain individuals. FDA had not licensed any DNA
Next-generation platforms use an interchangeable system of vaccines for use in humans, but had licensed one vaccine for use
components, allowing vaccines to be developed in a plug-and- in animals.
play fashion. Next-generation platforms use a carrier to deliver
genetic instructions for an antigen—the substance that How does it work?
stimulates an immune response—into the body. Platform based
approaches can be scaled up more rapidly, potentially DNA vaccine platforms contain genetic instructions that induce
accelerating vaccine development, and can target multiple the cell to make the antigen. The gene encoding the antigen is
pathogens (table 1). plugged into a DNA vector to make the vaccine. mRNA vaccine
platforms contain synthesized mRNA encoding the vaccine
Table 1: Examples of next-generation vaccine platforms antigen, which is then encapsulated in a lipid capsule to make
the vaccine. Viral vector vaccine platforms contain copies of
Vaccine Platform Description
genes encoding the vaccine antigen. The gene is plugged into a
DNA vaccines use synthetic DNA coding for an
viral vector to make the vaccine (fig. 1).
antigen. The synthetic DNA is inserted into a
DNA vector, which delivers it into the body. The
Figure 1: Vaccine platforms
body’s cells then convert the DNA to mRNA
which, in turn, is converted into the antigen.
DNA
Messenger RNA (mRNA) vaccines are
encapsulated genetic instructions that allow the
body’s cells to directly produce the antigen and
stimulate the immune system. Since mRNA is
naturally unstable, it is first stabilized and then
packaged in a carrier molecule. Lipid
mRNA nanoparticles—tiny spherical capsules made of
lipids—are the most frequently used carriers.
Viral vector vaccines use other viruses—
genetically engineered to remove their disease-
causing aspects—as the carrier to deliver the
DNA code for an antigen into the body. Viral
vector vaccines that reproduce themselves result
in more antigen production and thus stimulate a
Viral vector stronger immune response.
Source: GAO analysis. | GAO-22-104371
How mature is it?
Next-generation vaccine platforms are a recent development.
As of October 2021, the Food and Drug Administration (FDA)
had licensed two next-generation viral vector platform vaccines
for use in humans—one for dengue and one for Ebola, and had
issued an emergency use authorization (EUA) for a viral vector
COVID-19 vaccine. FDA had also issued EUAs for two mRNA
vaccines for COVID-19, and one of these vaccines had also been
Source: Davizro Photography/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 62
Nontraditional Methods
of Vaccination
Most vaccines are currently administered by injection under the skin or into the muscle. However, injection can be associated with pain and
cause anxiety for some individuals. Nontraditional ways of delivering vaccines such as via a nasal spray offer the potential for increased
public uptake, better immune responses, and perhaps lower dosages.
What is it? administering remains low. Researchers continue to focus on
trying to develop nontraditional routes of vaccination.
Three nontraditional approaches for administering vaccines
may address challenges associated with traditional injections. How does it work?
Dermal vaccines are delivered by microscopic needle patches
Injected vaccines elicit a systemic immune response in the
through the upper layer of the skin. Nasal vaccines are
body’s fluids, such as the blood. In contrast, vaccines
administered via either a mist or drops in the nasal cavity. Oral
administered via dermal, nasal, and oral routes produce an
vaccines are delivered in the form of a pill or liquid (table 1).
immune response in both the blood and in the mucous
All three approaches can eliminate the pain and anxiety that membranes—the protective lining in areas such as the mouth,
some people associate with traditional injections. Other nasal passages, and intestines. During this kind of immune
potential benefits include decreasing the requirement for cold response, the cells and antibodies in the mucous membranes
storage and reducing the need for trained personnel and block or destroy the invading microorganisms (also known as
injection supplies; these benefits may help increase vaccination pathogens). The immune response is helpful in blocking the
rates. Nontraditional approaches can also potentially result in early stages of infection since most pathogens infect the body
an improved immune response—the production of antibodies through the mucous membranes.
and activation of cells to fight a virus or some other
Dermal delivery uses patches covered with hundreds of
microorganism that can cause disease.
microscopic needles made from sugar mixed with a vaccine,
Table 1: Potential opportunities and challenges of which dissolve into the skin after penetrating through its upper
nontraditional vaccination methods layer. For nasal delivery, cells in the nasal cavity encounter
vaccines, stimulating an immune response in the respiratory
Nontraditional tract that blocks a pathogen from entering the body. Oral
vaccination vaccines are ideally absorbed in the intestines, which contain 70
methods Potential opportunities Potential challenges
to 80 percent of all antibody-producing cells in the body (fig. 1).
Dermal • Pain free • Device
• Lower dosages development for
Figure 1: Nontraditional vaccination methods
• Easy to administer simple, reliable, and
reproducible
• Does not require cold delivery of vaccines.
storage
Nasal • Pain free • Vaccine may not
• Cost effective remain in the nasal
• Easy to administer passage long
enough for effective
• Fewer supplies absorption.
Oral delivery • Pain free • Must be formulated
• Cost effective to protect against
• Easy to administer degradation in the
stomach.
• Fewer supplies
Source: GAO analysis. | GAO-22-104371
How mature is it?
The Food and Drug Administration (FDA) licensed the first oral
vaccine in the 1960s for polio; only a few other oral vaccines
have been licensed since then. More recently, dermal and nasal
vaccines have been developed for seasonal influenza. Although
many traditional (injected) vaccines have been successfully
developed and administered over the last century, the number
of vaccines available with nontraditional options of
Source: stevem/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 63
Monoclonal antibodies
Monoclonal antibodies are not vaccines. They are laboratory-made proteins that mimic the human immune system's ability to fight off
pathogens. These proteins can be developed quickly in response to potential pandemics and used to provide short-term protection against
infectious diseases—either as a treatment or as a preventative before someone is infected. They can also be used to complement the
human immune system to bolster the protective response in immunocompromised individuals, such as organ transplant recipients.
What is it? infectious diseases, such as cancer. Of more than 100
monoclonal antibodies licensed by the FDA, only seven are used
Monoclonal antibodies are laboratory-produced versions of to prevent or treat infectious diseases. The high cost is a limiting
specific proteins that have been isolated from the antibodies factor, as manufacturing is complex, expensive, and requires
naturally produced by the human immune system to respond to specialized personnel.
and neutralize invading pathogens. Monoclonal antibodies are
emerging as an important approach to preventing infections. A How does it work?
recent study showed that monoclonal antibodies can be
Monoclonal antibodies mimic the immune system by binding
effective at preventing malaria, an infectious disease that
directly to antigens, the components of a pathogen that
currently lacks an effective vaccine. An August 2021 study
stimulate an immune response, preventing them from initiating
reported that monoclonal antibodies reduced the risk of
the infection cycle. During the COVID-19 pandemic, monoclonal
unvaccinated or immunocompromised people developing any
antibody products were developed as therapeutics to treat
COVID-19 symptoms by 77 percent.
SARS-CoV-2 (the virus that causes COVID-19). As of October
Monoclonal antibodies are different from vaccines in that they 2021, there were four authorized monoclonal antibody
do not stimulate long-term protection (table 1). treatments for COVID-19. Clinical trial data have also shown
that monoclonal antibodies may be effective for pre-exposure
Table 1: Monoclonal antibodies and vaccines work differently prevention of COVID-19, but they have not been authorized or
to protect against disease. licensed for this use (fig.1).
Monoclonal
antibodies Vaccines Figure 1: Monoclonal antibody targeting SARS-CoV-2, the virus
What is it? A protein that binds to A modified pathogen or a that causes COVID-19
a pathogen to mitigate part of a pathogen that
effects of an infection triggers the immune system
How is it To provide treatment To stimulate the immune
used? or short-term system to fight against a
protection to avoid pathogen
infection
How quickly Immediately Several weeks after all
does it work? required doses are given
How long does Weeks to months Years to lifetime (some
the protection vaccines require boosters)
last?
Source: GAO analysis. | GAO-22-104371
Most monoclonal antibodies have been administered
intravenously, but some have been administered by
How mature is it? intramuscular or subcutaneous injection. Monoclonal
antibodies can target a specific pathogen or be combined into
Since their introduction in 1975, monoclonal antibodies have
mixtures known as cocktails to target a broad range of variants
been developed primarily for use as therapeutics against non-
of the same pathogen. A variant has one or more mutations
that differentiate it from other variants of the same pathogen in
circulation, and those mutations may protect the virus from
being neutralized by an existing monoclonal antibody or
vaccine.
Source: ktsdesign/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 64
Appendix III: Testing Technologies and Approaches
We identified six technologies and approaches that may improve vaccine testing. This
appendix provides five summaries of these technologies and approaches.
These summaries are based on documents we reviewed and interviews we conducted.
Specifically, we reviewed scientific literature describing current and developing tools,
interviewed experts from government, academia, the nonprofit sector, and industry, and
collaborated with the National Academies of Sciences, Engineering, and Medicine to convene
a 3-day expert meeting to discuss these technologies and approaches. Each summary includes
information on what the technology or approach is, its maturity, and how it works.
Vaccine Development GAO-22-104371 65
Organ Chips
Organ chips are small experimental laboratory tools that contain human cells and mimic how organs and systems in the body work. When
used individually, they allow researchers to study a particular part of an organ’s function. When linked together, they can mimic the
interconnectedness of multiple organs in the human body. Organ chips offer a potential alternative to traditional animal testing and could
eventually expedite the development and testing of vaccines and drugs, among other things.
What is it? How does it work?
Organ chips are designed to reproduce the functioning of Organ chips contain tiny channels that mimic the flow of
human organs or tissues as realistic models. Inside these chips, substances like blood and air through tissues and organs,
which are about the size of a computer memory stick, are tiny similar to what occurs in the human body. For example, a lung
channels lined with living human cells (fig. 1). Researchers organ chip may have a main channel that is divided in half
control the external and internal environment around the cells lengthwise to create a top and bottom. In the upper section,
to mimic certain conditions within the human body. For lung cells interact with air that flows through the channel. In
example, they can create movement to mimic breathing the lower section, blood vessel cells interact with the flow of a
motions in the lungs and muscle contractions in the heart. This liquid medium that imitates blood. Crucially, the divider
modeling allows researchers to replicate and study the between these sections is permeable, allowing the exchange of
structural and functional complexity of human organs. molecules between the different types of cells. Researchers can
then study the effects of bacterial or viral infections by
Figure 1: Example of an organ chip introducing the pathogen to the air flow channel. They can also
test drugs by administering the drug into the blood in the lower
channel (fig. 2).
Using organ chip technology in this way, researchers might be
able to study how SARS-CoV-2 infects the lungs when a patient
contracts COVID-19 without relying on animal studies, which
may not reliably predict human responses.
Figure 2: A chip containing lung cells and blood vessel cells can
be used to study the effects of pathogens or drugs in the
human lungs.
The interaction of multiple organs can be studied by linking two
or more organ chips and also by incorporating multiple lines of
cells from different organs onto one chip. Using these systems,
researchers may be able to gain a deeper understanding of how
a vaccine works or how a drug is absorbed, distributed, or
metabolized by the body.
How mature is it?
Organ chip technology has been in development for over a
decade. Recent advances allow for analyses using integrated
multi-chip systems to study complex interactions among
multiple organs and tissues, including liver, lungs, heart,
intestines, bone marrow, kidneys, and lymph nodes. However, Similarly, different types of organ chips could be used to
further advances in design may be needed to investigate some understand other pathogens or to study the effects of vaccines.
types of organ and cell functions. For example, more complex For example, in one study, researchers administered a flu
designs may be needed for chips containing multiple types of vaccine to lymph node chips to observe patient-specific
cells that differ from one another in the amount of time they antibody responses, which demonstrated the chip’s potential as
need to grow and their responses to various stimuli. a preclinical tool to study human responses to vaccines.
Source: luchschenF/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 66
Artificial Intelligence and
Machine Learning
Artificial intelligence and machine learning (AI/ML) techniques use computer systems and algorithms to produce data-driven insights that
allow vaccine developers to make discoveries during research and development (R&D) and clinical testing. Some of these insights may allow
for more efficient clinical trials and generate predictions that could result in safer, more effective vaccines in less time.
What is it? antigens for potential use in vaccines. Deep learning methods
can help researchers identify antibodies for their potential to
AI/ML is a set of advanced technologies that can perform bind to a given antigen, which may accelerate and improve the
complex tasks and analyze vast amounts of data to develop new development of a new vaccine.
insights, including for designing vaccines (table 1). Early AI
During clinical trials, researchers can use AI/ML to identify
technologies often used computer programs to make rules-
suitable participants, optimize design variables, and predict
based decisions. Later, the incorporation of mathematics and
responses (fig. 1). For example, using data sources such as
probability led to ML, which uses a variety of data analytics
electronic health records (EHR) and genomics data, researchers
approaches to improve prediction.
may determine who is suitable based on trial criteria. They can
Table 1: AI/ML techniques used in vaccine development then identify the optimal number of patients needed for the
trial. Once data collection begins, researchers can analyze the
AI/ML data coming in, which may help identify subgroups likely to
techniques Description
respond differently to various vaccines or dosages, among other
Artificial Intelligence (AI) refers to the capacity of
things.
computers or other machines to exhibit or simulate
intelligent behavior. AI-based approaches have been
Figure 1: Artificial intelligence (AI) and machine learning (ML)
used in vaccine design to predict potential
epitopes—the part of an antigen to which an can use various types of data to enhance vaccine development
Artificial antibody binds.
intelligence
Machine Learning (ML) is a family of statistical and
mathematical modeling techniques that use data to
train an algorithm or system to perform tasks. ML
has been used to identify antigens from protein
sequences.
Machine
learning
Deep Learning is a class of ML that processes input
data to provide outputs that can be used to extract
findings. Deep learning has been used to simulate
coronavirus spike proteins and identify possible
targets for vaccine design.
Deep
learning
Source: GAO analysis of literature; kornkun/stock.adobe.com. | GAO-22-104371
How mature is it?
AI/ML techniques have advanced to the point where they are
being used throughout vaccine development. However, the use AI/ML techniques can also help vaccine developers predict the
of AI/ML in clinical trials is less mature due to limitations on immune response a vaccine may induce. Using these techniques
access to patient data and other issues. Also, techniques like to analyze omics data from the blood of trial participants who
deep learning require large quantities of data which may not be have received the vaccine may allow researchers to predict
available during a clinical trial. whether someone will have a high or low antibody response
and the likelihood of experiencing an adverse event. This
How does it work?
approach has been used in vaccines developed against yellow
In the early stages of vaccine development, researchers use fever, influenza, and malaria, and may improve the ability to
AI/ML techniques to mine biological data to screen and identify estimate vaccine effectiveness.
Source: peshkov/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 67
Electronic Health Records
An electronic health record (EHR) is a digital record of a patient's medical information. EHRs could be used in clinical trials to streamline
patient recruitment and data collection, and improve data accuracy. EHRs can facilitate post-trial follow-up of large numbers of patients,
which can help researchers better understand how long a vaccine’s immunity lasts. EHRs also provide a data source that can be used to
generate real-world evidence included in prospective clinical investigations.
What is it? How does it work?
EHRs store patients’ health data, which include both structured EHRs could be used throughout the clinical trial process, subject
data (e.g., diagnosis codes and lab results) and unstructured to privacy protections. At the beginning, they can reduce the
narrative data (e.g., clinical notes about symptoms and need for paper-based recruitment and manual entry of
pathology reports). Because EHRs are used primarily in direct participant data. Researchers can search databases to identify
patient care, they are typically used and maintained by health people who meet the criteria to participate, then study
care providers. EHR systems may also allow clinical researchers coordinators can contact individuals to obtain consent to enroll
to access, combine, aggregate, and analyze many types of data them in the trial and use their EHR data. Participants could then
for research purposes (table 1), including vaccine studies. be assigned to either an experimental group that receives the
vaccine or a control group that receives a placebo. As the
Table 1: Examples of data typically stored and not stored in clinical trial proceeds, researchers can capture and analyze data
electronic health records (EHR) from EHRs—potentially during a patient’s visit to a clinic—which
Examples of Examples of may provide access to many types of data for review that can
structured data narrative data Data unlikely to be stored supplement the data collected for clinical trials and facilitate
stored in EHRs stored in EHRs in EHRs post-trial follow-up to assess safety and effectiveness (fig. 1).
• Date of birth • Symptoms of • Place of birth
• Sex illness Figure 1: Streamlining the clinical trial process with electronic
• • Gender identity
• Vital signs Family history health records (EHR)
• Most lab test of illness • Survivorship care
results • Meaning of planning
• Medications physical exam
findings • Living conditions
prescribed
• Diagnosis • Some lab test • Psychological distress
(coded) results
• Pathology • Patient-reported
reports outcomes
• Diagnosis
(descriptive)
Source: E. Kim et al., “The Evolving Use of Electronic Health
Records (EHR) for Research,” Seminars in Radiation Oncology, vol. 29, no. 4 (2019):
pp.354-361. | GAO-22-104371
How mature is it?
EHRs have been widely adopted in clinical care, but are not in
widespread use for clinical trials. Standardized data formats are
being developed, and new Department of Health and Human
Services rules are addressing interoperability issues. The rules
should help address that some EHR systems are not EHRs are also used to monitor vaccine safety once a vaccine has
interoperable with electronic data capture systems that manage been licensed and is given to patients. FDA’s Biologics
clinical trial data. As a result, researchers have not always been Effectiveness and Safety system monitors data in EHRs and
able to easily transmit data from EHRs for analysis. other sources to detect adverse events and study specific safety
Interoperable systems allow clinical care staff to enter data into questions for vaccines including for sub-populations such as
patient records during the patient’s visit and the patient’s individuals who are pregnant or have pre-existing conditions.
data—such as demographics, vital signs, and medications—
automatically populate forms or other records.
Source: metamorworks/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 68
Standardized Assays and
Common Control Groups
Using standardized assays and common control groups together can help vaccine developers better identify effective vaccine candidates.
With this approach, multiple vaccine developers use the same assays (tests that measure a vaccine’s immunogenicity, or ability to induce an
immune response) to test multiple vaccine candidates and share a single control group during the clinical trials for those vaccines.
What is it? How does it work?
Standardized assays are tests that vaccine developers may use To develop a standardized assay, researchers generally begin by
in evaluating candidates, allowing them to measure immune obtaining blood samples from patients who have contracted a
responses the same way (table 1). disease. This information helps vaccine developers understand
how a patient’s immune system responds to the pathogen and
Table 1: Selected assays used in vaccine development builds immunity. Developers can then find ways to measure
Purpose Assay description immune responses, such as developing tests to detect
Humoral antibody Measurement of total or functional pathogen-specific antibodies. They evaluate these assays for
response antibody levels in the blood precision and may refine them based on performance criteria
as vaccines are being developed. Researchers then write
Cell-mediated immune Measurement of immune cell responses
response upon exposure to specific antigens
standard protocols defining the methodology to allow the assay
to be used in the same way by other vaccine developers. This
Source: GAO analysis and M. Dotzert, “Assay Development: Vaccines,” Lab Manager, vol.
14, no. 5 (June 2019): pp.40-43. | GAO-22-104371
may involve preparing biological reference standards—
rigorously evaluated samples used to determine whether an
A common control group may be a single group of placebo- assay is functioning correctly—which can help ensure that data
receiving clinical trial participants that is shared by multiple produced in different laboratories are comparable.
vaccine developers. Members of a common control group do
not receive a vaccine. They generate clinical trial data that are Once developers have completed all preclinical testing
compared to data from participants in other groups who may requirements and agreed to the common control group design,
receive different vaccines or different versions or dosages enrollment of participants begins. Each person is assigned
(amounts) of the same vaccine. This approach eliminates the randomly to either a group in which they receive one of the
need for each developer to recruit its own control group, vaccine candidates or a common control group that receives a
reducing the total number of participants needed. In addition, placebo (fig. 1).
participants outside the control group have a greater chance of
Figure 1: Example of a possible trial design using standardized
receiving a vaccine candidate than a placebo, which may
assays and common control groups
increase clinical trial participation.
How mature is it?
Standardized assays have been used in vaccine trials, including
phase 3 clinical trials of COVID-19 vaccines, according to The
National Institutes of Health. Assays may require modifications
during the vaccine development process, which is a challenge to
standardization. However, some international organizations are
collaborating to develop standardized assays for use against
known pathogens in advance of potential future outbreaks to
enable faster development of vaccines.
Common control group trials were first used over 20 years ago
to accelerate the process of drug development. Since then, they
have been used mostly in phase 2 and phase 3 clinical trials of
different drugs and drug dosages. However, it may be difficult
to use common control groups in clinical trials of multiple Combining standardized assays with common control groups
vaccine candidates in part due to logistical challenges of allows for apples-to-apples comparisons of the vaccine
coordinating among multiple developers in a single trial. candidates. Investigating multiple vaccines at once could help
identify the most effective vaccines against a disease and
provide more rapid and reliable results.
Source: Jakub Krechowicz/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 69
Virtual Clinical Trials and
Wearable Devices
Virtual clinical trials, also referred to as decentralized trials, and wearable devices, also referred to as digital health technologies, work
together to capture health data remotely, potentially eliminating the need to travel to a clinic or office to participate in a clinical trial. This
approach makes it easier for more people to participate, thereby broadening the pool of potential candidates. Virtual clinical trials may also
streamline data collection and reduce errors by eliminating the need for staff to collect and record data.
What is it?
virtual trial begins with online recruiting followed by informed
Virtual clinical trials may use web-connected devices to extend consent and participant enrollment, also handled electronically.
the reach of clinical investigations to where participants live and If a vaccine is designed to be self-administered (e.g., dermal,
work without compromising study design (table 1). Once clinical nasal, or oral delivery) and does not require special storage, it
trial participants are connected electronically, they can submit could potentially be sent to participants’ homes in a fully virtual
their data via wearable devices as well as mobile phones and trial. However, vaccine trials would likely retain some features
tablets. Researchers then use the data to assess outcomes and of traditional trials such as in-person vaccination. Study staff
observe physical activity remotely. This approach has been may also prompt participants via apps and text messaging for
used, for example, to test new medicines and assess the effect adherence to other study protocols (e.g., reporting symptoms)
of behavioral interventions to treat depression. and conduct clinical evaluations via telemedicine. Participants
can perform some clinical procedures such as using a finger
Table 1: Comparison of traditional and virtual clinical trials stick device to obtain a drop of blood for analysis, results of
Clinical trial Traditional clinical trial Virtual clinical trial which may be mailed back to researchers. When wearable
element devices are used, the data would be collected and transmitted
Study design May use a randomized May use a randomized to researchers via a smartphone app or web‐based interface
control trial design control trial design (fig. 1).
Health monitoring On-site Remote
Figure 1: Possible data collection process for virtual trials
Patient reported Submitted periodically Submitted more
data during clinic visits frequently via devices
Source: GAO analysis. | GAO-22-104371
Wearable devices can look similar to commercially available
fitness trackers and sometimes use clothing-embedded sensors
to collect health data continuously as people go through their
daily routines. Many wearable devices measure heart rate and
blood pressure, allowing for monitoring of cardiac events.
Wearables have also been developed to measure sleep and
movement disorders, monitor glucose levels, and measure
tremors experienced by patients with Parkinson’s disease.
How mature is it?
The first virtual clinical trial began in 2011 but experienced
technical challenges and was not completed. Since then,
companies are increasingly leveraging digital capabilities to
conduct virtual trials. These advances allowed some planned
traditional trials to be conducted virtually during the COVID-19 Researchers might assess outcomes of virtual clinical trials by
pandemic. For example, researchers used some elements of conducting interviews remotely and tracking participants’
virtual trials—such as remote screening to determine patients’ electronic health records (EHR). For example, researchers can
risk status and remote reporting of symptoms and study data— connect telemedicine equipment such as blood glucose-
in clinical trials to test vaccines against COVID-19. monitoring devices via wireless data transmission to EHR
systems. This allows clinical data to be sent directly to patient
How does it work? records, enabling real-time data collection of more data for
While traditional clinical trials require a physical, centralized site faster clinical trials and more robust analysis.
where patients report for in-person visits, a
Source: matthew_100/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 70
Appendix IV: Manufacturing Technologies and Approaches
We identified five technologies and approaches, collectively known as bioprocess
intensification that may improve vaccine manufacturing. This appendix provides a summary of
these technologies and approaches.
This summary is based on documents we reviewed and interviews we conducted. Specifically,
we reviewed scientific literature describing current and developing tools, interviewed experts
from government, academia, the nonprofit sector, and the research industry, and
collaborated with the National Academies of Sciences, Engineering, and Medicine to convene
a 3-day expert meeting to discuss these technologies and approaches. Each summary includes
information on what the technology or approach is, its maturity, and how it works.
Vaccine Development GAO-22-104371 71
Bioprocess Intensification
Bioprocess intensification can improve vaccine manufacturing flexibility and productivity through flexible facilities, more productive
equipment, and improved technologies. To improve flexibility, vaccine manufacturers can use modular bioprocessing systems, single-use
systems, and cell-free synthesis that provide the ability to rapidly switch between vaccines, scale up production, or relocate production
capacity. To improve vaccine manufacturing productivity, manufacturers can use process optimization technologies to, for example,
improve the cells and growth ingredients used to produce vaccine antigens and automated, continuous processing systems that run with
fewer interruptions.
What is it? How does it work?
Bioprocess intensification combines flexible facilities, more Bioprocess intensification can be applied at different points in
productive equipment, and improved technologies to enhance the vaccine manufacturing process. Modular bioprocessing
vaccine manufacturing flexibility and productivity while reducing systems work by breaking manufacturing components into
costs and time. Modular bioprocessing systems have flexible smaller functional blocks, such as prefabricated rooms, which
infrastructure components, similar to building blocks, that may may be added into existing facilities to increase flexibility. These
replace the fixed rooms and areas dedicated to specific systems typically include single-use systems that replace fixed
bioprocessing steps and provide the ability to rapidly switch equipment and materials with disposable equipment and
between vaccines, scale up production, or relocate materials that are discarded after each use. This eliminates the
manufacturing capacity. Single-use systems are equipment and need for cleaning and sterilization required for fixed
materials composed primarily of disposable, sealed, pre- equipment. Continuous processing systems integrate and
sterilized plastic components designed to be used once. automate all manufacturing steps with few or no interruptions,
Continuous processing systems consist of automated equipment unlike traditional processes that stop after certain steps, such
that seamlessly integrates all vaccine production and processing as cell growth. Process optimization uses approaches to
steps, including filling and packaging—also known as fill-finish. improve the efficiency and productivity in each step of
Process optimization includes, but is not limited to, improving manufacturing. For example, improving cell growth
the cells and cell growth ingredients used to produce vaccine characteristics and growth ingredients used in antigen
antigens—the component of the vaccine that stimulates the production can greatly increase yields without adding capacity.
immune systems. Cell-free synthesis uses biological molecules in Cell-free synthesis combines purified biological molecules in
place of living cells to make the vaccine antigens (fig.1). reactor vessels to synthesize antigens, which are then
formulated into vaccines. This eliminates the need to grow
Figure 1: The three parts of bioprocess intensification large amounts of living cells to produce the antigen used in the
vaccine (fig.2).
Figure 2: Bioprocess intensification
How mature is it?
For decades, other industries, such as chemical manufacturing,
have used flexible facilities, more productive equipment, and
improved technologies similar to those used in bioprocess
intensification. Over the past 20 to 30 years, these three
categories have been used for pharmaceutical applications,
including vaccine manufacturing. For example, single-use
systems began to emerge in the early 1980s and continue to be
adopted over traditional fixed systems. Further, in the last two
decades, cell-free synthesis has surged to meet the increased
production demand of inexpensive proteins and small
molecules, most recently for generating the mRNA used in the
COVID-19 mRNA vaccines.
Source: whyframeshot/stock.adobe.com (header). | GAO-22-104371
Vaccine Development GAO-22-104371 72
Appendix V: Expert Participation
We collaborated with the National Academies of Sciences, Engineering, and Medicine to
convene a 3-day meeting of experts to inform our work on vaccine development; the meeting
was held virtually on January 25-28, 2021. The experts who participated in this meeting are
listed below. Many of these experts gave us additional assistance throughout our work,
including ten experts who provided additional assistance during our study by sending material
for our review or participating in interviews; and 9 experts who reviewed our draft report for
accuracy and provided technical comments.
Phyllis Arthur, MBA Dana Goldman, PhD
Vice President, Infectious Disease and Distinguished Professor of Pharmacy, Public
Diagnostics Policy Policy & Economics and Leonard D.
Biotechnology Innovation Organization Schaeffer Chair and Interim Dean of the
Sol Price School of Public Policy
Maria Elena Bottazzi, PhD University of Southern California
Associate Dean of the National School of
Tropical Medicine and Professor of Jesse Goodman, MD, MPH
Pediatrics and Molecular Virology & Director of the Center on Medical Product
Microbiology Access, Safety and Stewardship
Section Head, Pediatric Tropical Medicine (COMPASS)
Professor of Pediatrics and co-director, Texas Professor of Medicine and Infectious
Children’s Hospital Center for Vaccine Diseases
Development Georgetown University
Baylor College of Medicine
Tina Hernandez-Boussard, PhD, MS, MPH
James E. Crowe Jr., MD Associate Professor in Medicine (Biomedical
Director of the Vanderbilt Science Center Informatics), Biomedical Data Science,
and Professor of Pediatrics & Pathology Surgery & Epidemiology and Population
and Microbiology & Immunology and Health
Ann Scott Carrell Chair Stanford University
Vanderbilt University Medical Center
Peter J. Hotez, MD, PhD
Patricia M. Danzon, PhD Dean of the National School of Tropical
Celia Moh Professor Emeritus Medicine and Professor of Pediatrics and
Molecular Virology & Microbiology
The Wharton School, University of
Pennsylvania Texas Children’s Hospital Endowed Chair in
Tropical Pediatrics
Greg Frank, PhD Baylor College of Medicine
Senior Director of Infectious Disease Policy
Biotechnology Innovation Organization
Vaccine Development GAO-22-104371 73
Beth Junker, PhD Tracy Lieu, MD, MPH
Principal Consultant and Owner Director of the Division of Research
Bioprocess Advantage LLC Kaiser Permanente Northern California
Ruth A. Karron, MD Nicole Lurie, MD, MSPH
Professor of International Health and Director, CEPI-US and strategic advisor to the
Director, the Center for Immunization CEO, Coalition for Epidemic
Research Preparedness Initiatives (CEPI)
Johns Hopkins University Professor of Medicine
Founding Director George Washington University
Johns Hopkins Vaccine Initiative Senior Lecturer
Harvard University
Jason Kelly, PhD
Co-founder and CEO Jewel Mullen, MD, MPH, MPA
Gingko Bioworks Associate Dean and Associate Professor
University of Texas at Austin
Jerome Kim, MD
Dell Medical School
Director General
International Vaccine Institute Justin Sanchez, PhD
Life Sciences Research Fellow
Michael Kremer, PhD
Battelle Memorial Institute
Gates Professor of Developing Societies
Harvard University Christopher Snyder, PhD
Non-resident Fellow Joel Z. and Susan Hyatt Professor
Center for Global Development Dartmouth College
Kelvin Lee, PhD Thomas Thomou, PhD
Gore Professor of Chemical and Biomolecular Senior Scientist/Engineer
Engineering
Gryphon Technologies
University of Delaware
Eric Van Gieson, PhD
Program Manager
Biological Technologies Officer, DARPA
Vaccine Development GAO-22-104371 74
Appendix VI: GAO Contact and Staff Acknowledgments
GAO contact
Karen L. Howard, PhD, (202) 512-6888 or howardk@gao.gov
Staff acknowledgments
In addition to the contact named above, Sarah Harvey (Assistant Director), Robert Rivas
(Analyst-in-Charge), Nora Adkins, Cheron Brooks, Virginia Chanley, Mike Dickens, Kaitlin
Farquharson, Louise Fickel, Cory Gerlach, Cindy Korir-Morrison, Anika McMillon, Silda Nikaj,
Monica Perez-Nelson, and Michael Walton made key contributions to this report. Sean
Amberger, Patricia Edouard, and Eric Lee also contributed to this report.
(104371)
Vaccine Development GAO-22-104371 75
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