Summary
The global response to the COVID-19 pandemic has led to the emergence of new capabilities, technologies, processes, and policies for responding to the threat of major infectious diseases. While today, COVID-19 dominates the conversation around vaccines, the critical threat of both seasonal and pandemic influenza remains. Accordingly, at the request of the U.S. Department of Health and Human Services, the National Academy of Medicine (NAM) within the National Academies of Sciences, Engineering, and Medicine (the National Academies) undertook a series of four studies to examine how lessons learned from the response to COVID-19 and the resulting advances can best be applied to improve preparedness for and response to seasonal and pandemic influenza. The following report represents the findings, conclusions, and recommendations of one of these studies, focusing on vaccine research and development (R&D).
As many as 650,000 respiratory-related deaths per year worldwide result from influenza. Although vaccination is the most successful and cost-effective strategy for the prevention and control of seasonal influenza, uptake of vaccines is generally low, owing in part to a lack of availability and competing health priorities in many low- and middle-income countries (LMICs). Both global and domestic efforts, including the U.S. National Influenza Vaccine Modernization Strategy 2020–2030 and the World Health Organization (WHO) Global Influenza Strategy 2019–2030, articulated a need for more effective influenza vaccines, as well as modern manufacturing technologies that are adaptable and can be scaled to meet demand during a pandemic. The rapid development of COVID-19 vaccines has demonstrated
what can be achieved when there is extensive data sharing and researchers have the necessary resources and novel technologies to conduct and apply their research. This report documents the key drivers of success in this model and how it might be applied to optimize vaccine R&D to support the prevention and control of both seasonal and pandemic influenza. Given the scale of this threat, the committee urges expedient development of 4.15–8.31 billion courses of influenza vaccine to be distributed globally in a timely and equitable manner.
ABOUT THIS STUDY
The NAM initiative is focused on how to improve (1) the global design, composition, clinical trials, production, scale-up, and regulatory approval for influenza vaccines; (2) distribution of the vaccines; and (3) postapproval surveillance for adverse events. The initiative was spearheaded by a committee of domestic and international experts representing a range of sectors (e.g., government, academia, industry, civil society, international public health organizations) and a variety of salient disciplines. The international committee’s role included developing the Statements of Task for the four concurrent National Academies studies, each to be conducted by an ad hoc committee of experts in the respective topic. The present report details the findings of an ad hoc committee charged with identifying a framework, informed by the response to COVID-19, for optimizing vaccine research, development, and delivery in response to pandemic and seasonal influenza. The committee’s findings address four dimensions of vaccine R&D: (1) basic and translational science, (2) clinical science, (3) manufacturing science, and (4) regulatory science. These findings served as the basis for the committee’s recommendations within each of these four dimensions, directed at both U.S. and international actors, for developing a rapid capability to produce and distribute enough vaccine doses for the global population in a timely and equitable manner worldwide in response to both pandemic and seasonal influenza.
BASIC AND TRANSLATIONAL SCIENCE
Continuous funding streams are vital for vaccine R&D. While funding is typically available during pandemics, it is significantly lacking during interpandemic periods. This lack of funding often stalls R&D progress made during pandemic periods and leaves the world ill prepared for the next one. The vast majority of influenza vaccines are inactivated virus vaccines grown in eggs, with limited use of cell culture platforms. Production of pandemic vaccines would rely on the egg-based platform. Despite having the advantage of being an established process, there are limitations, in particular con-
cerning the production time. As seasonal egg-based influenza vaccines have low to moderate efficacy and require annual updates due to antigenic drift, significant funding is necessary to develop novel platforms and technologies that may lead to more efficacious vaccines. A priority focus for future basic and clinical research on influenza vaccines should be the investigation into how to overcome issues associated with viral antigenic drift for seasonal vaccines. COVID-19 has resulted in a paradigm shift in vaccine technology, presenting benefits of other vaccine platforms for fast development of pandemic vaccines and the improvement of seasonal vaccine effectiveness. When considering novel platforms for further development, other factors such as expanding manufacturing capacity, feasibility of scale-up in LMIC, effectiveness, speed, and cost must also be addressed. For each new platform, standardized assays, reagents, and animal models will be needed in addition to research on surrogate markers of protection for those vaccines not inducing hemagglutination-inhibiting antibodies. Furthermore, there is a need for research into novel adjuvants, and for licensing and capacity building for the manufacturing of adjuvants. These research efforts would facilitate making rational choices regarding platforms for vaccine development that take into account the effectiveness, the speed of development and production, and the costs. Investments in pandemic preparedness are not only critical for public health, they are economically beneficial. The cost of responding to a pandemic is estimated be $570 billion annually, while investments in pandemic preparedness would cost just $4.5 billion annually. Funding pandemic preparedness will allow a framework for international collaboration to be built, providing vital support for global vaccine development.
Recommendations
Recommendation 2-1: The U.S. Department of Health and Human Services, through the National Institute of Allergy and Infectious Diseases, the Biomedical Advanced Research and Development Authority, and the U.S. Department of Defense, as well as other corresponding governmental and funding agencies domestically and abroad, should invest, proportionate to the enormous costs of pandemics, in basic and translational research to reveal a diverse array of influenza vaccines, using different platforms, viral targets, adjuvants, and delivery systems. This will allow selection of the candidates most fit for purpose to be brought to authorization and sufficient production and distribution to optimize the control of influenza across diverse settings and phases of pandemics and epidemics.
Recommendation 2-2: The World Health Organization should advocate and coordinate with multilateral stakeholders (e.g., the Coalition for Epidemic Preparedness Innovations), governments, funding agencies, the vaccine industry, and philanthropic organizations to build global capacity for robust and internationally comparable preclinical, clinical, and immunological assessments of influenza vaccine candidates, including novel candidates that use innovative structures, targets, and delivery systems to potentially broaden or improve protection.
Recommendation 2-3: International research networks (e.g., the National Institutes of Health/U.S. Centers for Disease Control and Prevention funding networks) supported by governments and funding agencies, the World Health Organization, and the vaccine industry should support, carefully plan, and conduct multi-center international clinical trials and field studies to compare emerging vaccines with standard vaccines in, among others, geographically, demographically, and immunologically diverse populations to inform rational and situation-based use and manufacture of an extended array of vaccines.
Recommendation 2-4: National regulators should engage with the vaccine industry and academic researchers in the development, standardization, and implementation of innovative assays to evaluate vaccines that induce immunity through mechanisms other than strain-specific neutralizing hemagglutination-inhibiting antibodies in order to reach consensus on the validation of these assays that will allow approval or licensure of influenza vaccines based on a broader range of assays that reflect induction of immunity.
CLINICAL SCIENCE
Research for the next generation of influenza vaccines requires extensive investment in clinical development. However, given the costly nature of conducting clinical studies, many industries see little incentive. The expansion of clinical trials globally, particularly in LMICs, will decrease the risk of such large investments and fill the clinical funding gap. Despite the significant impact of influenza in LMICs, many lack seasonal vaccine programs owing to both a lack of funding and a lack of perceived urgency. To highlight the urgency of such seasonal influenza programs to local governments, burden-of-disease studies and cost–benefit analyses are needed. Furthermore, population-based studies of vaccine effectiveness for novel vaccines need to capture the diversity of racial, ethnic, socioeconomic, age, and medical conditions within and across countries. To control for other
variables that may bias effectiveness, electronic medical records can be used to provide context on comorbidities.
Clinical studies of influenza vaccines need to represent the diversity of the population studied, and high-risk groups should be prioritized in early studies so that vaccines can be made available to the most at-risk populations first. Clinical research into vaccines using novel platforms will require postapproval vaccine effectiveness studies and safety surveillance on a global scale; data sharing is essential for this purpose, as are survey-based approaches to monitor postapproval vaccine safety. Increasing involvement of LMICs in both clinical trials and distribution capacities is essential and will require a coordinated global pharmacovigilance system. For this purpose, lessons can be learned from community-engaged work that collaborates and partners with the local community.
Recommendations
Recommendation 3-1: The World Health Organization, in collaboration with national public health agencies (e.g., the U.S. Centers for Disease Control and Prevention, the European Centre for Disease Prevention and Control, the China Center for Disease Control and Prevention, and the Africa Centres for Disease Control and Prevention) should conduct burden-of-disease studies in low- and middle-income countries to understand factors such as the health and economic burden of influenza illness and barriers to immunization in adult, pregnant, and pediatric populations to ensure development of infrastructure and capacity needed for pandemic vaccine development and implementation. Cost–benefit analyses should include additional economic productivity losses caused by delayed access to a vaccine in a pandemic.
Recommendation 3-2: The International Coalition of Medicines Regulatory Authorities and the World Health Organization, in partnership with national regulatory (e.g., the U.S. Food and Drug Administration and the European Medicines Agency) and public health agencies (e.g., the U.S. Centers for Disease Control and Prevention, the European Centre for Disease Prevention and Control, the China Center for Disease Control and Prevention, and the Africa Centres for Disease Control and Prevention) should invest, on a global level, in data infrastructure and capacity building to conduct real-time sentinel site surveillance of vaccine safety and effectiveness of different vaccine products deployed for use in epidemics and pandemics in diverse populations (e.g., age group, gender, race/ethnicity, geographic, presence of comorbidities, preg-
nancy, and socioeconomics), including a plan to ensure coordination, collaboration, and data sharing across these sentinel surveillance sites.
Recommendation 3-3: The International Coalition of Medicines Regulatory Authorities and the World Health Organization (Global Advisory Committee on Vaccine Safety) should ensure international coordination and collaboration on the timely and transparent review of vaccine safety data during epidemics and pandemics to support real-time decision making about the use of vaccines. Safety data should be made available to support country-level benefit–risk assessments, particularly for low- and middle-income countries relying on regional data from sentinel sites conducting safety surveillance.
MANUFACTURING SCIENCE
As the majority of the world’s vaccine manufacturing capacity is located in high-income countries (HICs), they have the advantage of early access to pandemic vaccines. Early access to vaccines combined with the funds required to purchase them leads to the type of vaccine nationalism seen during the COVID-19 pandemic. Prioritizing the expansion of manufacturing capacity in LMICs will help avoid the delayed rollout of vaccines in LMICs that occurs when only HICs are afforded access. This would not only benefit LMICs, but could also benefit the entire world as it expedites the time to control the pandemic and limits the spread of virus variants. The global network of influenza centers of excellence could guide the effort to combat vaccine nationalism, in which countries make deals with manufacturers and ensure the supply to their own population first, resulting in global vaccine inequity, by increasing collaboration and expanding to ensure capacity building in LMICs. Additional factors causing delays in vaccine manufacturing during a pandemic include shortages of supplies such as lab reagents, consumables, and raw materials caused by increased demand and reduced production and delivery of raw materials. A current bottleneck for the production of pandemic influenza vaccines is the steady supply of embryonated chicken eggs. Exploration of novel platforms for vaccine production can complement conventional vaccine production and lower the risk of supply chain shortages. However, proprietary issues have not been resolved for novel platforms, which may be a limiting factor in expanding global manufacturing capacity. Public-sector investments and improvements to data-sharing infrastructure will increase vaccine manufacturers’ ability to mobilize quickly during the next pandemic. Financial aid provided by public investment may also incentivize vaccine manufacturers to assume more risk in building infrastructure to accommodate vaccine R&D in preparation for the next impending influenza pandemic.
Recommendations
Recommendation 4-1: The U.S. Department of Health and Human Services and the World Health Organization should develop a plan for a sufficient and self-sustainable global supply of influenza vaccines for pandemics. This includes
- Convening, supporting, and encouraging multi-national, public, and private vaccine manufacturers to benchmark, prioritize, and harmonize influenza vaccine manufacturing; and
- Enhancing and expanding support of the global influenza vaccine manufacturing network, creating manufacturing hubs for greater collaboration, and building capacity to address challenges in manufacturing in low- and middle-income countries.
Recommendation 4-2: Vaccine manufacturers should take a risk-based approach to pandemic influenza preparedness. This approach would be most effective if incentivized, and could include
- Participating during research and development, data sharing, technology adoption, and training activities with international partners;
- Expanding internal capacity to assess the production needs and their risks;
- Using scientific evidence to design strategies to reduce risks (e.g., World Health Organization prequalification, licensing, and marketing); and
- Formalizing technology transfer (scale-up and scale-out) activities, taking into consideration timelines and the outcomes for equitable costs, access, and distribution.
REGULATORY SCIENCE
The COVID-19 pandemic is a model for the future of regulatory science. Regulatory systems developed clear requirements and collaborated with industry partners to share data. This helped to conduct overlapping preclinical and early clinical phase studies, rapidly increasing the speed with which the COVID-19 vaccines were developed. Nevertheless, the process can be improved to accelerate the development of pandemic influenza vaccines. More data sharing between vaccine manufacturers during the preclinical and clinical development of vaccines for pandemics would be beneficial. Regulators must develop guidelines for how to conduct preclinical and early clinical trials during interpandemic periods and develop pathways for rapid review of vaccines for pandemic strains. Additionally, clear regulations for the development of seasonal vaccines
are needed, including correlates of protection, efficacy, and safety. If vaccine manufacturers use international standards for testing efficacy, it will ensure all vaccines meet set standards for correlates of protection while also streamlining development.
The COVID-19 pandemic also highlighted the importance of transparent communications with the public. The lack of transparency and clear communication from both vaccine manufacturers and government agencies contributed to vaccine hesitancy in many populations. Preventing vaccines from becoming politicized and properly communicating the risks and benefits, as well as safety information, could have instilled trust in the vaccines. To combat these issues, regulators should commit to releasing clinical trial data for independent analysis. Additionally, national regulators could collaborate with scientific leaders to establish coordinated communications with the public to help convey differences in vaccine recommendations across different countries and regions.
Recommendations
Recommendation 5-1: The U.S. Food and Drug Administration and other national regulators (e.g., European Medicines Agency) working with the scientific community and pharmaceutical industry should enhance comprehensive guidance for the development of influenza vaccines on novel platforms through Emergency Use Authorization to full licensure. This guidance should provide pathways for seasonal and pandemic influenza.
Recommendation 5-2: The U.S. Food and Drug Administration and other national regulators (e.g., European Medicines Agency) should commit to transparency in the oversight of clinical trials, review of data, authorization, and approval of pandemic influenza vaccines, including the release of facility inspection findings, clinical trial protocols, and clinical data that are the basis of decision making. Regulators should convene independent advisory committees to systematically review data, make recommendations, and build public understanding and confidence prior to the authorization or approval of novel vaccines.
Recommendation 5-3: The World Health Organization and the International Coalition of Medicines Regulatory Authorities should encourage and support the coordination between regulatory and public health agencies (e.g., the U.S. Centers for Disease Control and Prevention, the European Centre for Disease Prevention and Control, the China Center for Disease Control and Prevention, and the Africa Centres for Disease Control and Prevention) when announcing different decisions
on the same or similar vaccines, to explain the different underlying circumstances and judgments.
Recommendation 5-4: Vaccine manufacturers should adopt a code of conduct for press releases and other communications regarding vaccine trial results and other matters that emphasizes the critical role of regulatory review.
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