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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 3
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 4
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 5
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 6
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 7
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 8
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 9
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 10
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
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Page 11
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 12
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 13
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 14
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 15
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 16
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
×
Page 17
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative. Washington, DC: The National Academies Press. doi: 10.17226/26284.
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Summary As of October 6, 2021, the global number of cases of COVID-19 had surpassed 235 million, with deaths approaching 5 million worldwide.1 These figures are likely to be substantial underestimates. For example, a July 2021 study from the Center for Global Development (Anand et al., 2021) pro- vided an analysis of death numbers for India that suggested that the toll of 400,000 underestimated the true number by a factor of 10. Furthermore, in June 2021, economists estimated that the pandemic led to a 6.65 percent loss of global gross domestic product (GDP) in 2020 alone. COVID-19 is also likely to have lasting effects on global GDP due to the costs of fiscal stimuli, the value of excess deaths, and other factors, such as the loss of businesses and educational opportunities. These effects may lead to a 54.68 percent loss of total GDP from 2020 to 2030 (Yeyati and Filippini, 2021). Yet, from an epidemiological perspective, COVID-19 does not rep- resent a “worst-case” pandemic scenario, such as the 1918–19 influenza, which resulted in at least 50 million deaths worldwide (Taubenberger and Morens, 2006). Influenza pandemics have occurred repeatedly, and experts worry that the risk for an influenza pandemic may be even higher during the COVID-19 era due to changes in global and regional conditions affecting humans, animals, and their contact patterns. While it is difficult to predict when it will occur, a major influenza pandemic is more a matter of “when” than “if” (Kelland, 2019). Although the true burden of influenza is unknown, an estimated 1 billion people are infected by seasonal influenza annually and in virtually 1  https:// Johns Hopkins Coronavirus Resource Center, https://coronavirus.jhu.edu/ 1 PREPUBLICATION COPY—Uncorrected Proofs

2 THE INFLUENZA IMPERATIVE every country (WHO, 2019a). This affects almost an eighth of the world’s population every year (Palache et al., 2020). Among the large family of influenza viruses, a subgroup that predominately infects mammalian ani- mals and birds are considered potential pandemic strains. Similar to the viruses that have caused Severe Acute Respiratory Syndrome (SARS) and COVID-19, certain novel influenza A viruses might have the capability and opportunity to make the jump from animals to become highly infectious for humans and so cause a pandemic. Influenza pandemics are a serious threat, and, because of their respiratory mode of transmission and short incuba- tion period, they are capable of spreading rapidly around the world and causing high illness and death. Yet the public and policy makers are mainly only familiar with seasonal influenza and, paradoxically, often dismiss all influenza and a range of minor illnesses with similar symptoms as “just the flu.” To place the threat of pandemic influenza in context, if COVID-19 had the same case fatality rate as the 1918–1919 influenza, the total U.S. death toll alone would approach two million2 (Ewing, 2021). A pandemic caused by a novel influenza strain of moderate to severe lethality would likely cost the modern world economy trillions of dollars (GPMB, 2019). The year 2020 saw unprecedented innovation and scientific collabora- tion related to vaccine research and development, with special attention on the decades of work to develop messenger RNA (mRNA) technology and other rapid response platforms that were ready for and applied to produce highly effective vaccines for COVID-19. Three to four times more COVID-19 vaccine, almost 12 billion doses, are projected to be available by the end of 2021, compared to what was possible for all vaccines in 2019 (IFPMA, 2021). If we were experiencing pandemic influenza instead, would global stakeholders have been willing at the outset to embrace the newer, barely tested vaccine technologies, or would they have stayed with the familiar and well-tested largely egg-based approaches? According to 2019 estimates, if everything went right, 6.4 billion influenza vaccine doses could theoretically have been produced over 12 months, using mostly egg- based technologies (Sparrow et al., 2021). Based on commitments from industrial partners to the World Health Organization (WHO) Pandemic Influenza Preparedness (PIP) Framework, only about 400 million doses of pandemic vaccine would have been available for WHO to distribute glob- ally during that period. The reliance on largely egg-based technologies and the use of adjuvants (both of which have limited surge capacity) highlights the need for the world to be much better prepared to make and distribute vaccines to counter an influenza pandemic. 2  As of October 6, 2021, the confirmed U.S. death toll from COVID-19 was 705,404 ac- cording to data from the Johns Hopkins Coronavirus Resource Center, https://coronavirus. jhu.edu/. PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 3 The enormous innovations in vaccine development and production that emerged for COVID-19—supported by many new public–private partner- ships (PPPs)—suggest technological options for making greater quanti- ties of influenza vaccines more quickly. Much research and development (R&D) needs to be done to establish the general applicability of these new approaches to developing and manufacturing vaccines for influenza and other pathogens. For these technologies and platforms to be available and scaled up when the world needs them, workforce, regulatory capacity, and business models must also be in place. Readiness to respond to a pandemic requires a corresponding increase in the use of these facilities between pan- demics. This increased usage is critical for reducing the impact of seasonal influenza but will also help ensure that manufacturing facilities stay opera- tional between pandemics. The COVID-19 pandemic has laid bare the “fragility of our global system of preparedness and response to pandemics, and the fragmentation of our research and development ecosystem” (Lurie et al., 2021). It also provides a disruptive moment to significantly act upon pandemic prepared- ness and response (PPR)—including advancing new norms and frameworks for influenza. How should influenza fit within the wider PPR agenda, which is currently being advanced by the G7 via the UK Pandemic Prepared- ness Partnership and the G20 through its High-Level Independent Panel (HLIP) on Financing the Global Commons for Pandemic Preparedness and Response? What governance frameworks and regulations need to be safeguarded around influenza specifically, and what should be expanded from influenza to other respiratory pathogens with pandemic potential? With these questions in mind, an ad hoc committee of experts was formed under the auspices of the National Academies of Sciences, Engi- neering, and Medicine (National Academies) and tasked to examine recent experiences during COVID-19 and other major viral epidemics and identify ways to strengthen pandemic and seasonal influenza global coordination, partnerships, and financing. The committee’s deliberations were based on a single premise: starting with the first human detection of a novel influ- enza virus with pandemic potential, how can the global health community move as quickly as possible to develop and produce safe and effective vaccines and equitably immunize as many people as possible worldwide? The committee acknowledges that a universal influenza vaccine would be a complete game changer, by ensuring advance preparation rather than reactive development. The report’s chapters encompass the governance and financing structures required to support rapid developments to vac- cination at scale, including surveillance, pathogen sharing, partnerships for technology (R&D and vaccine optimization) and manufacturing (vaccine scale-up and manufacturing facilities), and access and financing (financing mechanisms to “push” and “pull,” procure, and nationally deploy influenza PREPUBLICATION COPY—Uncorrected Proofs

4 THE INFLUENZA IMPERATIVE vaccines). Based on its findings and conclusions, the committee draws seven overarching recommendations for how the urgent influenza threat should be conceptualized and prioritized as a crucial component of the broader global PPR agenda over the next 3–5 years. The committee acknowledges that its recommendations presume a degree of cohesion and commitment to a global common purpose across the G7 and G20, which cannot be taken for granted, despite the compel- ling economic and human case for collective action to reinforce PPR. The changing dynamics of international relations over the last decade or so have transformed the geopolitical context in which global health policy is made. Shifts in the balance of power in the international system; the rise of authoritarian states; diminished cohesion of democratic states; and the rise of nationalism and populism across a broad array of states are among the factors that have led to this transformation. The COVID-19 response has exposed sharp fissures in the international order, shaking confidence in the notion of a global community and revealing the powerful, complex, and somewhat contradictory interactions between global health priorities, domestic political imperatives, and other dimensions of geopolitical compe- tition and collaboration. Major powers in the G7 and G20 have simultane- ously supported efforts to promote equitable access to vaccines and actively engaged in “vaccine nationalism.” Meanwhile, “vaccine diplomacy” has been used to garner geopolitical and ideological advantage. One of the biggest and most sobering lessons from COVID-19 has been that in an in- fectious disease crisis of this magnitude, neither established arrangements, such as the International Health Regulations (IHR, 2016) nor newly created mechanisms, such as COVAX, can withstand the overwhelming pressures to prioritize national interests. The committee did not directly consider how to address these daunting geopolitical challenges, as doing so would involve venturing far beyond its mandate. However, the committee recognizes that overcoming these challenges, or at least mitigating their consequences for global health, is a prerequisite for success, for both the broader PPR agenda and the spe- cific influenza vaccine recommendations that this committee put forward. The committee adopted the basic assumption that a geopolitical context can be established in which one can speak meaningfully of a global com- munity able to take at least some degree of coordinated collective action, since much of what is proposed in the recommendations requires this as a foundation. This does not require global consensus on everything or mean that every country is involved in every effort, but it implies a base level of coordination among leading states. As a shorthand expression and recog- nizing that this is an imperfect depiction of the stakeholders involved, this report typically refers to the G7 and G20 as the nexus of such a global community. PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 5 The committee also recognizes that it is possible scope to construct some technical coordination mechanisms in a “flying under the radar” mode that is somewhat insulated from politics. However, the committee is skeptical about relying too much on such an approach. COVID-19 has repeatedly revealed how the intense political pressures that arise from a deadly pandemic can override technical, contractual, or legal consider- ations. As the G7 and G20 devise a new set of mechanisms to bolster PPR, including potentially new legal obligations (e.g., from a pandemic treaty or instrument, should this emerge), new governance arrangements (such as a Global Health Threats Board), and new means for financing (such as the HLIP’s proposal of a Global Health Threats Fund), it is important to recognize that when put to the test, these new arrangements are unlikely to work precisely as designed because national interests will once again prove almost impossible to withstand. But recognizing their limitations does not equate to believing that such arrangements have no value: they can be enormously helpful in shifting norms and behaviors, such as toward more equitable deployment of lifesaving medical tools. KEY FINDINGS AND RECOMMENDATIONS Governance and Coordination: Aligned Pandemic Preparedness and Response for Respiratory Pathogens with Pandemic Potential Among infectious diseases with pandemic potential, influenza stands out because its technical and policy systems, including for surveillance, the vaccine strain selection process, relations between the public and private sectors, and related access and benefit system (pertaining to pandemic influenza) are global and—at least compared to other pathogens—rela- tively well coordinated through WHO. These pre-existing arrangements constitute a functional, if limited, “ecosystem” to address seasonal and pandemic influenza. Despite many aspects of these mechanisms that need substantial strengthening, the starting point for influenza is very different from other pathogens of pandemic potential. The COVID-19 pandemic led to a wide recognition of the need to reinforce PPR for the various patho- gens potentially capable of causing a pandemic. A pressing need exists to integrate actions to strengthen preparedness for pandemic influenza with interventions to improve it for other pathogens, particularly other respira- tory viruses. Without undermining what is already in place, it is necessary to move away from disease-specific, siloed systems toward developing an integrated governance, financing, technical, and operational architecture capable of addressing all respiratory virus pandemic threats. An example in this direction related to surveillance would be the Global Influenza Surveil- lance and Response System “plus” (GISRS+) proposal. PREPUBLICATION COPY—Uncorrected Proofs

6 THE INFLUENZA IMPERATIVE Recommendation 1: WHO should develop an integrated agenda to strengthen preparedness and response for all respiratory pathogens of pandemic potential, which includes surveillance, information sharing, and the development, manufacturing, and deployment of vaccines and other essential components of the vaccine manufacturing supply chain. This agenda should comprise a key component of the overarching agenda for pandemic preparedness and response, encompass pandemic influenza, and build on existing mechanisms for coordination in the influenza arena. To accomplish this, member states should task WHO to do the following: a. Assume leadership for this agenda and, with collaboration from relevant multilateral partners (e.g., the Food and Agriculture Organization [FAO] and World Organization for Animal Health [OIE]), propose a framework for strengthened surveillance sys- tems and information sharing at country, regional, and global levels, to ensure rapid detection of new threats and to enable swift dissemination of information essential to accelerated vac- cine development. b. Work jointly with existing international and stakeholder orga- nizations with expertise in vaccine R&D, manufacturing coor- dination and supply chain management, and deployment (e.g., the Coalition for Epidemic Preparedness Innovations [CEPI], the United Nations Children’s Emergency Fund [UNICEF] and Gavi, the Vaccine Alliance), to develop, in consultation with vac- cine manufacturers, a framework for improved global coordina- tion of vaccine development, production, and deployment for respiratory pathogens with pandemic potential, which includes defined roles, responsibilities, and accountability structures. Surveillance: Stable Financing for Integrated, Modern, Timely Respiratory Virus Surveillance for Pathogens with Pandemic Potential Without stable financing of a modern, integrated surveillance system for respiratory pathogens with pandemic potential, we will continue to fight pandemics in the dark. In the information era, the lack of reliable, sustained, and globally connected systems is striking and has massive nega- tive ramifications for national, regional, and global health security. Surveil- lance system gaps reflect insufficient financing and political will, and top to bottom attention will be needed to build, more closely align, and inte- grate such systems. This is not a low- and middle-income country (LMIC) problem only; many high-income countries (HICs) have moved away from adequately financing surveillance systems, and many systems underperform in terms of rapidly identifying, assessing, and reporting potential threats. PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 7 Moreover, the known science of pandemic threats indicates that effec- tive surveillance systems must work across traditional sector silos, including human and animal health and agriculture, to identify and assess zoonotic threats and spillover events and rapidly disseminate the data and insights that these yield. Establishing and sustaining broader surveillance systems has been challenged by both scientific and cultural silos, including how to cover multiple pathogens in an integrated system, because certain aspects may differ greatly (e.g., different scientific expertise and specimen collec- tion requirements). However, all pathogens have significant commonalities (e.g., standardized data and systems), and an integrated approach to risk assessments would benefit from the efficiencies of shared platforms and approaches. Strengthening and broadening global influenza surveillance to support a broader approach to respiratory virus surveillance will require substan- tially greater and sustained multilateral investments in country, regional, and global surveillance. Surveillance is primarily a global and national risk assessment and mitigation issue. Each country’s surveillance system generates significant positive externalities (benefits that accrue to other countries). This also provides a strong argument for external financing for surveillance when domestic resources are inadequate. The IPPPR and other groups are working on recommendations for institutional mechanisms for surveillance, including for a global viral sur- veillance network. This committee’s findings and deliberations underscore that integrated viral surveillance should be structured to support country ownership and cover critical influenza data needs as an integrated system, including genomic sequences, specimens for testing, and viruses from both human and animal sources. Surveillance must be viewed as an essential foundation for preventing and responding to threats rapidly and effectively by furnishing information essential for developing medical countermea- sures. Enhancing such systems to monitor and assess a range of pandemic threats, including influenza and as-yet-unknown threats, will require a dedi- cated, sustained pool of financing at national, regional, and global levels that must be sustained, stable, and long term. Recommendation 2: With urgency (over the next 3-5 years), the G7 and G20 should ensure that increased investments are made in surveillance systems for pathogens with pandemic potential, which support and encompass every country and region, by doing the following: a. Creating incentives, structures, and pathways for key stakehold- ers to develop and implement integrated surveillance, which should include firmer support for zoonotic surveillance in the framework of One Health programs, such as through WHO/ OIE/FAO stakeholders. PREPUBLICATION COPY—Uncorrected Proofs

8 THE INFLUENZA IMPERATIVE b. Strengthening and financing regional surveillance structures and networks through partnerships between regional development banks and organizations. For example, in the South Asia and Southeast Asia regions this could be accomplished in conjunc- tion with the Association of Southeast Asian Nations (ASEAN), Asian Development Bank (ADB), and Asian Infrastructure Investment Bank [AIIB], and in the Middle East and North Africa with the Organization of Islamic Cooperation (OIC), Gulf Cooperation Council, and Islamic Development Bank (ISDB). c. Ensuring that the financing mechanism selected by the G7/G20 for PPR more broadly includes sustainable funding for surveil- lance and that this pooled funding is sufficient to enable surveil- lance for respiratory pathogens, especially encompassing those with pandemic potential, at the national and regional levels. d. This global funding mechanism’s governance should include relevant international agencies, such as the International Fund for Agricultural Development (IFAD), OIE, FAO, and World Food Program (WFP), in addition to multilateral and regional development banks and the WHO. Pathogen Sharing: Limitations and Potential of the PIP Framework and Nagoya Protocol The timely sharing of influenza viruses is essential for developing life- saving seasonal influenza vaccines, identifying antiviral drug resistance and potential pandemic virus strains, and providing early warning for out- breaks. The PIP Framework supports a critical WHO global surveillance system needed for influenza and establishes a multilateral agreement that places access and benefit sharing (ABS) and sharing of viruses of pandemic potential on an equal footing but avoids a bilateral transactional approach to such sharing. It reflects the importance of transparency, equity, efficiency, and the accountability shared by countries, industry, and WHO. If a new global pandemic treaty or international instrument is negoti- ated (see Chapter 3), it will provide an opportunity to incorporate and consolidate diplomatic gains from the earlier PIP Framework negotiations and agreements as foundational elements for new multilateral solutions. Having such a multilateral instrument could eliminate the challenge of negotiating the sharing of viruses and benefits in the midst of a pan- demic, ensuring greater predictability, and saving critical time and at- tention needed during a full response. The principles agreed upon in the PIP Framework could be incorporated into the foundations of any future pandemic instrument. PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 9 Seasonal pathogen sharing has increasingly been negatively impacted by the Nagoya Protocol, resulting in the need in some instances to choose alternate virus strains for vaccines (WHO, 2019b). In a pandemic, delays in sharing viruses and associated information could have very serious implica- tions for delaying the response. A similar delay in sharing genetic sequence data is also possible, due to the uncertainty about whether it falls under the PIP Framework and Nagoya Protocol. The rapid ramp-up of genomic surveillance for SARS-CoV-2 variants and the use of such data for vaccine development underscores the urgency of ensuring rapid access and sharing of genetic sequence data during pandemic situations. Recommendation 3: The World Health Assembly (WHA) should ex- plicitly clarify that the PIP Framework covers genetic sequence data. The WHA should also use established PIP Framework principles as a foundation for future WHO member state agreements, or advocate for their use in agreements negotiated by other international organizations, so that the access and benefit and information-sharing principles cover a broader range of pathogens and their genetic sequence data. To ac- complish this, the WHA should, with support of the United Nations, do the following: a. Establish accountability and compliance monitoring for member states and other parties in the PIP Framework and future agree- ments on access and benefit sharing through regular reviews and meetings of member states, and by building or strengthening norms and holding leaders accountable for following through on commitments. b. Incorporate the principles of equity, shared accountability, and multilateralism in any future pandemic treaty or instrument and ensure that the surveillance systems that can rapidly detect, as- sess, report, and share these viruses are publicly recognized to be a global public good. c. Develop a mechanism for countries to share viruses openly and rapidly, including their genetic sequences and other essential supporting laboratory information and epidemiological data for both risk assessment and risk management (developing vac- cines, therapeutics, and diagnostics), while setting up incentives for industry and member states to share benefits and products (vaccines, therapeutics, and diagnostics), and to facilitate trans- ferring technology. This requires a recognition of the concerns of industry over intellectual property. This mechanism should include regular public reporting as part of a transparency and monitoring system to hold countries and governments account- able for their level of pandemic preparedness and response. PREPUBLICATION COPY—Uncorrected Proofs

10 THE INFLUENZA IMPERATIVE d. Request that the WHO secretariat approach the Convention on Biological Diversity (CBD) secretariat to initiate a process for a new international agreement or instrument to be established as a “special international instrument” under Article 4.4 of the Nagoya Protocol (allowing the agreement to bypass some Nagoya Protocol requirements while remaining consistent with its objectives). The new international agreement or instrument could either be negotiated as an additional protocol to the CBD alongside the Nagoya Protocol, be a component of a possible future pandemic treaty, or be negotiated within WHO as a new ad hoc international agreement. The special international instru- ment should address the sharing of genetic sequence data and other necessary information, such as important epidemiological and laboratory data, in addition to the pathogen samples. The Meeting of the Parties to the Nagoya Protocol, in collaboration with WHO, should recommend that Parties to the Protocol facilitate and streamline national implementation procedures to facilitate the timely international sharing of pathogens in line with the urgency of responding to an outbreak. The Meeting should also acknowledge that genetic sequences of both hu- man and animal pathogens are essential for modern science to adequately assess and respond to outbreak emergencies and to develop optimal vaccines, diagnostic tests, and other critical materials. Consideration should also be given to reinforcing that any ABS portion of the agreement not deter innovation or act as a disincentive for industry participation. Public-Private Partnerships to Accelerate Vaccine Development: Structuring Global Partnerships to Support R&D for Influenza Platform Technologies Public-private partnerships (PPPs) with industry before and during the COVID-19 pandemic have allowed highly efficacious platform technology– based vaccines to be developed. Platform technologies could revolutionize the effectiveness, speed, and ability to scale up production of influenza vac- cines and overcome some intrinsic constraints of the current egg-dominated ecosystem. This establishes a necessity of innovation for influenza vac- cines to shorten manufacturing time lines, increase global manufacturing capacity, and improve effectiveness. The goal in the next 3–5 years would be to progressively pursue development and assessment of new platform technologies to improve vaccine effectiveness, expand the options for scal- ability and production, and optimize their methods, in parallel to pursuing the “ultimate prize,” a universal influenza vaccine (see Recommendation PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 11 5). As highlighted by the Center for Infectious Disease Research and Policy (CIDRAP) Influenza Vaccine Roadmap, because of influenza’s high muta- tion rate and other characteristics, this will require significant investment in early R&D, including support of Phase I–III clinical trials and vaccine dose optimization. It will also require recognizing intellectual property issues, to foster a continued willingness of industry to form synergistic partnerships. The difficulty is in how to scale up industry partnerships and apply them globally, especially to support a geographically distributed manufac- turing hub model. Several existing organizations (Coalition for Epidemic Preparedness Innovations [CEPI], Biomedical Advanced Research and De- velopment Authority [BARDA], and the new HERA Incubator) may be able to lead large-scale R&D and clinical trials for influenza platform technologies, including large-scale global action in LMICs, if they are given expanded mandates matched with appropriate funding and can identify stable markets for their products. As a PPP with a multilateral approach, CEPI is well positioned to ad- dress the coordination and cost-effectiveness challenges for influenza R&D on a global scale. However, BARDA and HERA have similar capacities for advanced vaccine development, at the early, middle, and late stages. Giving BARDA a broader remit may allow it to overcome a limitation of its Operation Warp Speed (OWS): that it only focused on U.S. needs and did not account for global needs or engage with a broader set of global stakeholders and partners.3 Recommendation 4: The Global Health Threats Board or similar gov- ernance structure created by the G7/G20 PPR agenda, should negotiate to extend the mandates of CEPI, BARDA, the HERA Incubator, and equivalents elsewhere as appropriate, to support government-industry partnerships for R&D for influenza and other respiratory viruses with pandemic potential. These voluntary partnerships should focus on op- timizing each industry partner’s platform, using the following structure: a. The G7 and G20 member nations (e.g., through the Global Health Threats Board) should name a global coordination body to specifically coordinate global and regional government-indus- try partnerships for influenza vaccines. CEPI is the existing multi- lateral global coordination vehicle for R&D, has access principles built in, and is a possible organization to assume this role. 3  The committee wishes to highlight that its membership includes Richard Hatchett, the Chief Executive Officer of CEPI, and Charlotte Weller, Head of Prevention at the Wellcome Trust, who chairs the CEPI Investors Council in a voluntary capacity. Recommendations 4 and 5 include actions in which CEPI could play a significant role. These recommendations are based on a consensus from all committee members based on the evidence available. PREPUBLICATION COPY—Uncorrected Proofs

12 THE INFLUENZA IMPERATIVE b. Countries that fund vaccine R&D should ensure that R&D for pandemic influenza is part of their funding portfolio and strive to identify investment synergies to maximize returns on invest- ments. Regional organizations should support the mobilization of government-industry partnerships, such as the Africa Centres for Disease Control, Association of Southeast Asian Nations, Gulf Cooperation Council, and Europe 2020’s Innovation Union (funded by HORIZON 2020) and its successor. c. Government-industry partnerships should have affiliated teams to identify promising technologies, optimize them for the field (e.g., identify adjuvants that enhance vaccine products on a small scale, to provide directionality in what to do during a surge), and consider investments required to reach efficiency yields. These partnerships should support Phase I–III clinical trials, as recommended by the United Kingdom/G7 PPP, as well as early dosing trials. They should also build-in workforce development training for areas of expertise required to be ‘at the table’ for technology transfer of these products. d. Government-industry partnerships should share workforce de- velopment requirements with CEPI, the WHO, and other rel- evant multilateral partners, to help countries identify and fill gaps in ministries of health, labor, and economics expertise before a pandemic. An Influenza Vaccine Moon Shot: Financing and Organizing for Transformational Universal Vaccine R&D, Licensure, and Procurement Seasonal influenza vaccines are reformulated annually to target the viral antigens that are anticipated to circulate in the northern and southern hemi- spheres that year. Influenza can also develop significant mutations (genetic shift) and present a pandemic virus for which there is no existing popula- tion immunity. A universal influenza vaccine would, in theory, be able to induce immunity against most or all influenza A virus strains, including future pandemic strains. The availability of such a vaccine is the subject of ongoing research and would be a significant game changer for both pandemic and seasonal influenza preparedness and response and vaccine markets. Developing such a vaccine remains a difficult scientific problem with no guarantee that a vaccine can be developed that will provide long- term protection in people of all age groups. However, a universal influenza vaccine would be transformational. Developing improved influenza vaccine technologies will require ma- jor intensification of fundamental and applied research. Substantive new sources of funding are needed to attract an infusion of new actors and PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 13 new disciplines (e.g., computational and systems biology, bioinformatics, artificial intelligence, deep learning, machine learning, and HIV/AIDS and cancer immunotherapy research communities) (BMGF, 2021). Push incen- tives will be critical to fully enable cross-disciplinary problem solving and achieve and demonstrate a proof of concept, while pull incentives, such as advance market commitments (AMCs), will be needed for sustainability of a commercial product in the influenza vaccine market. Kremer and Glennerster (2004) originally proposed the AMC to encourage research on vaccines against technologically distant targets, such as malaria; it can be usefully deployed as an incentive for individuals, groups, and organizations to solve the difficult biology problems implicit in the quest for a universal influenza vaccine. Establishing push and pull incentives would also drive private sector engagement in demonstrating proof of concept and offset any potential concerns about the sustainability of the influenza vaccine market. Successfully developing a universal influenza vaccine will require galva- nizing intense and sustained effort across multiple partners toward a hugely ambitious goal, hence the committee’s use of the expression “moon shot.” This endeavor could be expanded to encompass a similar quest for a more broadly protective vaccine against coronaviruses with pandemic potential; that would be a substantial step toward reducing the societal disruption caused by pandemics and the current global inequities related to vaccine availability and distribution. Partnerships, such as CEPI, that involve gov- ernments and private, philanthropic, and civil society organizations could be incentivized to lead or coordinate the push for a universal influenza vac- cine; for CEPI, an expanded mandate—accompanied by funding—would be needed for it to assume the leadership needed to create push mechanisms and foster pre-competitive scientific research. Recommendation 5: The Global Health Threats Board or similar gov- ernance structure created by the G7/G20 PPR agenda, working with other relevant organizations, should initiate a dedicated “moon-shot” program to incentivize development, licensure, and eventual procure- ment of a universal influenza vaccine candidate as a matter of priority. This program’s structure and funding should include: (1) a “push” element for universal influenza vaccine R&D, which could be led by a variety of entities, including CEPI with input from its Scientific Advi- sory Committee, BARDA, the HERA Incubator, the WHO, the United States CDC, or other agencies that operate beyond the vaccine ex- ploratory science phase and have a stake in market shaping, and (2) a complementary pull element (an AMC) to ensure procurement of resultant universal influenza vaccines, with technical leadership from Gavi and UNICEF (as a procurement agency for Gavi). This influenza moon-shot should be coupled with a parallel effort for coronaviruses PREPUBLICATION COPY—Uncorrected Proofs

14 THE INFLUENZA IMPERATIVE or other respiratory viruses with pandemic potential that produce vari- ants of concern. Financing for the push and pull elements for both virus families should do the following: a. Receive funding from multilateral actors, development banks, philanthropies (e.g., Wellcome Trust and Bill and Melinda Gates Foundation), and regional governance structures, including but not limited to: the Organisation for Economic Co-Operation and Development (OECD), G20, World Bank/International Monetary Fund (IMF), regional development banks, the World Trade Organization (WTO), European Union (EU), and African Union (AU). This funding should be separately and individu- ally supported by trade and global financing institutions of the United States, China, and the EU, such as the European Investment Bank (EIB) and Asian Infrastructure Investment Bank (AIIB). b. Include participation from middle-income countries. The price for participation for these countries should be value-based and tiered; it should be determined by a value assessment (Health Technology Assessment) as part of the AMC. A financial in- termediary such as a multilateral development bank should underwrite middle-income countries’ own value-based AMCs, so countries do not need to put scarce resources aside until an effective product is approved. c. Include country-specific tiered prices for guaranteed volumes of vaccines to multiple developers that meet the minimum efficacy threshold, to provide an incentive to retain multiple potential innovators. This would hedge risk against late failure of one or more early candidates and protect against the possibility of safety risks after widespread deployments that require restricted use or result in the first entrant’s withdrawal from the market. d. Include a requirement for successful vaccine innovator(s) to license their vaccines to other suppliers or manufacturers at low or zero cost, as a condition of accessing this guaranteed market. This will help facilitate widespread scale-up across all countries. e. Be carefully costed over the next 1-2 years, to determine the scale of funding for this moon-shot that could reasonably derisk investments in influenza vaccine technologies. Manufacturing Scale-Up and Supporting Geographically Distributed Hubs for Influenza Vaccine Manufacturing and Supply Chain Capacity Regional or “geographically distributed” manufacturing hubs offer promise in helping counter vaccine nationalism and promoting equitable PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 15 access through self-sufficiency. However, distributing manufacturing does not offer a full solution for addressing issues of vaccine equity, and it should be balanced with increasing the overall scale of global vaccine production capacity that can be applied to producing pandemic vaccines. Greater scale in global manufacturing capacity reduces the probability and likely extent of rationing in a pandemic; greater geographic distribution of that capac- ity reduces the inequalities of access that might arise from such rationing. Moreover, vaccine manufacturing capacity is not entirely fungible. As it is difficult to predict the optimal platform for each pathogen with pandemic potential, it is also important to strive for diversification of the number of facilities, their locations, and the types of platforms they can manufacture. Distributed manufacturing hubs face several barriers to sustainability and success: they (1) require strong government commitment and industry involvement, (2) must comply with Good Manufacturing Practices and operate in a robust policy and regulatory environment, (3) require a strong business model (in terms of both demand for vaccines and the potential to manufacture other products for regional or global needs or keep production of pandemic or other vaccines at levels high enough for the facilities to stay “warm”), (4) must undertake workforce training for technology transfer and regulatory capacity, and (5) must have a business case that includes a provision for national plans (who will get vaccines, where, and how). No global institutional architecture exists to handle manufacturing coordina- tion and market-based issues. A business model for pandemic influenza vaccines requires a business plan for keeping manufacturing facilities functioning and sustained between pandemics. Current demands for seasonal influenza vaccine vary widely among countries and are not sufficient to support the expansion required to meet pandemic demands. However, if the technology platforms are appro- priate for making vaccines for other pathogens, vaccines could be produced in “peacetime” for other priority pathogens, such as MERS, Zika, Ebola, and dengue, or current diseases that require routine immunization (e.g., polio). Physical factories and research facilities might also be used for prod- ucts other than vaccines, such as mRNA-based therapeutics. Newly built factories and facilities will also need to have the flexibility to diversify their production, adopt a culture of Good Manufacturing Practices, and develop strong regulatory oversight. In addition to providing critical ingredients and manufacturing components, geographically distributed supply chain hubs present a market opportunity for countries to invest as suppliers of the bags, filters, and other items required for vaccine supply chains. Recommendation 6: The Global Health Threats Board or similar gov- ernance structure created by the G7/G20 PPR agenda should initiate a long-term (10-20+ years) multilateral partnership to track emerging PREPUBLICATION COPY—Uncorrected Proofs

16 THE INFLUENZA IMPERATIVE technologies that may be targets for technology transfer for vaccines for influenza; promote industry partnerships with geographically dis- tributed hubs; and provide technical training. To do so, it should do the following: a. Identify or create an international entity to assume responsi- bility for catalyzing voluntary technology transfer initiatives for platform technologies, including influenza vaccines. The structure’s governance should build on both the WHO and COVAX’s work on the COVID-19 mRNA hub, expanding it to include a diverse portfolio of technologies capable of providing protection against diverse threats with pandemic potential, and the COVAX Vaccine Manufacturing Taskforce, expanding it to work with vaccine manufacturing bodies to identify supply chain inputs and needs across a variety of vaccine candidates. b. Ensure that this entity promotes the development of platforms suited to the production of vaccines for other pathogens of national or regional importance in addition to seasonal in- fluenza—or products such as therapeutics–including tracking technologies coming onto the market and building platforms for voluntary industry collaboration. c. Develop or assist with the development of plans for geographi- cally distributed hub training requirements, such as vaccine regulatory needs and vaccine product sourcing. d. Encourage countries considering warming their manufacturing capacity for influenza vaccines and vaccines for other pathogens with pandemic potential to consider whether their focus should instead be on building new production capacity of key manu- facturing inputs for vaccine manufacturing. e. Be given dedicated funding to support these activities from the World Bank and regional development banks, in conjunction with the International Finance Corporation (IFC). Last Mile to the Goal of Vaccination: Generating Influenza Vaccine Demand through Globally Coordinated Deployment Activities Vaccines do not save lives; vaccination saves lives. Many countries, par- ticularly LMICs, lack adult vaccine deployment plans, systems, and experi- ence, including for seasonal and pandemic influenza. Even in countries such as the United States, COVID-19 has demonstrated how vaccine availability and success at achieving high vaccination rates are different issues—and that both present serious challenges. Countries need to build and sustain vaccine deployment capability, especially for adolescents and adults. This is PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 17 essential for both attaining public health benefits and “warming” and not “chilling” market support for vaccines and related programs. Vaccine financing programs often focus more on procurement than on supporting the programmatic infrastructure essential to ensuring that vaccines are effectively used in the field. Deployment activities require proper technical guidance, operational plans and capacity, and designated financial resources for vaccination operations to proceed effectively. UNI- CEF and Gavi are well positioned to take the lead on global coordination for vaccine deployment, particularly in LMICs, while WHO can leverage its expertise in providing technical guidance on national pandemic and vaccination planning and country readiness assessments. Countries must take the lead on developing the operational capacities necessary for vac- cination programs. Recommendation 7: UNICEF, Gavi, and relevant national and regional organizations (including governments) should be given funding explic- itly allocated for introducing and deploying next-generation seasonal influenza vaccines to underpin scaled-up manufacturing capacity. WHO regional offices should urgently work with countries to do more exten- sive assessments of their readiness to reach appropriate populations, including adults and high-risk groups, to enable work plans by 2023, which include the following: a. An analysis of what infrastructure (e.g., data and digitization of immunization records) built for COVID can be adapted, strengthened, and sustained for at least one additional adult and one adolescent vaccine. b. Advising member states on best practices used in countries that had high immunization rates during COVID-19. c. Assisting member states to look at their data and logistics sys- tems for monitoring coverage and for tracking safety (phar- macovigilance) and on the options for adopting no-fault compensation as part of patient safety mechanisms. Influenza presents a major pandemic threat, requiring urgent global coordination and partnerships. For optimal effectiveness, efficiency, sustain- ability, and impact, “countering the pandemic threat of influenza” should be reframed to “countering the pandemic threat of influenza within a wider respiratory pathogen” PPR framework. This move toward an integrated framework for respiratory pathogens with pandemic potential can only occur with large, dedicated financial investments, particularly targeting LMICs. Countering influenza is a global imperative on public health, eco- nomic, and equity levels. PREPUBLICATION COPY—Uncorrected Proofs

18 THE INFLUENZA IMPERATIVE REFERENCES Anand, A., Sandefur, J., and Subramanian, A. 2021. Three new estimates of India’s all-cause excess mortality during the COVID-19 Pandemic. . https://www.cgdev.org/publication/ three-new-estimates-indias-all-cause-excess-mortality-during-covid-19-pandemic. BMGF (Bill and Melinda Gates Foundation). 2021. Global grand challenges. Ending the pandemic threat: A grand challenge for universal influenza vaccine development. https:// gcgh.grandchallenges.org/challenge/ending-pandemic-threat-grand-challenge-universal- influenza-vaccine-development (accessed October 21, 2021) Ewing, E. T. 2021. Health Affairs Blog. https://www.healthaffairs.org/do/10.1377/hblog 20210329.51293/full/ (accessed July 16, 2021). GPMB (Global Preparedness Monitoring Board). 2019. Geneva, Switzerland: World Health Organization. IFPMA (International Federation of Pharmaceutical Manufacturers and Associations). 2021. Towards vaccinating the world: Landscape of current Covid-19 supply chain and manufacturing capacity, potential challenges, initial responses, and possible “solution space”—a Discussion Document. https://www.ifpma.org/wp-content/uploads/2021/03/ Summit_Landscape_Discussion_Document.pdf. Kelland, K. 2019. https://www.reuters.com/article/us-health-flu-who/world-must-prepare-for- inevitable-next-flu-pandemic-who-says-idUSKBN1QS1EP (accessed August 19, 2021). Kremer, M. and Glennerster, R. 2004. Strong Medicine: Creating Incentives for Pharmaceutical Research on Neglected Diseases. Princeton University Press. http://www.jstor.org/stable/j. ctt1dr365r. Lurie, N., G. T. Keusch, and V. J. Dzau. 2021. Urgent lessons from COVID 19: Why the world needs a standing, coordinated system and sustainable financing for global research and development. 397(10280):1229–1236. Palache, A, T. Tsai, Y. Vasiliev, A. Abelin, R. Hollingsworth, B. Taylor, and P. Barbosa. 2020. Global influenza vaccine distribution survey demonstrates urgency of implementation of Objective 3 of WHO influenza strategy 2019–2030. 6(2). Sparrow, E., J. G. Wood, C. Chadwick, A. T. Newall, S. Torvaldsen, A. Moen, and G. Torelli. 2021. Global production capacity of seasonal and pandemic influenza vaccines in 2019. 39(3):512–520. Taubenberger, J.K, and Morens, D.M. 2006. 1918 Influenza: the mother of all pandemics. Emerging Infectious Diseases 12(1):15-22. U.S. Senate, Committee on Foreign Relations, Subcommittee on Multilateral International Development, Multilateral Institutions, and International Economic, Energy, and Envi- ronmental Policy. 2017. . June 20, 2017. Washington, DC. Yeyati, E. L., and Filippini, F. 2021. Brookings Global Working Paper #158. Global Economy and Development program at Brookings. www.brookings.edu/global. WHO (World Health Organization). 2016. . Geneva, Switzerland: World Health Organization. https://www.who.int/publications/i/item/9789241580496(accessed October 21, 2021). WHO. 2019a. Geneva, Switzerland: World Health Organization. https://apps.who.int/iris/ bitstream/handle/10665/311184/9789241515320-eng.pdf, accessed October 21, 2021 WHO. 2019b. The public health implications of implementation of the Nagoya Proto- col: Report by the Director-General. https://apps.who.int/gb/ebwha/pdf_files/WHA72/ A72_32-en PREPUBLICATION COPY—Uncorrected Proofs

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Countering the Pandemic Threat Through Global Coordination on Vaccines: The Influenza Imperative Get This Book
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The COVID-19 pandemic has laid bare the fragility of the global system of preparedness and response to pandemics and the fragmentation of our research and development ecosystem. The pandemic has provided a disruptive moment to advance new norms and frameworks for influenza. It also has demonstrated how innovative global public-private partnerships and coordination mechanisms can lead to rapid successes in viral vaccine research, manufacturing, and risk pooling.

Countering the Pandemic Threat Through Global Coordination on Vaccines identifies ways to strengthen pandemic and seasonal influenza global coordination, partnerships, and financing. This report presents seven overarching recommendations for how the urgent influenza threat should be conceptualized and prioritized within the global pandemic preparedness and response agenda in the future.

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