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Suggested Citation:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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:"6 Recommendations and the Path Forward." 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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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

6 Recommendations and the Path Forward SITUATING INFLUENZA IN THE BROADER PANDEMIC PREPAREDNESS AND RESPONSE (PPR) CONTEXT Efforts to strengthen global coordination, partnerships, and financing for pandemic and seasonal influenza vaccines are an integral and essential part of the world’s overall efforts to reinforce these for the level of PPR needed to address any pandemic threat. A significant window of oppor- tunity exists now to strengthen the world’s overall PPR architecture. For example, the Independent Panel for Pandemic Preparedness and Response (IPPPR), G7/UK International Pandemic Preparedness Partnership (PPP), G20 High-Level Independent Panel on Financing the Global Commons for Pandemic Preparedness and Response (HLIP), and proposals for a pandemic treaty or instrument, have all been active in 2021. Preparing for influenza as one of, but not the sole, major pandemic threat recognizes that, epidemiologically, seasonal influenza imposes a major, annual societal burden across countries during non-pandemic years and that this family of viruses also causes influenza pandemics, which could disrupt society as much or more than any other known microbiological threat. The core requirements for strengthening national and global influenza PPR systems and capabilities are foundational for the PPR agenda, includ- ing surveillance, pathogen sharing, vaccine technologies, manufacturing capacity, intellectual property (IP), regulatory issues, and vaccine delivery (which encompasses vaccine acceptance and demand for a broader range of microbiological threats). An influenza pandemic is an essential PPR scenario for which national authorities must plan. Given historical patterns, the 153 PREPUBLICATION COPY—Uncorrected Proofs

154 THE INFLUENZA IMPERATIVE present and known existence of specific influenza viruses of concern, ongo- ing conditions that favor the emergence of another influenza pandemic, and the severe global experience with COVID-19, it is incumbent upon decision makers to materially strengthen PPR broadly and influenza PPR specifically. It is important to undertake this in a way that reduces the health and public health consequences of pandemics caused by influenza and other pathogens and acknowledges their economic and societal impact. While integrating such efforts into the broader PPR agenda makes sense, we must also recognize two points. First, the starting point with influenza is different than for other pathogens; well-established, although underfunded, networks and legal arrangements exist to meet the twin chal- lenges of seasonal and pandemic influenza, and especially the frequent need to update the antigenic composition of vaccine. These provide systems that, in concept, can be extended to include other pathogens (as has already hap- pened with GISRS with regard to SARS-COV-2), although the uniqueness of different pathogens also means that such extensions cannot be achieved blindly. It is essential to ensure that integration into the broader agenda does not undermine what is already working well in existing influenza- focused networks. Second, like all pathogens, influenza has distinctive characteristics, of which the most striking are the following: 1. Some influenza viruses create predictable, annual “seasonal” epi- demics of disease, while others can spill over from their normal animal hosts and become infectious in and transmissible among humans at unpredictable times; 2. The limited global use of antiviral therapeutics and diagnostic tests, underscoring the importance of vaccines; 3. The well-established and relatively well-understood and monitored nature of the zoonotic links, compared to many other emerging infectious diseases; and 4. The long historical pattern of pandemics, including the 1918–1919 pandemic, and the capacity of influenza viruses to cause another highly severe pandemic. Acknowledging and acting upon the core principle of fair and equitable access to vaccines is a required foundation for broad and sustained support for the global coordination mechanisms and agreements necessary for a PPR agenda for respiratory pathogens, including vaccines for pandemic influenza. There are two complementary ways to approach equitable allocation of vaccines: creating specific frameworks that include equity considerations directly and scaling up and distributing manufacturing to reduce scarcity. International or regional frameworks can strengthen global coordina- tion and time lines, while national plans are necessary to ensure nationally PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 155 and locally appropriate approaches for vaccine deployment and vaccina- tion. However, the COVID-19 pandemic has underscored that even access and benefit-sharing agreements (ABSs) alone might not be adequate to counter vaccine nationalism. The PIP Framework, in particular, is un- tested and, in its current form, would not provide timely and equitable quantities of vaccines for low- and middle- income countries (LMICs). The COVID-19 experience suggests that the scalability, size, and sustain- ability of the vaccine supply is an important complementary requirement to strengthen equitable access to vaccines under urgent conditions and ensure that vaccine manufacturing capacity and immunization programs are able to reach those at highest risk. In this context, acceptance of the principles of equity and fostering of innovation are twin pillars. Governance innovations for influenza vaccines are therefore necessary. These vaccines have severe constraints on production capacity and time lines, including those related to the present dominance of egg-based meth- ods. Investment in multiple platforms will benefit the timely availability of adequate amounts of influenza vaccine under pandemic conditions. While at least 22 (see Table 4-1) COVID-19 vaccines have been produced, scaling up influenza capacity requires platform technologies. Improving influenza vaccines’ breadth of protection (efficacy and ability to protect high-risk groups) and duration of protection must also be a priority, especially given the impact they have already demonstrated. Above all, a dedicated and well-resourced effort to develop a universal influenza vaccine that can provide durable protection against any influenza virus that is capable of causing serious human infections could take the threat of influenza—both seasonal and pandemic—off the table. The importance of scaling up surge manufacturing capacity for in- fluenza vaccines cannot be overstated. Any significant global rationing of limited vaccine capacity during a future pandemic will inevitably lead to a repeat of vaccine nationalism. More geographically distributed vaccine manufacturing might help somewhat in terms of ensuring that particular countries or geographic regions have access to vaccines but will not au- tomatically lead to equitable allocation. Places that gain manufacturing capacity may well behave in ways similar to existing manufacturing hubs, resulting in distributed vaccine nationalism, which is better than the sta- tus quo but probably still leaves the poorest countries and communities at acute disadvantage. The realpolitik of pandemic politics suggests that actors in the G7 and G20, such as the United States, that possess vaccine manufacturing facilities and leading-edge scientific capabilities, will remain unwilling to give up their places in the vaccine “queue.” A more realistic path is to persuade such actors to make the queue move faster by investing in greater surge capacity. This core conclusion informs a number of the report’s recommendations. PREPUBLICATION COPY—Uncorrected Proofs

156 THE INFLUENZA IMPERATIVE Achieving an equitable global allocation ultimately requires balanc- ing global frameworks and regulations (top-down), enhanced funding for deployment and national planning (bottom-up), and supply and demand considerations (preventing scarcity). With COVID-19, this balance was not reached by high-income countries (HICs) and the number of “deals” made along the way, leading to vaccine nationalism, contracting delays, and a lack of transparency about the vaccine supply. For an influenza pandemic, creating norms through a strengthened PIP Framework or similar instru- ment and/or binding commitments, combined with structural solutions to reduce the period of extreme vaccine scarcity (such as procuring stockpiles and setting pre-existing procurement contracts), may allow establishing a “grand bargain.” Crucially, the future business case for influenza must recognize that the seasonal influenza vaccine market alone will not be suf- ficient to drive pandemic production. When approaching global coordination, partnerships, and financing for influenza and other respiratory pathogens with pandemic potential, it is vital to consider the underlying grand bargain that must be reached among stakeholders. It is based on a concept of support with obligations, or an understanding that each involved party—including but not limited to industry, sovereign states, and multilateral and bilateral agencies—should give information, products, funding, or infrastructure of value (e.g., viral sequences, obligations to build surveillance capacity, investments into new technologies). They therefore must expect to receive certain benefits (e.g., reasonable access to vaccines, funding for government investments, IP pro- tections). In other words, a balance must be struck between multilaterals and industry contributing money or innovations and the sharing of benefits accruing from these innovations. This grand bargain forms the centerpiece of how to respond to a global public good—and how to encourage the high- and middle-income country in- vestments that will be required for the PPR agenda. Each recommendation in this report should be viewed according to this global public good framework, with some recommendations focusing more on ensuring that benefits are shared with member states on the medical countermeasures side (e.g., patho- gen-sharing systems), others focusing more on assurances for contributors that positive externalities are delivered by member states (e.g., strings attached to global surveillance funding), and others recognizing the importance of volun- tary industry partnerships (e.g., the risk of disincentivizing innovation). Given this context, the committee’s core recommendations address the following: • Significantly reinforcing global influenza surveillance as part of a broader upgrade of disease surveillance; • Incentivizing pathogen and genetic sequence sharing (for influenza and other pathogens); PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 157 • Building a coordination structure for sustained industry partner- ships to optimize companies’ platform technologies for efficient vaccine production and efficacy; • Creating a combination of push/pull incentives (e.g., AMCs) and resources to make the development of next-generation and, ideally, universal influenza vaccines a priority; • Incentivizing the development of sustainable, geographically dis- tributed hubs to scale up vaccine production and relevant supply chains, through a global partnership program coordinated by CEPI or another organization with a global reach; • Ensuring that financing solutions for global surveillance encom- passes all pathogens with regional or global pandemic potential, includes zoonotic components, and incentivizes pathogen and ge- netic sequence sharing; and • Building demand and national pandemic and adult vaccination planning capacity by ensuring that adequate funding is available to procure, deploy, and deliver next-generation influenza vaccines to any population group identified to be at increased risk. The precise financing vehicles for each of these elements should be solved as part of the broader PPR financing solution rather than influenza specific. Some recommendations are targeted at the G7 and G20, with the understanding that the “Global Health Threats entity” ultimately put forward by these initiatives should take a leadership role in their imple- mentation. This should not be taken as de-emphasizing the importance of other parties, such as the “Group of 77” (G77), industry, and civil society organizations, in global negotiations and discussions, and the committee includes examples of such parties that should be involved in implementing each recommendation. In proposing the G7 and G20 Global Health Threats entity’s leadership, the committee is not offering a precise view on the rela- tive merits of the various proposals for a Global Health Threats Board or Council by the G20, G7, United States, or United Kingdom, as this involves considerations beyond its Statement of Task. CONCLUSIONS AND RECOMMENDATIONS 1: Governance and Coordination to Support Aligned Vaccine Production and Scale-up for Respiratory Pathogens with Pandemic Potential Among infectious diseases, the technical and policy systems related to influenza, including for surveillance (GISRS), the vaccine strain selection process, and related access and benefit sharing governance frameworks (PIP PREPUBLICATION COPY—Uncorrected Proofs

158 THE INFLUENZA IMPERATIVE Framework) are global and relatively well coordinated through WHO. In many respects, influenza vaccine development represents a uniquely close functional relationship or ecosystem among scientists, governments, and the private sector. For example, the annual process to identify relevant strains to include in seasonal vaccines involves formal and informal discussions between public health practitioners, academics, and regulators regarding the preparation and sharing of reagents. However, beyond the process of strain selection, the development and manufacturing processes for influenza vaccines are relatively uncoordinated and in the hands of the private sector, with wide variability across national policies and programs. This reflects differences among nations in their vaccination priorities and WHO’s long-standing challenges in engagement with industry. The private sector and industry are not limited to research and development (R&D) pharmaceutical companies. In the United States and most emerging economies, including China and India, the private clini- cal sector is dominant, public and private health insurance companies are major policy-influencing actors (e.g., U.S. Medicare was an original major driver for influenza vaccine use), and many large universities involved in R&D are private sector entities. Most of these fall outside the purview of WHO and even the ministries of health of other nations. Summary of findings: Scaling up production of influenza vaccines is limited by the number of companies and production processes, limited markets where the burden of illness is uncertain, and limited coordination between the human and animal sectors. Programs supporting platform technology R&D and industry partnerships to scale up vaccine production and address supply chain chokeholds are often performed in a semi-isolated context. This is true for influenza and other respiratory pathogens with pandemic potential. The COVID-19 pandemic has also demonstrated that—like influ- enza—these other pathogens may become “endemic” such that coordina- tion will be critical for producing, procuring, and distributing vaccines. This reinforces the need to move away from historical siloed systems toward a single architecture for the global coordination of PPR, in the spirit of the GISRS+ and GLEWS+ proposals. Conclusion 1A. Global coordination for vaccines and vaccination will not be successful without including both public (world governments) and private actors—including civil society and the pharmaceutical and biotechnology industries. WHO is well placed to provide normative guidance, technical support for integrated surveillance, and regulatory support for vaccine licensure for the coordination of global, regional, and national programs for PPR that recognize the importance of oper- ating across multiple pandemic threats. PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 159 Conclusion 1B. WHO is less well positioned to support activities that require deep engagement with the private sector and industry, including vaccine manufacturing, supply chains, and deployment across multiple pathogens with pandemic potential. 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 FAO and OIE), propose a framework for strengthened surveillance systems and infor- mation sharing at country, regional, and global levels to ensure rapid detection of new threats and enable swift dissemination of information essential to accelerated vaccine development. b. Work jointly with existing international organizations with ex- pertise in vaccine research and development, manufacturing co- ordination 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 vaccine manufacturers, a framework for improved global coor- dination of vaccine production and deployment for respiratory pathogens with pandemic potential that includes defined roles, responsibilities, and accountability mechanisms. 2: Sustainable Financing for Integrated, Modern, Timely Respiratory Virus Surveillance for Pathogens with Pandemic Potential The ongoing and dynamic emergence and spread of coronavirus vari- ants has reinforced that surveillance systems are critical to assess risk and serve multiple purposes for a country’s priority-setting for health. Robust and timely surveillance systems are at the heart of public health and essen- tial for evidence-based country vaccination systems—and, more broadly, for nearly every aspect of a country’s pandemic response. They provide the data and insights needed to set priorities and monitor the impact of interventions. They enable governments to know which pathogens are PREPUBLICATION COPY—Uncorrected Proofs

160 THE INFLUENZA IMPERATIVE circulating; establish baselines of disease levels, so trends and deviations can be monitored; provide background information useful for determining the safety and efficacy of therapeutics and vaccines and predictive value of diagnostic tests; and support making disease control decisions related to outbreaks. For diseases with epidemic and pandemic potential, they provide the signals needed to act and as disease early warning systems; they are the global “smoke detectors” that can keep emerging sparks from becoming a global fire. Additionally, pathogen-focused surveillance provides essential information for formulating effective vaccines and assessing the effective- ness of available treatments (e.g., antiviral drug resistance). The concept of “surveillance” is often considered from the lens of vi- ral data (“pathogen” surveillance), but in the twenty-first century, it also encompasses other components of early warning systems, including data on social media and human movement. Several new initiatives have been launched, based on this recognition that genomic surveillance and early warning data gathering capabilities across multiple pathogens must be built to allow the world to contain pandemic threats within 100 days of an out- break. These include the UK Global Pandemic Radar and the Rockefeller Foundation’s Pandemic Prevention Institute (Rockefeller Foundation 2021). Without national surveillance infrastructure and robust regional surveil- lance systems for both pathogens and epidemiological trends, countries are left in the dark about upcoming threats, which has massive ramifications for national, regional, and global health security. Determining how to expand funding for these surveillance activities for viruses with pandemic potential, including influenza, is therefore critical. Summary of findings: Surveillance system gaps are related to both financ- ing and barriers for more closely aligning or integrating these systems. They are far from being an LMIC problem; many HICs have moved away from financing surveillance systems efficiently, and many financed systems underperform in terms of accuracy, scope, and transparency. This is at least in part due to lack of political buy-in and country leadership. Robust surveillance systems require working across traditional sector silos, particularly to identify zoonotic threats and spillover events. One of the key challenges for developing broader surveillance systems is how to cover multiple pathogens, including zoonotic surveillance for influenza, which has not been funded in a sustained way. Surveillance represents a prime example of how ministries and organizations, particularly those in the animal and health sectors, can develop misaligned objectives that con- tribute to silos based upon competition for influence, power, and funding. It is critical for ministries of health to be joined by other relevant minis- tries, such as ministries of agriculture and of the interior, in surveillance programs. Ministries of the interior are often the main actors (next to prime ministers or presidents) in terms of decision-making “power” during PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 161 emergencies, including pandemics. Coordination, information sharing, and collaboration among intragovernmental agencies will improve the align- ment of objectives across governments. WHO and other international organizations cannot direct national ministries to take certain steps. They can, however, offer technical and managerial guidance and support and suggest policy solutions and mecha- nisms to facilitate multilateral agreements at the country level and provide close follow-up. For example, the PIP Framework resulted from prolonged international negotiations within WHO, which produced an agreement that provided financial backing to member states to improve national surveillance systems that participate in the WHO GISRS network. The same agreement provided access to potential pandemic influenza viruses and the sharing of vaccines, antiviral medicines, and other benefits in a pandemic. However, the PIP Framework does not generate enough money to strengthen GISRS in all places. Global and regional influenza surveillance should not only be enhanced to include both traditional and nontraditional data that can help to iden- tify an emerging threat earlier but have an overall financing solution that encompasses human and animal influenza and incorporates pathogen and genetic sequence sharing as routine practices. This will require substantially greater multilateral investments in country and global surveillance. Perhaps the most crucial premise for this is recognizing that surveillance is primarily a global risk assessment and mitigation—not a development—issue. The economic theory argument is very compelling for surveillance of influenza and other pathogens with pandemic potential. Yet, while surveillance is a “best buy” in terms of cost effectiveness, strengthening these systems re- quires more than incentives. Each country’s surveillance system has strong positive externalities. This makes surveillance an area with a strong logic for sustained domestic and external financing, as with France’s support to the Pasteur Institutes in Africa. This funding is best conceptualized as being part of how the world as a whole addresses extreme risks. It should not be forced to compete with other development priorities. Domestic and external funding, accompanied by synchronous, con- sistent, and ideally coordinated laws and legal instruments, may enable national surveillance systems to be regionally operational and interdepen- dent (e.g., through sharing technical expertise, capital goods, operating ex- penditures and approaches, and information). The World Bank’s Regional Disease Surveillance Systems Enhancement (REDISSE) model provides an example of how ministries of finance can be regionally linked for surveil- lance activities through regional grants or loan obligations (West African Health Organization, n.d.).1 The East-Africa Public Health Laboratory 1  https://www.wahooas.org/web-ooas/en/projets/redisse-regional-disease-surveillance- systems-enhancement-project-west-africa PREPUBLICATION COPY—Uncorrected Proofs

162 THE INFLUENZA IMPERATIVE Networking Project also shows how national laboratories can function with regional interdependence. Both have received political buy-in and guidance from the African Union (AU). The IPPPR and other groups are working on recommendations for institutional mechanisms for surveillance, including a global viral surveillance network. This study’s findings and deliberations underscore that integrated viral surveillance should be structured to sup- port country ownership and cover critical influenza data needs, including genomic sequence data and integrated zoonotic surveillance. Enhancing surveillance systems to protect against a range of pandemic threats will require a dedicated, sustained pool of financing that can be applied nationally and regionally and does not divert funding from other development priorities. Surveillance must be viewed as an essential element to maintain public health and second-order consequences of economic and societal well-being if it is to attract sustained, stable, long-term financing. Its benefits must be framed more broadly, such as access to medical coun- termeasures downstream. Conclusion 2. The amounts and allocation of funding for surveillance should be sufficient to develop integrated surveillance systems that include all forms of influenza (human and animal) at a minimum and, ideally, encompass other respiratory pathogens with pandemic poten- tial. Others are giving financial estimates (see Chapter 5)—which we draw on—for how much should go into strengthening surveillance, and our recommendations focus on how to make certain that influ- enza is given sufficient weight. This funding could be used to initiate or strengthen country and regional surveillance networks, in line with the REDISSE model. Recommendation 2: With urgency, the G7 and G20 should ensure that increased investments are made in surveillance systems for pathogens with pandemic potential, including influenza, and encompassing every country and region, by doing the following: a. Creating incentives, structures, and pathways for key stake- holders to develop and implement stronger integrated surveil- lance capacities and infrastructure, including firmer support for zoonotic surveillance under the One Health framework, bring- ing together stakeholders such as through the World Health Organization, the World Organization for Animal Health (OIE), and the Food and Agriculture Organization (FAO) and their counterparts at regional and national levels. b. Strengthening and financing regional surveillance infrastruc- ture, capacities, and networks through partnerships among re- gional organizations, regional development banks, and relevant PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 163 human, animal and plant health institutions. For example, in Southeast Asia, this could be accomplished in conjunction with the Association of Southeast Asian Nations, Asian Development Bank, and Asian Infrastructure Investment Bank, and in the Middle East and North Africa with the Organization of Islamic Cooperation, Gulf Cooperation Council, and Islamic Development Bank. c. Ensuring that the G7/G20’s overall approach to financing PPR, when this is ultimately determined, includes adequate and sus- tainable funding for surveillance and that this is sufficient to enable substantial reinforcement of zoonotic surveillance for respiratory pathogens with pandemic potential. Moreover, this global funding mechanism’s governance should, in addition to WHO, include relevant international agencies across the zoo- notic divide, such as the International Fund for Agricultural Development, OIE, FAO, and the World Food Program, as well as multilateral and regional development banks and other global health organizations. 3: Limits and Potential of the PIP Framework and Nagoya Protocol for Pathogen Sharing The timely sharing of influenza viruses is essential for developing life- saving seasonal vaccines, identifying potential pandemic viral strains, and providing early warning for outbreaks. The PIP Framework supports criti- cal surveillance needed for influenza and establishes a multilateral system that places equal importance on ABS and sharing viruses of pandemic potential but avoids a bilateral transactional approach to such sharing. It reflects the importance of transparency, equity, and the accountability shared by countries, industry, and WHO. The current controversy at the World Trade Organization around the IP waiver for COVID-19 technologies is a consequence of the lack of a careful and planned approach to related ABS. The balance between virus, genetic sequence, and benefit sharing must consider public investment, global needs, and private rights and incentives, but it cannot be ignored. ABS is an essential aspect of equity and is needed to garner global support, while IP is a paramount necessity for industry’s wholehearted support and ongoing investments in innovation. Momentum is building for a new pandemic instrument, providing an opportunity to incorporate diplomatic gains from earlier negotiations and agreements into new multilateral solu- tions. Such an instrument would eliminate the challenge of negotiating in the midst of a pandemic threat, ensuring predictability and a general mu- tually agreed framework and saving the critical time needed to put a full PREPUBLICATION COPY—Uncorrected Proofs

164 THE INFLUENZA IMPERATIVE response in place. More specifically, the principles agreed upon in the PIP Framework, which are essentially consistent with those of the CBD, could be incorporated into the foundations of any future multilateral instrument for pandemics. Certain pros and cons to devising such an instrument go beyond the committee’s mandate and are highlighted briefly in this chapter’s final section. Summary of findings: The PIP Framework is built on the need for trans- parency, equity, efficiency, and accountability of countries, industry, and WHO. Beyond access to vaccines and medicines at reduced prices, other essential benefits can include updated epidemiological information, capac- ity building, training, and publications. It stands in contrast to the bilateral approach espoused by the Nagoya Protocol and approaches sharing benefits according to the shared need of all countries for early warning, prepara- tion against pandemic threats, and access to vaccines, diagnostic tests, and medicines needed to protect their populations. However, the PIP Framework has limitations: it does not specifically cover genetic sequence data and only covers influenza viruses with pan- demic potential and not seasonal influenza viruses or other viruses that might cause a pandemic. Its ability to ensure the availability of vaccines and antiviral medications under pandemic conditions and distribute them equitably remains untested and raises the question of whether the vaccine nationalism prominent early in the COVID-19 response would be repeated for an influenza pandemic. While it remains theoretically possible for the framework to be expanded to include seasonal influenza, other viruses, and genetic sequence data, WHO member states and other key stakeholders, including leading pharmaceutical companies, have not achieved consensus on the feasibility of doing so. Expanding the scope of the PIP Framework to non-influenza viruses, in particular, would raise the substantial challenge of extending its commitments of sharing, close cooperation, and division of labor in the absence of an established framework, such as GISRS. The underlying core principles of the PIP Framework remain highly relevant and should be incorporated into a pandemic treaty or other fu- ture international instrument: (1) giving equal weight to sharing of viruses and benefits, (2) ensuring shared responsibility and accountability among countries, WHO, and the private sector (although both industry and civil society operate at the international law level through member states), (3) recognizing the fundamental importance of equity and responding to coun- try needs, particularly for LMICs, and (4) putting WHO at the center of negotiation and making sure that benefits flow multilaterally through it and not bilaterally. Another layer of the PIP Framework has less to do with core principles and more to do with the specific ways in which it is implemented. This layer is customizable and can be negotiated for multilateral agreements covering PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 165 ABS for pathogens with pandemic potential. Three of these implementation considerations are particularly salient. First, part of the money spent on the PIP Framework is contributed by industry annually. A future multilateral agreement would need to carefully consider that platform and recombinant technologies are bringing new firms into the market, perhaps leading to no well-defined group of firms that produce influenza vaccines (with a similar trend for vaccines for other pathogens with pandemic potential). Heavily taxing industry through required shares in an ABS framework may also negatively incentivize firms to provide inputs into the vaccine system. At the same time, the financial contribution by industry to the PIP Framework reflects the benefits industry derives from participation in and maintaining an equitable and reasonable system of financial and other contributions. Second, beyond supporting surveillance, PIP Framework funds are used to help countries and regions to develop capacities and capabilities, such as regulatory reform, that allow them to respond faster during a pandemic. The COVID-19 response has demonstrated the importance of these invest- ments for broader PPR, and a future agreement would need to carefully consider which benefits to finance at the country level. Third, the details of benefit-sharing mechanisms, such as the legally binding SMTA-2s, could easily change and be approached differently in a future agreement. A pan- demic treaty negotiation is likely to be prolonged and take several years, and additional time would be needed for it to enter into force. Negotia- tions for the WHO Framework Convention on Tobacco Control (FCTC), for instance, took four years, had its first protocol adopted 7 years after its mother convention came into force, and took another 6 years to enter into force itself. A pandemic treaty or instrument is best viewed as a mid- to long-term systemic solution, leaving open the need for more immediately applicable mechanisms. Delays in sharing samples, sequences, and information have serious implications for delaying a pandemic response. Every player—including national influenza centers (NICs), countries, vaccine manufacturers, and WHO—can exhibit both immediate self-serving and collaborative behav- iors. It is therefore critical to encourage and enable rapid sharing and characterization of samples. In a pandemic, lack of timely sharing of vi- ruses and associated information could have very serious implications for delaying the response (WHO, 2021a). Sharing genetic sequence data also has a major gap, due to an uncertainty about whether it falls under the PIP Framework and Nagoya Protocol. The rapid ramp-up of genomic surveil- lance for SARS-CoV-2 virus variants underscores the need to ensure rapid access to genetic information. Conclusion 3A. This is the time for the foundational principles of the PIP Framework to be incorporated into future multilateral agreements covering access and benefits for all pathogens with pandemic potential. PREPUBLICATION COPY—Uncorrected Proofs

166 THE INFLUENZA IMPERATIVE Benefit sharing should be seen and acted upon as a routine responsibil- ity of the global vaccine system and not in a narrow and transactional way or as a selective and ad hoc activity. Industry may be best incentiv- ized to produce necessary vaccines through platform technologies and ensure that they are distributed equitably when mechanisms for ABS are visible and built into procurement contracts (i.e., with fair access principles up front). Conclusion 3B. A new agreement should address and resolve issues raised by the Nagoya Protocol for sharing influenza viruses and other pathogens with pandemic potential, including genetic sequence data. 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 agreements, or advocate their use for agreements conducted by other international organizations, so that the access and benefit and information-sharing principles cover a broad range of pathogens and their genetic sequence data. To accomplish this, the WHA should, with the 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 annual meetings of member states, and by building or strengthening norms and holding leaders responsible for follow- ing through on commitments. b. Incorporate the principles of equity, shared accountability, and multilateralism in any future pandemic treaty or framework and recognize that the surveillance systems that can rapidly detect these viruses are a global public good. c. Develop a mechanism for countries to openly and rapidly share viruses, their genetic sequences, and other essential supporting and epidemiological data for both risk assessment and risk man- agement (developing vaccines, therapeutics, and diagnostics), while setting up incentives for industry and member states to share benefits, share products (vaccines, therapeutics, and diag- nostics), and facilitate technology transfer. This requires recog- nizing the concerns of industry over intellectual property and successful resolution of these issues. Such mechanisms should include regular public reporting as part of a monitoring system to hold countries and governments accountable for their level of PPR. PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 167 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 be negotiated as an additional protocol to the CBD along- side 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. It should also acknowledge that genetic sequences of both human 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 does not deter innovation or act as a disincentive for industry participation. 4: Public–Private Partnerships to Accelerate Vaccine Development: Structuring Global Partnerships to Support R&D for Influenza Platform Technologies Vaccine development and production for pandemic influenza and emerging infectious diseases has traditionally suffered market failures, in large part because of the combined unknowns of whether (and when) a pandemic will hit and whether pandemic response products will be effec- tive. This has created significant hurdles for vaccines, such as those for Zika and Middle East Respiratory Syndrome (MERS), to cross the finish line as commercial products. Seasonal influenza vaccines, and potential vaccines for endemic diseases, such as malaria and tuberculosis, provide a more certain product in terms of market predictability and certainty. Public–private partnerships with industry before and during the COVID-19 pandemic have allowed highly efficacious platform technology– based vaccines to be developed. Platform technologies could revolutionize PREPUBLICATION COPY—Uncorrected Proofs

168 THE INFLUENZA IMPERATIVE the effectiveness, speed, and ability to scale up production of influenza vac- cines, due to intrinsic constraints with the current egg-dominated vaccine ecosystem. The strong market for COVID-19 vaccines (potentially includ- ing boosters if the disease becomes endemic) may not, however, represent a workable model for creating sustainable markets for all emerging infectious diseases and the associated vaccine R&D. Because of the high mutation rate and other characteristics of the influenza virus, developing platform tech- nologies for pandemic and seasonal influenza viruses will require significant investment and a continued willingness of industry to form productive, synergistic partnerships. Summary of findings: Successfully responding to the “necessity” of plat- form innovation for influenza vaccines requires a combination of early R&D incentives, including support of Phase I–III clinical trials for plat- form- and recombinant-based technologies. Vaccine manufacturers will share efficiencies of their production (“yield”) but often only with partners. Encouraging and incentivizing voluntary industry partnerships will assist with developing platform technologies—and initiating their technology transfer—and should also be designed to support the partnerships needed for a universal influenza vaccine moon shot (see Recommendation 5). Vaccine development and production time lines have been accelerated for other diseases through well-financed partnerships, such as Operation Warp Speed (OWS) for COVID-19, the HERA Incubator (COVID-19), CEPI’s early manufacturing investments, and Gavi’s advance market com- mitment (AMC) for pneumococcus and COVID-19 vaccines. Each of these schemes helped to spur healthy competition in developing novel vaccines, at least partly because their incentives package of R&D funding, up-front guarantees for advance purchase agreements, and technical support was applied mostly at once. Other examples of productive government–industry partnerships include DARPA’s Autonomous Diagnostics to Enable Preven- tion and Therapeutics program, launched in 2013, which has primarily sup- ported vaccine and antibody programs against the chikungunya virus, and the BARDA-supported funding of Zika vaccine program toxicology studies, Phase 1 clinical trials, and associated manufacturing activities (awarded in 2016). Both programs supported mRNA technology development at Moderna.2 Government involvement helps to avoid competitive issues, and government financing incentivizes industry to focus on a platform’s optimi- zation, which will likely be unique for each technology. Such government–industry partnerships could be extended to include relevant academic organizations, scientific R&D institutes or programs, and foundations that support them (e.g., the Mo Ibrahim Foundation). Clinical 2  https://www.modernatx.com/ecosystem/strategic-collaborators/mrna-strategic-collabora tors-government-organizations PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 169 trials can also be institutionalized on a stronger base through partnerships, building on existing programs (e.g., the European and Developing Coun- tries Clinical Trials Partnership). The difficulty is in how to scale up such partnerships and apply them globally, especially to support a geographically distributed manufacturing hub model. The Sabin-Aspen Vaccine Science and Policy Group (2019) proposed creating a new entity to support platform innovation for influenza vaccines, but at the time (2018), there was little appetite for creating a new global organization. Several existing organizations 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 that are matched with appropriate funding and can identify stable markets for their products, including CEPI, BARDA, and the HERA Incubator. CEPI has an existing platform with scientific expertise and networks that span the first three steps in the process: preclinical development, clinical development, and scale-up. As Yamey et al. (2020) argued, adding funding for the advanced development of vaccines could provide transaction cost efficiency compared to launching a new mechanism, and large investments could allow CEPI to extend its expertise to Phase III trials and potentially technology transfer. The CEPI 2.0 agenda demonstrates CEPI’s strategic in- terest in helping to extend platform technologies more broadly for respira- tory viral families that present recurrent and critical threats, or “prototype pathogens.” With its current level of funding, its interest in influenza would primarily be in developing influenza vaccine platforms as a way to situate the collective responsibility among major R&D funders (e.g., G7 and G20) and as a springboard for industry to move toward testing platforms against a range of pandemic-potential pathogens. Fostering scale-up and promoting equity in access to products de- veloped through these partnerships will require close collaboration with geographically distributed manufacturing hubs (see Recommendation 6). As a public–private partnership with a multilateral approach, CEPI is well positioned to address cost-effectiveness thresholds for influenza R&D on a global scale. BARDA and HERA have similar capacities for advanced vac- cine development, at the early, middle, and late stages. OWS, for instance, has been called a “souped-up BARDA” and is an example of what might work for influenza vaccine platform development, both for R&D and for manufacturing scalability to have surge capacity during a pandemic. OWS attributes include its strong central management, sufficient funding for its objectives, and high level of oversight. These enabled it to be involved in all operational aspects of manufacturing for Moderna’s COVID-19 vaccine, in- cluding accessing and ordering raw materials, obtaining special equipment and machinery, hiring and training talent, and validating work to support scale-up (see Chapter 4). Giving BARDA a broader remit may allow it to overcome a limitation of OWS: it did not account for global need by build- PREPUBLICATION COPY—Uncorrected Proofs

170 THE INFLUENZA IMPERATIVE ing out the way that the United States works with industry. Additionally, it will be important to improve coordination for influenza vaccine research at CEPI and/or HERA and BARDA with institutional R&D capabilities beyond the United States, particularly in Germany (e.g., the Max Planck Institutes), Japan, and South Korea, and to engage regional entities for R&D mobilization. Encouraging governments and regional bodies to conceptualize R&D using an industrial policy framework may further promote resource alloca- tion (staff and funding) to vaccine-related industry partnerships in the long term. Many successful East Asian economies, such as Japan, South Korea, China, Vietnam, Singapore, and Taiwan, have strong industrial policies, which could be expanded to include pandemic preparedness and R&D pri- ority areas and may open-up the larger sources of funding required to push forward platform innovation and generate markets for emerging infectious disease vaccines. Conclusion 4A. The goal in the next 3–5 years should be to progres- sively pursue development and assessment of new platform technolo- gies to improve the effectiveness of vaccines, expand the options for production of influenza vaccines, and optimize their production to enhance the speed and volume of manufacturing in parallel to pursuing the “ultimate prize,” a universal influenza vaccine. It could take the threat of influenza—seasonal and pandemic—off the table. Conclusion 4B. Manufacturing thought leaders from industry and aca- demia need to develop new ways of working together to more rapidly advance new technologies and to optimize production (e.g., increas- ing yield efficiency) before a crisis to meet the public health goal of producing more vaccines sooner while ensuring that the process does not sacrifice safety. Because of the competitive nature of the vaccine business, this sharing should take place under the auspices of govern- ment partnerships, with appropriate intellectual property protections, while also recognizing the public health function of the products being developed. Conclusion 4C. The COVID-19 pandemic has underscored that pan- demic viruses may become endemic, or linger on as “seasonal” viruses, in addition to influenza. Vaccine capacity should anticipate vaccination needs beyond a pandemic. Recommendation 4: The Global Health Threats Board or similar gov- ernance structure created by the G7/G20 PPR agenda should negotiate PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 171 to extend the mandates of CEPI,3 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 should nominate a global coordination body to specifically coordinate global and regional government–in- dustry partnerships for influenza vaccines. CEPI is the existing multilateral global coordination vehicle for vaccine R&D and is a possible organization to assume this role, either on its own or in coordination with others, not least because CEPI already in- corporates access principles into its arrangements with industry. b. Countries that fund vaccine R&D should ensure that pandemic influenza R&D is part of their funding portfolio and strive to identify investment synergies to maximize returns on invest- ments. Entities such as BARDA, the HERA Incubator, and other BARDA-like organizations elsewhere (e.g., the Paul-Ehrlich- Institute of the Federal Institute for Vaccines and Biomedicines in Germany and the Academy of Military Medical Sciences in China) should support government–industry partnerships for R&D for influenza and other respiratory viruses with pandemic potential. c. Regional organizations such as the Africa Centres for Disease Control and Prevention (Africa CDC), the Association of Southeast Asian Nations, the Gulf Cooperation Council, and Europe 2020’s Innovation Union (funded by HORIZON 2020) and its successor, should support the mobilization of govern- ment–industry partnerships for influenza vaccine R&D and the development of regional manufacturing hubs. d. Government–industry partnerships for influenza vaccine R&D and manufacturing should have affiliated teams to identify promising technologies, optimize them for the field (e.g., iden- tify 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 recom- 3  The committee wishes to highlight that its membership includes Richard Hatchett, the Chief Executive Officer of the Coalition for Epidemic Preparedness Innovations (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

172 THE INFLUENZA IMPERATIVE mended by the United Kingdom/G7 PPP, as well as early dosing trials. e. Government–industry partnerships for influenza vaccine R&D and manufacturing should share workforce development re- quirements with CEPI, WHO, and other relevant multilateral partners to help countries identify and fill gaps in ministries of health, labor, and economics expertise before a pandemic. They should also incorporate workforce development training for areas of expertise required to enable accelerated technology transfer. 5: An Influenza Vaccine Moon Shot: Financing for Transformational Universal Influenza Vaccine R&D, Licensure, and Procurement Universal influenza vaccines would be a complete game changer for pandemic preparedness and seasonal influenza vaccine markets. However, this is a science and not an engineering problem, these vaccines are a long shot, and there is no guarantee that any amount of money invested would yield a product broadly effective across all current and future influenza strains and provide long-term protection in people of all age groups. Uni- versal vaccines are a problem that must be solved independently for each set of pathogens. Yet, as Harris (2021) argued, even ”failed” attempts at vaccine production—such as for HIV—often generate scientific findings that can revolutionize vaccines for other diseases. This reinforces the prin- ciple of multidisciplinary problem solving. The platform technologies used for COVID-19 are arguably descendants of successful vaccines developed for Ebola, MERS, SARS-CoV-1, and human papillomavirus, and mRNA technology is being applied to new fields, such as vascular and cardiac regeneration (AstraZeneca, 2021) and immuno-oncology (personalized can- cer vaccines). Influenza poses such a high pandemic risk that, even with just a 20 percent chance of developing a successful universal vaccine, it is still worth investing billions. Such activities have not been dedicated funding pro- portional to their potential benefits, for both influenza and developing technologies that may be relevant for other pathogens. Transformational changes for influenza vaccine technologies will require new actors to push forward fundamental and applied research, coupled with substantive new sources of funding. While “moon shot” may be seen as a cliché, it is a useful shorthand for describing a massive concerted effort to achieve a specific, ambitious goal that has not received the requisite global resources. Summary of findings: For influenza and other pathogens with pandemic potential, industry is often insufficiently certain of the government interests PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 173 and regulatory pathway to bring a profitable product to the market. Solv- ing a limited number of science problems for influenza and demonstrating a commercial pathway is essential to drive the broad and durable changes necessary for influenza vaccines. The Sabin-Aspen Vaccine Science and Policy Group, acknowledging that influenza was outside of CEPI’s scope, called for establishing an entity dedicated to universal influenza vaccine development, which would embrace the need for innovation to invigorate the influenza vaccine landscape in 2018, and BMGF launched a $12 million “Ending the Pandemic Threat” Grand Challenge for universal influenza vaccine development that year. More recently, the CIDRAP Influenza Vac- cine Road Map called for exploring the feasibility of a “mission-driven” R&D public–private partnership for universal influenza vaccines, with robust funding. It underscores the importance of working with industry to derisk vaccine R&D and develop a market for producing improved or universal influenza vaccines. The scale of investment in universal influenza vaccines to date (mil- lions) is nowhere near that required (billions) to incentivize the risky under- taking of universal influenza vaccine R&D. Both push and pull incentives will be critical to demonstrate a proof of concept for the market of influ- enza vaccines. A massive push will be required to elicit pre-competitive scientific and biological analyses for vaccine targets. CEPI’s mission (CEPI, 2021b) is to “stimulate and accelerate the development of vaccines against emerging infectious diseases and enable access to these vaccines for people during outbreaks,” based on an understanding that the market potential for these vaccines is limited. An expanded mandate for CEPI may allow it to lead a universal influenza vaccine push structure—which has suffered a challenging market potential—on a global, multilateral scale, if supported by sufficient funding. Push incentives could be complemented by large-scale pull incentives. AMCs have most commonly been used by HIC donors to incentivize pro- duction and capacity for proven vaccine approaches, rather than to drive new science. For example, the G7 and BMGF committed to buy a new vac- cine against LMIC-specific strains of pneumococcal disease, which Gavi is now using to vaccinate children in numerous developing countries.4 Finally, and most importantly, the world can obtain early and equitable access to priority lifesaving vaccines with assurances of sustainable and affordable supply in the future. Kremer and Glennerster (2004) originally proposed the AMC to encourage research on vaccines against technologically distant targets such as malaria; the instrument can be usefully deployed as an in- 4  Kenya Marks the Global Roll-out of Pneumococcal Vaccine. Bill and Melinda Gates Foun- dation website, https://www.gatesfoundation.org/ideas/media-center/press-releases/2011/02/ kenya-marks-the-global-rollout-of-pneumococcal-vaccine PREPUBLICATION COPY—Uncorrected Proofs

174 THE INFLUENZA IMPERATIVE centive to solve hard biology problems, such as those implicit in a universal influenza vaccine. Conclusion 5A. A concerted effort is needed to demonstrate the direc- tion that pharmaceutical companies should be moving in within the influenza space, toward transformation next-generation technologies and universal influenza vaccine targets. A moon shot for a universal influenza vaccine, consisting of push and pull incentives, should be ini- tiated. Acknowledging current global inequities of vaccine availability, both should include equitable access provisions. Conclusion 5B. Like influenza, SARS-CoV-2 and other pandemic vi- ruses and their variants may linger on as “seasonal” pathogens in the future, and vaccine capacity should therefore anticipate vaccine needs beyond the acute phase of a pandemic and provide incentives for their production. Conclusion 5C. The influenza moon shot should include a similar quest for more broadly protective (“variant-proof”) vaccines against corona- viruses with pandemic potential. 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 by other agencies that operate beyond the vaccine exploratory 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. 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 PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 175 and Development (OECD), G20, World Bank/International Monetary Fund (IMF), regional development banks, World Trade Organization, European Union (EU), and AU. This fund- ing should be separately and individually supported by trade and global financing institutions of the United States, China, and the EU, such as the European Investment Bank and Asian Infrastructure Investment Bank. 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 deployment 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/manufacturers at low or zero cost, as a condition of accessing this guaranteed mar- ket. This would 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. 6: Supporting Geographically Distributed Hubs for Influenza Vaccine Manufacturing and Supply Chain Capacity Regional hubs offer promise in countering vaccine nationalism and promoting equitable access through self-sufficiency. However, distributing manufacturing does not offer a full solution for addressing issues of vac- cine equity. It has historically sometimes led to lower-quality products or provided incentives for elevated prices, such as for antiretrovirals. During the COVID-19 pandemic, nearly all vaccine candidates, with the exception of Pfizer’s, were push funded, but this resulted in a major market failure in terms of access, with many low-income countries receiving just 2 percent PREPUBLICATION COPY—Uncorrected Proofs

176 THE INFLUENZA IMPERATIVE coverage as of June 2021. As seen during the COVID-19 pandemic, vaccine nationalism may also persist within regions during times of scarcity, even when regional organizations, such as the AU, call for solidarity. It is most productive to think of balancing the scale of production and regional diversification as complementary “belts and suspenders.” Increas- ing scale does not directly address principles of equity but can help prevent vaccine hoarding. Conversely, regional diversification keeps countries more engaged, but the redundancy it creates does not guarantee that all countries in each region will benefit (and may, in fact, merely promote distributed vaccine nationalism). When designing regional hubs, care must be taken to not over-diversify or assume that—unless every continent has capacity for influenza and other vaccine production—a continent cannot be guaranteed to get supplies. Indeed, it may be better to use the label “geographically distributed manufacturing hubs” rather than “regional hubs,” to avoid a presupposition that facilities must be distributed precisely by WHO regions. Such geographically distributed manufacturing hubs are the best direc- tion, but the precise balance of scale and diversification may ultimately depend on the vaccine technologies that emerge. Care must be taken not to advocate for a norm in which areas without regional capacity do not get served during a pandemic. As it is difficult to predict the optimal platform for each pathogen with pandemic potential, it is important to strive for diversification in terms of the number of facilities, their locations, and the types of platforms they can manufacture. Summary of findings: As underscored by the WHO’s Global Action Plan (GAP) for influenza vaccines and recent WHO and IFPMA surveys (see Chapter 4), the current influenza vaccine manufacturing capacity would be insufficient to vaccinate the world during a pandemic, even over 12 months. New technologies may compress this time line, but capacity would still need to be expanded at least threefold to avoid shortages fueling vaccine nationalism. Regionally distributed manufacturing hubs are a way to provide this scaled-up vaccine manufacturing in LMICs. However, they face several challenges. First, to be sustainable, they must have both government com- mitment and strong industry involvement. Second, to be successful, par- ticularly in geographic areas that currently lack manufacturing capacity for mRNA and other platform technologies (e.g., Africa), new facilities and partnerships will require a strong business model. This has traditionally been problematic for influenza because vaccines have had poor local and regional markets, due in large part to egg-based vaccines’ low efficacy and lack of national vaccination plans. Platform technologies may provide a so- lution, but only if hubs can keep their facilities “warm” (actively producing vaccines or other products) between pandemics. Third, to have the capac- PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 177 ity to develop a product that can be licensed and exported, they require workforce training for technology transfer and regulatory capacity. This is a largely unregulated field; while CEPI recently launched a survey with governments (CEPI, 2021c) to map the landscape of vaccine manufactur- ing capacity and capability in Africa, Southeast Asia, the Middle East, and Latin America, regional manufacturers have struggled to know what other manufacturers are working on and where they may obtain relevant techni- cal advice and training. Fourth, to be successful, a business model must further include provision for developing plans for who will get vaccines, where, and how. Keeping national plans updated is the biggest challenge for developing regional capacity (every country must be willing and able to receive a vaccine, if it is made at a hub outside of its borders). The GAP program focused on egg-based technologies, and any future global partnerships for diversified manufacturing and supply chain coor- dination should be designed to sustain newer technologies and provide long-term demand certainties. Manufacturers deeply entrenched in seasonal influenza have a residual commitment to argue that it needs to retain sepa- rate capacity. Including increasing seasonal influenza vaccine demand as a principle for expanding global manufacturing (WHO, 2021b) capacity remains important—but current demands for seasonal production are not sufficient to support expansion to meet the demands during a pandemic. A business model for pandemic influenza vaccines requires a business plan for manufacturing facilities to keep them functioning between pandemics. In addition to seasonal influenza, assuming that platforms are appropri- ate, vaccines could be produced in “peacetime” for other regional priority pathogens, such as MERS (which has a relatively small market but would be an “easy” target for applying coronavirus platform technologies), Zika, Ebola, and dengue or, if applicable, current vaccine-preventable diseases that require routine immunization (e.g., polio). Market shaping and procurement for these products, such as Gavi’s activities for pneumococcal vaccines, is critical. This downstream market is- sue is different from upstream technology and R&D issues and not specific to influenza. However, no global institutional architecture exists to handle this issue, and development finance institutions often struggle to develop business cases for vaccines for a pandemic with uncertain timing. During COVID-19, CEPI performed early manufacturing scale-up, and BARDA supported scale-up through OWS, but this manufacturing support was provided after the pandemic began. In April 2021, WHO issued a global call for “expression of interest” in establishing COVID-19 mRNA vaccine technology transfer hubs, which could scale up production and access to COVID-19 vaccines. In partnership with COVAX, the Africa CDC, a net- work of universities, and an industry consortium (Biovac, Afrigen Biologics and Vaccines), the first COVID-19 mRNA vaccine technology transfer hub PREPUBLICATION COPY—Uncorrected Proofs

178 THE INFLUENZA IMPERATIVE is planned for South Africa (WHO, 2021c). This is a crucial step in build- ing geographically distributed manufacturing hub capacity, but additional investments will be necessary on a much larger scale. Furthermore, one cannot think about distribution and redundancy in terms of manufacturing and regulation alone. During COVID-19, supply chains broke down, and these have often been the reason that we could not produce more vaccines faster. Geographical distribution is about not only having factories and research facilities but also ensuring that these factories have key inputs that they need to produce vaccines and the flex- ibility to diversify their production. Developing geographically distributed supply chain hubs in parallel to manufacturing facilities presents a market opportunity for countries to invest as suppliers in the bags, filters, and other items required for vaccine supply chains. Supply chains are complicated by the fact that decisions about requirements (bioreactor bags, etc.) are made at the company level, such that pieces are often not interoperable or stan- dardized between companies and may not meet the distribution capabilities of LMICs. Changes will not be enacted unless they have an umbrella that protects industry, but changes are required because current supply chains represent a bottleneck for vaccine scale-up. Supply chains are often treated like they are just something you need for manufacturing, but being a sup- plier is also a business. CEPI has provided support for the geographically distributed hub realm in three major ways, in the capacity of a “utility infielder” or catalyst. First, it has looked for bilateral arrangements between specific and willing partners and considered how they can be supported to facilitate technology transfer (e.g., facilitating a licensing agreement between AstraZeneca and the Serum Institute of India for COVID-19 vaccine supplies for LMICs). Second, it has provided technical support to regional efforts for capacity building, for example through a memorandum of understanding with the African Union during COVID-19 (CEPI 2021d)). Third, it has worked with development banks to provide technical support to LMICs and other clients for developing funding proposals (CEPI, 2020), in the context of distributed vaccine manufacturing. Conclusion 6A. Scaling up production of pandemic influenza vaccines requires investment in manufacturing, which may be best accomplished through technological assistance for and investments in geographically distributed hubs—facilities that can produce platform technologies both for evolving influenza vaccines and other targets. Supply chain com- modity production requires similar attributes to vaccine production. Conclusion 6B. Developing an ecosystem for geographically distrib- uted manufacturing hubs requires holistic consideration of the require- PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 179 ments for sustainability and success, including technology transfer and workforce development for platform technologies; regulatory capacity to produce vaccines; and a business model that creates a “peacetime” market for products developed using platform technologies (with the ability to rapidly switch to pandemic production mode). A sustainable business model should address the “demand” (see Recommendation 7) for the products developed, such as their ability to be introduced into national or other immunization programs (including the burden of ill- ness and appetite), and account for how new vaccines may need to be scaled up at different times of year (not traditional influenza seasons) and at different intervals. This requires actively considering new tech- nologies coming onto the market and tying them to industry strategies and partnerships with appropriate manufacturing facilities. Conclusion 6C. Like manufacturing, geographically distributed supply chains should be coordinated, dual use, and interoperable, backed by a sustainable business model and redundancy. Forming geographically distributed manufacturing and supply chain hubs, which are capable of scaling up platform technologies in the context of a pandemic and in environments currently underserved by technology, will require sus- tained international investment and technical training. This training should include long-term, targeted workforce development, under the auspices of a plan to transition to local ownership and staffing. 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 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 respon- sibility for catalyzing technology transfer initiatives for plat- form technologies, including influenza vaccines. The structure’s governance should build on both the WHO’s and COVAX’s work on the COVID-19 mRNA hub, expanding it to include a diverse portfolio of technologies capable of providing protec- tion 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 variety of vaccine candidates. b. Ensure that this entity promotes the development of platforms PREPUBLICATION COPY—Uncorrected Proofs

180 THE INFLUENZA IMPERATIVE that are suited to vaccine production for other vaccines or na- tional importance in addition to seasonal influenza, including tracking technologies coming onto the market and building platforms for industry voluntary 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 capacity should actually be in building new suppliers of key manufactur- ing inputs. e. Be given dedicated funding to support these activities from the World Bank, regional development banks, and the International Finance Corporation (IFC). 7: Last Mile to the Goal of Vaccination: Generating Influenza Vaccine Demand Through Globally Coordinated Deployment Activities Vaccines do not save lives, vaccination saves lives. Deployment capabil- ity does not automatically exist just because many vaccines are available. Even in countries such as the United States, the COVID-19 pandemic has demonstrated how vaccine availability and success at achieving high vacci- nation rates are different issues and present serious challenges. Experiences with the ACT Accelerator show how multilateral actors and governments alike consistently underestimated the challenges at the deployment end of the vaccination chain. Countries therefore need to build and sustain deploy- ment capability. This is particularly necessary because deployment is not just about the public health benefits of getting vaccines into arms; demand can also have a “warming” or “chilling” effect on vaccine markets. Scaling up delivery capacity quickly can also provide a window where people are very motivated because the disease is at its highest prevalence. This creates a strong financial sustainability market, particularly for upcoming geographi- cally distributed manufacturing facilities, to invest in national plans and infrastructure for deployment. Summary of findings: Vaccine financing programs often focus more on procurement than the programmatic needs to ensure that vaccines be- come vaccinations. Many countries, particularly LMICs, lack adult vaccine deployment plans and experience, including for seasonal and pandemic influenza. Deployment activities require proper technical guidance and designated financial resources, but care should be taken not to frame de- ployment as a positive externality. UNICEF and Gavi have decades-long PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 181 experience in deployment planning, implementation, supply chains, moni- toring, and policies. Both are well positioned to take the lead on global coordination for vaccine deployment, particularly in LMICs. Large nongov- ernmental organizations (NGOs) active in the field, such as the Bangladesh Rural Advancement Committee in Bangladesh, can also play a crucial role in engagement and vaccine confidence at the local community level. WHO has expertise in providing technical guidance on national pandemic and vaccination planning and country readiness assessments, including reaching high-risk populations. Conclusion 7A. A vaccine market supported by an immunization pro- gram able to deliver vaccines coupled with a population demand for these vaccines are essential elements to ensure a sustainable vaccine manufacturing base. Stronger national plans for deployment of seasonal influenza vaccines (using next-generation/platform technologies) and recognizing that vaccines will increasingly be available across the human lifespan (WHO, 2021d) are essential factors for vaccine markets and have a strong public health rationale. Gavi, UNICEF, and WHO can facilitate national and regional coordination for deployment activities. 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: • An analysis of what infrastructure (e.g., data and digitization of immunization records) was built for COVID and how it can be strengthened and sustained for at least one adult and one adolescent vaccine. • Advising member states on best practices used in countries that had high immunization rates during COVID-19. • Assisting member states to look at their data and logistics sys- tems for monitoring coverage and for tracking safety (pharma- covigilance) and on the need for no-fault compensation as part of patient safety mechanisms. THE PATH FORWARD “In a historically unprecedented way, security for people around the world now depends on global cooperation. Acting and investing collectively for PREPUBLICATION COPY—Uncorrected Proofs

182 THE INFLUENZA IMPERATIVE pandemic security, together with climate change, represents the primary international challenge of our times. Failure to establish the basis for international cooperation will make it almost impossible to address these existential challenges.” A Global Deal for Our Pandemic Age. Report of the G20 High-Level In- dependent Panel (HLIP) on Financing the Global Commons for Pandemic Preparedness and Response. June 2021 In its deliberations, the Committee on Global Coordination, Part- nerships, and Financing Recommendations for Advancing Pandemic and Seasonal Influenza Vaccine Preparedness and Response arrived at a set of views similar to those of the G20 HLIP, although these had not yet been released yet. The terms “coordination,” “partnerships,” and “financing” in the committee’s title represent three key areas on which our future ability to protect the global human population from catastrophic pandemics depend. It is the committee’s hope that its messages on the crucial need to improve progress in each of these three areas are clear. This study was completed in a much shorter time than is allowed for typical National Academies consensus studies, with only 5 months for both deliberations and report drafting. The Statement of Task was also very broad and asked the committee to reflect upon lessons learned for gov- ernance and financing from the COVID-19 pandemic response—which is itself still in active motion. Most of the committee’s deliberations took place before critical reports from the PPR agenda were released, particularly the G20’s HLIP. Furthermore, many additional PPR-related reports from the G7, G20 and many other actors—as well as the World Health Assembly’s discussions on a potential pandemic treaty or instrument—are upcoming in late 2021 and 2022. In this context, the committee fully acknowledges that it was unable to delve deeply into many relevant topics and some of its recommendations lack specificity in actors. The latter imprecision is necessary and deliberate; it enables the recommendations to, as much as possible, be aligned with the evolving global infrastructural architecture and roles designed in real time by the G7 and G20’s PPR agendas. We hope that one of the principal tasks of the G7 and G20 will be to identify more specific actors, institutional arrangements, and financing mechanisms for pandemic threats—including influenza—to ensure accountability and provide necessary resources. A first task of the emergent Global Health Threats Board (or the entity designed with this mandate) should be to develop a pathway for providing this level of specificity. The committee explicitly devised its recommendations on the assump- tion that the G7 and G20 will pursue a coordinated approach to PPR, with a governance mechanism and potentially a new international pandemic PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 183 governance instrument. However, the committee recognizes that this as- sumption is not a forgone conclusion, despite the compelling economic and human case for collective action to reinforce PPR. Because international coordination mechanisms, including a pandemic treaty or special inter- national instrument, may not withstand nationalistic impulses that such an agreement inevitably generates, it is all the more important to mini- mize dependence on such mechanisms. This underscores the importance of (1) advancing vaccine science as much as possible, (2) building as much manufacturing scale as possible, and (3) identifying the components of the influenza and PPR system that can be made neutral or resilient to national pressures. 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 exposed sharp fissures in the international order, shaking confi- dence 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 geopoliti- cal competition and collaboration. Major powers in the G7 and G20 have simultaneously supported efforts to promote equitable access to vaccines and actively engaged in “vaccine nationalism.” Meanwhile “vaccine di- plomacy” has been used to garner geopolitical and ideological advantage. One of the biggest and most sobering lessons from COVID-19 is that in an infectious disease crisis of this magnitude, neither established arrange- ments, such as the IHR, 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 daunt- ing geopolitical challenges, as doing so would have involved 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 PPR agenda and the specific in- fluenza vaccine recommendations that this committee put forward. That a geopolitical context can be established in which one can speak meaningfully of a “global community” able to take at least some degree of coordinated collective action is, in a sense, a basic assumption that the committee ad- opted, 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 PREPUBLICATION COPY—Uncorrected Proofs

184 THE INFLUENZA IMPERATIVE recognizing 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. The committee also recognizes that there may be scope to construct some technical coordination mechanisms in more of a “flying under the radar” mode and thus somewhat insulated from politics. However, the committee is skeptical about relying too much on such an approach. CO- VID-19 has repeatedly revealed how the intense political pressures that arise from a deadly pandemic can override technical, contractual, or legal considerations. As the G7 and G20 devise a new set of arrangements for PPR, including potential legal obligations (e.g., from a pandemic treaty or instrument, should such emerge), governance mechanisms (such as a Global Health Threats Board) and financing programs (such as the HLIP’s pro- posed Global Health Threats Fund), it is important to recognize that when put to the test, these new arrangements are unlikely to work as precisely as designed. Once again, national interests will 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. The committee wishes to highlight several critical areas that are essen- tial for refinement of the PPR agenda and either fell outside of the Statement of Task or were unable to be fully analyzed within the study’s time frame. We list them below, view them as having equal levels of priority, and recom- mend that all be more fully addressed or explored over the next 2–3 years. First, the term “sustainability” is often used and considered narrowly, rather than holistically. Sustainability is inseparable from a number of un- certainties about the future and global trends, which means that the next major epidemic or pandemic may look very different than COVID-19. For example, an influenza pandemic could be milder or more severe in terms of transmissibility and lethality and could be regional or global. Rapid urbanization patterns and global warming may also change the types and trajectories of emerging infectious diseases. This uncertain landscape must be considered when designing “sustainable” influenza and respiratory PPR initiatives for the future. One clearly visible trend amid this uncertainty is vaccine confidence. COVID-19 has changed the way that the world—and public health professionals—view vaccine confidence and hesitancy. Up- take of available vaccines is likely to be even lower in the context of the “known” threat of influenza, where vaccines have often had low efficacy. Much more work should be done on pre-pandemic communication strate- gies and national planning that could improve vaccine confidence across diseases and lead to increased recognition of the dangers of influenza among members of the public. This will require careful country surveys and risk PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 185 assessments, which extend beyond the capacity of this study. Phenomena such as the current vaccine hesitancy in the United States would appear to be partly the result of politicization but could occur elsewhere under other circumstances. Second, there has been frequent “hand-waving” about the importance of One Health. What remains blurry is how the coordination between ani- mal and human health can be made more effective and efficient. One Health accomplishments have been mostly based on rhetoric or goodwill between specific individuals working at particular organizations rather than a truly effective set of processes. The OIE, FAO, WHO, and UNEP are all critical actors in developing such processes, and these institutions have seen some recent momentum for One Health, such as a recent announcement about the establishment of an expert panel (WHO, 2021e) comprising represen- tatives from these four agencies and designed to strengthen and deepen their cooperation around the emergence and spread of zoonotic diseases. Much more work is needed to align objectives across these institutions in the context of pandemic threats and back these objectives with dedicated financial resources. We mostly considered this realm from the perspective of surveillance financing for influenza and respiratory pathogens with pan- demic potential, but this funding is best seen as the tip of the iceberg in terms of the One Health collaboration required for zoonotic disease PPR. Even the current debate and terminology of PPR understates the importance of prevention, particularly pre-spillover prevention. Third, a pandemic “treaty,” if well designed, could provide a good op- portunity to move from rhetoric to multilateral action on One Health for influenza and other respiratory pathogens with pandemic potential. This “treaty” could go in multiple directions, and we have endorsed principles that should be used as its foundations—but not a particular pathway for its negotiation. A convention (along the lines of the FCTC) agreement, or other framework pathway, could be pursued. Treaties or other pathways can exist between as few as two countries. Binding commitments or con- ventions for global access and countermeasure development programs are also good examples of agreements that might not involve a high percentage of the world’s countries. The FCTC is an example of a truly global treaty, but the G7 and G20 together would also cover a significant portion of the world population if they were involved exclusively in a treaty, convention, or other framework for pandemic preparedness. How a treaty (or alterna- tive framework) is negotiated—and whether most LMICs and HICs sign on to it—will have major implications for how the world conceptualizes pandemic threats. Wide sign-on by the United States, China, and a high number of LMICs and HICs will be necessary for this treaty or framework to embrace pandemic preparedness as a global public good, rather than merely an issue of global security. Careful consideration of the PIP Frame- PREPUBLICATION COPY—Uncorrected Proofs

186 THE INFLUENZA IMPERATIVE work’s core principles and the aforementioned “grand bargain” will be essential for successful negotiations. Fourth, ambiguity remains about the right size for a sustainable vac- cine market that would allow for a sufficient surge during an influenza pandemic. Particularly with the possibility for “platform-agnostic” pro- duction with next-generation vaccines (i.e., the ability for geographically distributed hubs or central manufacturers to produce mRNA or recombi- nant vaccines, beyond seasonal influenza, during “peacetime”), it will be critical to consider how to balance obsolete capacity between pandemics and the need for surge potential when a pandemic strikes. This will require in-depth market analyses, with careful consideration of pricing pressures and business response. Such an analysis will be instrumental in allowing the proposed global manufacturing hub coordination actor (e.g., CEPI) to develop plans that balance the inefficiencies of having multiple small, distributed manufacturing facilities with the cost efficiencies of centralized manufacturing facilities. Unfortunately, this important analysis extended beyond the resources and time allotted for this study. Lastly, more work should be done to determine the size of public sub- sidy that would be required to sustain this specific level of manufacturing capacity and the magnitude of public funding that would be required to meaningfully move forward with a universal influenza moon shot. This costing will be critical for priority-setting for influenza in the PPR agenda. We hope that by advancing a global public goods framework for influ- enza, which links—and prioritizes—it with other respiratory viral diseases with pandemic potential, influenza will be recognized as a serious pandemic threat and afforded funding commensurate with its economic and public health risks. It will be critical for HICs and MICs to extend their resource allocation for PPR. In advancing this framework, we recognize the prin- ciples of equity and human rights, which have not been fully embraced by global coordination mechanisms during COVID-19. At the same time, we underscore that it is critical to remember that obligations attached to indus- try through partnerships or ABS will determine how industry reacts—and both transformative R&D and sustainable vaccine markets are unlikely to emerge without strong industry support. The path forward for global influenza PPR will require engagement of and coordination among diverse actors, spanning civil society, industry, national entities, bilateral organiza- tions, and multilateral organizations. Each actor will need to recognize the need to temper self-interest to counter the pandemic threat and address the influenza imperative. PREPUBLICATION COPY—Uncorrected Proofs

RECOMMENDATIONS AND THE PATH FORWARD 187 REFERENCES AstraZeneca. 2021. Entering a new era in vascular and cardiac regeneration research. https:// www.astrazeneca.com/what-science-can-do/topics/next-generation-therapeutics/entering- a-new-era-in-vascular-and-cardiac-regeneration-research.html (accessed August 12, 2021). CEPI (Coalition for Epidemic Preparedness Innovations). 2020. Call for Proposals: Achiev- ing an unprecedented acceleration of vaccine development and global manufacturing capacity to prevent COVID-19. https://cepi.net/wp-content/uploads/2020/05/Call-text_ COVID-19_CFP-2C_04052020_website.pdf (accessed August 12, 2021). CEPI. 2021a. CEPI 2022–2026 Strategy. https://cepi.net/wp-content/uploads/2021/03/CEPI- 2.0_Strategy-2022-26-Mar21.pdf (accessed August 12, 2021). CEPI. 2021b. Our mission: New vaccines for a safer world. https://cepi.net/about/whyweexist/ (accessed August 12, 2021). CEPI. 2021c. Survey launched by CEPI to track multinational vaccine manufacturing capacity for use in future epidemics and pandemics. https://cepi.net/news_cepi/survey-launched-by- cepi-to-track-multinational-vaccine-manufacturing-capacity-for-use-in-future-epidemics- and-pandemics/. (accessed August 12, 2021). CEPI. 2021d. CEPI and the African Union join forces to boost African vaccine R&D and manufacturing. https://cepi.net/news_cepi/cepi-and-the-african-union-join-forces-to- boost-african-vaccine-rd-and-manufacturing/ (accessed August 12, 2021). EAPHLP (East Africa Public Health Laboratory Project). 2021. East Africa Public Health Laboratory Networking Project. https://www.eac.int/health/disease-prevention/east- africa-public-health-laboratory-networking-project (accessed August 12, 2021). Harris, J.E. 2021. The Repeated Setbacks of HIV Vaccine Development Laid the Groundwork for Sars-Cov-2 Vaccines. Working Paper 28587, National Bureau of Economic Research. Cambridge, MA. http://www.nber.org/papers/w28587 (accessed August 12, 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. Rockefeller Foundation. 2021. The Rockefeller Foundation announces key grants and col- laborations to strengthen global genomic sequencing and data sharing. Press release 06/09/2021. https://www.rockefellerfoundation.org/news/the-rockefeller-foundation- announces-key-grants-and-collaborations-toward-the-creation-of-a-pandemic- prevention-institute/ (accessed August 12, 2021). Sabin-Aspen Vaccine Science and Policy Group. 2019. Accelerating the development of a universal influenza vaccine: A report from the Sabin-Aspen Vaccine Science and Policy Group. https://www.influenzer.org/app/uploads/2020/01/sabin-aspen-report-digital.pdf (accessed August 12, 2021). Snyder, C.M., K. Hoyt, D. Gouglas, T. Johnston, and J. Robinson. 2020. Designing pull fund- ing for a Covid-19 vaccine. Health Affairs 39(9): 1633–1642 West African Health Organization. n.d. The Regional Disease Surveillance Systems Enhance- ment (REDISSE) Project in West Africa. https://www.wahooas.org/web-ooas/en/projets/ redisse-regional-disease-surveillance-systems-enhancement-project-west-africa (accessed August 12, 2021). WHO (World Health Organization). 2021a. The public health implications of implementa- tion of the Nagoya Protocol: Report by the WHO Director-General. EB148/21. https:// apps.who.int/gb/ebwha/pdf_files/EB148/B148_21-en.pdf (accessed August 12, 2021). WHO. 2021b. Global Action Plan for Influenza Vaccines: FAQ. https://www.who.int/ influenza_vaccines_plan/resources/gap_faq.pdf?ua=1. (accessed August 12, 2021). PREPUBLICATION COPY—Uncorrected Proofs

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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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