for which national authorities must plan. Given historical patterns, the present and known existence of specific influenza viruses of concern, ongoing conditions that favor the emergence of another influenza pandemic, and the severe global experience with COVID-19, it is incumbent on 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 from that/those for other pathogens; well-established, although underfunded, networks and legal arrangements exist to meet the twin challenges 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 happened with Global Influenza Surveillance and Response System [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:

• The influenza viruses creating predictable, annual “seasonal” epidemics of disease and also some spilling over from their normal animal hosts to become infectious in, and transmissible among, humans at unpredictable times;
• The limited global use of antiviral therapeutics and diagnostic tests, underscoring the importance of vaccines;
• The well-established and relatively well-understood and monitored nature of the zoonotic links, compared to many other emerging infectious diseases; and
• 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 on 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.

in greater surge capacity. This core conclusion informs a number of the report’s recommendations.

Achieving an equitable global allocation ultimately requires balancing 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 instrument 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 sufficient 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 protections). 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 investments 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., pathogen-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 voluntary 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);
• Building a coordination structure for sustained industry partnerships to optimize companies’ platform technologies for efficient vaccine production and efficacy;
• Creating a combination of push/pull incentives (e.g., advance market commitments [AMCs]) and resources to make the development of next-generation and, ideally, universal influenza vaccines a priority;
• Incentivizing the development of sustainable, geographically distributed 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 encompasses all pathogens with regional or global pandemic potential, includes zoonotic components, and incentivizes pathogen and genetic 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 implementation. 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 relative 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 ABS governance frameworks (PIP Framework) are global and relatively well coordinated through the World Health Organization (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 clinical 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 influenza—these other pathogens may become “endemic” such that coordination 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 Global Early Warning System for Major Animal Diseases (GLEWS+) proposals.

2: Sustainable Financing for Integrated, Modern, Timely Respiratory Virus Surveillance for Pathogens with Pandemic Potential

The ongoing and dynamic emergence and spread of coronavirus variants 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 essential 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 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 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 effectiveness of available treatments (e.g., antiviral drug resistance).

The concept of “surveillance” is often considered from the lens of viral 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 outbreak. These include the UK Global Pandemic Radar and The Rockefeller Foundation’s Pandemic Prevention Institute (The Rockefeller Foundation, 2021). Without national surveillance infrastructure and robust regional surveillance 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 financing 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 on competition for influence, power, and funding. It is critical for ministries of health to be joined by other relevant ministries, 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 emergencies, including pandemics. Coordination, information sharing, and collaboration among intragovernmental agencies will improve the alignment 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 mechanisms 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 identify an emerging threat earlier but also 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 requires 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, consistent, and ideally coordinated laws and legal instruments, may enable national surveillance systems to be regionally operational and interdependent (e.g., through sharing technical expertise, capital goods, operating expenditures 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 surveillance activities through regional grants or loan obligations (West African Health Organization, n.d.).¹ The East-Africa Public Health Laboratory 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 support 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 countermeasures downstream.

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¹ See https://www.wahooas.org/web-ooas/en/projets/redisse-regional-disease-surveillance-systems-enhancement-project-west-africa (accessed December 30, 2021).

3: Limits and Potential of the PIP Framework and Nagoya Protocol for Pathogen Sharing

The timely sharing of influenza viruses is essential for developing lifesaving seasonal vaccines, identifying potential pandemic viral strains, and providing early warning for outbreaks. The PIP Framework supports critical 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 solutions. Such an instrument would eliminate the challenge of negotiating in the midst of a pandemic threat, ensuring predictability and a general mutually agreed framework and saving the critical time needed to put a full response in place. More specifically, the principles agreed upon in the PIP Framework, which are essentially consistent with those of the Convention on Biological Diversity (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 transparency, 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, capacity 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, preparation 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 pandemic 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 future 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 country 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 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 investments 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 standard material transfer agreements 2 (SMTA-2s), could easily change and be approached differently in a future agreement. A pandemic treaty negotiation is likely to be prolonged and take several years, and additional time would be needed for it to enter into force. Negotiations for the WHO Framework Convention on Tobacco Control (FCTC), for instance, took 4 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 Centres (NICs), countries, vaccine manufacturers, and WHO—can exhibit both immediate self-serving and collaborative behaviors. It is therefore critical to encourage and enable rapid sharing and characterization of samples. In a pandemic, lack of timely sharing of viruses 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.

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 effective. 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 the effectiveness, speed, and ability to scale up production of influenza vaccines, due to intrinsic constraints with the current egg-dominated vaccine ecosystem. The strong market for COVID-19 vaccines (potentially including 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 technologies 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 platform innovation for influenza vaccines requires a combination of early R&D incentives, including support of Phase I–III clinical trials for platform- 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 moonshot (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 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 Prevention and Therapeutics program, launched in 2013, which has primarily supported vaccine and antibody programs against the chikungunya virus, and the Biomedical Advanced Research and Development Authority (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 optimization, 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 trials can also be institutionalized on a stronger base through partnerships, building on existing programs (e.g., the European and Developing Countries 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 interest in helping to extend platform technologies more broadly for respiratory 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 developed 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 iW well positioned to address cost-effectiveness thresholds for influenza R&D on a global scale. BARDA and HERA have similar capacities for advanced vaccine development, at the early, middle, and late stages. OWS, for instance,

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² See https://www.modernatx.com/ecosystem/strategic-collaborators/mrna-strategic-collaborators-government-organizations (accessed December 19, 2021).

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, including 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 building 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 Institute), 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 allocation (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 priority areas and may open-up the larger sources of funding required to push forward platform innovation and generate markets for emerging infectious disease vaccines.

5: An Influenza Vaccine Moonshot: 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. Universal 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 principle 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 cancer 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 proportional 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 “moonshot” 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 and regulatory pathway to bring a profitable product to the market. Solving 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 the Bill & Melinda Gates Foundation (BMGF) launched a $12 million “Ending the Pandemic Threat” Grand Challenge for universal influenza vaccine development that year. More recently, the Center for Infectious Disease Research and Policy (CIDRAP) Influenza Vaccine 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 (millions) is nowhere near that required (billions) to incentivize the risky undertaking of universal influenza vaccine R&D. Both push and pull incentives will be critical to demonstrate a proof of concept for the market of influenza vaccines. A massive push will be required to elicit pre-competitive scientific and biological analyses for vaccine targets. CEPI’s mission (CEPI, 2021a) 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 production and capacity for proven vaccine approaches, rather than to drive new science. For example, the G7 and BMGF committed to buy a new vaccine against LMIC-specific strains of pneumococcal disease, which Gavi is now using to vaccinate children in numerous developing countries (BMGF, n.d.). 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 incentive to solve hard biology problems, such as those implicit in a universal influenza vaccine.

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 vaccine 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 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.

a survey with governments (CEPI, 2021b) to map the landscape of vaccine manufacturing 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 technical 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 coordination 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 separate capacity. 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 appropriate, vaccines could be produced during times of no disease pandemics 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 issue 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 COVID-19 Vaccines Global Access (COVAX), the Africa CDC, a network of universities, and an industry consortium (Biovac, Afrigen Biologics and Vaccines), the first COVID-19 mRNA vaccine technology transfer hub is planned for South Africa (WHO, 2021c). This is a crucial step in building geographically distributed manu-

facturing 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 flexibility 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 standardized 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 supplier 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 AU 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.

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 capability 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 vaccination 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 deployment 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 geographically 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 become 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 deployment as a positive externality. UNICEF and Gavi have decades-long 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 nongovernmental 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.

THE PATH FORWARD

In its deliberations, the Committee on Global Coordination, Partnerships, 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 on lessons learned for governance 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 WHA’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 assumption that the G7 and G20 will pursue a coordinated approach to PPR, with a governance mechanism and potentially a new international pandemic governance instrument. However, the committee recognizes that this assumption 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 minimize 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 confidence in the notion of a “global community” and revealing the powerful, complex, and somewhat contradictory interactions between global health priorities, domestic political imperatives, and other dimensions of geopolitical 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 diplomacy” 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 arrangements, such as the International Health Regulations, nor newly created mechanisms, such as COVAX, can withstand the overwhelming pressures to prioritize national interests.

The committee did not directly consider how to address these daunting geopolitical challenges, as doing so would 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 influenza 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 adopted, 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 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. COVID-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 HLIP’s proposed 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 essential 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 recommend 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 uncertainties about the future and global trends, which means that the next major epidemic or pandemic may look very different from 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. Uptake 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 strategies 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 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

animal 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 World Organisation for Animal Health, the Food and Agriculture Organization of the United Nations, WHO, and the United Nations Environment Programme 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 representatives 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 pandemic 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 opportunity 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 conventions 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 alternative 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 Framework’s core principles and the aforementioned “grand bargain” will be essential for successful negotiations.

Fourth, ambiguity remains about the right size for a sustainable vaccine market that would allow for a sufficient surge during an influenza pandemic.

Particularly with the possibility for “platform-agnostic” production with next-generation vaccines (i.e., the ability for geographically distributed hubs or central manufacturers to produce mRNA or recombinant vaccines, beyond seasonal influenza, during times of no disease pandemics), 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 subsidy 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 moonshot. 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 influenza, 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 middle-income countries to extend their resource allocation for PPR. In advancing this framework, we recognize the principles 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 industry 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 organizations, 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.

REFERENCES