6

Barriers, Incentives, and Innovations for Sustainable Manufacturing

The global effort to produce a vaccine against the COVID-19 virus has highlighted several issues pertinent to sustainable manufacturing. COVID-19 vaccine development demonstrated the importance of innovation and revealed structural barriers that can hinder progress in times of greatest need. Challenges in rapid vaccine development have led to a discussion of tradeoffs in the regulatory pathway for a vaccine when addressing issues of speed, quality, safety, and transparency of the clinical development process during a pandemic. Additionally, future pandemic preparedness can be facilitated by a series of incentives that can offset barriers and foster innovation.

The discussion of these and related issues in this chapter is presented in five sections: tradeoffs involved in pandemic and seasonal influenza vaccine development and manufacturing; comparison of tradeoffs of different vaccine platforms; barriers that impede the rapid translation from clinical to large-scale commercial manufacturing; incentives for manufacturing platform innovation; and incentives for safety, efficacy, and data transparency in manufacturing, and disincentives for bypassing regulatory guidelines.

Table 6-1 summarizes the recommendations in this chapter, delineated by the U.S. and regional or global actors identified for their implementation.

TRADEOFFS IN VACCINE DEVELOPMENT AND MANUFACTURING

The global effort to produce a vaccine against the COVID-19 virus has highlighted that during a future influenza pandemic with high associated morbidity and mortality, the risk-benefit assessment of immediate

TABLE 6-1 Summary of Recommendations on Barriers, Incentives, and Innovations for Sustainable Manufacturing

regulatory imperatives for vaccine manufacturing and use may differ from those for seasonal influenza vaccines that are manufactured on a regular schedule. Factors such as speed, safety, and quality have to be considered alongside the complexity of the manufacturing process and the need for transparency of clinical trial data. While it is true that challenges exist and priorities can be competing, the rapid emergence of vaccines in response to the COVID-19 pandemic demonstrates how the goals of speed, efficacy, and quality can all be achieved in the manufacturing process, even for novel vaccines. The Pfizer mRNA vaccine was approved for emergency use in the United States just 8 months after clinical trials began (Ball, 2021). Much of this success was due to the novel mRNA technology platform that proved to be highly effective in inducing protection against SARS-CoV-2, the virus that causes COVID-19.

Concerns have been raised as to whether speeding up vaccine manufacturing can compromise quality. Vaccine quality, which has implications for safety, is a principal characteristic that cannot be minimized, even in pandemic scenarios when time is critical. Again, the COVID-19 pandemic has revealed that quality and timeliness can both be compatible goals, but these factors have to be intentionally addressed. The approach in a pan-

demic is incremental, allowing use of a vaccine more broadly when there are safety and efficacy data based on information from fewer participants in clinical trials. Full licensure awaits more data collected as the pandemic evolves. Risks to vaccine quality are possible if, for example, there is a shortage of trained personnel with the specialized skills needed to run the vaccine manufacturing processes (GAO, 2021). When manufacturers are developing vaccines, stringent regulatory requirements can help ensure that quality is not suffering for the sake of speed.

Another tradeoff is that between superior efficacy and dose sparing and ease of administration. Some highly efficacious vaccines require multiple injections or the addition of an adjuvant to safely achieve efficacy. At the same time, using the smallest amount of antigen to achieve immunity is desirable for dose sparing and maximizing resource efficiency (Chakraborty et al., 2021). Single-dose vaccines also significantly reduce the burden on the supply chain, as fewer vaccines and related supplies need to be manufactured and transported. For a vaccine intended to be distributed globally during a pandemic, the speed of development for a particular platform needs to be weighed against whether the manufacturing process for that vaccine will be scalable, affordable, and have sufficient thermostability to be distributed globally. For example, the mRNA COVID-19 vaccines that require ultra-cold storage are highly efficacious, but they may be challenging to transport and store in low- and middle-income countries (LMICs), where cold chain infrastructure is limited (WHO and UNICEF, 2021). As shown in Table 6-2, every platform has advantages and disadvantages. It is likely that the future will see vaccine developers explore every technology available as they continue to respond to both seasonal and pandemic influenza. It is important to consider that, even with the successful rapid development of safe and effective COVID-19 vaccines, some vaccines may not be appropriate for every context given localized logistical constraints (see Chapter 4).

Tradeoffs for Different Vaccine Platforms

Tradeoffs are evident among the various platforms for influenza vaccines. While traditional egg-based influenza vaccine production technology has a good safety profile, acceptable tolerability, and dominates today’s available vaccines due to its relatively simple technology and low cost, the committee believes other viable options can speed the development and production of vaccines for seasonal and pandemic influenza and reduce the dependence on a supply of chicken eggs (see Chapter 2). Limitations with egg-based influenza vaccine production (Matthews, 2006) have driven and expanded the use of other vaccine platform technologies for manufacturing influenza vaccines in high-resource settings. Alternate technologies have already been

TABLE 6-2 Advantages and Disadvantages of Technology Platforms Used to Develop Vaccines

NOTE: NA = not applicable.

^a Since the publication of the source article (Li et al., 2020), the Comirnaty mRNA vaccine produced by Pfizer obtained regulatory approval (FDA, 2021b).
SOURCE: Li et al., 2020, p. 109.

implemented: World Health Organization (WHO) recommendations are now routinely established for cell-based vaccines, indicating that this is becoming a mainstream technology (WHO, 2021). Protein subunit-based technologies are also approved and used, but this method has been shown to produce inferior immune responses in comparison with more conventional approaches (Zhang et al., 2015). While a number of promising novel vaccine technologies have been evaluated in early clinical trials, only a few (e.g., newer adjuvants and vectored vaccines) have yet to advance to commercial-scale manufacturing that is suitable and scalable for seasonal and pandemic influenza vaccine use (Rockman et al., 2020b). There needs to be greater momentum to improve the overall characteristics of these technologies so they can be readily used for influenza, particularly during a pandemic.

While COVID-19 has revealed the potential for innovative vaccine platforms, these advancements need to be evaluated in the light of the cur-

rent ecosystem of vaccine manufacturing capacity. For influenza vaccines, egg-based production dominates a majority of the market, and manufacturing capacity is largely suited to this platform. While novel technologies are promising, responding to pandemic or seasonal influenza in the near future will likely rely on egg-based technologies. Shifting toward novel platforms in countries that have sustainable manufacturing using existing platforms may not be the most efficient use of resources in every case. Selecting the appropriate platforms to develop will depend on localized contexts, including existing capacity and resource availability.

Broad Considerations for Vaccine Platforms

The complexity of the manufacturing processes is a significant consideration when exploring any platform. Some platform technologies require

a sophisticated infrastructure and highly trained workforce to install, use in manufacturing, and maintain within specifications. Egg-based production has fairly simple technology requirements and does not require a sophisticated infrastructure, which is why LMICs use it extensively. However, there is complexity in handling the eggs as well as in the manufacturing process. Egg-based production exemplifies two types of complexities—complexity inherent in the technology and complexity in the manufacturing process. The committee agrees that the least favorable scenario is to take a highly complex technology that has complexity built into it and then add a highly complex manufacturing process. The ideal platform incorporates complex technology with low complexity in the actual manufacturing process. For example, mRNA production is inherently high technology, but the process can be done in a modular unit with a relatively low-complexity, hands-on manufacturing process (Pardi et al., 2018). However, the lipid formulation may require a large, highly trained workforce to monitor microfluidics, set up tubing, and manage other aspects of the process. If the formulation has a complex, hands-on manufacturing process, mRNA vaccine production may not be sustainable in a low-resource setting.

The extensive global COVID-19 vaccine portfolio has demonstrated the value of simultaneous vaccine development using multiple vaccine platform technologies. The next generation of influenza vaccines would also benefit from investments in a diversified portfolio of vaccine candidates. Multiple influenza vaccines based on multiple vaccine technologies would be advantageous to prepare for a pandemic response, rather than relying primarily on eggs, as does 90 percent of the current influenza industry (Bender, 2019).

The different characteristics of seasonal and pandemic influenza also has to be considered when identifying the most effective platform for a given setting. Vaccine technologies suitable for seasonal influenza use may not be fit-for-purpose for use during an influenza pandemic. For example, a country attempting to catch up with an unforeseen pandemic using a vaccine technology that is scalable, but will take 6 months to produce, will largely miss the benefit of immunization as a public health intervention. The same technology for a seasonal influenza vaccine would hold great promise, even with a 6-month production cycle time, because it could be used for the anticipated upcoming influenza season. Therefore, some novel technologies will have different value propositions for their applicability to pandemic and seasonal influenza based on the vaccine production timeline and scale needed.

Dose-sparing approaches, including new adjuvants and new vaccine delivery technologies, hold the promise of maximizing vaccine coverage when vaccine supply is constrained. However, dose-sparing regimens and routes of administration, adjuvant production, and new delivery technologies can create more supply to manage. For example, adjuvants, although they may enhance immune response, require a variety of additional components

that could place further demands on the supply chain (Rele, 2021). Using low dead-volume syringes can also contribute to dose sparing—they can increase the number of doses that can be extracted from each vial when compared to standard syringes—but this limited supply item represents another component that could add supply chain complexity and stress (Moutinho, 2021). A sustainable influenza market is critical for anticipating the supply and demand for these components and determining the benefits and drawbacks of dose-sparing approaches.

Technologies that are amenable to alternate forms of administration and delivery take into account the route and availabilities of supplies. For example, alternate methods of distribution, such as oral vaccine delivery or transdermal vaccines, may be more advantageous during a pandemic when needed equipment is in short supply. This kind of problem is evident from the COVID-19 pandemic when a lack of syringes was reported (CDC, 2020). Other advantages of oral over the traditional injection-based formulations include improved safety and compliance, as well as easier manufacturing and administration of the vaccine (Ramirez et al., 2017).

Broad tradeoffs of various vaccine manufacturing platforms along the dimensions of efficiency, speed, scale, flexibility, and replicability exist. These tradeoffs have to be assessed to determine context-specific suitability. In countries with large sustainable seasonal influenza vaccine markets that rely on egg-based vaccine production, novel technologies may not be needed for pandemic vaccine response. However, in countries where a sustainable egg-based seasonal influenza vaccine market does not exist, other vaccine platform technologies (e.g., protein subunit, cell based, mRNA, and plant based), dose-sparing approaches (e.g., adjuvants), and alternative routes of administration (e.g., self-administered skin patches or oral) may be better suited to address the urgent needs during a pandemic. There is a need for a diversified portfolio of vaccine platforms as the acceptability of different vaccines varies.

Equitable access to the various options of the vaccine portfolio for countries has demand-side benefits that are important to address. Though availability of multiple vaccines may introduce complexities in forecasting and allocation (as discussed in Chapter 4), these challenges have to be accounted for, and operational innovations have to be considered, in order to facilitate vaccine equity and access. Technology tradeoffs also include approaches to improve manufacturing throughput (e.g., dose sparing) and innovations for more efficient delivery (e.g., patches). These innovations are costly initially and will often require a comprehensive assessment for sustainable influenza manufacturing. Vaccines and technology platform capabilities are dynamically evolving over time, which affects the tradeoff dynamic. Such an assessment can also inform design of a globally distributed influenza vaccine network (as discussed in Chapter 3).

mRNA as a Potential Platform for Influenza Vaccines

Given the successes of mRNA vaccine technology for COVID-19 vaccine use, this technology also holds promise for influenza vaccines. Additional research is needed to assess the suitability of the mRNA platform for influenza vaccine development. Even if mRNA vaccines are effective in inducing immunity against the virus, there are several tradeoffs that would have to be considered when using mRNA technology for a disease of global concern. The need for manufacturing and storage in ultra-cold conditions for current mRNA vaccines can increase the cost of manufacturing and may greatly reduce the feasibility for mass use in low-resource settings (Kis et al., 2021; see Chapter 4). Refinements of the manufacturing processes and formulation may lead to compositions with greater thermostabilty that are more suitable and feasible for use in low-resource settings (Sandbrink and Shattock, 2020). Whether those compositions provide well-tolerated, highly efficacious, durable responses against influenza at a price affordable for LMICs remains to be determined.

The Biomedical Advanced Research and Development Authority (BARDA) and the Coalition for Epidemic Preparedness Innovations (CEPI) provided funding to vaccine developers for advancing platforms to prepare COVID-19 candidate vaccines (Keusch and Lurie, 2020; see Appendix A), which highlighted the importance of funding mechanisms in expanding and sustaining development efforts. The need for additional consideration of the application to LMICs is especially critical given the associated resource constraints of competing health priorities and domestic health financing restrictions (Kraigsley et al., 2021).

COVID-19 has also highlighted the importance of regional vaccine manufacturing for sustainability and equitable vaccine access. Increasing the global distribution of influenza vaccine manufacturing depends on progress in technology transfer, which has been made over the past few decades as a result of the WHO Global Action Plan for Influenza Vaccines (GAP) program (see Chapter 5 and Appendix A). Under GAP, 14 LMICs received grants to develop local influenza vaccine manufacturing capacity, and those grants included support for regulatory framework development. By the end of the program, 10 countries met criteria for regulatory functionality, and 5 had developed newly licensed influenza vaccines. However, with the changing landscape of vaccine development, gaps remain in technology transfer. Absent the time to develop comprehensive and highly robust critical quality attributes and critical process parameters, as well as well-defined process space, technology transfer for mRNA vaccines can be challenging and risky (Hatchett et al., 2021; Rosa et al., 2021). Scale-up of vaccine manufacturing for COVID-19, including the mRNA vaccine, also highlights one of the biggest hurdles in decentralizing manufacturing to local production: the

lack of a highly trained workforce knowledgeable in all complex manufacturing processes (e.g., lipid and microfluidics experts), as well as enabling functions, such as quality control and assurance (Hatchett et al., 2021; see also Chapter 3, “Training and Readiness of Critical Workforce Personnel”).

BARRIERS TO VACCINE MANUFACTURING AND INNOVATION

There are several barriers that hamper manufacturers’ ability to rapidly move from producing enough vaccine for clinical trials to shipping massive quantities across the globe—in addition to the supply chain issues discussed in Chapter 3—that need to be considered for future vaccine development and manufacturing. The primary barriers addressed by the committee relate to either regulatory hurdles or manufacturer liability. Gaining regulatory approval is a lengthy process, especially for vaccines that are developed from novel platforms, and can result in delayed vaccine distribution in emergency scenarios. Liability for novel vaccines similarly presents a significant risk to manufacturers, which serves as a disincentive for innovation. These barriers underlie many of the challenges to vaccine development; the rest of this section discusses solutions and incentives to counteract these barriers.

Regulatory Approval

As medical products that are administered to otherwise healthy persons to prevent disease, vaccines are held to a very high standard for safety and effectiveness (Ellenberg and Chen, 1997). Proof of meeting these requirements is routinely required of vaccine manufacturers seeking to introduce a new product. Obtaining regulatory approval of novel vaccine products for use during a pandemic has to account for the standard requirements and the associated challenges that exist for any vaccine to be approved. (See Chapter 2 for an overview of regulatory concerns in the United States and globally for vaccines and more specifically for seasonal influenza vaccines.)

The time required to conduct vaccine trials, conduct laboratory assays, and obtain regulatory approval for a vaccine has historically taken 10–15 years (Gavi, 2020a). This long time window may be acceptable for creating an improved product for an existing vaccine or a vaccine to prevent an infection with low mortality or low risks, but it is not a feasible timeline for a pandemic scenario. In the event of a pandemic, time is a limited resource in the process of acquiring the essential tools, including one or more vaccines, to mitigate the impact of a novel infection. In obtaining regulatory approval for a pandemic vaccine, finding ways to compress the time required to receive approval while ensuring the safety and effectiveness of the product have to be a priority.

Several significant factors influence the trajectory of the pandemic vaccine approval process. They begin with the cause of the pandemic itself and whether it is relatively common and understood, like an influenza strain; a less common sporadically occurring infection, like Ebola; or a novel infection, like COVID-19. The vaccines themselves and their formulation comprise another variable. An influenza vaccine that uses previously approved platforms with a new strain can require a far simpler approval process than a significantly modified product, such as one using a new adjuvant, or one with a completely new technology being introduced.

The 2009 influenza A (H1N1pdm09) pandemic is an example of a relatively simple process for regulatory approval. A new influenza strain was identified after the seasonal vaccines had begun production. The monovalent vaccine for H1N1 was produced using existing vaccine production platforms and received approval in the United States as a supplement to the seasonal vaccine (Weir and Gruber, 2016). In contrast, the existence of COVID-19 as a novel virus coincided with the emergence of new vaccine technology, most notably, mRNA vaccines. These vaccines have offered the opportunity to respond rapidly and effectively to COVID-19, but they rely on a relatively new platform that does not have the long history of safety and effectiveness of other vaccines (CDC, 2021; Pardi et al., 2018). Even so, “mRNA vaccines have been held to the same rigorous safety and effectiveness standards as all other types of vaccines in the United States” (CDC, 2021, section 4).

Multiple factors were essential for the swift development, testing, and ultimate approval of multiple candidate vaccines for COVID-19. There were collaboration and clear channels of communication between the public and private sectors. In the United States, this process occurred with involvement from the highest levels of government health agencies and manufacturers (Corey et al., 2020). The issuance of an Emergency Use Authorization (by the U.S. Food and Drug Administration [FDA]) to allow use of the vaccines in specific population segments while additional trials continued, along with safety surveillance monitoring, was critical to

beginning vaccination programs for COVID-19 less than 1 year after the first case was identified (GAO, 2021). While H1N1 and COVID-19 each provide examples of expediting approvals in the United States and globally, the development and use of a novel vaccine for Ebola provides a different view of the global approval process. Despite the development of vaccine candidates in the decade before the 2014 outbreak, clinical trials did not proceed due to the difficulty of testing their safety and effectiveness in populations absent an outbreak of the disease. However, with clinical trials beginning shortly after the 2014 outbreak began, a vaccine was developed, tested, and approved within about 5 years as a result of collaboration and the harmonization of rules by major partners. Regulatory authorities in the United States, Canada, Europe, and Africa, along with leadership from WHO, facilitated standardization and allowed for trials to take place while the product was manufactured and became available for the trial and compassionate use applications. This collaboration allowed for clear communication and transparency among the partners and enabled an essential level of trust in the results (Wolf et al., 2020). Similar challenges can be identified for developing and testing new vaccines for use in the event of a reemergence or bioterror use of diseases, such as smallpox or anthrax.

Multiple vaccines were rapidly developed and deployed during the COVID-19 pandemic using various technology platforms, each with unique properties, advantages, and disadvantages (Wagner et al., 2021). Along with the accelerated timeline was an understanding that speed does not compromise necessary regulatory requirements for data collection and evaluation of clinical product safety and efficacy. Addressing regulatory gaps for influenza vaccine technologies needs to balance speed with regulatory requirements. These gaps include national regulatory pre-approved manufacturing changes, global streamlining of vaccine approval (harmonization, convergence, or reliance), and WHO prequalification, as well as subsequent vaccine lot release, and the need for clinical evidence and globally accepted immune correlates of protection. In smaller countries and in LMICs, the lack of sufficient regulatory structure and the many variations in rules from one country to another can be formidable barriers to achieving local approval of a new product. Even with WHO approval of a vaccine, the challenges posed at the country-specific level can be overwhelming (Hayman et al., 2021). WHO and national leaders need to help with harmonization of requirements as an essential step to overcoming the complexity of variations posed by national boundaries (Wolf et al., 2020).

The lessons learned from developing vaccines for each of the cases provide a valuable roadmap for the approval of future pandemic vaccines. Examples from COVID-19 and Ebola reveal key considerations for advancing future vaccine development. In a public health emergency, it is critical to minimize the time involved and the total duration of necessary trials

without compromising safety or efficacy. Inherent in this approach is identifying options for expediting the regulatory process, including consideration of key differences and similarities between completely new products and those built on existing platforms. For example, there could be expedited review for products that simply insert a new strain, such as with seasonal influenza. Coordination, including public–private partnerships, is crucial to successfully launching a pandemic vaccine. Success in timely development of a vaccine is also dependent on working closely with regulatory authorities. WHO engagement and leadership has proven critical for the global approval processes. Harmonization of requirements for labeling and packaging can help expedite the process.

Risk for Vaccine Developers and Manufacturers

Clinical development of vaccines and their production were driven primarily by the public sector through 1940, followed by a rise in public–private partnerships, which eventually gave way to private-sector dominance toward the end of the 20th century (Griesenauer and Kinch, 2017). However, in recent years, many large pharmaceutical companies have migrated away from early-stage research activities for the development of novel vaccines. This is in part due to weak return on investments from an industry perspective. While effective vaccines are essential public health tools, costs associated with designing, testing, and manufacturing vaccines that have limited commercial markets has created disincentives for companies to invest in research and development (Rodrigues and Plotkin, 2020). Importantly, vaccine innovation has slowed because of development costs (Hosangadi et al., 2020), but innovation is what is needed to improve the uptake of vaccines. For example, increasing the duration of influenza vaccine efficacy through a universal vaccine could create greater demand and increase industry’s return on investment. Other novel technologies to improve antigen delivery and vaccine delivery, such as microneedle patches, could further increase influenza vaccine demand (Pollard and Bijker, 2021).

The global demand for a COVID-19 vaccine triggered substantial investment in various vaccine technologies, including applying novel platforms, such as mRNA. These technologies had not previously seen widespread use largely due to the risk incurred by manufacturers to initiate research into novel technologies. Vaccine development is a high-risk enterprise for pharmaceutical companies; the process for a vaccine candidate can take upward of 10 years and require more than $1 billion, and it carries a 94 percent chance of failure (Billington et al., 2020). For influenza, the current global system is adapted to egg-based vaccine development platforms. Seasonal influenza vaccines do not have to undergo lengthy and expensive

clinical trials, as the basic platform has long been accepted as safe. Similarly, pandemic vaccines produced by these accepted platforms can be rapidly approved. In contrast, a vaccine developed using a novel platform must undergo extensive and costly clinical trials (Knobler et al., 2020).

Even after clinical trials are complete, other structural gaps, such as unclear regulatory pathways, can hinder vaccine rollout and return on investment (Billington et al., 2020). With this current system, there is little incentive for vaccine manufacturers to invest in the development of innovative platforms (Osterholm et al., 2012a). In addition, developing vaccines on a global scale relies on increased manufacturing capacity. Other factors, such as uncertain demand for vaccines, further increase risk (Kazaz et al., 2021). Developing vaccines using novel platforms requires incentives that reduce the risk of innovation, resulting in potentially more efficient vaccines that can be produced more rapidly, especially at the scale and in the timeframe needed for a pandemic. In the future, incentives will be needed to sustain innovation beyond a pandemic (Knobler et al., 2020).

Currently, there are several mechanisms in place that can de-risk vaccine manufacturing for novel platforms. Direct grants can subsidize research and are often provided in university or government laboratory settings. In the United States, the National Institutes of Health is an example of a publicly funded institution that promotes basic research on vaccine development. Similarly, tax credits can be applied to promote research and development among pharmaceutical companies. Both mechanisms aim to incentivize research and development by reducing initial costs. Drawbacks include differing research priorities between the funding body, such as the government, and the research institution (Mueller-Langer, 2013).

To address uncertainty in vaccine demand, advanced market commitments, which secure bulk purchases of vaccines at set prices, can be established. This approach has been implemented successfully by Gavi, a multilateral institution that procures vaccines to facilitate access in vulnerable populations. In 2009, Gavi agreed to purchase large amounts of a recently licensed pneumococcal conjugate vaccine (Gavi, 2020b): this both incentivized pharmaceutical companies to produce the vaccines and guaranteed pricing for the consumer. Similar agreements could be established for other vaccines, though these agreements alone would likely be insufficient for a global pandemic scenario. Public investment would also be needed to promote manufacturing capacity, acquire materials, and enable technology transfers for timely vaccine development (Gavi, 2020b).

Global manufacturing capacity requires consistent production to remain viable. Facilities are costly to maintain and cannot be sustained by developing a product only during pandemic times; they have to be in continual production (Smith et al., 2011). One solution is to use facilities to produce seasonal influenza vaccine. By producing annual vaccines, facilities

will have a more reliable business model for production, and have more experience in vaccine manufacturing, in a pandemic situation.

Liability for Vaccine Developers and Manufacturers

The possibility of incurring liability associated with a new vaccine technology is a significant barrier to innovation. In emergencies, companies may be reluctant to make vaccines available on the basis of only preliminary safety data, even after determining that the benefits outweigh the risks (Billington et al., 2020). During COVID-19, for example, large pharmaceutical companies would not release a product under an emergency authorization unless there was liability protection of some type (Halabi et al., 2020). However, during an influenza pandemic, insurance may not be available initially, or the potential liability from a vaccine that rapidly entered production may be too great, which could limit supplies at the very time when the vaccines are most needed.

For the COVID-19 vaccines, manufacturers looked to countries receiving and administering the vaccines to indemnify them against product liability claims. At the same time, vaccinated individuals who experience unexpected serious adverse events deserve compensation. COVAX¹ developed a system to provide compensation to those individuals in any of the 92 economies, supported by Gavi and the COVAX Advance Market Commitment (COVAX, 2020). These mechanisms are only in place when introducing the vaccine; after a product is licensed and the public health emergency has ended, liability is held by the manufacturer. Though little empirical evidence has been collected to date on the effectiveness of such programs, similar mechanisms can be assessed for appropriateness in future scenarios.

One solution would be to invoke the Public Readiness and Emergency Preparedness Act, which “provides immunity from liability,” except in the case of willful misconduct, “for claims of loss … resulting from administration or use of countermeasures to diseases, threats and conditions,” that the Secretary of the U.S. Department of Health and Human Services determines “to constitute a present, or credible risk of a future public health emergency” (HHS, 2021). This immunity would extend to entities and individuals involved in the development, manufacture, testing, distribution, administration, and use of such countermeasures, including vaccines. Such a declaration was made in February 2020 for the COVID-19 pandemic (CRS, 2021).

Vaccines are safe but because they are used to prevent rather than treat disease, they receive a high level of scrutiny to ensure the safety of the

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¹ COVAX is the acronym for COVID-19 Vaccines Global Access; see fn. 9 and the text discussion in Chapter 2.

products. Despite the added safeguards, there have been instances where severe adverse reactions could have been attributed to the influenza vaccine, although these events remain extremely rare (less than 1 case for every 1 million seasonal influenza vaccine doses) (Trombetta et al., 2018). Despite the rare occurrence, vaccine-associated risks are not zero and therefore a no-fault compensation system needs to be considered to boost public confidence in the process and to ensure vaccine manufacturers agree to procurement and shipping contracts to ensure a steady supply of vaccines, particularly during a pandemic (Halabi and Omer, 2017; Halabi et al., 2020).

Different models have been used and proposed to ensure liability protection for vaccine manufacturers. A scoping exercise conducted in 2018 found 25 jurisdictions with no-fault compensation programs, primarily at the central or federal government level (15 of 25), with funding from the government (Mungwira et al., 2020). Four countries implemented compensation programs at the province level and two were administered by the insurance sector. Given only 25 out of 194 WHO member states indicated a system for liability coverage, additional models were explored to consider a more comprehensive liability protection program for vaccines used throughout the world (Halabi et al., 2020). A global vaccine injury compensation system would aim to overcome real and perceived inequities faced by low-income countries. WHO has an insurance program for emergency use vaccines (albeit small) where recipient countries agree to indemnify all parties involved across the entire supply chain, and in return, WHO provides compensation to people with serious adverse reactions to the vaccine or the vaccination (Halabi et al., 2020). Table 6-3 describes the components of the WHO program, as well as two other options for housing a vaccine injury compensation system. Table 6-4 lays out the pros and cons to each possibility. The key to a WHO- or COVAX-like system is having a centralized mechanism to negotiate with different vaccine manufacturers while avoiding time-consuming negotiations over indemnity and other legal complexities.

A centralized system would give countries the option of buying into a group liability protection arrangement. Another option, organized through a supranational body like the World Bank, could provide protection at the highest level but would necessitate participation by all countries or risk the appearance of suboptimal protection if only LMICs joined. While the World Bank does not have specific expertise related to health products, the Multilateral Investment Guarantee Agency (MIGA) is a member of the World Bank Group: with MIGA, along with other such risk underwriting functions and its in-house expertise in LMIC health systems, the World Bank has the capacity to bring together the necessary elements to create a global indemnity structure. Advantages to using the World Bank as the organizing

TABLE 6-3 Non-U.S. Funding Options for No-Fault Compensation Mechanisms

NOTE: CEPI = Coalition for Epidemic Preparedness Innovations; WHO = World Health Organization.

TABLE 6-4 Pros and Cons of Options for Housing a Vaccine Injury Compensation System

structure were explored in relation to an Ebola vaccine (Attaran and Wilson, 2015): one benefit the authors suggest is the World Bank’s ability to develop an international no-fault compensation scheme for vaccine injuries. This system could be particularly attractive to small, yet well-resourced countries as more cost effective than setting up a national arrangement.

Regardless of the system, it would be unwise for countries to use a mix of protections in which some vaccines have liability protection built into the agreement while other vaccines, possibly domestically produced, do not. Such a mix of liability protections would undoubtedly raise questions of equity as to who gets liability-protected vaccines and who does not. The question of equity is also relevant to how the protection is funded. For a mechanism under a multilateral organization like the World Bank, high- and middle-income countries could be expected to pay a premium for the service while low-income countries could have the expense covered through

a World Bank grant. In accepting vaccine candidates for coverage within this arrangement, manufacturers would produce data demonstrating safety and efficacy. While the vaccine could be purchased by individuals or nations with the financial means to do so, it would not be part of the options of the supranational organization. If the vaccine did not go through WHO prequalification, it would not be eligible for liability protection.

In considerations for removing liability barriers to innovation, the committee concludes that a centralized system is needed for managing no-fault compensation requests covering injuries due to vaccines and vaccinations during public health emergencies. A global indemnity mechanism for vaccine-related injuries available to countries regardless of their mechanism of procurement and financing will ensure quicker adoption of WHO emergency use listed or prequalified vaccines. Such a mechanism will also give more market certainty to manufacturers to invest the appropriate capacity and incentivize them to participate in the WHO emergency use listing or prequalification process. The United States, with its expertise in designing vaccine compensation systems, could support international organizations and nongovernmental organizations in establishing no-fault compensation systems to ensure that individuals who suffer injuries related to administration of vaccines receive compensation without the need for litigation.

FACILITATING MANUFACTURING INNOVATION

Rapid Translation from Clinical to Large-Scale Manufacturing

One goal of innovation in vaccine research and development for pandemic preparedness is to facilitate rapid translation from clinical trial stages to large-scale commercial and sustainable manufacturing. Such rapid translation was accomplished during the COVID-19 pandemic and, to a lesser degree, with the Ebola epidemic of 2014–2016. Vaccines for COVID-19 entered into clinical trials less than 4 months after the SARS-CoV-2 genome was released, with some countries approving the first vaccines for emergency use approximately 7 months later (Ball, 2021). The Ebola virus has been associated with the Ebola disease since the 1970s (Breman et al., 2016), and preclinical studies of several vaccines had been completed before the 2014 pandemic. Vaccine development became a higher priority during the West Africa outbreak of 2014–2016, which was the largest recorded Ebola epidemic. Clinical development for the rVSV∆G-ZEBOV-GP (Ervebo^TM) vaccine began in 2014. It received an FDA licensure and WHO prequalification in 2019 (Wolf et al., 2021). Although the difference in speed of development between the Ebola and COVID-19 vaccines is evident, the approval timeline for both was significantly shorter than the average length of time for novel vaccine approval, which is frequently

longer than 10 years (Billington et al., 2020). In addition to technological advancement and extensive global coordination, years of previous research with Ebola and coronaviruses (i.e., SARS, MERS) facilitated the development of vaccines for them (Wolf et al., 2020).

The rapid development of SARS-CoV-2 and Ebola vaccine candidates was largely attributed to innovators in government and academic laboratories and small biotechnology companies with grants from the U.S. government (Gaviria and Kilic, 2021; Warfield and Aman, 2016). In the case of Ebola, the National Institutes of Health and the U.S. Department of Defense supported early research leading to four Ebola vaccine platforms that could be quickly transitioned into clinical trials during the 2014 outbreak, with support from international funding organizations. A number of larger pharmaceutical companies later partnered with the smaller biotechnology innovators to develop, manufacture, and deliver vaccines during the Ebola outbreak (Warfield and Aman, 2016).

These alliances were instrumental for leveraging the expertise and resources of each partner. New biotechnology companies have the expertise to develop innovative products and may have experience in preclinical and Phase I clinical trials for “proof of concept,” but they are often inexperienced in scale-up and manufacturing and lack comprehensive regulatory experience. In the midst of a pandemic, the time needed to find an experienced partner to assist in further product development may result in critical delays in meeting population needs as quickly as possible. If a vaccine candidate comes from a small biotech company with funding through a government entity, such as BARDA, or a global public entity, such as CEPI, grants stipulating how biotechnology companies will achieve large-scale manufacturing or partner with a large pharmaceutical company would maximize speed and fluidity throughout the entire vaccine manufacturing process. The smaller company would not have to engage in a partnership with a larger pharmaceutical company as long as a plan is in place to achieve large-scale manufacturing of the innovation. As is evident from the example of Ebola, collaboration between government entities, biotechnology innovators, and experienced vaccine manufacturers contributed to the emergence of new vaccine candidates (Warfield and Aman, 2016). Future strategies are needed to ensure that partnerships between the new biotechnology innovator and successful, experienced vaccine-related companies can be implemented immediately once the need for pandemic or new seasonal influenza vaccines is identified.

Incentivizing Innovation for Improved Vaccines

In 2009, only seven manufacturers produced the majority of the world’s influenza vaccines. By 2019, the number of manufacturers increased to 32, with expanded global distribution (Rockman et al., 2020a). This increase can be attributed to programs such as the WHO Global Action Plan for Influenza Vaccines (GAP) program, which focused on developing manufacturing capacity (Rockman et al., 2020a), but also required incentives to address the risks discussed above. In general, as noted above, manufacturers have been reluctant to invest in the development of seasonal influenza vaccines because of low demand (Osterholm et al., 2012a), the significant investment cost (Røttingen, 2016), and the lengthy time for development (Osterholm et al., 2012a). Given that the last new influenza vaccine to receive approval—FluMist, a live attenuated influenza vaccine—took almost 30 years from concept to regulatory approval and more than $1 billion to move from late preclinical trials to approval, the investment disincentives are substantial (Osterholm et al., 2012a). However, the value of the global influenza vaccine market is projected to increase, reaching $7.34 billion for a typical seasonal influenza year by 2026, compared to a value of $4.05 billion in 2018 (Fortune Business Insights, 2020). This anticipated increase is attributed to the growing global prevalence of influenza and the increased funding of research programs.

Addressing the low uptake of influenza vaccine by LMICs would create a larger market for manufacturers. Low uptake in LMICs is partly driven by competing health priorities, as influenza is often not seen as a serious disease (Kraigsley et al., 2021). Coupled with the generally lower efficacy of seasonal influenza vaccines and limited data on burden of disease (see Chapter 2), investment in influenza vaccination schedules is often not prioritized (Ortiz and Neuzil, 2019; Osterholm et al., 2012b). The fact that seasonal influenza vaccination requires a costly vaccination campaign every year among the general population also imposes a heavy burden on many LMICs (Kraigsley et al., 2021). Despite these challenges, seasonal influenza vaccination programs can help countries develop more robust health systems by maintaining protocols for vaccine distribution and adult vaccination, which can be useful if other outbreaks occur (Kraigsley et al., 2021; WHO, 2019).

Another challenge to vaccine uptake is that there is a lack of effective messaging about the risks of influenza and the benefits of vaccination (Su et al., 2021), even when efficacy is low (Sah et al., 2018). Developing

improved vaccines could serve to increase confidence in vaccines, which may increase demand. Innovation with more efficient influenza vaccine platforms could drive a feedback loop that creates a more lucrative market, thereby incentivizing manufacturers to continue innovating. Incentives for developing vaccines with more consistent effectiveness and broader public acceptance will help to stabilize the demand for vaccines and improve the return on investment (Osterholm et al., 2012a). Without stable global demand, there will be little incentive for manufacturers to develop improved vaccines.

Developing a truly universal influenza vaccine, administered as a childhood vaccine series with no or minimal needs for a booster, similar to the DTaP vaccine (for tetanus, diphtheria, and whooping cough), would represent a huge advance and likely reward its developer. Currently, a prototype of a universal vaccine has shown promise in early clinical trials (Nachbagauer et al., 2021), but this vaccine does not target all influenza A viruses or any influenza B viruses. The developers estimate it will take at least another 2 years to target the remaining influenza virus families (Cohen, 2020). A large prize could incentivize biopharmaceutical companies to invest in this and other novel approaches, as could extending the priority review voucher program (of FDA) to include new influenza vaccines (Mezher et al., 2020). While financial incentives could motivate companies to innovate, regulatory challenges will also need to be addressed: see Perroud, Appendix A.

Until manufacturing influenza vaccines becomes a more lucrative enterprise, funding to initiate innovation is essential. Providing incentives for companies to innovate could spark a cycle of creative products for addressing seasonal, as well as pandemic, influenza. Whether an advanced market commitment by sponsors could solve the problem of inadequate market incentives for research into vaccines for diseases of developing countries was explored in 2005 by a working group convened by the Center for Global Development (Levine et al., 2005). The group’s approach was later endorsed by G7 finance ministers and supported by six donors (Canada, Italy, Norway, the United Kingdom, Russia, and the Gates Foundation), committing a total of $1.5 billion as an incentive to develop a vaccine against strains of pneumococcus disease prevalent in low-income countries (CGD, 2021). It is important to note that this example relates to adaptation and expansion of manufacturing for an existing vaccine. Costs associated with novel vaccines are likely to be significantly greater.

An advanced market agreement would reduce uncertainty and improve predictability for vaccine manufacturers. However, it is important to ensure that manufacturers that receive public funding will indeed deploy their expertise to action during a pandemic. Public-sector investments are needed to ensure that novel and alternative technologies are developed for influenza

pandemic responses. Policy instruments can also be used to enhance capacity. Financial investment from governments, development institutions, and other agencies can incentivize manufacturers to expand capacities. A combination of loans, subsidies, and volume guarantees (investor guarantees that a given volume of vaccine will be purchased) are three strategies that can be combined and applied to appropriate contexts in order to maximize production capacity (Kazaz et al., 2021). The study of a proposed globally distributed influenza vaccine manufacturing network (see Recommendation 3-1 in Chapter 3) may guide at what stage in the production chain additional incentives for manufacturing capacity are most needed.

Transparency and Other Mechanisms to Ensure Vaccine Safety, Efficacy, and Quality of Production

Approving vaccines for emergency use was a critical step in the COVID-19 response. In the United States, vaccines can receive FDA emergency use approval after sufficient Phase 3 clinical trial data indicates that EUA issuance would yield more benefits than risks (FDA, 2021a). With the rapid emergence of multiple vaccine candidates developed under different national regulatory standards, concern has arisen over vaccine quality,

which is linked to the issue of transparency of clinical trial data. A hasty approval of the vaccine candidate Covaxin raised questions about transparency, as did the lack of recorded informed consents from participants of the Phase 3 trials for Covaxin (Thiagarajan, 2021). When two incidents occurred, one death after a dose of Covaxin and one case of acute neuroencephalopathy following administration of Covishield, a different vaccine, both were difficult to explain given the lack of transparency surrounding the trials (Bhuyan, 2021; Thiagarajan, 2021). Such lack of transparency erodes public trust in the vaccine development, approval, and manufacturing processes.

Further questions about Covaxin emerged when Anvisa, the Brazilian Health Regulatory Agency, suspended the vaccine’s emergency use application due to a failure to submit mandatory documents for the vaccine (Reuters, 2021). Tension in Brazil further played out publicly after Anvisa declined to authorize the imported Russian Sputnik V vaccine due to quality and safety concerns, which included being denied access to the quality control center and some vaccine production sites (Moutinho and Wadman, 2021). Russia approved its COVID-19 vaccine from the country’s Gamaleya National Center of Epidemiology and Microbiology for emergency use before publishing its Phase 1 and 2 data and without conducting Phase 3 trials—a standard ethical procedure for all vaccines to establish safety and efficacy data prior to approval (Baraniuk, 2021). Although data were later published, concerns lingered as to whether the vaccine had been thoroughly investigated (Petersen et al., 2020). Similar questions surrounded the Ad5-nCoV vaccine from the company CanSino Biologics, which published Phase 1 and 2 data then received regulatory approval for its use in the military without the completion of the Phase 3 trial (Kyriakidis et al., 2021).

Transparency is crucial so the scientific community can review study designs and results. It is also necessary so the public understands and has confidence in the processes, which can reduce vaccine hesitancy and lead to increased vaccine uptake. Transparency is important for open decision making and increasing confidence in vaccines (Nature, 2020a). If used in an open and transparent manner, the committee finds that press releases can be a method that manufacturers use to communicate with the public to provide a better understanding of clinical trial design and how to interpret the study results. Press releases are a first step toward transparency, but publication of a trial’s study protocol is the “gold standard” because it allows scientists and public health experts to analyze the trial. To that end, four manufacturers (AstraZeneca, Pfizer and BioNTech, Moderna, and Johnson & Johnson) made their full study protocols available for public scrutiny (Mahase, 2020). The press release and protocol information could be published along with a slide deck of detailed information that is also published in a peer-reviewed article. These efforts could be part of best

practice guidelines for manufacturers and researchers during a public health emergency, while uploading vaccine clinical trials into a public database could be standard practice for vaccines.

Clinical trial registries are used to inform researchers of ongoing studies (Mayer and Huser, 2020). Registering clinical trials and reporting their results in a timely manner is considered an ethical and scientific obligation of all researchers. WHO compiled a set of 14 minimal standards it believes should be contained in every primary registry and recognized 17 such public registries. In a comparative study rating of the 17 WHO primary registries plus the U.S. system, Clinicaltrials.gov, researchers uncovered widely divergent quality of the primary registries’ compliance with minimal standards (Venugopal and Saberwal, 2021). The COVID-19 pandemic demonstrated the need for open sharing of clinical trial information as some national regulatory authorities grappled with which vaccines to approve for emergency use. While there are arguments for setting up a single worldwide registry as well as maintaining local registries, during a pandemic when the need for sharing is greatest, having one site that stores all vaccine clinical trial data and information could speed communication across the research community. This approach would require that the registry has acceptable functionality and information is accurately and comprehensively uploaded.

ClinicalTrials.gov is the largest registry in the world with over 382,000 research studies uploaded from 220 different countries and territories (NLM, 2021). In 2016, FDA issued requirements and procedures for registering and submitting summary results for certain clinical trials into ClinicalTrials.gov; the National Institutes of Health (NIH) subsequently adopted a policy mandating all clinical trials funded in full or in part by NIH to be registered on the site (Humphreys, 2019). A caveat to the requirement is that if the responsible party believes a protocol contains trade secrets or confidential commercial information, the responsible party may redact that information (HHS, 2016). A study has found a lack of timely reporting of overall clinical trial results on public registries or through academic publication, along with an evidence gap for the safety of drugs being repurposed for COVID-19 (Rodgers et al., 2021). Failure to share clinical trial results publicly is especially concerning during a pandemic, when rapid sharing of clinical trial data and information can build public trust and potentially save lives. The committee agrees that all vaccine clinical trials need to be entered into a readily available database registry and trial protocols need to be made available.

Prior to approval for emergency or regular use, each vaccine candidate is thoroughly assessed by regulators for safety, efficacy, and pharmaceutical quality, often with input from independent scientific advisory committees. Evidence of vaccine safety and efficacy is gathered throughout all phases of vaccine development and submitted to regulators for review as part of

the approval process. Once approved, vaccine manufacturers are required to follow Good Manufacturing Practices (GMPs), a system of stringent regulatory standards to ensure that products meet quality requirements (WHO, 2015). Regulators monitor data to confirm the composition, purity, and potency of the produced vaccines and to ensure the manufacturing process at each site is well-controlled and consistent. The requirements for EUA for COVID-19 vaccines are similar to licensure (Weir, 2020). To enable FDA to conduct a meaningful review, an EUA request “must include chemistry, manufacturing, and controls data, identification of the manufacturing site(s), and information with respect to current GMP” (Weir, 2020). Confidence in and reproducibility of safety and efficacy results depends on establishing and maintaining high standards for vaccine quality control and manufacturing.

In developing COVID-19 vaccines, ensuring harmonized guidelines for vaccine approval was a significant challenge. A review of the global regulatory landscape revealed 50 distinct regulatory pathways for accelerated vaccine approval (Simpson et al., 2020). Although WHO’s emergency use listing serves as a global process for ensuring safety and efficacy of vaccines used by UN agencies and Gavi, the number of different pathways reveals challenges in streamlining processes to ensure that vaccines produced under different standards meet criteria for global distribution. Ensuring that vaccines from different pathways all meet WHO listing standards for global use requires a significant investment of resources. In addition, even after vaccines have attained a WHO listing, countries must still assess whether or not the vaccine meets their specific requirements (Nature, 2020b). Regulatory harmonization and more agreement on international vaccine standards could mitigate some of these barriers and allow safe, effective vaccines to reach target populations more efficiently in the event of a public health emergency.

During a pandemic, as was evidenced during COVID-19, there is a need for rapid scale-up of production immediately after a vaccine is approved. Some companies have the capacity to complete the entire manufacturing process themselves while other companies rely on contracts with third-party firms and pharmaceutical industry partners to work together (Moscicki, 2021; Mukherjee, 2021). For example, Moderna collaborated with Lonza to manufacture Moderna’s vaccine at facilities in Visp, Switzerland, and Portsmouth, New Hampshire, while the fill and finish stages (putting vaccine into glass vials) was done by other partners in Spain and the United States (King, 2021). This example speaks to the complexity of manufacturing and the challenges faced by regulators in keeping up with the demand for vaccine approvals and inspections. To keep up with the demand while maintaining oversight of foreign-manufactured medical products during the COVID-19 pandemic, FDA is leveraging inspection reports of regulators in the Euro-

pean Union and the United Kingdom under the Pharmaceutical Annex of the U.S.–EU mutual recognition agreement (MRA) (FDA, 2020). The MRA is a formal agreement between FDA and regulators in the European Union and the United Kingdom that allows drug inspectors to rely on inspections conducted in each other’s jurisdictions (FDA, 2021c).

Transparency of inspections and clinical data are key for countries to be able to make decisions about whether or not to purchase vaccines during a pandemic. Advanced product specifications are needed (both for safety and efficacy and for storage and distribution) to permit each country to assess which vaccines to consider for their populations and which to manufacture locally, if a country has that capacity. A cadre of certified international regulators could be used to inspect facilities, although this would require the establishment of a new inspection body. To achieve this, in the event of a pandemic a global entity could maintain and deploy a small team of international regulatory inspectors who have experience in both normal and pandemic regulatory pathways. The inspection team would provide a cadre to conduct just-in-time inspections of pandemic influenza manufacturing facilities. This model could be used for all pandemics and not just influenza, although it is not certain whether the WHO prequalification program would be the best entity to host such an initiative. The program would in all likelihood involve stringent regulatory authorities, such as FDA’s Office of International Programs, and engage the U.S. Department of State in its work with global agencies.

There is a need for an expedited but stringent regulatory inspection and audit process for ensuring safety, efficacy, and manufacturing quality of vaccines during a pandemic. WHO has proposed the establishment of a treaty for pandemic preparedness and planning, which includes bolstering supply chain resilience. During the World Health Assembly on May 31, 2021, all 194 WHO member nations agreed to pursue discussions on a treaty (EU, 2021). The committee agrees that such a treaty should be pursued, with a focus on addressing supply chain gaps that have been revealed throughout the course of the COVID-19 pandemic. Although treaties are slow and challenging to negotiate, such a treaty is the most promising long-term solution for addressing a global issue as pressing as pandemic preparedness. Unanimous support for ongoing discussion reveals that a treaty, though a lofty goal, has the support to be feasible in years to come.

For global public health, there needs to be assurance that vaccines produced by manufacturers and purchased by countries have WHO emergency use listing or prequalification status to ensure quality of production at all sites. Harmonized guidelines—on the accepted steps in the regulatory pathway for seasonal influenza vaccine development, demonstration of safety and efficacy, and manufacturing before release of vaccine for population-based use—could accelerate timelines for vaccine production and release

in pandemic response (Wolf et al., 2020) while assuring quality and safety. Strengthening national regulatory competency in LMICs in coordination with harmonized international regulations could further this aim (see Perroud, Appendix A).

In order to ensure global quality and uphold stringent standards, disincentives are also needed to discourage manufacturers from bypassing good clinical practices. For example, adherence to GMPs could be added as a condition of acceptance into a global indemnity program, along with a WHO emergency use listing or prequalification status. Manufacturers that bypass good clinical practices would not qualify to be included in any no-fault compensation system set up, regardless of its structure. Without a no-fault compensation system, the manufacturer liability could be a great enough risk to deter vaccine manufacturing with low-quality standards. Exclusion from no-fault compensation systems could serve as a barrier to exporting vaccines and discourage manufacturers from disregarding Good Manufacturing Practices.

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