Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines (2022) / Chapter Skim
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6 Barriers, Incentives, and Innovations for Sustainable Manufacturing
6 Barriers, Incentives, and Innovations for Sustainable Manufacturing
Pages 155-188
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From page 155... ...
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.
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scaled manufacturing • G20 Recommendation 6-3: Incentivizing sustainable manufacturing platforms through improved vaccines • World Bank Recommendation 6-4: De-risking vaccine uptake: Global indemnity • WHO Recommendation 6-5: Ensuring • HHS safe and efficacious quality • FDA vaccine production 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.
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From page 157... ...
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)
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From page 158... ...
. 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)
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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.
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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.
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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.
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. Under GAP, 14 LMICs received grants to develop local influenza vaccine manufacturing capacity, and those grants included support for regulatory framework development.
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The assessment should inform a decision-making framework for future investments that recognizes the dynamically evolving nature of technologies and tradeoffs for different platforms. 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.
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From page 164... ...
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.
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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.
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Seasonal influenza vaccines do not have to undergo lengthy and expensive
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. One solution is to use facilities to produce seasonal influenza vaccine.
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. 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)
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. Different models have been used and proposed to ensure liability protection for vaccine manufacturers.
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, distributors, or suppliers; general revenues Eligibility • Based on • Criteria jointly • Existing criteria for other temporal developed by vaccines that are eligible for relationship CEPI; Gavi, compensation on programs, between the Vaccine including vaccines deployed immunization Alliance; and under criteria for a national and serious the WHO that public health emergency, e.g., adverse event could include "balance of probabilities" temporal or "compelling" evidence association or of a relationship between tables of injuries immunization and serious based on phase adverse event 3 trial data Administration • WHO • Third-party • Designation national judicial or compensation- claims of administrative authorities claims personnel administrator, and insurance- including claimers claims administrators administration services available from global insurers Elements of • Lump-sum • Lump-sum • Nationally determined Compensation payment based payment based compensation (based on lost on weighted on weighted wages, nonreimbursed medical average of average of expenses, disability pension, claims histories claims histories and noneconomic loss, and for injury for injury including death benefits) compensation compensation in national in national systems adjusted systems adjusted for relative for relative purchasing value purchasing value NOTE: CEPI = Coalition for Epidemic Preparedness Innovations; WHO = World Health Organization.
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From page 171... ...
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.
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From page 172... ...
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)
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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)
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From page 174... ...
. 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)
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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.
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RECOMMENDATION 6-3(a) : The G20 should provide substantial monetary and other incentives -- such as intellectual property volun tary licensing, advanced market commitments, and priority review vouchers -- administered through a future structure for financing, procurement, and deployment for pandemic vaccines, to develop im proved seasonal and pandemic influenza vaccines that would increase uptake and demand, leading to sustainable manufacturing capacity investments.
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. Such lack of transparency erodes public trust in the vaccine development, approval, and manufacturing processes.
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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.
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. 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.
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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 populationbased use -- could accelerate timelines for vaccine production and release
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should prioritize efforts for the creation of a treaty mechanism for pandemic influenza vaccine manufacturing countries whereby they agree to undergo plant inspections by independent inspectors and only export vaccines that are approved through WHO's emergency use list ing procedures or prequalification program.
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2021. SARS-CoV-2 vaccines in advanced clinical trials: Where do we stand?
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2020a. Can vaccine clinical trials be sped up safely for CO VID-19?
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2020. Lessons from COVID-19: Advancing development of universal influenza vaccines.
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2020a. Pandemic influenza vaccines: What did we learn from the 2009 pandemic and are we better prepared now?
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Alternative models for influenza vaccine R&D fi nancing. Paper presented at Third WHO consultation on Global Action Plan on Influenza Vaccines (GAP III)
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2015. Advancements in the de velopment of subunit influenza vaccines.
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