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Appendix A Review of Previous Recommendations for Pandemic Vaccine Manufacturing Janamarie Perroud This paper reviews the recommendations, gaps in implementation, and subsequent guidance on sustainable incorporation of these recommenda- tions in the future from previous studies of vaccine manufacturing. It covers reports and guidance documents providing recommendations relating to pandemic vaccine manufacturing following the SARS, H1N1, Ebola, and COVID-19 outbreaks. The paper focuses on global recommendations, with the inclusion of some geographically specific recommendations. The literature search on which this paper is based was representative rather than exhaustive: it covered recommendations from 33 peer-reviewed and grey literature sources from different perspectives, periods, and out- break circumstances during the years during and following the disease out- breaks. A summary of these recommendations and their sources are shown in Table A-1 at the end of this paper. Table A-2 shows recommendations that have not been implemented in two categories: (1) vaccine develop- ment and production technologies and (2) pandemic vaccine production processes. There was significant thematic overlap in recommendation topics across reports, which can be categorized in five areas: â¢ innovation in vaccine development and production technologies, â¢ optimization of pandemic vaccine production processes, â¢ regulatory harmonization, â¢ stakeholder coordination, and â¢ sustainable funding. 193
194 GLOBALLY RESILIENT SUPPLY CHAINS The rest of this paper discusses each of these areas in turn; the final section presents my conclusions from this review. INNOVATION IN VACCINE DEVELOPMENT AND PRODUCTION TECHNOLOGIES The measure of a pandemic vaccine manufacturing system is the suc- cessful production of vaccines as efficiently as possible while maintaining the safety and efficacy of the product. Vaccine technologies differ in their manufacturing exigencies and thus have a strong bearing on production capacities. Therefore, research and development (R&D) technologies that optimize downstream processes and permit rapid scale-up, while maintain- ing standards of quality, are critical in ensuring large volume production of pandemic vaccines (Hosangadi et al., 2020). To this end, a key area of pandemic vaccine manufacturing recommendations centers on the improve- ment of manufacturing capacities through development and application of better vaccine technologies. In 2006, the World Health Organizationâs Global Action Plan for In- fluenza Vaccines (GAP) urged the development of more potent and effective vaccine candidates (WHO, 2006). One recommended advancement was the development and improvement of non-egg-based technologies that provide more manufacturing flexibility and efficiency (ASPR, 2020; WHO, 2006). Such recommendations have consistently been made over the past 15 years. Alternative technologies, such as cell-based and recombinant vaccines, have been developed and are available in certain high-income markets, including the United States. However, the majority of influenza vaccines around the globe are still produced in chicken eggs and cell-based technologies, which have been cited as too costly (Presidentâs Council of Economic Advisors, 2019). Thus, many recommendations have highlighted the need for further funding and technology transfer to support the global diversification of influenza vaccine technologies. Other recommendations called for a focus on vaccine R&D efforts that have the potential to largely benefit low- and middle-income countries (LMICs), such as the development of long-lasting generic influenza A vac- cines (NASEM, 2019; WHO, 2016a, 2017b). This technology could be an attractive option for LMICs, as it would reduce the burden of adopting annual seasonal influenza vaccine programs. These programs would in turn improve pandemic vaccine production through the capacity to meet routine influenza vaccine demands (NASEM, 2019; WHO, 2016a). There have been numerous advances in influenza vaccine technologies since the initiation of GAP, with support (such as government agency-focused contracts) to en- sure the development and dissemination of new influenza virus backbones (PCAST, 2010). However, given the scientific, regulatory, and financial barri-
APPENDIX A 195 ers, a universal vaccine without the need for adaptation across strains has yet to be achieved, as discussed in Chapter 6 of this report. The World Health Organization (WHO) reaffirmed the goal of developing such a vaccine in its 10-year review of the GAP in 2016 (WHO GAP Advisory Group, 2016). Recommendations following the H1N1 and Ebola outbreaks encour- aged development and adoption of more flexible manufacturing capacities, such as vaccine platform technologies through which a single manufactur- ing mechanism can be used for several vaccines (ASPR, 2020; EOP, 2018; HHS, 2010; Hosangadi et al., 2020; Newland et al., 2021). These technolo- gies have the potential to increase speed of emergency vaccine production, minimize the financial burden of novel vaccine development within the technology, and facilitate streamlined regulatory approvals (Adalja et al., 2019). The use and iterative refinement of platform technologies can accel- erate the development process by shortening preclinical phases (Hosangadi et al., 2020), as illustrated in the advancement of certain COVID-19 vac- cines (Sell et al., 2021). The mRNA vaccine platform developed for SARS and MERS by the Vaccine Research Center at the National Institutes of Health (NIH) was mobilized for COVID-19 when its genetic sequence was published. Additionally, the Biomedical Advanced Research and Develop- ment Authority, in the U.S. Department of Health and Human Services, and the Coalition for Epidemic Preparedness Innovations (CEPI) provided fund- ing to vaccine developers advancing these platforms to prepare COVID-19 candidate vaccines (Keusch and Lurie, 2020), highlighting the importance of funding mechanisms in expanding and sustaining development efforts. Alternative recommendations to facilitate rapid availability of pan- demic influenza vaccines have included the development of mock-up âpan- demic-likeâ vaccines designed to protect against anticipated pandemic virus characteristics (WHO, 2004). This approach requires developing vaccine candidates that match influenza subtypes that have been tested in advance and are ready for scale-up at the time of pandemic strain emergence. As such, a vaccine would not match the exact pandemic strain antigenically and it would not prevent infection, but it could reduce the pandemic burden until a specialized vaccine is developed (IOM, 2004). Mock-up vaccines were developed for influenza from which a pandemic version of the vaccine was developed and deployed in response to the H1N1 pandemic (Duffy et al., 2014). There has been no mention of mock-up vaccines in recommenda- tions made after the H1N1 pandemic: see Table A-1. OPTIMIZATION OF PANDEMIC VACCINE PRODUCTION PROCESSES Recommendations following the SARS outbreak, and, subsequently, Ebola and COVID-19, broadly called for planning to increase vaccine
196 GLOBALLY RESILIENT SUPPLY CHAINS manufacturing capacity for large-scale testing and production of pandemic vaccines (CEPI, 2016; EOP, 2018; IOM, 2004; NVAC, 2020). In response to earlier outbreaks, such as SARS, recommendations made to address production limitations emphasized the establishment of national and inter- national antigen stockpiles (WHO, 2004). One such recommendation to institute a WHO avian flu stockpile called for stockpile provisions from the increased production and dona- tion of doses by manufacturers (WHO, 2018). Manufacturers responded positively with pledges to donate 110 million of the 150 million doses of vaccine to establish the stockpile. However, these pledges did not come to fruition as the H1N1 pandemic that followed illustrated the likelihood of a poor antigen match between H5N1 (avian flu) vaccines and a pandemic influenza strain (SAGE, 2013). This experience revealed stockpiles as an un- reliable mechanism to respond to manufacturing constraints for pandemic influenza vaccines because stockpiles, by nature, cannot store vaccines for novel pathogens (Hosangadi et al., 2020). The WHO Strategic Advisory Group of Experts on Immunization (SAGE) reversed its recommendation in light of this experience, subsequently relying on the Pandemic Influenza Preparedness (PIP) framework agreements to secure pandemic influenza vaccines in real time during a pandemic (SAGE, 2013). Nevertheless, some stockpiles are still maintained for viruses responsible for recurring out- breaks of stable pathogens, with recommendations to monitor and manage stockpiles in order to provide manufacturers with demand forecasts, signal production needs for replenishment, and mitigate risks of stockpile deple- tion (ECDC, 2017). Another prominent recommendation to address the manufacturing ca- pacity constraints for pandemic influenza vaccines has been to globally increase and sustain seasonal influenza vaccine programs. This approach helps generate demand for production and stimulates increased capacity that can be leveraged for an influenza pandemic response (Abelin et al., 2011; ASPR, 2020; WHO, 2006, 2011). Between 2014 and 2018, there was a slight increase from 59 percent to 61 percent of WHO member states adapt- ing their national policies to adopt seasonal influenza vaccines. However, 85 percent of the countries that did not have an influenza program were LMICs (Morales et al., 2021). This illustrates the need for additional consideration of the application of these recommendations to LMICs, especially given the associated resource constraints faced from competing health priorities and domestic health financing restrictions (Kraigsley et al., 2021). The resource limitations of LMICs are also a barrier in deploying a distributed vaccine manufacturing structure due to the recurrent costs for development and production of vaccines matching seasonal strains (WHO, 2017b). Additionally, there were recommendations for the development of sea- sonal influenza programs to be coupled with a global recommendation pro-
APPENDIX A 197 cess to inform the switch to pandemic vaccine production in consultation with technical advisory bodies, including SAGE and the Global Influenza Surveillance and Response System (WHO, 2017a). Other recommendations included updating global vaccine manufacturing preparedness plans for switching from seasonal to pandemic vaccine manufacturing (WHO, 2019) and subsequent manufacturer switch contingency plans (Lurie et al., 2021; WHO, 2004), as there is limited guidance available on implementing these switch strategies. To this end, several recommendations also highlighted the need for knowledge transfer and technical support to establish and bolster local manufacturing capacity in LMICs with new technologies favorable to pan- demic production (Sell et al., 2021; WHO, 2011, 2016a, 2017b, 2018). Technical support could be particularly useful for implementing recom- mendations for geographically distributed manufacturing (ASPR, 2020; Hosangadi et al., 2020; Sell et al., 2021). Developing local capacities through distributed manufacturing increases resilience of the supply chain by avoiding overreliance on centralized manufacturing sites often controlled by industrialized countries. Distributed manufacturing also mitigates the concentrated risk of production delays when relying on few centralized cites for production (Hosangadi et al., 2020). This possibility was illus- trated during the second wave COVID-19 surge in India in the spring of 2021, when the Serum Institute of India, one of the largest vaccine produc- ers in the world and under license to produce the Astra Zeneca vaccine, experienced delays (COVAX, 2021b). Overall, significant adoption of such distributed manufacturing strategy remains an aspiration. REGULATORY HARMONIZATION A key theme in the recommendations coming from a range of stake- holders, including manufacturers, academia, governments, and interna- tional agencies is the need for improved regulatory and licensing practices. A traditional approach to vaccine manufacturing is to establish highly spe- cialized sites to reduce costs and meet regulatory requirements (Hosangadi et al., 2020). Such a specialized approach limits the capacity for the rapid development and production of novel vaccines required for a pandemic response. The adoption of new vaccine platform technologies appropriate for distributed manufacturing networks has been suggested for rapid pan- demic response (Sell et al., 2021). Regulatory approvals across agencies, countries, and regions required to produce and distribute vaccine products globally present a challenge to adoption of these recommendations. Regu- latory agencies have differing requirements that must often be addressed individually at high costs in both time and money, both of which are scarce resources in a pandemic response (WHO, 2004).
198 GLOBALLY RESILIENT SUPPLY CHAINS In response to these regulatory challenges, recommendations have called for the design of flexible international regulatory approaches (HHS, 2010; Hosangadi et al., 2020) and support (Lurie et al., 2021), which in- clude clearer pathways to approval (WHO, 2010), and harmonization of candidate licensure and marketing approvals in order to accelerate time- lines for vaccine production and release in pandemic response (WHO, 2004; Wolf et al., 2020). Maintaining open and active dialogue between manufacturers and regulatory officials (Kusters et al., 2009; Wolf et al., 2020) throughout this process has been encouraged. Additionally, there have been recommendations to strengthen national regulatory competency in LMICs (WHO, 2016a) in coordination with harmonized international regulations. Steps have been taken to reconcile regulatory requirements through networks such as the European Medicines Agency, the African Vac- cine Regulatory Forum, and the WHO International Coalition of Medicines Regulatory Authorities, yet differences and inconsistencies persist. A CEPI analysis of regulatory agencies indicated differences are still prominent in a range of issues including genetic modification, trials in pregnant women, and vial labeling (Eyes of the world, 2010). STAKEHOLDER COORDINATION Given the interdependence of vaccine development, production, regula- tion, and distribution, pandemic vaccine manufacturing has consistently faced challenges in timely scale-up. In a review of barriers to information resulting from the lack of reliable systems and statutes for sharing epidemio- logical, genomic, and clinical data in the Ebola response, the Independent Panel on the Global Response to Ebola of Harvard University and the Lon- don School of Hygiene & Tropical Medicine (LSHTM) recommended that WHO lead the development of a global framework of norms and rules for R&D including provisions for access to benefits of research (Moon et al., 2015). In line with this recommendation, the WHO R&D blueprint global strategy and preparedness plan was adopted at the World Health Assembly in 2016. This WHO-convened platform was designed to provide technical guidance and coordination to facilitate R&D activities for prioritized patho- gens including vaccine products. However, this framework did not include the binding rules recommended by the HarvardâLSHTM independent panel (WHO, 2016b), without which stakeholder adherence cannot be guaran- teed. One example of this was observed early in the COVID-19 pandemic, when certain stakeholders were not eager to participate in broader global collaboration, further highlighting the need for clarified stakeholder agree- ments and accountability (Keusch and Lurie, 2020). Beyond the establishment of an R&D framework, recommendations following the Ebola response also called for joint coordination and man-
APPENDIX A 199 agement of pandemic vaccine research, development, manufacturing, and distribution efforts. With the mission to accelerate the development of vac- cines against emerging infectious diseases and enable equitable access to these vaccines for people during outbreaks, CEPI was launched at Davos in 2017 as an end-to-end coordinating mechanism. However, despite its proactive efforts, lacking backing from a global financing mechanism with the means to secure the scale, CEPI has been constrained in facilitating the high level of pandemic vaccine development needed for effective COVID-19 pandemic response. In order to properly maintain CEPIâs efforts, sustain- able funding would be needed (Lurie et al., 2021). Another challenge in stakeholder coordination for pandemic vaccine manufacturing is the allocation of resources needed to produce vaccines and prepare them for distribution. For most influenza vaccine technologies, this process begins with sharing the candidate vaccine viruses and refer- ence reagents needed for vaccine development and production with vaccine manufacturers. These materials are critical as both egg-based and cell-based vaccine production require the candidate vaccine viruses to replicate and process with their respective technologies (PCAST, 2010). The PIP frame- work stipulates provision of candidate vaccine viruses, sequences of influ- enza viruses, and reference reagents to vaccine manufactures on request as a part of a broader collaborative benefit-sharing system across global agencies and manufacturers (SAGE, 2013; WHO, 2018). However, this framework is limited to influenza viruses of pandemic potential and thus has not met the needs of non-influenza epidemics, such as Ebola, SARS, and COVID-19. In the spring 2021 the COVAX manufacturing task force was estab- lished to address bottlenecks in COVID-19 vaccine manufacturing, such as shortages in materials and components and limited fill-finish capacity by matching manufacturers with suppliers, funding and leveraging the global vaccine community (COVAX, 2021a) (see Chapter 3 of the report). The disease-specific nature of this mechanism and the broader COVAX initia- tive further highlights concerns of sustainability in addressing these needs in future pandemic situations. As a result, there have been many recommenda- tions for a mechanism to coordinate the interdependent powers that affect pandemic vaccine manufacturing in order to effectively and efficiently supply pandemic vaccines to the global population be established and set for de- ployment at the front end of any future pandemic (Keusch and Lurie, 2020). There is also a broader need to address issues of intellectual property rights in order to enable commercial production capability in pandemic circumstances (Bollyky and Patrick, 2020; WHO, 2004). One recommen- dation aimed at facilitating access to critical intellectual property called for the creation of a patent pool for the SARS genomic sequence to similarly facilitate vaccine development and manufacturing (Simon et al., 2005). This recommendation had willing parties and support from the WHO
200 GLOBALLY RESILIENT SUPPLY CHAINS SARS Consultation Group and the NIH Office of Technology Transfer in the United States. However due to regulatory barriers, this venture stalled. When the SARS epidemic threat receded, resources were turned elsewhere, and this attempt was left in limbo (Levy et al., 2010). While the patent-pool approach to information access was not realized for the SARS sequence, some believe it warrants further attention as a tool to facilitate and elucidate vaccine licensing processes and the associated costs (Simon et al., 2005). Similarly, patent pooling or sharing for pandemic vaccines could be explored as a compromise to full patent waivers (Gonsalves and Yamey, 2021). SUSTAINABLE FUNDING In response to the avian influenza outbreaks in the early 2000s, global stakeholders including WHO, vaccine manufacturers, licensing agencies, and government representatives urged governments to regard pandemic vaccines as a public health good (WHO, 2004). Yet, the current vaccine de- velopment manufacturing system is still largely driven by profit incentives, and uncertain precrisis demand blocks pandemic vaccine development and production. In the case of COVID-19, the heavy burden of disease across high-income countries has worked in favor of this system. However, for certain outbreaks such as H1N1 and Ebola, it has not been as favorable (Lurie et al., 2021). Analysis of the H1N1 and Ebola responses made clear that invest- ments in health infrastructure, including vaccine manufacturing capacity, have been inadequate despite formal commitments of national govern- ments to do so under the 2005 International Health Regulations (Moon et al., 2015). In response, several recommendations have systematically called for the provision of sustainable and flexible financing for pandemic vaccine manufacturing (ASPR, 2020; Bollyky and Patrick, 2020; CEPI, 2016; PCAST, 2010). Conservative recommendations focus on developing localized financial incentives and protections (Bollyky and Patrick, 2020; Lurie et al., 2021; PCAST, 2010; WHO, 2004), such as advanced bilateral agreements between manufacturers and individual governments (Abelin et al., 2011; NASEM, 2019; WHO, 2010, 2011) to reduce vaccine manufac- turersâ financial risk of R&D efforts. While these methods have met the market needs in the current circumstance with COVID-19, there are only a select few high-income countries with the means to address such financial and liability risks, leaving LMICs to lag behind in engagement with manu- facturers (Keusch and Lurie, 2020). COVAX, the vaccination pillar of the Access to COVID-19 Tools Accelerator (ACT-A), has demonstrated some successful global market commitments and procurements that have driven production. However,
APPENDIX A 201 financing ACT-A has depended primarily on donor funds for humanitarian assistance to LMICs, which may not have provided enough incentive for development and manufacturing were it not for the separate investments by high-income countries in COVID-19 vaccines (Lurie et al., 2021). Rapid development and manufacturing of COVID-19 vaccines was made pos- sible by significant direct investments to developers and manufacturers by high-income countries. Such direct intervention cannot be guaranteed in the future, particularly if the burden lies predominantly in LMICs, as was seen with the challenges in securing such funding in response to the Ebola epidemic (Moon et al., 2015). In light of this experience, recommendations after the Ebola epidemic advocated for the establishment of a global vaccine R&D financing facil- ity that pools and manages funds across global stakeholders (Moon et al., 2015). An initiative of such scale brings challenges in governance, accounting for the slow progress to act on these recommendations. There are, however, ongoing discussions of how such an effort may best be put into practice. In its report Money and Microbes: Strengthening Research Capacity to Prevent Epidemics, the World Bank (2018) proposed holding a multidonor fund for pandemic vaccine activities (International Vaccines Task Force, 2018), a recommendation that was echoed by a 2020 report to the WHO Global Health Monitoring Board (Keusch and Lurie, 2020). However, this proposal has also been held under some scrutiny due to the World Bankâs mandate focusing on supporting country needs rather than centralized R&D efforts (Lurie et al., 2021). The International Monetary Fund has also come forward with a pro- posal for a financing mechanism via a rapid credit window. The proposed mechanism is designed to provide an initial $30 billion to LMICs to cover vaccine financing needs via advanced purchase agreements through 2022, which would facilitate collective action through such mechanisms as COVAX and remain in place for future pandemic responses (Hicklin and Brown, 2021). More avant-garde funding alternatives circulating include financ- ing pandemic vaccine development with bonds through research-backed obligations that are able to balance risk through their large scale (Vu et al., 2020). While the answer of which mechanism will most sustainably meet the recommendations for global financing for pandemic vaccine development and manufacturing is still up for debate, the recent G20 (2021) report offers alternatives and recommendations to inform the operationalization of such a funding mechanism (see also Lurie et al., 2021). CONCLUSION The recommendations identified in this review highlight that pandemic vaccine manufacturing capacity is impacted by each phase of the pandemic
202 GLOBALLY RESILIENT SUPPLY CHAINS vaccine process, from R&D to demand for doses. Recommendations con- fronted both individual components of this process and needs for broader coordination in support of activities. In addressing pandemic manufactur- ing capacity, recommendations emphasize investment in research and devel- opment of more efficient and flexible production technologies, including the use of cell-based technologies and vaccine platforms that can more readily be mobilized for pandemic manufacturing. Recommendations addressing production capacity have evolved given recent experiences with outbreaks, shifting emphasis away from stockpiles as a mechanism for ensuring pandemic influenza vaccine supply to the develop- ment of stronger manufacturing capacity driven by established demand for seasonal influenza vaccines. Regulatory and licensing requirements were also highlighted as a key barrier to the rapid development and production at scale given the heterogeneity of requirements from different agencies around the world. Recommendations called for harmonization and flexibility of these regulatory requirements in order to support swift transitions to pandemic vaccine manufacturing. Given the complexity of the vaccine ecosystem across development, licensing, production, and distribution, recommendations have recently placed a greater emphasis on developing a dedicated mechanism for stakeholder coordination in both manufacturing planning and response. Each of these areas of recommendation faces challenges in implementa- tion due to a scarcity of sustainable funding for the associated activities. While there seems to be consensus on the need for global allocation of funding for pandemic vaccine preparedness and production, the means of financing is subject to differing opinions that will require consensus to move forward. A crosscutting issue in pandemic vaccine manufacturing is the inability to meet urgent pandemic demands resulting from the lack of unified global response and support.
TABLE A-1 Pandemic Vaccine Manufacturing Recommendations in Chronological Order Degree of Adoption of Recommendations Unknown Not Adopted Slight Progress Moderate Progress Fully Adopted Recommending Body Context Manufacturing Recommendations Identified Actors SARS WHO (2004) Expedite the development of 1. License mock-up pandemic vaccines. 1.â3. Vaccine pandemic vaccines. 2. Address issues of IP rights in order to manufacturers enable commercial production capability. 4. Governments 3. Develop manufacturer contingency plans for switching from seasonal to pandemic production. 4. Provide financial support and incentives for vaccine developing and licensing in absence of market incentives. WHO (Simon et al., Recommend formation of Create a patent pool for SARS genomic CDC, Health Canada, 2005) a patent pool for SARS sequence to facilitate vaccine development and HKU/Veritech, Erasmus genomic sequence. manufacturing. Medical Center/ CoroNovative, and regulatory agencies continued 203
TABLE A-1 Continued 204 Recommending Body Context Manufacturing Recommendations Identified Actors SARS WHO (2006) Increase the pandemic 1. Increase seasonal influenza vaccine 1. WHO regional (continued) vaccine supply and thereby production through demand from offices, member state reduce the gap between the introduction and maintenance of seasonal governments, and potential vaccine demand influenza vaccination programs. donor agencies and supply anticipated 2. Evaluate and develop vaccine and delivery 2. WHO-led collaborative during an influenza technologies. consortium of pandemic. 3. Improve manufacturing capacity through laboratories better production yields, and additional 3. Established and new production plants. vaccine manufacturers SAGE (2007) Recommend WHO stockpile Produce and donate avian flu vaccines to the Vaccine manufacturers of avian flu vaccine. WHO stockpile. IOM (2004) Provide recommendations Prepare vaccine candidates for future pandemic Unspecified that could shape responses threats. to future microbial threats Improve surge production capacity given lessons learned from mechanisms. the SARS epidemic. Kusters et al. (2009) Address issues faced 1. Address manufacturing capacity gaps to 1. National reference in development and adhere with biosafety level requirements centers manufacturing of SARS for emerging epidemic viruses. 2. Vaccine manufacturers vaccine. 2. Maintain open and active dialogue between and regulatory agencies manufacturers and regulatory officials. H1N1 PCAST (2010) Provide guidance in Address large-scale supply delays at the 1. NIAID and BARDA achieving rapid and reliable beginning (virus optimized for manufacturing) 2. U.S. government and production of effective and at the end of the process (fill-finish) of vaccine manufacturers vaccines, at a sufficient scale influenza vaccine manufacturing through 3. U.S. agencies, including to protect all of the nationâs 1. R&D efforts, BARDA, CDC, and residents, in response to 2. production capacity building, and FDA the emergence of pandemic 3. financial and management incentives influenza. for influenza vaccine development and production enterprise.
HHS (2010) Address infectious disease 1. Develop efficient and expandable vaccine HHS vaccines and vaccination- manufacturing approaches, including multi- related issues for the use technologies, and identify best practices United States and its global for oversight. partners. 2. Improve access to pilot lot manufacturing facilities. 3. Promote harmonization of international vaccine regulatory standards for licensure. 4. Provide technical assistance to developing country vaccine manufacturers in production of safe and effective vaccines. WHO (2010) Review the performance Prepare and update vaccine legal and WHO Pandemic Influenza of the WHO Pandemic regulatory processes through A(H1N1) Vaccine Influenza A(H1N1) Vaccine 1. clearer government and manufacturer Deployment Initiative Deployment Initiative and agreements, and collaborators, including identify action points to 2. approval and licensing changes to technical agencies, donor improve upon the systems accelerate pandemic vaccine manufacturing governments, and private- established to respond more process. sector organizations effectively to the needs of countries in the future. IFPMA, IVS Review the contributions Address bottlenecks impeding efficient 1. WHO network International Task of R&D-based influenza manufacturer production of vaccines in 2. International regulatory Force (Abelin et al., vaccine producers in the pandemic circumstances, including: community 2011) H1N1 pandemic response 1. rapid virus selection and sharing, 3. Vaccine manufacturers and identify areas for 2. streamlined regulation processes, and national improvements for future 3. advanced agreements for vaccines, and governments responses. 4. increased seasonal vaccine programs. 4. National policy makers continued 205
TABLE A-1 Continued 206 Recommending Body Context Manufacturing Recommendations Identified Actors H1N1 WHO (2011) Recommend improvements 1. Improve influenza vaccine production 1. WHO and member (continued) to 2005 International capacity through global technology and states Health Regulations function material sharing. 2. WHO, member given the 2009 experience 2. Ensure appropriate agreements in place states, and vaccine with pandemic influenza A with vaccine manufacturers in order to manufacturers (H1N1). supply pandemic influenza vaccines to low- 3. Member states resource countries. 3. Develop/maintain seasonal influenza programs where appropriate, which facilitate pandemic influenza preparedness through infrastructure. ECDC (2017) Aid countries in identifying 1. Establish mechanisms for adequate access EU member state policy gaps in pandemic to pandemic vaccine materials (i.e., viruses) makers preparedness; improve for local manufacturing. plans; advocate for and 2. Monitor stockpiles to provide vaccine prioritize resources to demands to manufacturers. close those gaps; and guide 3. Assess the production and administration requests for support to timing in order to properly incorporate ECDC, the WHO Regional vaccine rollout plans. Office for Europe, or other agencies and donors. WHO (2017a) Inform and harmonize Collaborate among technical advisory bodies SAGE, GISRS, and WHO national and international in developing recommendations to move from pandemic preparedness and seasonal to pandemic vaccine production and response efforts. among virus strains.
WHO (2017b) Provide early guidance for Emphasize R&D efforts on technologies for Vaccine manufacturers the improvement of current long-lasting generic influenza A vaccination to influenza vaccines and facilitate pandemic vaccine manufacturing in the development of new LMIC settings. influenza vaccines. WHO (2018) Provide directives for 1. Provide PIP candidate vaccine viruses and 1. WHO GISRS improving the WHO GISRS reference reagents to vaccine manufactures laboratories for pandemic influenza upon request. 2. The WHO response and protection. 2. Establish and maintain pandemic influenza director-general stockpiles through support of manufacturer 3. Influenza vaccine production allocations and donations. manufacturers 3. Develop production capacity in developing countries through technology and knowledge transfer. NASEM (2019) Examine the extent of 1. Expedite development of a universal Unspecified lessons learned from pandemic influenza vaccine. influenza pandemics and 2. Increase investment in medical research and other major outbreaks development for diseases that largely affect and discuss how they the poor. could be applied further to 3. Encourage advanced agreements for H1N1 ensure that countries are vaccine distribution and delivery. sufficiently ready for future pandemics. continued 207
TABLE A-1 Continued 208 Recommending Body Context Manufacturing Recommendations Identified Actors Ebola Harvard-LSHTM Review global Ebola Ensure equitable access to benefits of the 1. Governments, the Independent Panel on epidemic response and research to accelerate pandemic vaccine scientific research the Global Response recommendation of manufacturing timelines through: community, industry, to Ebola (Moon et al., warranted and feasible 1. developing a framework of norms and rules and NGOs, led by 2015) reforms. for R&D during and between outbreaks, WHO and 2. Research funders 2. establishing a global R&D financing facility for vaccines. The governments of Launch the CEPI to 1. Build integrated planning tools and CEPI Norway and India, coordinate and finance sustain investments for end-to-end the Bill & Melinda vaccine development against capabilities through joint coordination and Gates Foundation, the emerging infectious diseases management. Wellcome Trust, and with epidemic potential. 2. Plan manufacturing surge capacity. the World Economic 3. Develop coordination mechanisms for Forum (CEPI, 2016) financing large-scale clinical testing and manufacturing during epidemics. Executive Office of the Direct U.S. government 1. Prioritize development of innovative U.S. government President (EOP, 2018) activities to assess, prevent, vaccine technologies, such as modular detect, prepare for, respond platforms. to, and recover from 2. Increase global manufacturing capacities, biological threats. including surge capacity. The World Bank Strengthen clinical research Establish a rapid financing vehicle to build The World Bank Group Group (2018), capacity in LMICs through country R&D capacity and support outbreak- International Vaccines strategic investment. related research with WHO R&D blueprint Task Force on insights. Strengthening Country Capacity for Vaccine Research
NVAC (2020) Recommend goals for the 1. Enhance vaccine production systems. HHS updated 2020 national 2. Increase data use in vaccine forecasting. vaccine plan reflecting 3. Strengthen manufacturing partnerships and updated immunization infrastructure. priorities across the lifespan. COVID-19 BARDA (Newland et Provide a strategy yielding 1. Develop influenza vaccines offering broad BARDA, in collaboration al., 2021) a sustainable end-to-end multi-strain protection for stockpiles. with other U.S. agencies, solution for manufacturing 2. Invest in vaccine platforms and international agencies, and pandemic influenza vaccines manufacturing processes that achieve a vaccine manufacturers in extremely compressed shorter timeline to first dose. timelines on demand 3. Accelerate regulatory and licensing and provide a robust processes of new technologies and infrastructure to develop approaches. and produce vaccines for 4. Improve operational coordination between other pandemic pathogens. the public and private sectors at all stages of production. Council on Foreign Review global preparedness Provide environment conducive to Unspecified policy makers Relations (Bollyky and and response to COVID-19 manufacturer engagement in pandemic vaccine Patrick, 2020) and their lessons for future production through pandemic preparedness. 1. intellectual property accessibility, 2. financial incentives, and 3. legal protections. Hosangadi et al. Apply findings and lessons 1. Invest in platform vaccine technologies and 1.â2. Countries with (2020) from qualitative studies distributed manufacturing technologies. sufficient resources on pandemic vaccine 2. Design flexible regulatory approaches to 3. Governments, NGOs, manufacturing and facilitate these advancements. and philanthropic administration to inform 3. Provide financial support for pandemic organizations the vaccine response to vaccine production. COVID-19. 209 continued
TABLE A-1 Continued 210 Recommending Body Context Manufacturing Recommendations Identified Actors COVID-19 Merck Sharp & Review experience Improve global and regional collaboration and WHO, in partnership (continued) Dohme Corporation of development and harmonization of candidate approvals and with regional and national (Wolf et al., 2020) manufacturing of licensure in order to accelerate manufacturing regulatory authorities Ebola Zaire vaccine in pandemic response. for recommendation in vaccine development and manufacturing efforts for COVID-19. National Provide strategic objectives 1. Strengthen and diversify influenza U.S. government Influenza Vaccine to meet Executive Order manufacturing through development of Modernization Task 13887 on Modernizing non-egg-based influenza vaccines. Force (ASPR, 2020) Influenza Vaccines in the 2. Provide sustainable and flexible financing United States to Promote for vaccine candidates and platforms. National Security and Public 3. Improve and sustain domestic production Health. platforms and increase and sustain seasonal influenza vaccine production with these technologies and platforms that can be leveraged for pandemic response. COVAX Identify and resolve issues 1. Address shortages of raw materials and COVAX Manufacturing manufacturing task impeding equitable access to single-use materials and expedite cross- Task Force force (COVAX, vaccines through COVAX. border transit of these materials, vaccine 2021a) components, and finished products. 2. Match-up manufacturers who are experiencing specific shortages with those who might have the necessary supplies. 3. Leverage the capabilities of the global vaccine community, including manufacturers to address short-term, medium-term, and long-term COVID-19 vaccine manufacturing challenges and bottlenecks.
Lurie et al. (2021) Review gaps in achieving 1. Develop a framework and threshold for 1.â2. The global system, an efficient and effective activationÂ linking R&D preparedness and comprised of 195 end-to-end R&D pandemic response. member nations of the preparedness and response 2. Establish a coordinated mechanism United Nations and its ecosystem and identify that aligns R&D with manufacturing, agencies priorities for improved and procurement, distribution, and delivery. 3. The global financial faster functionality. 3. Sufficiently fund coordinating mechanisms system national linking pandemic vaccine R&D and whole-of-government manufacturing. treasuries, the World Bank Group, regional and central banks, major private international banks, the consortium of global scientific agencies and research funders, and independent foundations Sell et al. (2021) Provide recommendations 1. Invest in platform vaccine technologies The global community from key informant insights providing flexibility to accelerate on how to improve global manufacturing capabilities. vaccine manufacturing 2. Develop flexible modular manufacturing efforts in order to be able technologies. to respond to pandemic or 3. Enable distributed manufacturing through other emergency needs. localized capacity. 4. Implement new regulatory approaches to facilitate these advancements. continued 211
TABLE A-1 Continued 212 Recommending Body Context Manufacturing Recommendations Identified Actors General WHO GAP Advisory Review 10-year performance 1. Coordinate influenza vaccine R&D efforts WHO secretariat Group (2016) of GAP in addressing the with stakeholders including manufactures. expected shortfall of global 2. Provide technical assistance to vaccine supply in the event manufacturers establishing themselves in of a pandemic and identify developing countries in order to support related issues requiring local production capacity. WHO leadership. WHO (2016a) Recommend policies 1. Strengthen national regulatory competency. LMIC governments enabling local influenza 2. Develop new influenza vaccines that are Vaccine manufacturers vaccine production in higher-yielding, faster to produce, broader LMICs. in protection, and longer-lasting. WHO (2019) Highlight goals and 1. Engage with funding and research partners WHO secretariat priorities to enhance global including global philanthropies, academia, and national pandemic and industry to promote research and preparedness, to combat innovation for influenza vaccines. the ongoing threat of 2. Provide technical assistance to countries zoonotic influenza, and to and collaborate with external partners improve seasonal influenza to support optimization of resources to prevention and control in all provide equitable access to a sufficient countries. supply of vaccines. 3. Develop global vaccine preparedness guidance including plans for switching from seasonal to pandemic vaccine manufacturing.
NOTE: ASPR = HHS Assistant Secretary for Preparedness and Response; BARDA = Biomedical Advanced Research and Development Authority (in HHS); CDC = Centers for Disease Control and Prevention; CEPI = Coalition for Epidemic Preparedness Innovations; COVAX = COVID-19 Vac- cines Global Access; ECDC = European CDC; EU = European Union; FDA = U.S. Food and Drug Administration; GAP = Global Action Plan for Influenza Vaccines; GISRS = Global Influenza Surveillance and Response System; HHS = U.S. Department of Health and Human Services; IFPMA = International Federation of Pharmaceutical Manufacturers & Associations; IOM = Institute of Medicine; IP = intellectual property; IVS = Influ- enza Vaccine Supply; LMIC = low- and middle-income country; LSHTM = London School of Hygiene & Tropical Medicine; NASEM = National Academies of Sciences, Engineering, and Medicine; NGOs = nongovernmental organizations; NIAID = National Institute of Allergy and Infectious Diseases; NVAC = National Vaccine Advisory Committee; PCAST = Presidentâs Council of Advisors on Science and Technology; R&D = research and development; SAGE = WHO Strategic Advisory Group of Experts on Immunization; SARS = severe acute respiratory syndrome; WHO = World Health Organization. 213
TABLE A-2 Trends in Unimplemented Pandemic Vaccine Manufacturing Recommendations 214 Date of Initial Theme Recommendation Recommendation Individual Recommendations Vaccine Development and Development and adoption of 2006 Evaluate and develop vaccine and delivery technologies Production Technologies more efficient (non-egg-based) (WHO, 2006). vaccine production technologies Improve manufacturing capacity through better production yields (WHO, 2006). Develop efficient and expandable vaccine manufacturing approaches including multi-use technologies and identify best practices for oversight (HHS, 2010). Strengthen and diversify influenza manufacturing through development of non-egg-based influenza vaccines (ASPR, 2020). Development of generic 2016 Develop new influenza vaccines that are higher-yielding, influenza vaccine faster to produce, broader in protection, and longer- lasting (WHO, 2016a). Emphasize R&D efforts on technologies for long-lasting generic influenza A vaccination to facilitate pandemic vaccine manufacturing in LMIC settings (WHO, 2017b). Expedite development of a universal pandemic influenza vaccine (NASEM, 2019). Develop influenza vaccines offering broad multi-strain protection for stockpiles (Newland et al., 2021). Investment in vaccine platform 2018 Prioritize development of innovative vaccine technologies production technologies such as modular platforms (EOP, 2018).
Invest in platform vaccine technologies and distributed manufacturing technologies (Hosangadi et al., 2020). Invest in vaccine platforms and manufacturing processes that achieve a shorter timeline to first dose (Newland et al., 2021). Invest in platform vaccine technologies providing flexibility to accelerate manufacturing capabilities; develop flexible modular manufacturing technologies (Sell et al., 2021). Advanced development of 2009 Prepare vaccine candidates for future pandemic threats vaccine candidates for viruses of (IOM, 2004). pandemic potential Increase investment in medical research and development for diseases that largely affect the poor (NASEM, 2019). Pandemic Vaccine Establishment of pandemic 2007 Produce and donate avian flu vaccines to the WHO Production Processes influenza vaccine stockpiles stockpile (SAGE, 2007). Establish and maintain pandemic influenza stockpiles through support of manufacturer production allocations and donations (WHO, 2018). continued 215
TABLE A-2 Continued 216 Date of Initial Theme Recommendation Recommendation Individual Recommendations Pandemic Vaccine Increase seasonal influenza 2006 Increase seasonal influenza vaccine production through Production Processes vaccine programs in order demand from introduction and maintenance of seasonal (continued) to bolster routine vaccine influenza vaccination programs (WHO, 2006). manufacturing capacity Increase seasonal vaccine programs (Abelin et al., 2011). Develop/maintain seasonal influenza programs where appropriate, which facilitate pandemic influenza preparedness through infrastructure (WHO, 2011). Develop global vaccine preparedness guidance including plans for switching from seasonal to pandemic vaccine manufacturing (WHO, 2019). Establish switch strategies 2017 Collaborate among technical advisory bodies in between routine and pandemic developing recommendations to move from seasonal to vaccine manufacturing pandemic vaccine production and among virus strains (WHO, 2017b). Develop manufacturer contingency plans for switching from seasonal to pandemic production (WHO, 2004). Improve and sustain domestic production platforms and increase and sustain seasonal influenza vaccine production with these technologies and platforms that can be leveraged for pandemic response (ASPR, 2020). Support technology transfer 2010 Provide technical assistance to developing-country vaccine to LMICs in establishing manufacturers in production of safe and effective vaccines manufacturing capacity (HHS, 2010). Provide technical assistance to manufacturers establishing themselves in developing countries in order to support local production capacity (WHO GAP Advisory Group, 2016).
Develop production capacity in developing countries through technology and knowledge transfer (WHO, 2018). Establish distributed 2006 Improve manufacturing capacity through additional manufacturing mechanisms production plants (WHO, 2006). Address manufacturing capacity gaps to adhere with biosafety level requirements for emerging epidemic viruses (Kusters et al., 2009). Enable distributed manufacturing through localized capacity (Sell et al., 2021). Enhance vaccine production 2010 Improve surge production capacity mechanisms (IOM, capacity for pandemic 2004). preparedness Enhance vaccine production capacity building (PCAST, 2010). Improve access to pilot lot manufacturing facilities (HHS, 2010). Plan manufacturing surge capacity (CEPI, 2016). Increase global manufacturing capacities including surge capacity (EOP, 2018). Enhance vaccine production systems (NVAC, 2020). NOTE: ASPR = Office of the Assistant Secretary for Preparedness and Response (in HHS); EOP = Executive Office of the President; HHS = U.S. Department of Health and Human Services; IOM = Institute of Medicine; LMIC = low- and middle-income country; NASEM = National Academies of Sciences, Engineering, and Medicine; SAGE = Strategic Advisory Group of Experts on Immunization; WHO = World Health Organization. 217
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