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 recommendations 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 outbreak circumstances during the years during and following the disease outbreaks. 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 development 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:
- innovation in vaccine development and production technologies,
- optimization of pandemic vaccine production processes,
- regulatory harmonization,
- stakeholder coordination, and
- sustainable funding.
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 successful 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 maintaining 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 improvement of manufacturing capacities through development and application of better vaccine technologies.
In 2006, the World Health Organization’s Global Action Plan for Influenza 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 (President’s 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 vaccines (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 ensure the development and dissemination of new influenza virus backbones (PCAST, 2010). However, given the scientific, regulatory, and financial barri-
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 encouraged development and adoption of more flexible manufacturing capacities, such as vaccine platform technologies through which a single manufacturing mechanism can be used for several vaccines (ASPR, 2020; EOP, 2018; HHS, 2010; Hosangadi et al., 2020; Newland et al., 2021). These technologies 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 accelerate the development process by shortening preclinical phases (Hosangadi et al., 2020), as illustrated in the advancement of certain COVID-19 vaccines (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 Development Authority, in the U.S. Department of Health and Human Services, and the Coalition for Epidemic Preparedness Innovations (CEPI) provided funding 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 pandemic influenza vaccines have included the development of mock-up “pandemic-like” 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 recommendations 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
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 international antigen stockpiles (WHO, 2004).
One such recommendation to institute a WHO avian flu stockpile called for stockpile provisions from the increased production and donation 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 unreliable 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 outbreaks 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 depletion (ECDC, 2017).
Another prominent recommendation to address the manufacturing capacity 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 adapting 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 seasonal influenza programs to be coupled with a global recommendation pro-
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 pandemic production (Sell et al., 2021; WHO, 2011, 2016a, 2017b, 2018). Technical support could be particularly useful for implementing recommendations 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 illustrated 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 producers 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 stakeholders, including manufacturers, academia, governments, and international agencies is the need for improved regulatory and licensing practices. A traditional approach to vaccine manufacturing is to establish highly specialized 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 pandemic 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. Regulatory 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).
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 include clearer pathways to approval (WHO, 2010), and harmonization of candidate licensure and marketing approvals in order to accelerate timelines 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 Vaccine 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, regulation, 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 epidemiological, genomic, and clinical data in the Ebola response, the Independent Panel on the Global Response to Ebola of Harvard University and the London 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 pathogens including vaccine products. However, this framework did not include the binding rules recommended by the Harvard–LSHTM independent panel (WHO, 2016b), without which stakeholder adherence cannot be guaranteed. 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 agreements 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-
agement of pandemic vaccine research, development, manufacturing, and distribution efforts. With the mission to accelerate the development of vaccines 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 CEPI’s efforts, sustainable 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 reference 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 framework stipulates provision of candidate vaccine viruses, sequences of influenza 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 established 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 initiative further highlights concerns of sustainability in addressing these needs in future pandemic situations. As a result, there have been many recommendations 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 deployment 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 recommendation 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
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 development 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 investments in health infrastructure, including vaccine manufacturing capacity, have been inadequate despite formal commitments of national governments 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 manufacturers’ 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 manufacturers (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,
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 possible 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 facility 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 Bank’s 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 proposal 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 financing 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
vaccine process, from R&D to demand for doses. Recommendations confronted both individual components of this process and needs for broader coordination in support of activities. In addressing pandemic manufacturing capacity, recommendations emphasize investment in research and development 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 development 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 implementation 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 pandemic vaccines. |
1. License mock-up pandemic vaccines. 2. Address issues of IP rights in order to enable commercial production capability. 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. |
1.–3. Vaccine manufacturers
4. Governments |
| WHO (Simon et al., 2005) | Recommend formation of a patent pool for SARS genomic sequence. |
Create a patent pool for SARS genomic sequence to facilitate vaccine development and manufacturing. |
CDC, Health Canada, HKU/Veritech, Erasmus Medical Center/ CoroNovative, and regulatory agencies | |
| Recommending Body | Context | Manufacturing Recommendations | Identified Actors | |
|---|---|---|---|---|
| WHO (2006) | Increase the pandemic vaccine supply and thereby reduce the gap between the potential vaccine demand and supply anticipated during an influenza pandemic. |
1. Increase seasonal influenza vaccine production through demand from introduction and maintenance of seasonal influenza vaccination programs. 2. Evaluate and develop vaccine and delivery technologies. 3. Improve manufacturing capacity through better production yields, and additional production plants. |
1. WHO regional offices, member state governments, and donor agencies 2. WHO-led collaborative consortium of laboratories 3. Established and new vaccine manufacturers |
|
| SAGE (2007) | Recommend WHO stockpile of avian flu vaccine. |
Produce and donate avian flu vaccines to the WHO stockpile. |
Vaccine manufacturers | |
| IOM (2004) | Provide recommendations that could shape responses to future microbial threats given lessons learned from the SARS epidemic. |
Prepare vaccine candidates for future pandemic threats. Improve surge production capacity mechanisms. |
Unspecified | |
| Kusters et al. (2009) | Address issues faced in development and manufacturing of SARS vaccine. |
1. Address manufacturing capacity gaps to adhere with biosafety level requirements for emerging epidemic viruses. 2. Maintain open and active dialogue between manufacturers and regulatory officials. |
1. National reference centers 2. Vaccine manufacturers and regulatory agencies |
|
| H1N1 | PCAST (2010) | Provide guidance in achieving rapid and reliable production of effective vaccines, at a sufficient scale to protect all of the nation’s residents, in response to the emergence of pandemic influenza. |
Address large-scale supply delays at the beginning (virus optimized for manufacturing) and at the end of the process (fill-finish) of influenza vaccine manufacturing through
1. R&D efforts, 2. production capacity building, and 3. financial and management incentives for influenza vaccine development and production enterprise. |
1. NIAID and BARDA 2. U.S. government and vaccine manufacturers 3. U.S. agencies, including BARDA, CDC, and FDA |
| Recommending Body | Context | Manufacturing Recommendations | Identified Actors | |
|---|---|---|---|---|
| HHS (2010) | Address infectious disease vaccines and vaccination-related issues for the United States and its global partners. |
1. Develop efficient and expandable vaccine manufacturing approaches, including multi-use technologies, and identify best practices for oversight. 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. |
HHS | |
| WHO (2010) | Review the performance of the WHO Pandemic Influenza A(H1N1) Vaccine Deployment Initiative and identify action points to improve upon the systems established to respond more effectively to the needs of countries in the future. |
Prepare and update vaccine legal and regulatory processes through
1. clearer government and manufacturer agreements, and 2. approval and licensing changes to accelerate pandemic vaccine manufacturing process. |
WHO Pandemic Influenza A(H1N1) Vaccine Deployment Initiative collaborators, including technical agencies, donor governments, and private-sector organizations | |
| IFPMA, IVS International Task Force (Abelin et al., 2011) | Review the contributions of R&D-based influenza vaccine producers in the H1N1 pandemic response and identify areas for improvements for future responses. |
Address bottlenecks impeding efficient manufacturer production of vaccines in pandemic circumstances, including:
1. rapid virus selection and sharing, 2. streamlined regulation processes, 3. advanced agreements for vaccines, and 4. increased seasonal vaccine programs. |
1. WHO network 2. International regulatory community 3. Vaccine manufacturers and national governments 4. National policy makers |
| Recommending Body | Context | Manufacturing Recommendations | Identified Actors | |
|---|---|---|---|---|
| WHO (2011) | Recommend improvements to 2005 International Health Regulations function given the 2009 experience with pandemic influenza A (H1N1). |
1. Improve influenza vaccine production capacity through global technology and material sharing. 2. Ensure appropriate agreements in place with vaccine manufacturers in order to supply pandemic influenza vaccines to low-resource countries. 3. Develop/maintain seasonal influenza programs where appropriate, which facilitate pandemic influenza preparedness through infrastructure. |
1. WHO and member states 2. WHO, member states, and vaccine manufacturers 3. Member states |
|
| ECDC (2017) | Aid countries in identifying gaps in pandemic preparedness; improve plans; advocate for and prioritize resources to close those gaps; and guide requests for support to ECDC, the WHO Regional Office for Europe, or other agencies and donors. |
1. Establish mechanisms for adequate access to pandemic vaccine materials (i.e., viruses) for local manufacturing. 2. Monitor stockpiles to provide vaccine demands to manufacturers. 3. Assess the production and administration timing in order to properly incorporate vaccine rollout plans. |
EU member state policy makers | |
| WHO (2017a) | Inform and harmonize national and international pandemic preparedness and response efforts. |
Collaborate among technical advisory bodies in developing recommendations to move from seasonal to pandemic vaccine production and among virus strains. |
SAGE, GISRS, and WHO |
| Recommending Body | Context | Manufacturing Recommendations | Identified Actors | |
|---|---|---|---|---|
| WHO (2017b) | Provide early guidance for the improvement of current influenza vaccines and the development of new influenza vaccines. |
Emphasize R&D efforts on technologies for long-lasting generic influenza A vaccination to facilitate pandemic vaccine manufacturing in LMIC settings. |
Vaccine manufacturers | |
| WHO (2018) | Provide directives for improving the WHO GISRS for pandemic influenza response and protection. |
1. Provide PIP candidate vaccine viruses and reference reagents to vaccine manufactures upon request. 2. Establish and maintain pandemic influenza stockpiles through support of manufacturer production allocations and donations. 3. Develop production capacity in developing countries through technology and knowledge transfer. |
1. WHO GISRS laboratories 2. The WHO director-general 3. Influenza vaccine manufacturers |
|
| NASEM (2019) | Examine the extent of lessons learned from influenza pandemics and other major outbreaks and discuss how they could be applied further to ensure that countries are sufficiently ready for future pandemics. |
1. Expedite development of a universal pandemic influenza vaccine. 2. Increase investment in medical research and development for diseases that largely affect the poor. 3. Encourage advanced agreements for H1N1 vaccine distribution and delivery. |
Unspecified |
| Recommending Body | Context | Manufacturing Recommendations | Identified Actors | |
|---|---|---|---|---|
| Ebola | Harvard-LSHTM Independent Panel on the Global Response to Ebola (Moon et al., 2015) | Review global Ebola epidemic response and recommendation of warranted and feasible reforms. |
Ensure equitable access to benefits of the research to accelerate pandemic vaccine manufacturing timelines through: 1. developing a framework of norms and rules for R&D during and between outbreaks, and 2. establishing a global R&D financing facility for vaccines. |
1. Governments, the scientific research community, industry, and NGOs, led by WHO 2. Research funders |
| The governments of Norway and India, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the World Economic Forum (CEPI, 2016) | Launch the CEPI to coordinate and finance vaccine development against emerging infectious diseases with epidemic potential. |
1. Build integrated planning tools and sustain investments for end-to-end capabilities through joint coordination and management. 2. Plan manufacturing surge capacity. 3. Develop coordination mechanisms for financing large-scale clinical testing and manufacturing during epidemics. |
CEPI | |
| Executive Office of the President (EOP, 2018) | Direct U.S. government activities to assess, prevent, detect, prepare for, respond to, and recover from biological threats. |
1. Prioritize development of innovative vaccine technologies, such as modular platforms. 2. Increase global manufacturing capacities, including surge capacity. |
U.S. government | |
| The World Bank Group (2018), International Vaccines Task Force on Strengthening Country Capacity for Vaccine Research | Strengthen clinical research capacity in LMICs through strategic investment. |
Establish a rapid financing vehicle to build country R&D capacity and support outbreak-related research with WHO R&D blueprint insights. |
The World Bank Group |
| Recommending Body | Context | Manufacturing Recommendations | Identified Actors | |
|---|---|---|---|---|
| NVAC (2020) | Recommend goals for the updated 2020 national vaccine plan reflecting updated immunization priorities across the lifespan. |
1. Enhance vaccine production systems. 2. Increase data use in vaccine forecasting. 3. Strengthen manufacturing partnerships and infrastructure. |
HHS | |
| COVID-19 | BARDA (Newland et al., 2021) | Provide a strategy yielding a sustainable end-to-end solution for manufacturing pandemic influenza vaccines in extremely compressed timelines on demand and provide a robust infrastructure to develop and produce vaccines for other pandemic pathogens. |
1. Develop influenza vaccines offering broad multi-strain protection for stockpiles. 2. Invest in vaccine platforms and manufacturing processes that achieve a shorter timeline to first dose. 3. Accelerate regulatory and licensing processes of new technologies and approaches. 4. Improve operational coordination between the public and private sectors at all stages of production. |
BARDA, in collaboration with other U.S. agencies, international agencies, and vaccine manufacturers |
| Council on Foreign Relations (Bollyky and Patrick, 2020) | Review global preparedness and response to COVID-19 and their lessons for future pandemic preparedness. |
Provide environment conducive to manufacturer engagement in pandemic vaccine production through
1. intellectual property accessibility, 2. financial incentives, and 3. legal protections. |
Unspecified policy makers | |
| Hosangadi et al. (2020) | Apply findings and lessons from qualitative studies on pandemic vaccine manufacturing and administration to inform the vaccine response to COVID-19. |
1. Invest in platform vaccine technologies and distributed manufacturing technologies. 2. Design flexible regulatory approaches to facilitate these advancements. 3. Provide financial support for pandemic vaccine production. |
1.–2. Countries with sufficient resources 3. Governments, NGOs, and philanthropic organizations |
| Recommending Body | Context | Manufacturing Recommendations | Identified Actors | |
|---|---|---|---|---|
| Merck Sharp & Dohme Corporation (Wolf et al., 2020) | Review experience of development and manufacturing of Ebola Zaire vaccine for recommendation in vaccine development and manufacturing efforts for COVID-19. |
Improve global and regional collaboration and harmonization of candidate approvals and licensure in order to accelerate manufacturing in pandemic response. |
WHO, in partnership with regional and national regulatory authorities | |
| National Influenza Vaccine Modernization Task Force (ASPR, 2020) | Provide strategic objectives to meet Executive Order 13887 on Modernizing Influenza Vaccines in the United States to Promote National Security and Public Health. |
1. Strengthen and diversify influenza manufacturing through development of non-egg-based influenza vaccines. 2. Provide sustainable and flexible financing for vaccine candidates and platforms. 3. 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. |
U.S. government | |
| COVAX manufacturing task force (COVAX, 2021a) | Identify and resolve issues impeding equitable access to vaccines through COVAX. |
1. Address shortages of raw materials and single-use materials and expedite cross-border transit of these materials, vaccine 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. |
COVAX Manufacturing Task Force |
| Recommending Body | Context | Manufacturing Recommendations | Identified Actors | |
|---|---|---|---|---|
| Lurie et al. (2021) | Review gaps in achieving an efficient and effective end-to-end R&D pandemic preparedness and response ecosystem and identify priorities for improved and faster functionality. |
1. Develop a framework and threshold for activation linking R&D preparedness and response. 2. Establish a coordinated mechanism that aligns R&D with manufacturing, procurement, distribution, and delivery. 3. Sufficiently fund coordinating mechanisms linking pandemic vaccine R&D and manufacturing. |
1.–2. The global system, comprised of 195 member nations of the United Nations and its agencies 3. The global financial system national whole-of-government 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 from key informant insights on how to improve global vaccine manufacturing efforts in order to be able to respond to pandemic or other emergency needs. |
1. Invest in platform vaccine technologies providing flexibility to accelerate manufacturing capabilities. 2. Develop flexible modular manufacturing technologies. 3. Enable distributed manufacturing through localized capacity. 4. Implement new regulatory approaches to facilitate these advancements. |
The global community |
| Recommending Body | Context | Manufacturing Recommendations | Identified Actors | |
|---|---|---|---|---|
| General | WHO GAP Advisory Group (2016) | Review 10-year performance of GAP in addressing the expected shortfall of global vaccine supply in the event of a pandemic and identify related issues requiring WHO leadership. |
1. Coordinate influenza vaccine R&D efforts with stakeholders including manufactures. 2. Provide technical assistance to manufacturers establishing themselves in developing countries in order to support local production capacity. |
WHO secretariat |
| WHO (2016a) | Recommend policies enabling local influenza vaccine production in LMICs. |
1. Strengthen national regulatory competency. 2. Develop new influenza vaccines that are higher-yielding, faster to produce, broader in protection, and longer-lasting. |
LMIC governments Vaccine manufacturers |
|
| WHO (2019) | Highlight goals and priorities to enhance global and national pandemic preparedness, to combat the ongoing threat of zoonotic influenza, and to improve seasonal influenza prevention and control in all countries. |
1. Engage with funding and research partners including global philanthropies, academia, and industry to promote research and innovation for influenza vaccines. 2. Provide technical assistance to countries and collaborate with external partners to support optimization of resources to provide equitable access to a sufficient supply of vaccines. 3. Develop global vaccine preparedness guidance including plans for switching from seasonal to pandemic vaccine manufacturing. |
WHO secretariat |
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 Vaccines 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 = Influenza 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 = President’s 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.
TABLE A-2 Trends in Unimplemented Pandemic Vaccine Manufacturing Recommendations
| Theme | Recommendation | Date of Initial Recommendation | Individual Recommendations |
|---|---|---|---|
| Vaccine Development and Production Technologies | Development and adoption of more efficient (non-egg-based) vaccine production technologies | 2006 |
Evaluate and develop vaccine and delivery technologies (WHO, 2006). 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 influenza vaccine | 2016 |
Develop new influenza vaccines that are higher-yielding, 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 production technologies | 2018 |
Prioritize development of innovative vaccine 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 vaccine candidates for viruses of pandemic potential | 2009 |
Prepare vaccine candidates for future pandemic threats (IOM, 2004). Increase investment in medical research and development for diseases that largely affect the poor (NASEM, 2019). |
|
| Pandemic Vaccine Production Processes | Establishment of pandemic influenza vaccine stockpiles | 2007 |
Produce and donate avian flu vaccines to the WHO stockpile (SAGE, 2007). Establish and maintain pandemic influenza stockpiles through support of manufacturer production allocations and donations (WHO, 2018). |
| Theme | Recommendation | Date of Initial Recommendation | Individual Recommendations |
|---|---|---|---|
| Increase seasonal influenza vaccine programs in order to bolster routine vaccine manufacturing capacity | 2006 |
Increase seasonal influenza vaccine production through demand from introduction and maintenance of seasonal influenza vaccination programs (WHO, 2006). 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 between routine and pandemic vaccine manufacturing | 2017 |
Collaborate among technical advisory bodies in developing recommendations to move from seasonal to 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 to LMICs in establishing manufacturing capacity | 2010 |
Provide technical assistance to developing-country vaccine manufacturers in production of safe and effective vaccines (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 manufacturing mechanisms | 2006 |
Improve manufacturing capacity through additional 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 capacity for pandemic preparedness | 2010 |
Improve surge production capacity mechanisms (IOM, 2004). 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.
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