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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/26285.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/26285.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/26285.
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Page 19
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/26285.
×
Page 20
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/26285.
×
Page 21
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/26285.
×
Page 22
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/26285.
×
Page 23
Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/26285.
×
Page 24

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

1 Introduction Throughout history, the world has witnessed myriad infectious diseases from known and unknown pathogens that have upended societies and taken a dramatic toll on the health and well-being of populations (Morens and Fauci, 2020). Viruses, especially those caused by respiratory pathogens, such as SARS-CoV-2, the virus that causes COVID-19, have demonstrated the importance of preparedness for future outbreaks. The COVID-19 pan- demic is particularly noteworthy in its close link to influenza and the inevi- table implications that it will have on the way governments, policy makers, scientists, civil society, and others plan for the next pandemic, whenever it may occur. It is widely agreed that another influenza pandemic is likely to occur, although “it is difficult to predict when or where it will appear or how severe it will be” (Taubenberger et al., 2007). These factors make it critically important for the world to be prepared when it happens. During the 20th century, three influenza pandemics—in 1918, 1957, and 1968—are estimated to have killed more than 50 million people world- wide (Johnson and Mueller, 2002; Kilbourne, 2006). Although the most recent influenza pandemic, caused by H1N1 in 2009, was relatively mild because of the virus’s low pathogenicity for most adults, a recent simulation by the Institute for Disease Modeling projected that during the 6-month lead time to produce a vaccine effective against a new, more pathogenic pandemic influenza virus, worldwide deaths could approach 33 million people (Gates, 2018). In a typical non-pandemic year, seasonal influenza outbreaks cause 3–5 million cases of severe illness and between 290,000 and 650,000 deaths worldwide (WHO, 2018). The 2017–2018 influenza season in the United 17 PREPUBLICATION COPY—Uncorrected Proofs

18 GLOBALLY RESILIENT SUPPLY CHAINS States, which the Centers for Disease Control and Prevention (CDC) clas- sified as a high-severity season, affected some 45 million people, caused 810,000 hospitalizations, and led to 61,000 deaths (CDC, 2019). While the CDC classified influenza in the next 2 years, 2018–2019 and 2019–2020, as being only moderately severe, each was atypical in its own way. The 2018–2019 influenza season was the longest in a decade (Xu et al., 2019). The 2019–2020 season severely affected younger people, hospitalizing more children aged 0–4 and adults aged 18–49 in the United States than did the 2009 H1N1 pandemic (CDC, 2020b). Both the 2018–2019 and 2019–2020 influenza seasons saw two waves of activity, each caused predominantly by different strains of that year’s virus (CDC, 2020a,b) (see Chapter 2 for a discussion of influenza virus strains). Considering these variable factors, even seasonal influenza is a significant health burden that should not be underestimated. In the United States, the 2020–2021 influenza season was remarkably mild, with just over 2,000 cases reported to the CDC, but this outcome did not reflect a weak virus or a high rate of vaccination (CDC, 2021). Rather, experts concluded, it was a result of the behavior changes and global shutdown caused by the COVID-19 pandemic, which also exposed gaps in pandemic preparedness and highlighted the fragility of the vaccine supply chain and distribution channels (GPMB, 2020). UNDERSTANDING INFLUENZA VIRUSES Vaccines are one of the best and most effective defenses against seasonal and pandemic influenza (CDC, 2021; WHO, 2019). Work in this field dates back to the years following the 1918 H1N1 pandemic, and the first influ- enza vaccine clinical trials began in the mid-1930s. (Barberis et al., 2016). In 1945, U.S. authorities had approved the first such vaccine for widespread public use (Weir and Gruber, 2016). Producing the vaccine required a la- borious process of injecting the virus into millions of embryonated chicken eggs, allowing the virus to replicate for several days, harvesting virus- containing fluid from the eggs, inactivating the virus, and purifying the inactivated virus. Today, despite more than 75 years of scientific progress, including the advent of modern molecular and cellular biology, the vast majority of the world’s influenza vaccine supply still comes from this egg- based production process (Pérez Rubio and Eiros, 2018). Although this method has been shown to produce safe and effective vac- cines, it takes approximately 6 months to complete—if all goes well—and have a vaccine ready for public distribution (Gerdil, 2003). This lengthy process creates a potentially serious problem. Viruses have the propensity to mutate, which can produce changes in the target antigens of protective immunity—the two different proteins on the virus’s surface that trigger an PREPUBLICATION COPY—Uncorrected Proofs

INTRODUCTION 19 immune response (Tosh et al., 2010). This mutational process is called anti- genic drift. The discovery of antigenic drift means that new vaccines must be developed based on the circulating strain (Webster and Govorkova, 2014). The discovery of antigenic drift highlighted three issues: (1) the possibility that antigenic drift could occur during the 6-month manufacturing period, which could lead to producing a vaccine that was less effective or even inef- fective against the influenza virus circulating in the population at the time of vaccine administration (Boni, 2008); (2) the need for continuous surveillance and characterization of circulating influenza viruses to identify antigenic drift (Ziegler et al., 2018); and (3) the likelihood of having to produce a new influenza vaccine regularly, if not annually (Cox et al., 2015). Often, the mutations associated with antigenic drift are small enough that even if the then-current vaccine is not fully effective, enough of the population will have encountered similar influenza viruses to prevent widespread mortality. In some instances, however, an influenza virus can exchange genetic ma- terial with other influenza viruses, which causes antigen-altering changes, known as antigenic shift. If this occurs, the resulting virus may become one unlike any other that humans have encountered previously and against which no one will have developed any immunity (Kotey et al., 2019; Web- ster and Govorkova, 2014). If such a new virus is highly transmissible, as many influenza viruses are, a pandemic can result: that is, the virus spreads rapidly around the globe and kills millions of people (Morens and Fauci, 2020). This is the phenomenon that occurred with the SARS-CoV-2 coronavirus. When this kind of pandemic occurs, the best option for stopping the new virus in its tracks, or at least controlling it at manageable levels, is to develop, manufacture, and distribute a vaccine as quickly, efficiently, and widely as possible. However, there is a crucial difference between SARS- CoV-2 and influenza—the incubation period. For SARS-CoV-2, the median incubation period is 5–6 days; for influenza, it is 2 days (Carrat et al., 2008; Quesada et al., 2021). This difference means the window of opportunity for a vaccine to be developed and deployed to contribute to preventing most of the disease and death for a pandemic influenza will be significantly shorter than it was for SARS-CoV-2. In an emerging pandemic scenario, counter- measures such as social distancing, contact tracing, and personal protective equipment would need to be used in the interim to mitigate disease spread while a vaccine is in development. While these measures are important in slowing the spread, they are not intended to and cannot stop the spread. COMMITTEE TASK AND APPROACH At the request of the Office of Global Affairs of the U.S. Department of Health and Human Services (HHS), the National Academies of Sci- PREPUBLICATION COPY—Uncorrected Proofs

20 GLOBALLY RESILIENT SUPPLY CHAINS ences, Engineering, and Medicine (the National Academies) convened the Committee on Advancing Pandemic and Seasonal Influenza Vaccine Pre- paredness and Response—Issues of Vaccine Distribution and Supply Chain (the committee) to develop recommendations to bolster global vaccine manufacturing, distribution, and supply chains for future seasonal and pan- demic influenza events. This committee is one of four convened as part of a rapid-response initiative to explore the current state of knowledge about and provide recommendations to improve the global design, composition, clinical trials, production, scale-up, regulatory approval, and distribution of influenza vaccines, including post-approval surveillance for adverse events. The three other committees are charged to examine vaccine research and development; public health interventions and countermeasures; and global coordination, partnerships, and financing as needed components to prepar- ing for and responding to pandemic and seasonal influenza.1 This report addresses the challenges of manufacturing and distributing vaccines for both seasonal and pandemic influenza, highlighting the critical components of vaccine manufacturing and distribution and offering recom- mendations that address gaps in the current global vaccine infrastructure. The full charge to the committee is in Box 1-1. The committee included 12 members with academic and professional expertise in vaccine development, epidemiology, medicine, supply chain management, medical logistics and emergency preparedness, global public health, stockpiling, and biomanu- facturing. Biographies of committee members are provided in Appendix B. In developing this report and its recommendations, the committee deliberated for approximately seven months (mid-March 2021 through August 2021) and held six virtual meetings of 2–3 days each. Three of these meetings included sessions open to the public (all public meeting agendas can be found in Appendix C). The committee’s recommendations are directed at each of the stakeholders in the global vaccine supply chain, the entities involved in vaccine manufacturing, distribution, and logistics, as well as policy makers. As specified in the committee’s statement of task, the committee was charged with reviewing past efforts to respond to the 2009 influenza pan- demic, as well as those caused by other infectious agents, and identifying critical gaps in the end-to-end supply chain that includes manufacturing, distribution, and delivery of influenza vaccines. It was also charged with identifying how lessons learned during the COVID-19 pandemic could be 1  Information about the larger project and the other three committees is available at https:// www.nationalacademies.org/our-work/advancing-pandemic-and-seasonal-influenza-vaccine- preparedness-and-response-harnessing-lessons-from-the-efforts-to-mitigate-the-covid-19- pandemic (accessed October 9, 2021). PREPUBLICATION COPY—Uncorrected Proofs

INTRODUCTION 21 BOX 1-1 Statement of Task An ad hoc committee under the auspices of the National Academies of Sciences, Engineering, and Medicine will examine supply chain and distribution challenges related to vaccines and vaccinations during the COVID-19 response and explore their implications for pandemic and seasonal influenza. Specifically, the committee will: 1) Review recommendations for pandemic vaccine manufacturing fol- lowing SARS, H1N1, Ebola, and COVID-19 responses and assess where recommendations were not implemented and how they can be incorporated more sustainably for future influenza outbreaks; 2) Review promising tools, technical innovations and institutional processes to identify enabling factors for national vaccine distribu- tion readiness that facilitate equitable distribution and efficient use of resources, including in low-resource countries (e.g., cold-chain management, rapid regulatory prequalification procedures, liability and indemnification frameworks, and strengthening technical ca- pacity of National Immunization Technical Advisory Groups); 3) Identify critical gaps in vaccine delivery, including inventory unpre- dictability and inadequate cold-chain capacity, and recommend priority actions at the regional and global levels to address them to create foundational delivery platforms for pandemic influenza; 4) Identify critical inputs for influenza vaccine manufacturing (e.g., adjuvants, needles, glass vials, lipids, etc.) and highlight existing mechanisms for tracking these inputs for ensuring sufficient and redundant production, storage, and availability in each region dur- ing global, large-scale vaccination efforts; 5) Identify how novel technologies and advances in translational research and science derived from the ongoing COVID-19 pan- demic can be adapted to scale-up and sustain influenza vaccine manufacturing and distribution capacities, especially for multiple products; 6) Identify barriers impeding the rapid translation of clinical trial man- ufacturing supply for pandemic vaccines to commercial supply and recommend strategies to address these barriers. These may include lack of financing and limited knowledge of technology transfer; 7) Review incentives that effectively encourage investments in vac- cine manufacturing, including those used during COVID-19 re- sponse, and recommend those that could be successfully applied to pandemic influenza vaccine manufacturing, especially actions and policies encouraging routine operations of facilities. PREPUBLICATION COPY—Uncorrected Proofs

22 GLOBALLY RESILIENT SUPPLY CHAINS applied to influenza vaccine production. To assist the committee’s work, it commissioned a paper to lay out those previous efforts; that paper, by Janamarie Perroud, is Appendix A. The committee notes that it chose not to consider the following issues, given the study timeline, the nature of the task, and the broad scope of the committee’s charge: • supply chain and logistics on a country-specific level; • influenza vaccine clinical trial research and development; and • global partnerships and coordination for influenza vaccines. Addressing country-specific supply chain and logistics issues would be a significant undertaking, and findings for any particular country may not be applicable to any other country. In order to maintain a global focus, the committee aimed to detail broadly applicable supply chain considerations. The other two topics listed, vaccine research and development and global partnerships for influenza, are the subject of two of the other consensus studies that are part of an overall National Academies’ activity (see fn. 1). STRUCTURE OF THE REPORT The organization of this report generally follows the statement of task. Chapter 2 provides foundational information on influenza viruses, the basics of the global influenza surveillance and vaccine manufacturing infrastructure, and a broad overview of the planning and coordination of the supply chain. Chapter 3 discusses critical components for vaccine manufacturing, as well as manufacturing networks. Chapter 4 describes the characteristics of an effective influenza vaccine and their implications for manufacturing and distribution. Chapter 5 examines preparedness, logis- tics, and data capture for vaccine distribution, and Chapter 6 considers the barriers, incentives, innovations, and other factors for sustainable vaccine manufacturing. Chapter 7 charts a way forward to better support influenza vaccine supply chains in the future. Appendix A is a paper by Janamarie Perroud, commissioned by the committee, which reviews selected vaccine manufacturing recommenda- tions and the status of their implementation. Appendix B presents the biographies of the committee members and National Academies’ staff who participated in preparing this report. Appendix C provides the agendas for the open, public meetings of the committee, including the names and affili- ations of the experts who contributed to the committee’s work. PREPUBLICATION COPY—Uncorrected Proofs

INTRODUCTION 23 REFERENCES Barberis, I., P. Myles, S. K. Ault, N. L. Bragazzi, and M. Martini. 2016. History and evolution of influenza control through vaccination: From the first monovalent vaccine to universal vaccines. Journal of Preventive Medicine and Hygiene 57(3):E115-E120. Boni, M. F. 2008. Vaccination and antigenic drift in influenza. Vaccine 26:C8-C14. Carrat, F., E. Vergu, N. M. Ferguson, M. Lemaitre, S. Cauchemez, S. Leach, and A.-J. Valleron. 2008. Time lines of infection and disease in human influenza: A review of volunteer chal- lenge studies. American Journal of Epidemiology 167(7):775-785. CDC (Centers for Disease Control and Prevention). 2019. 2017-2018 estimated influenza illnesses, medical visits, hospitalizations, and deaths and estimated influenza illnesses, medical visits, hospitalizations, and deaths averted by vaccination in the United States. https://www.cdc.gov/flu/about/burden-averted/2017-2018.htm#:~:text=CDC%20esti- mates%20that%20influenza%20was,severe%20seasonal%20influenza%20can%20be (accessed October 9, 2021). CDC. 2020a. Estimated influenza illnesses, medical visits, hospitalizations, and deaths in the United States—2018–2019 influenza season. https://www.cdc.gov/flu/about/ burden/2018-2019.html (accessed October 9, 2021). CDC. 2020b. Estimated influenza illnesses, medical visits, hospitalizations, and deaths in the United States—2019–2020 influenza season. https://www.cdc.gov/flu/about/ burden/2019-2020.html (accessed October 9, 2021). CDC. 2021. 2020-21 influenza season summary FAQ. Preventive steps. https://www.cdc. gov/flu/prevent/preventionseason/faq-flu-season-2020-2021.htm (accessed. September 9, 2021). Cox, N. J., J. Hickling, R. Jones, G. F. Rimmelzwaan, L. C. Lambert, J. Boslego, L. Rudenko, L. Yeolekar, J. S. Robertson, J. Hombach, and J. R. Ortiz. 2015. Report on the second WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses: Geneva, Switzerland, 5-7 May 2014. Vaccine 33(48):6503-6510. Gates, B. 2018. Innovation for pandemics. New England Journal of Medicine 378(22):2057-2060. Gerdil, C. 2003. The annual production cycle for influenza vaccine. Vaccine 21(16):1776-1779. GPMB (Global Preparedness Monitoring Board). 2020. A world in disorder:Global Prepared- ness Monitoring Board Annual Report. Geneva: World Health Organization. Johnson, N. P., and J. Mueller. 2002. Updating the accounts: Global mortality of the 1918- 1920 “Spanish” influenza pandemic. Bulletin of the History of Medicine 76(1):105-115. Kilbourne, E. D. 2006. Influenza pandemics of the 20th century. Emerging Infectious Diseases 12(1):9-14. Kotey, E., D. Lukosaityte, O. Quaye, W. Ampofo, G. Awandare, and M. Iqbal. 2019. Current and novel approaches in influenza management. Vaccines (Basel) 7(2). Morens, D. M., and A. S. Fauci. 2020. Emerging pandemic diseases: How we got to COVID-19. Cell 182(5):1077-1092. Pérez Rubio, A., and J. M. Eiros. 2018. Cell culture-derived flu vaccine: Present and future. Human Vaccines & Immunotherapeutics 14(8):1874-1882. Quesada, J. A., A. López-Pineda, V. F. Gil-Guillén, J. M. Arriero-Marín, F. Gutiérrez, and C. Carratala-Munuera. 2021. Incubation period of COVID-19: A systematic review and meta-analysis. Revista clinica Española 221(2):109-117. Taubenberger, J. K., D. M. Morens, and A. S. Fauci. 2007. The next influenza pandemic: Can it be predicted? Journal of the American Medical Association 297(18):2025-2027. Tosh, P. K., R. M. Jacobson, and G. A. Poland. 2010. Influenza vaccines: From surveillance through production to protection. Mayo Clinic Proceedings 85(3):257-273. PREPUBLICATION COPY—Uncorrected Proofs

24 GLOBALLY RESILIENT SUPPLY CHAINS Webster, R. G., and E. A. Govorkova. 2014. Continuing challenges in influenza. Annals of the New York Academy of Sciences 1323(1):115-139. Weir, J. P., and M. F. Gruber. 2016. An overview of the regulation of influenza vaccines in the united states. Influenza Other Respiratory Viruses 10(5):354-360. WHO (World Health Organization). 2018. Ask the expert: Influenza Q&A. https://www.who. int/en/news-room/fact-sheets/detail/influenza-(seasonal) (accessed April 7, 2021). WHO. 2019. Five simple steps to protect against flu. https://www.who.int/news-room/feature- stories/detail/five-simple-steps-to-protect-against-flu (accessed October 9, 2021). Xu, X., L. Blanton, A. I. A. Elal, N. Alabi, J. Barnes, M. Biggerstaff, L. Brammer, A. P. Budd, E. Burns, C. N. Cummings, S. Garg, R. Kondor, L. Gubareva, K. Kniss, S. Nyanseor, A. O’Halloran, M. Rolfes, W. Sessions, V. G. Dugan, A. M. Fry, D. E. Wentworth, J. Stevens, and D. Jernigan. 2019. Update: Influenza activity in the United States during the 2018- 19 season and composition of the 2019-20 influenza vaccine. Morbidity and Mortality Weekly Report 68(24):544-551. Ziegler, T., A. Mamahit, and N. J. Cox. 2018. 65 years of influenza surveillance by a World Health Organization-coordinated global network. Influenza Other Respiratory Viruses 12(5):558-565. PREPUBLICATION COPY—Uncorrected Proofs

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Influenza viruses, both seasonal and pandemic, have the potential to disrupt the health and well-being of populations around the world. The global response to the COVID-19 pandemic and prior public health emergencies of international concern illustrate the importance of global preparedness and coordination among governments, academia, scientists, policy makers, nongovernmental organizations, the private sector, and the public to address the threat of pandemic influenza. These health emergencies have revealed opportunities to enhance global vaccine infrastructure, manufacturing, distribution, and administration.

Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines outlines key findings and recommendations to bolster vaccine distribution, manufacturing, and supply chains for future seasonal and pandemic influenza events. This report addresses the challenges of manufacturing and distributing vaccines for both seasonal and pandemic influenza, highlighting the critical components of vaccine manufacturing and distribution and offering recommendations that would address gaps in the current global vaccine infrastructure.

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