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2 Influenza Virus and Influenza Vaccines: A Primer This chapter provides an overview of basic facts about the human influenza virus and the available vaccines. The first portion of the text focuses on the virus and surveillance for outbreaks and variations, while the rest of the chapter focuses on vaccines. The information in this section is intended to provide background necessary for better understanding the subsequent chapters. This chapter does not include or directly address any recommendations by the committee. Influenza viruses, a diverse group of viruses within the Orthomyxo- viridae family, are significant yet under-prioritized pathogens of global significance. These viruses cause the respiratory disease that is commonly referred to as âinfluenza,â with symptoms that range in severity. While most cases are in fact mild, seasonal influenza causes a high burden of disease globally. Millions of severe cases, hundreds of thousands of deaths, and billions of dollars of economic loss are attributed to seasonal influenza every year (Iuliano et al., 2018; Putri et al., 2018). Global health experts have long warned of the risks of influenza and the need for preparedness, not only for the seasonal influenza variants, but also for variants with the potential to cause a pandemic. The dynamic nature of influenza stems from the diverse characteristics of this family of viruses. There are four genera of influenza virus, known as types A, B, C, and D: see Table 2-1. A key characteristic of influenza viruses, and particularly type A viruses, is their rapid rate of mutation and evolution, which produces great antigenic variability (Gerdil, 2003). The propensity for mutation enables the virus to change significantly from year 25
26 GLOBALLY RESILIENT SUPPLY CHAINS to year and, therefore, evade a personâs acquired immunity from either prior infections or vaccines. Spreading easily through the air when an infected person coughs, sneezes, or vocalizes, particularly in close spaces and indoors, influenza is highly infectious. A person may also be infected by touching surfaces contaminated with the virus. These characteristics combine to make influenza a constant challenge for protecting the publicâs health (CDC, 2018a). In this chapter, the committee provides an overview of seasonal and pandemic influenza viruses and the production platforms that manufacturers use today, as well as ones they may use in the near future, to produce both seasonal and pandemic influenza vaccines. This chapter also describes the global disease surveillance network that informs vaccine production and the current incentives for companies to manufac- ture influenza vaccines. TABLE 2-1 Key Characteristics of Influenza Subtypes Influenza Type Key Characteristics A Subtypes of influenza A are based on two proteins on the surface of the virus: hemagglutinin (H or HA) and neuraminidase (N or NA). There are 18 different hemagglutinin subtypes (H1 through H18) and 11 different neuraminidase subtypes (N1 through N11). Although there are potentially 198 different influenza A subtype combinations, only 131 subtypes have been detected in nature (CDC, 2019b). Type A virusesâ rapid mutation rate and evolution produces great antigenic variability (Gerdil, 2003). B Influenza B viruses are classified according to two genetic lineages known as B/Yamagata and B/Victoria. Influenza B viruses mutate more slowly than influenza A viruses (Valesano et al., 2020). Data suggest that influenza B viruses are more infective in children than adults, though research on influenza B viruses lags research on influenza A viruses (Bui et al., 2019). Influenza surveillance data from recent years show co-circulation of influenza B viruses from lineages both in the United States and around the world (McCullers et al., 2004), with influenza B becoming the most prominent circulating strain of influenza every 4â5 years (Sharma et al., 2019). C Infections with C viruses are typically mild and are not thought to cause human influenza epidemics, though they can cause cold-like symptoms and acute respiratory illness in children (Sederdahl and Williams, 2020). D The D subtype primarily infects pigs and cattle and is not known to infect or cause illness in humans (CDC, 2019b; Su et al., 2017).
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 27 SEASONAL AND PANDEMIC INFLUENZA VIRUSES Seasonal Viruses Influenza viruses circulate globally and mutate often, which prevents humans from developing an extended or lifelong immunity, as is possible with more stable viruses. Because of this characteristic, there is the potential for serious influenza outbreaks every year. Although isolated outbreaks of influenza cases may occur throughout the year, most infections occur in an annual season that centers around the winter in each hemisphere (CDC, 2019b). The typical influenza season begins in the fall months and gradu- ally rises, peaking in the winter months, and declines as spring approaches. The ease with which the virus spreads through the air primarily in enclosed spaces is largely responsible for the surge during winter months, when people spend more time indoors. Environmental factors, such as airflow, ambient temperature, and relative humidity levels may also play a role in the viability and transmissibility of the virus (Lowen et al., 2007). Every influenza infection provides an opportunity for the virus to mutate. The World Health Organization (WHO) estimates that, globally, there are 1 billion cases of influenza, 3â5 million severe cases, and 290,000â 650,000 influenza-related deaths each year (WHO, 2019). The large num- ber of infections provides at least as many chances as there are cases for new variants to emerge. Pandemic Viruses Pandemic influenza is a global outbreak that affects a much larger seg- ment of the population than a normal influenza season. WHO considers a potential pandemic variant to be an influenza virus for which people have little or no immunity and that is capable of sustained human-to-human transmission. Strains of pandemic potential represent an unknown and un- predictable threat, as they have the potential to mutate and spread rapidly. Such variations can emerge at any time among the commonly circulating influenza strains (WHO, 2018).1 Pandemic strains can also be the result of a spread of an influenza variant from animals to humans. Poultry and swine raised for food are very common reservoirs of influenza virus variants that can be transmitted to humans, although only a very few of these variants can effectively replicate and be transmitted among humans (CDC, 2020a). In a normal influenza season, 10 percent or less of the population is infected; in contrast, a pandemic variant may infect more than twice as 1âA new type A virus is the most likely cause of a pandemic.
28 GLOBALLY RESILIENT SUPPLY CHAINS many people (Molinari et al., 2007). The 1918 pandemic is estimated to have infected more than one-third of the worldwide population (CDC, 2019a). With such widespread infection, an influenza pandemic has the potential to overwhelm available medical resources, and having more people seriously ill can have wide-ranging effects on society and the economy, with the potential for severe economic downturns (World Bank, 2021). Pandemic influenza is likely to occur as a result of the widespread cir- culation of a novel strain that humans have not had prior exposure to and therefore may lack a sufficient antibody response. There may also not be an effective vaccine available to counter a novel variant, which increases the likelihood of more people developing serious illness (Paules and Fauci, 2019). In some instances, a pandemic is the result of a strain that some age or geographic segments of a population may have been exposed to previously, but to which significant segments have no prior exposure. Past pandemics have been notable for their impact on the global population or large segments that had no prior exposure or vaccine-induced immunity. The 1918 (H1N1) influenza pandemic was particularly deadly at the time before effective vaccines and other medical countermeasures had been developed. Pandemics in 1957â1958 (H2N2), 1968 (H3N2), and 2009 (H1N1) particularly affected segments of the population that were more vulnerable due to either advanced age or lack of prior exposure to a similar variant (CDC, 2018b). With at least four instances of influenza pandemics in the past century, the threat of pandemics remains a real concern (CDC, 2018b). The emergence of the H1N1 influenza variant in 2009 demonstrated the ongoing threat of pandemic influenza. The suddenness with which it emerged and rapidly spread caught people largely unprepared. The timing of its appearance may have contributed to challenges with vaccine develop- ment and distribution in conjunction with the seasonal vaccine produced that year (Jhaveri, 2020). Responses by policy makers and limited capacity to adjust production and distribution may have further influenced the out- come (Jhaveri, 2020; Leung and Nicoll, 2010). While the pandemic caused fewer deaths than anticipated, it served as an alert for public health authori- ties about the challenges of new influenza viruses (Kaplan et al., 2013). SARS-CoV-2 The most destructive pandemic since 1918 was not attributed to an influenza virus, but a coronavirus. The COVID-19 pandemic, caused by SARS-CoV-2, has illustrated the global impact of a pandemic, similar to that of 1918. The sudden emergence of an easily transmissible, novel virus with no available vaccine or known pharmaceutical countermeasures al-
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 29 lowed it to spread very rapidly and with deadly impact. Potentially com- plicating the identification of the pandemic and the health system response was that COVID-19 emerged during the Northern Hemisphereâs influenza season. Inadequate testing capability and the overlap with traditional in- fluenza may have hindered identification of COVID-19âs spread and full scope (Rubin, 2020). Lack of sufficient testing capacity also limited the ability to track and trace the spread of the virus, which may have resulted in patients being misdiagnosed and receiving inappropriate treatments. It will be years after the COVID-19 pandemic has ended before its impact can be fully assessed. However, as of August 2021, less than 2 years since WHO first identified a cluster of cases of âpneumonia of unknown causeâ in Wuhan, China (WHO, 2021b), WHO already counts more than 200 million confirmed cases and 4 million deaths (WHO, 2021f), numbers that will increase as the pandemic continues. The current experience with the COVID-19 pandemic demonstrates the need for robust surveillance and testing capacity to identify viral threats and ensure sufficient resources for effective prevention and treatment. SURVEILLANCE In 1952, WHO created the Global Influenza Surveillance and Response System (GISRS) to monitor the evolution of influenza viruses around the world. GISRS monitors for variations in human and animal influenza vi- ruses that may have the potential to spread in a wider human population as a pandemic variant. Over the course of a year, GISRS gathers data from more than 140 national influenza centers in 123 WHO member states (WHO, 2021c) that collect virus specimens in their country, perform a pre- liminary genetic analysis, and then ship representative clinical specimens and isolated viruses to one of the regional WHO Collaborating Centres in Atlanta, Memphis, London, Beijing, Tokyo, or Melbourne (CDC, 2020b): see Figure 2-1. The collaborating centers conduct advanced antigenic and genetic analyses that form the basis for WHO recommendations on the composition of a given yearâs seasonal influenza vaccine. WHO makes these recommendations in February for the Northern Hemisphere and in August for the Southern Hemisphere (Hampson et al., 2017; Ziegler et al., 2018). GISRS develops vaccine viruses suitable for vaccine production and reagents for assessing vaccine potency. It also issues guidance on ap- propriate risk management measures, including the use of antiviral drugs (Hay and McCauley, 2018). Monitoring for the risk of potential pandemic variants may also in- clude surveillance of influenza outbreaks in nonhuman animals in order to assess their potential transmissibility to humans. Of particular interest and concern are type A variants that emerge in poultry and swine raised
30 GLOBALLY RESILIENT SUPPLY CHAINS FIGURE 2-1 WHO Global Influenza Surveillance and Response System. SOURCE: WHO, 2021c. for food consumption (Fouchier et al., 2003). The 1918, 1957â1958, and 1968 pandemics all resulted from an avian variant (CDC, 2018b). Swine viruses are well known to be easily transmissible to humans. Ad- ditionally, influenzas in animals that may have close contact with farm animals or humans, such as other small mammals or birds, can also be a starting point for new variants that may ultimately produce a pandemic strain (Borkenhagen et al., 2019). Viruses may circulate in livestock well in advance of when they may appear in humans; therefore, monitoring animal viruses can provide an early warning. Examples of this have been seen in outbreaks in other countries, such as H5N1 in China (Peiris et al., 2012). In the United States, the U.S. Department of Agriculture (USDA) conducts surveillance for animal infections, including influenza (USDA, 2020). Other countries, such as those in the European Union, also have animal health surveillance systems in place (European Commission, n.d.). However, surveillance systems in many countries are less sophisticated, if they exist at all, leaving critical weaknesses in monitoring for the potential development of new influenza variants in animals. In the United States, the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health have been involved in efforts to expand and strengthen animal surveillance capabilities both domestically and globally (CDC, 2020c; NIAID, 2017).
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 31 VACCINE DEVELOPMENT Seasonal Influenza Vaccines Producing influenza vaccines depends on a complex manufacturing process. The time required to produce and distribute sufficient supplies of vaccine for each season takes a minimum of 4â6 months and can take up to 1 year (Sparrow et al., 2021). Before vaccine production can begin, manufacturers need to know what A and B subtypes to include in a given yearâs vaccine. As noted above, the process of identifying the subtypes for inclusion in the seasonal vaccine involves data from WHOâs GISRS and the U.S. CDC. While advisory committees have a role in recommending strains for inclusion, the ultimate decision on the composition of the vaccine is up to each nation and its regulatory authorities. In the United States, this final determination is made by the U.S. Food and Drug Administration (FDA). To be prepared to begin the manufacturing process as soon as the composi- tion of the annual vaccine has been determined, producers begin growing some of the most likely candidate viruses a month or more in advance of the final decision (CDC, 2020b). Table 2-2 summarizes the stages of seasonal influenza vaccine development and manufacturing. Figure 2-2 shows the timeline from surveillance and strain selection to availability of vaccines for seasonal influenza. TABLE 2-2 Stages of and Data for Seasonal Influenza Vaccine Development and Manufacturing Stage of Development Data Collected Strain Selection Data from the World Health Organization and the Global Influenza Surveillance and Response System based on global surveillance. National data from surveillance for influenza activity. Production of Reassortants Laboratory data on strains and potential use for vaccine production. Includes assessment of suitability for vaccine production and ultimate approval for use. Production and Calibration of Laboratory testing of strains and potential Reagents interactions. Annual License Approval Data based on past use of the same platforms. Additional data based on laboratory observations. After Approval Safety surveillance through reporting systems, such as the Vaccine Adverse Event Reporting System, and data surveillance systems, such the Vaccine Safety Datalink and Sentinel.
32 GLOBALLY RESILIENT SUPPLY CHAINS FIGURE 2-2 Egg-based influenza vaccine manufacturing and timeline. SOURCE: Lee, 2021. Current seasonal influenza vaccines only work against specific strains, so new vaccines need to be developed each year. Due to differences in when the seasons occur and the potential for variations, the vaccine needs to be different in the Northern and Southern Hemispheres. This in turn requires a sophisticated surveillance system to monitor the shifting of dominant strains in circulation. Monitoring global influenza infections allows for more ac- curate prediction of the impact a virus may have in a given year and for the potential to prepare effective vaccines (Hay and McCauley, 2018). However, vaccines for the Northern Hemisphereâs annual winter influenza season have to be prepared while the Southern Hemisphere is in the midst of its annual season. Therefore, if a new variant emerges in the Southern Hemisphere, there is an increased likelihood that the vaccine prepared for the Northern Hemisphere will be less effective. Global travel makes it very likely that a new variant that emerges in one hemisphere will be quickly transported to the other hemisphere (Baker et al., 2010). Vaccine effectiveness can vary from year to year depending on how well matched the vaccine strains are to the strains in circulation. Many other variables, including the vaccine plat- form, characteristics of the strain, and the ability of the individuals receiving the vaccine to develop an effective immune response, all contribute to varia- tions in effectiveness from year to year (Belongia et al., 2020). Pandemic Influenza Vaccines For previous influenza pandemics, researchers and vaccine manufac- turers focused efforts on refining existing production platforms that bal- ance speed and quality, with less emphasis on developing new platforms.
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 33 Innovations with new platforms emerged in response to the COVID-19 pandemic, which capitalized on three decades of research on messenger RNA (mRNA) vaccines. In the 1990s, researchers began efforts to use mRNA as an alternative approach to stimulate immunity to a variety of pathogens. Investments paid off more than a decade later in the successful development of mRNA vaccines with efficacy, speed, and quality (Marti- non et al., 1993; Sandbrink and Shattock, 2020). Facing a future potential influenza pandemic, some observers have suggested that efficacy, as well as the perception of quality, could be compromised as a vaccine moves quickly through development, testing, authorization, and distribution. As has been seen with first-generation COVID-19 vaccines, questions about quality, including safety and effectiveness, could lead to vaccine hesitancy by some segments of the public (Kim et al., 2021). As is discussed further below in the section on vaccine approval, it will be important for regulators and public health officials to explain the steps taken to ensure vaccine quality and allow vaccines to be distributed to the public. VACCINE PRODUCTION Seasonal Influenza Vaccines Manufacturing vaccines requires complex and sophisticated production facilities that in turn require substantial financial investment to construct and maintain. Construction of new vaccine manufacturing facilities can cost upwards of $500 million (Plotkin et al., 2017). Once a standard manufactur- ing facility is constructed, it takes approximately $60 million to produce 20 million doses of an egg-based vaccine in one season (Friede, 2013). The ma- jority of seasonal influenza vaccines are an inactivated influenza virus (IIV) vaccine (89.6 percent of global production capacity) (Sparrow et al., 2021). IIV vaccines are typically given as a single-dose intramuscular injection.2 A live attenuated influenza virus (LAIV) vaccine is made from attenuated, or weakened, viruses and is given as a nasal spray (Dormitzer et al., 2012).3 All influenza vaccines available in the United States and most of the world are made by private-sector manufacturers using one of three methods: egg- based, cell-based, or recombinant. The characteristics of selected seasonal in- fluenza vaccines licensed for use in the United States are shown in Table 2-3. 2âIIVs are approved for use by WHO for people 6 months and older, including women who are pregnant and people with chronic medical conditions. WHO recommends that children aged 6 months to 8 years who have not received a seasonal influenza vaccine during the previ- ous influenza season receive two doses at least 4 weeks apart. 3âLAIV is approved by WHO for use in people aged 2â49 years, excluding women who are pregnant or people who have underlying medical conditions. Only one dose is needed, except that WHO recommends that children aged 2â8 who have not received a seasonal influenza vaccine during the previous influenza season to receive two doses at least 4 weeks apart.
34 GLOBALLY RESILIENT SUPPLY CHAINS TABLE 2-3 Comparative Characteristics of Selected Seasonal Influenza Vaccines Vaccine Type Recombinant Egg-Based Inactivated Cell-Based Inactivated Hemagglutinin (HA) Characteristic Virus Vaccine Virus Vaccine Vaccine Immunogen Influenza virions produced in eggs or Insect cells are lysed Production cell cultures are purified and lysed with with detergent to release detergent to release hemagglutinin (HA) and HA oligomers, which neuraminidase (NA) oligomers, which form form ârosettesâ; does ârosettesâ not contain NA Required Seeds Candidate vaccine CVV âseedâ must be Recombinant vaccine virus (CVV) âseedâ producedâtypically virus âseedâ must be must be producedâ several weeks; generally, producedâtypically typically several several suitable CVVs several weeks; does weeks; possibly very become available not need CVV, just HA few suitable CVVs sequence become available Mutation Risk Propagation of Production of CVV Product made from CVV in eggs selects in mammalian cells stable (cell isolate) gene mutations that minimizes risk of sequence; negligible decrease antigenic mutation and potential mutation risk, but relatedness to native impact on vaccine glycosylation may vary virus and may impact effectiveness depending on host cells vaccine effectiveness Immunogen Variable, depending Variable, depending Consistent productivity Yields on virus strain; on virus strain; may be independent of virus often improved by improved by further strain; additional further passaging passaging or reassorting optimization of process or reassorting CVV CVV possible (with increased risk of further mutations) Vaccine Low: eggs are a Greater than egg-based; improvement may be Manufacture relatively inexpensive possible with process optimization and larger Cost production platform production scale Current GSK Seqirus Protein Sciences Corp. U.S.-Licensed Sanofi Pasteur (now Sanofi Pasteur) Manufacturers Seqirus Current Share of 85â90 percent 10â15 percent 1â2 percent U.S. Market NOTES: Based on influenza vaccines licensed for use in the United States. See text for discussion. SOURCE: Adapted from Barr et al., 2018, p. 2.
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 35 Approximately 82 percent of the projected U.S. vaccine supply pro- duced for the 2021â2022 influenza season used egg-based manufacturing technology, with the remaining produced using the other two methods (CDC, 2021c). For the same season, FDA approved vaccines produced by six manufacturers. A recent study (Sparrow et al., 2021) estimated that global capacity in 2019 for producing influenza vaccines was 1.48 billion doses, with the potential maximum annual capacity of between 4.15 and 8.31 billion doses for a pandemic influenza vaccine.4 The Sparrow et al. (2021) study also provides insight on facilities and their geographic distribution. As of 2019, 40 influenza vaccine bulk manufacturing facilities were found to be in operation; they included all vaccine types (IIV, LAIV; egg- and cell-based, recombinant) and stages of development (substance, formulation, and fill-finish). The study found that vaccine production occurred in most regions of the world except for Africa. However, geographic distribution is unequal: there were no facilities in low- income countries, 5 in lower-middle income countries, 15 in upper-middle income countries, and 20 in high-income countries. Table 2-4 depicts the number of active influenza vaccine production facilities by WHO region (Sparrow et al., 2021). Nearly 90 percent of seasonal influenza vaccines are IIV; there are only four manufacturers of LAIVs, located in India, China, the United Kingdom, and the Russian Federation. Together, these four facilities account for 5 percent of seasonal influenza vaccine production capacity. There are two licensed recombinant vaccines, manufactured by Sanofi Pasteur in China, France, Japan, Mexico, and the United States and by CPL Biologicals in India (Sparrow et al., 2021). TABLE 2-4 Influenza Vaccine Manufacturing Facilities by WHO Region WHO Region Number of Production Facilities African Region 0 Region of the Americas 7 Eastern Mediterranean Region 1 European Region 9 South-East Asia Region 3 Western Pacific Region 20 SOURCE: Sparrow et al., 2021, p. 524. 4âTwo doses of a pandemic vaccine are likely to be required to elicit an adequate immune response, though one of the COVID-19 vaccines involves only one dose.
36 GLOBALLY RESILIENT SUPPLY CHAINS Pandemic Influenza Vaccines The need for a separate vaccine for a pandemic variant presents chal- lenges related to production timelines and capacity. Production of pandemic influenza vaccines will require similar steps to production of seasonal vac- cines. The timeline from identification of a pandemic strain until deploy- ment of the first mass batch of vaccines is at least 6 months, an estimate that could be lengthened by supply shortages or capacity occupied by pro- duction of a seasonal vaccine at the manufacturing facilities (CDC, 2020b). Timing of the entire process can present challenges, as was the case in 2009 when the H1N1 pandemic strain was identified after the production cycle for the seasonal vaccine had begun (IOM, 2010). The procedure for manu- facturers to âswitchâ from seasonal to pandemic vaccine manufacturing, should a pandemic occur, still requires additional guidance. WHO has iden- tified this need in its Global Influenza Strategy 2019â2030 (WHO, 2019). The expected increase in demand for doses of a pandemic vaccine over that of a seasonal influenza vaccine would necessitate expanding the num- ber of facilities producing the pandemic vaccine. Facilities worldwide could take several months to reach maximum production. In many cases, produc- tion increases could be accomplished by repurposing facilities from produc- ing other types of vaccines and biological products (Sparrow et al., 2021). This shift in production could create shortages of these other products. VACCINE PRODUCTION PLATFORMS Egg-Based Vaccines Egg-based manufacturing is used to make two different types of sea- sonal influenza vaccines, one containing inactivated virus that is adminis- tered as an injection, the other using live attenuated, or weakened, virus that is administered by nasal spray. In the United States, the production pro- cess starts with the CDC or another GISRS laboratory creating candidate vaccine viruses (CVVs), or seed viruses, by combining the neuraminidase (NA) and hemagglutinin (HA) genes5 from the WHO-identified viruses with six genes of a commonly used human influenza virus that is adapted to grow well in chicken eggs (CDC, 2017). This is done for each of two A and one or two B strains that will be included in the current yearâs vaccine. The CVVs are sent to contracted laboratories, where they are injected into eggs to grow virus stocks that undergo testing to determine the optimum growth conditions, to improve virus yield by acclimating the virus to grow- ing in eggs, and to determine whether a sufficient amount of virus is present 5âThe HA gene is a surface glycoprotein of influenza A virus that infects the host by binding to the host receptor protein; the NA gene is a receptor-destroying enzyme that is involved in release of the virus from the host cell.
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 37 in the eggs. The CVVs are analyzed to determine whether they comply with FDA requirements for good laboratory practices for vaccine development to ensure suitability for human use. After these steps, CDC orders the contracted laboratories to ship the CVVs to manufacturers and to WHO Collaborating Centres (CDC, 2017). Once manufacturers receive the CVVs, the viruses are injected into embryonated chicken eggs, which are then incubated for several days to allow the virus to replicate (CDC, 2021b). The eggs are then chilled to humanely stop embryo maturation, and allantoic fluid containing the virus is harvested from the eggs. For inactivated influenza vaccines, the viruses are then inactivated, the viral antigens are purified, and preservatives and sometimes an adjuvant are added to create the vaccine (Tregoning et al., 2018): see Box 2-1. The vaccine is then packaged for distribution. Cell-Based Vaccines FDA approved the first cell-based influenza vaccine in 2012. This pro- cess starts with growing influenza CVVs, either in eggs or cell culture. Man- ufacturers then inoculate the CVVs into cultured mammalian Madin-Darby Canine Kidney (MDCK) cells (Seitz et al., 2010), which are then grown in a BOX 2-1 Adjuvants for Influenza Vaccines Adjuvants are substances added to a vaccine to boost the immune response to the vaccineâs antigens by improving the ability of the host immune system to recognize the administered antigen as foreign and respond to it. In the case of influenza vaccines, adjuvants are used to boost responses in populations with poor immune responses, including individuals who are immunosuppressed (Dikow et al., 2011; Yam et al., 2014) and in the very young and very old (Siegrist and Aspinall, 2009); to increase the immunogenicity of a particular antigen; to acceler- ate the responses to a vaccine, such as during a pandemic; and to enable dose sparing when the amount of vaccine is limited. Adjuvants that have been used in licensed influenza vaccines (Tregoning et al., 2018) include â¢ alum and other aluminum salts; â¢ MF59, an oil-in-water emulsion containing squalene, polysorbate 80, and sorbitan trioleate; â¢ AF03, an oil-in-water adjuvant containing squalene, montane 80, and EumulginÂ® B 1Â PH; and â¢ virosomes (sometimes called liposomes), a spherical cell-like structure made from phospholipids in water that incorporate an influenza antigen on the surface of the resulting vesicle.
38 GLOBALLY RESILIENT SUPPLY CHAINS bioreactor for several days. The virus-containing fluid is harvested from the cells and purified. Prior to the 2019â2020 influenza season, the CVVs used in cell-based manufacturing were still produced in eggs. For the 2020â2021 influenza season, all four influenza viruses used in the quadrivalent (con- taining four influenza virus strains) cell-based vaccines were also produced in a cell-based system, making the vaccine egg free (CDC, 2021a).6 Cell-based manufacturing has several potential advantages over egg- based production. Cell-based manufacturing has the potential to be started more quickly than egg-based production because the MDCK cells are kept frozen and banked, ensuring an adequate supply of cells to start vaccine production (George et al., 2010). In addition, virus production in a bioreactor is more flexible and scalable and not vulnerable to egg shortages. Cell-based manufacturing can also produce vaccines that offer the potential to provide better protection against influenza without the use of adjuvants. The viruses used to make cell-based vaccines may be more similar to the circulating wild influenza viruses, given that they do not have to be adapted to grow in chicken eggs (Izurieta et al., 2020). However, cell-based vaccines are more expensive than egg-based vac- cines (Chen et al., 2020). In addition, conditions inside the cells used to produce vaccine can give rise to mutations in the HA gene that affect the stability of the resulting virus and can reduce the vaccineâs potency (Romanova, 2017). Recombinant Vaccines Recombinant influenza vaccines are created synthetically. Production is not dependent on having embryonated chicken eggs and does not require having CVVs that are adapted for growth in eggs. Recombinant vaccines are made by incorporating the HA gene from the viruses identified by WHO into a baculovirus,7 which acts as a delivery vehicle for the HA gene into an FDA-qualified host cell line (either mammalian or insect). The infected cells then produce the HA antigen, which is harvested, purified, and packaged with the HA antigen from the other WHO-identified viruses, also produced this way, as a recombinant influenza vaccine (Richards et al., 2020). The recombinant process is currently the fastest method for making in- fluenza vaccines (Yadav et al., 2020), and it offers the potential for creating antigens that trigger different components of the immune system to respond to an influenza virus (Richards et al., 2020; Schotsaert et al., 2009; Shim 6âA quadrivalent vaccine is one that works by stimulating an immune response against four different antigens, such as four different viruses or other microorganisms.Â 7âBaculoviruses are insect pathogenic viruses that areÂ used as tools to produce recombinant proteins.Â
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 39 et al., 2011). This potential could allow for the production of vaccines that are more broadly protective against influenza virus strains that are not well neutralized by egg-based vaccines, such as the A(H3N2) strain that appears to cause more serious illness in older adults (Belongia et al., 2020). Evidence also suggests that recombinant influenza vaccines can produce stronger immune responses among older adults (Dunkle et al., 2017). Recombinant vaccines generally require use of an adjuvant to maximize their potential for inducing immunity. Adjuvants also offer the opportunity to improve the efficacy of some influenza vaccine platforms that may offer advantages over traditional vaccines, but on their own would prompt a weaker immune response (Zhu et al., 2021). A major challenge facing recombinant influenza vaccines has been the regulatory process. Currently, FDA has approved one recombinant influ- enza vaccine, a process that took 17 years, and vaccines for novel influenza variants could take longer (Cox et al., 2015). In 2020, the European Com- mission approved its first and only quadrivalent recombinant influenza vac- cine for adults 18 years and older (Sanofi, 2020). As with the U.S. approval process, the European Medicines Agency took many years to approve its version of the vaccine. Novel Vaccine Platforms While the egg-based, cell-based, and recombinant vaccine platforms have proven sufficient for producing safe and effective influenza vaccines for both seasonal and pandemic influenza, research on other platforms continues. These include nucleic acid vaccines, such as the mRNA vaccines that proved critical to taming the COVID-19 pandemic, as well as virus- like particle vaccines, computationally optimized broadly reactive antigen vaccines, synthetic viruses, nanoparticle-based vaccines, and viral vector vaccines: see Table 2-5. This section discusses nucleic acid and viral vector vaccines, as these have been most advanced as a result of the COVID-19 pandemic. Reviews of additional novel vaccine platforms can be found in Kotey et al. (2019). Nucleic Acid Vaccines Nucleic acidâbased influenza vaccines have been the subject of research for more than 20 years. This group of vaccines incorporates genetic mate- rial from a virus to trigger an immune response in the vaccine recipient. Nucleic acid vaccines are promising as they have the potential to create a stronger immune response than some traditional vaccine platforms (Qin et al., 2021). The speed with which two mRNA vaccines were developed to protect against SARS-CoV-2, which causes COVID-19, has prompted a re-
40 GLOBALLY RESILIENT SUPPLY CHAINS TABLE 2-5 Novel Technology Platforms for Producing Influenza Vaccines Vaccines Design Virus-Like Particle Vaccines (VLP) Self-assembling viral matrices that express a single or multivalent viral surface proteins Computationally Optimized Broadly VLPs bearing computationally optimized viral Reactive Antigen Vaccines surface proteins Synthetic Virus Generation of replication-incompetent viruses bearing genetically attenuated genomic sequences Epitope Epitope-rich proteins of viruses, designed to induce protective epitope-targeted antibodies Antigen-Presenting Cell (APC) APC-targeted delivery of immunogenic viral Inducible proteins to induce quicker and T-cell responses Nanoparticle Based Self-assembling nano-molecules that carry a single or multivalent viral surface protein Viral-Vectored Mainly involves use of dissimilar viral matrices as carriers of specific viral protein SOURCE: Kotey et al., 2019, p. 58. newed interest in the potential to develop mRNA vaccines against influenza A and B viruses. Current work suggests that mRNA vaccines developed against influenza could induce broad protective immune responses and have the potential to address the shortcomings of the vaccines currently available (Scorza and Pardi, 2018; Zhuang et al., 2020). In particular, the relative ease with which mRNA vaccines can be updated once the genome sequence of an emerging influenza virus strain has been accurately identi- fied would be a distinct advantage, especially if a pandemic strain emerges. Moreover, the quality of the mRNA vaccines that were developed at a record pace bodes well for balancing the issue of speed versus efficacy. One potential issue for mRNA influenza vaccines could be their instability at ambient and refrigerator temperatures, as evidenced by the need to store the COVID-19 mRNA vaccines at below-freezing temperatures. However, rational design of optimally stabilized mRNA vaccine formulations could address that shortcoming (Crommelin et al., 2021), given that there is a significant body of research on stabilizing mRNA molecules (Kaczmarek et al., 2017; Kowalski et al., 2019; Sahin et al., 2014). Viral Vector Vaccines Viral vector vaccines are designed to mimic natural infections by using a naturally infectious human virus, such as an adenovirus, variola virus, or alphavirus, that has been modified to also produce influenza proteins that
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 41 can trigger a broadly protective immune response (Berthoud et al., 2011; de Vries and Rimmelzwaan, 2016; Kim et al., 2017; Lingel et al., 2017). In fact, the ability of the viral vector itself to trigger an immune response suggests that the viral vector could serve as both a delivery vehicle for influenza antigens and as an adjuvant (Sebastian and Lambe, 2018). Viral vectorâbased vaccines can induce a broad immune response involving both B-cell and T-cell responses (de Vries and Rimmelzwaan, 2016; Demminger et al., 2020), though prior exposure to the parent virus can attenuate that response. Currently, three different types of viral-vectored influenza vac- cines are in clinical trials (Sebastian and Lambe, 2018). PRODUCTION CHALLENGES Multiple potential challenges can affect when influenza vaccines are ready for widespread administration. Delays in the strain selection pro- cess can have a major effect on the timing of vaccine production because they delay the production of the vaccine seed strain. Production can also be affected by shortages of antigen, limited availability of an adjuvant, insufficient supply of other critical components for vaccine manufacturing (i.e., vials, cell-media, and bioreactor bags), delays in the fill-finish pro- cess, and limited supply of ancillary supplies for vaccine administration (i.e., needles, syringes) (Sparrow et al., 2021; Ulmer et al., 2006; Weir and Gruber, 2016). Delays in each component can have variable implications for the delay of a vaccination campaign: see Figure 2-3. For example, a situation in which antigen availability is the limiting factor for vaccine manufacturing will result in less of a delay than if syringes are the limit- ing factor. While the United States has invested heavily in antigen production, cell-based production capacity, and ensuring a plentiful supply of chicken eggs, investments in adjuvant production and fill-finish capacity would be needed to ensure that vaccine production can proceed as quickly as possible in the case of an influenza pandemic to meet U.S. vaccine needs (PCAST, 2010). As discussed above, facilities to produce vaccines are complex and require a major investment in a manufacturing plant and the skilled staff to carry out the process (RÃ¸ttingen, 2016). The specific equipment needed, along with the knowledge and skills of the production staff, may also vary by platform. There are limited numbers of such facilities (see Table 2-4, above), and they include those that ordinarily produce seasonal influenza, as well as other vaccines and biological products. In the event that any of these facilities needs to be repurposed for pandemic vaccine production, it will likely affect the supply of other products that would otherwise have been produced and can create temporary shortages that last from a few months to over 1 year.
42 GLOBALLY RESILIENT SUPPLY CHAINS FIGURE 2-3 Influenza vaccine response capability. SOURCE: Bright, 2021. Economic Considerations Despite the significant health burden of seasonal influenza (WHO, 2019), worldwide demand for vaccine is low and unpredictable, especially in low- and middle-income countries (LMICs) (Bresee, 2019), largely due to low prioritization of preventing seasonal influenza. Among the top rea- sons that these countries lack national influenza vaccination programs are âa lack of perceived risk from influenzaâ and âcompeting public health prioritiesâ (Kraigsley et al., 2021), thus contributing to low demand for the vaccine. The burdens of other high-priority diseases and socioeconomic issues and tight budgets may require policy and decision makers to conduct complex risk-benefit analyses and make decisions regarding policy and investment priorities (Kraigsley et al., 2021). LMICs are also less likely than their wealthier counterparts to have vaccine policies and platforms for vaccine delivery and technical assistance. They also face challenges due to a lack of financing for vaccine introduction (Ortiz et al., 2016). When countries do have vaccine production capacity, it may be focused on making vaccines deemed more critical for local needs. Providing annual influenza vaccines to a majority of their population can be too expensive for countries with relatively low per capita gross do- mestic product. These countries may also lack the infrastructure to produce and distribute their own vaccine supplies, further limiting their ability to mount an effective vaccination program. If seasonal influenza vaccines were seen as more effective in preventing serious illness and greater consideration
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 43 was given to the burden of disease from influenza and its related costs, such as the medical costs from hospitalizations and the lost productivity due to missed work days, seasonal influenza prevention and control might become a higher priority (Ortiz and Neuzil, 2019). However, some LMICs may still have other underfunded and more burdensome health needs that they choose to prioritize ahead of influenza (Kraigsley et al., 2021). Compounding the issues of cost and perceived risk, seasonal influenza vaccine effectiveness tends to be low, and the link between vaccination and reduced mortality is not clear in many LMICs. This may be due to the fact that burden-of-disease estimates for influenza often do not exist for LMICs; lack of data serves as a barrier to policy implementation for influenza vac- cination (Ortiz and Neuzil, 2019). These factors may make it difficult to demonstrate the positive effects of vaccination, especially when vaccine uptake and acceptability is low. Because the benefit of vaccinating for seasonal influenza may be less obvious than vaccinating for other diseases (like pneumococcal conjugate or rotavirus), policy makers may be less likely to prioritize influenza vaccination (Ortiz and Neuzil, 2019). Producing seasonal influenza vaccines in LMICs is not usually lucrative because there is low demand. Demand is also variable from year to year, and it could be affected by issues that are difficult to forecast, such as the emergence of a pandemic strain. When demand is low, increased manufacturing capacity could be unsustainable (Chick et al., 2008; Gellin and Ampofo, 2014). Low demand for influenza vaccines may result in the lack of a market for manufacturers. Vaccine Supply Chains Like any manufactured product, the vaccine supply chain can be viewed in terms of its supply and end-product delivery streams. The steps in the process are commonly described as being either âupstreamâ or âdown- streamâ components. Raw materials get formulated into intermediary products before manufacturers convert them into finished states that can be shipped and delivered for distribution and use (Laudon and Laudon, 2012). Upstream processes involve steps prior to primary manufacturing, and downstream processes involve steps in the post-manufacturing phase. Upstream processes in the vaccine supply chain involve development of the CVVs and identifying appropriate adjuvants and other raw materials needed for producing the vaccine and its packaging. Downstream processes include distribution of vaccines both across and within countries. Both segments of the downstream supply chain pose challenges. For ex- ample, transporting vaccines and needed materials to countries often relies on commercial flights for shipping cargo (IATA, 2021). The global supply chain was disrupted during the COVID-19 pandemic because of flight
44 GLOBALLY RESILIENT SUPPLY CHAINS cancellations, trade restrictions, and closed national borders, all of which restricted the flow of goods (Nelson, 2020). LMICs also experienced chal- lenges with vaccine storage and delivery during the COVID-19 pandemic (Hatchett et al., 2021). Vaccine design parameters affect the manufactur- ing and supply chain as shown: see Figure 2-4. The makeup, formulation, and critical inputs required to produce the vaccine all affect the timing and complexity of the manufacturing process. Procurement and Regulation Multiple strategies and mechanisms exist for countries to obtain vac- cine supplies, including direct involvement of governments in their financ- ing, procurement, and distribution, and in some cases, their development and manufacturing. Nongovernmental organizations play a significant role, particularly for smaller countries and for LMICs. Two common procure- ment strategies are bilateral agreements and pooled procurement. Bilateral Agreements Under bilateral agreements, governments can enter into advance pur- chase agreements with vaccine manufacturers to procure doses of a vaccine ahead of when they will be needed. Such agreements are legally binding FIGURE 2-4 Vaccine manufacturing network.
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 45 contracts: a government or other entity commits to purchasing from a vac- cine manufacturer a specific number or percentage of doses of a potential vaccine at a negotiated price if it is developed, licensed, and manufactured. For the manufacturer, these bilateral agreements incentivize investment in vaccine research and development. For the government or other purchaser, they often secure priority access to vaccines and manufacturing capacity if the vaccine development is successful and need remains high (Phelan et al., 2020). This approach is how many high-income countries reserved doses of the COVID-19 vaccine and, before it, the H1N1 vaccine. However, these agreements may contribute to inequalities in vaccine access and reduce collaborative financing among nations. This outcome was observed with both COVID-19 and H1N1. For COVID-19, some lower-income countries that were unable to secure doses early in the pan- demic may have received vaccines later; for H1N1, some LMICs may have received vaccines after the pandemic had peaked (Phelan et al., 2020). Pooled Procurement A pooled procurement strategy is considered a primary enabler of strengthening long-term supply chains. In this model, a single entity pur- chases vaccines on behalf of multiple countries or in coordination with multiple buyers. This approach serves to both mitigate risks and increase incentives. This mechanism also increases visibility and assists manufac- turers in forecasting demand, which assists with planning throughout the manufacturing process (Hatchett et al., 2021). UNICEF, WHO, and Gavi8 have collaborated to facilitate vaccine ac- cess. UNICEF uses pooled procurement to supply vaccines for routine im- munizations and in response to disease outbreaks (Hatchett et al., 2021). UNICEF has procured seasonal influenza vaccine in limited quantities and faces challenges meeting demand due to a lack of accurate demand forecast- ing within countries (see Chapter 4). Furthermore, UNICEF may receive country requests for vaccines that were not reflected in forecasting, making it more difficult to plan and fulfill requests (UNICEF, 2020). Timeliness and accuracy of country forecasts and sufficient funding present barriers to vaccine procurement. The Pan American Health Organization (PAHO) has used pooled pro- curement since 1977. PAHO countries pool resources to obtain vaccines and related supplies at low prices (WTO, 2020). PAHO focuses on prod- ucts related to infectious diseases, including malaria, tuberculosis, and HIV (PAHO, 2021). It has expanded these efforts to include COVID-19. As of 8âGavi, the Vaccine Alliance (known simply as Gavi), is a publicâprivate global health part- nership with the goal of increasing access to immunization in lower-income countries.
46 GLOBALLY RESILIENT SUPPLY CHAINS September 2021, PAHOâs strategic fund has provided more than 31 million people with access to COVID-19-related products, including medicines, diagnostic tests, and personal protective equipment (PAHO, 2021). As an- other example of pooled procurement, Gavi is funding a stockpile of Ebola vaccines, which will be accessible to countries through UNICEFâs pooled procurement mechanism (Gavi, 2021a). An important consideration is that pooled procurement will not be as effective if manufacturers have engaged in bilateral agreements (WHO, 2020). During COVID-19, COVAX was established to be the primary mechanism for procurement and distribution of COVID-19 vaccines; see discussion in the following section.9 Challenges and Opportunities for Equitable Vaccine Distribution Despite the efforts to increase global manufacturing capacity and access for influenza vaccines, several barriers remain that result in inequitable dis- tribution. Countries with no national manufacturing capacity may be at a significant disadvantage for procuring vaccines depending on whether they have sufficient resources to readily meet their needs through purchasing products from other countries. As of 2019, 80 percent of pandemic influ- enza vaccine manufacturing facilities were located in high-income coun- tries, which have only 16 percent of the worldâs population (Sparrow et al., 2021). Vaccines produced in these facilities are more rapidly available within the country of production. Delivery to countries with no national manufacturing requires additional steps in procurement, including licensing and trade agreements (see Chapter 6). In addition, as noted above, LMICs face challenges in financing the purchase of vaccines, physical infrastructure (cold storage, transportation), and governance structures to support their allocation and distribution. In April 2020, the Access to COVID-19 Tools Accelerator (ACT-A) was launched with support from WHO, the World Bank, and several other part- ners in the philanthropy, global health, and industry sectors (see Chapter 5). In recognition that global access to supplies to combat COVID-19 would be a significant challenge, this collaborative framework was designed to âac- celerate development, production, and equitable access to COVID-19 tests, treatments and vaccines,â with a focus on LMICs (WHO, 2021e). ACT-A is comprised of four pillars for diagnostics, therapeutics, vaccines, and health systems connection (WHO, 2021d). The vaccine pillar is COVAX, a global initiative to enable equitable access to COVID-19 vaccines to LMICs 9âCOVAX, the acronym for COVID-19 Vaccines Global Access, is co-led by Gavi, the Coali- tion for Epidemic Preparedness Innovations (CEPI), and WHO; its aim is to accelerate the de- velopment and manufacture of COVID-19 vaccines and to guarantee fair and equitable access for every country in the world; UNICEF is a delivery partner (Gavi, 2021c); see text below.
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 47 (Phelan et al., 2020). Participation in COVAX, however, is not restricted to LMICs. Higher-income countries join COVAX to leverage the pooled procurement benefits COVAX offers but self-finance their purchases. By August 2020, 172 countries had joined COVAX (WHO, 2021a). On behalf of participating countries, COVAX negotiated contracts with several vaccine manufacturers whose products have been approved for emergency use by WHO. COVAX was designed to procure enough vaccines to cover 20 percent of the population of its participating countries. Ninety- two LMICs (collectively called the AMC92) will receive their 20 percent vaccine share free of cost, financed by donors (Gavi, 2021b). COVAXâs four partners (see fn. 9) co-lead the COVAX facility, which receives funds from donor countries to purchase vaccines from manufacturers. The facility is the platform on which governments who are involved in COVAX can access the portfolio of procured vaccines (Phelan et al., 2020). Regulation of Influenza Vaccines Governments and multinational authorities regulate vaccines to en- sure that standards for safety and effectiveness of these potentially life- saving products are met at the highest levels and any harm is minimized (Ellenberg and Chen, 1997). Regulators also help to ensure that no coun- terfeit products are being substituted for legitimate, safe, and effective products. U.S. Regulation In the United States, FDA treats influenza vaccines, both seasonal and pandemic, as a biological product, giving the Center for Biological Evaluation and Research (CBER) authority for licensing new vaccines and approving annual modifications to previously approved seasonal influenza vaccines. Guidance issued by CBER provides two pathways for approval of a new vaccine: a traditional biologics license application (BLA) or an accelerated BLA pathway (CBER, 2007; Weir and Gruber, 2016). Both routes require demonstrations of product safety and efficacy and that the manufacturing produces consistent product. The main difference is in what needs to be demonstrated: the traditional pathway requires demonstrating effectiveness against influenza illness in an adequate and well-controlled clinical study and proof of immunogenicity in populations that might not have been included in the clinical trial, such as children under age 5 and adults aged 65 and older; the accelerated approval is based on âadequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict
48 GLOBALLY RESILIENT SUPPLY CHAINS clinical benefitâ (CBER, 2007, p. 7). CBER considers a hemagglutination inhibition antibody response to be an acceptable surrogate marker that is likely to predict clinical benefit.10 Seasonal influenza vaccines approved through the accelerated pathway require the BLAâs sponsor to conduct fur- ther studies to verify and describe the vaccineâs clinical benefit and include detailed plans for post-marketing safety surveillance (CBER, 2007). For seasonal influenza vaccines, which must be updated annually, or at least periodically, FDA allows manufacturers of an approved inactivated or recombinant vaccine to submit a supplement to its license rather than requiring new clinical data. Manufacturers of vaccines containing live at- tenuated virus are required to conduct a clinical study in approximately 300 adults to verify that the virus is indeed attenuated (Weir and Gruber, 2016). For a pandemic influenza vaccine, approval can also occur through the traditional or accelerated pathways (CBER, 2007). If a manufacturer holds a U.S. license for an approved seasonal influenza vaccine and the manufacturing process used to make the pandemic vaccine is the same as for the approved seasonal vaccine, CBER will approve a product contain- ing inactivated virus based on the hemagglutination inhibition antibody response, with the added requirement of a detailed post-marketing surveil- lance plan. Vaccines containing live attenuated virus can also use the hem- agglutination inhibition antibody response, as well as alternative endpoints that assess other immunological processes that live attenuated viruses can activate. Pandemic influenza vaccines manufactured using a process that has not been approved as part of a previous BLA are held to the standards for accelerated approval (CBER, 2007). During the COVID-19 pandemic, FDA granted three manufacturers Emergency Use Authorization (EUA) for COVID-19 vaccines, two for mRNA vaccines and one for a recombinant vaccine (FDA, 2021b; GAO, 2021). As of August 23, 2021, one of the mRNA vaccines has full FDA approval. According to FDA, an EUA is a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the COVID-19 pandemic. Under such an authorization, âFDA may allow the use of unapproved medical products, or unapproved uses of approved medical products in an emergency to di- agnose, treat, or prevent serious or life-threatening diseases or conditions when certain statutory criteria have been met, including that there are no adequate, approved, and available alternativesâ (FDA, 2021b). Manufac- turers decide whether and when to submit an EUA request to FDA. Once submitted, FDA evaluates the request to determine whether the relevant statutory criteria are met, taking into account the totality of the scientific 10âThe hemagglutination inhibition is an assay used to titrate the antibody response to a viral infection.
INFLUENZA VIRUS AND INFLUENZA VACCINES: A PRIMER 49 evidence that is available: this allows the agency to weigh quality assurance data against the need for speed in granting an EUA request (FDA, 2021a). One criticism of FDA in the context of its EUA of the COVID-19 vaccines has been that it did not sufficiently explain to the public what an EUA means regarding safety and efficacy and why the EUA mechanism was allowed, rather than requiring full regulatory approval and licensing authorization.11 Some people refused COVID-19 vaccines because they had emergency use rather than full regulatory approval (Fritts, 2021). Global Regulation The worldwide regulation of vaccines is directed through various na- tional regulatory entities, such as those in the United Kingdom, Australia, and the European Union. WHO is the primary agency involved in â[apply- ing] international standards to â¦ determine whether vaccines are safe and effective,â particularly for vaccines used by LMICs (WHO, 2021d, para. 3). WHOâs prequalification process advises UN agencies that procure and distribute vaccines (including UNICEF) on the safety and efficacy of the vaccines, accounting for the conditions of individual national immunization programs (Dellepiane and Wood, 2015). As of 1992, âall vaccines used in national immunization programs should meet WHO requirementsâ (Del- lepiane and Wood, 2015, p. 54). The prequalification process also accounts for programmatic suitability: for example, âvaccines filled in non-auto dis- able pre-filled syringes are not acceptable for prequalification due to the risk of re-use and unsafe disposalâ (Dellepiane and Wood, 2015, p. 55). The program includes a network of laboratories worldwide that test vaccines based on prequalification standards. Independent testing ensures quality. After gaining prequalification status, vaccines are monitored through a post-prequalification monitoring process for ongoing quality assurance (Palkonyay and Fatima, 2016). Multiple factors, individually or in combination, can contribute to lim- ited influenza vaccine access in individual countries. Limited manufacturing capacity of influenza vaccines in LMICs is a significant barrier to expanding vaccine access. Procurement mechanisms for influenza vaccines are rela- tively recent, as no influenza vaccines had obtained WHO prequalification prior to 2006. This situation changed when the prequalification program was adapted to address the H5N1 virus threat in the mid-2000s (Palkonyay and Fatima, 2016). In 2006, WHO initiated the Global Action Plan for Influenza Vaccines (GAP) to build capacity for vaccine manufacturing and 11âIn July 2021, the two manufacturers of mRNA COVID-19 vaccines announced they were filing the required application to gain full regulatory approval for their vaccines; in September one received the full approval.
50 GLOBALLY RESILIENT SUPPLY CHAINS to facilitate access to pandemic influenza vaccines (Sparrow et al., 2021). GAP aimed to achieve this goal by following a technology transfer model, in which vaccine manufacturers in LMICs received training and technical assistance to develop sustainable in-country manufacturing (Grohmann et al., 2016). Through GAP, pandemic and seasonal influenza vaccines gained WHO prequalification (Palkonyay and Fatima, 2016). In response to the influenza threats of H5N1 in 2006 and H1N1 in 2009, the expedited pro- cess was developed and applied to prequalify both seasonal and pandemic vaccines (Palkonyay and Fatima, 2016). The Pandemic Influenza Preparedness (PIP) framework was established by WHO in 2011. It brings together stakeholders to implement a global approach to pandemic influenza preparedness and response. PIP is focused on improving and strengthening the sharing of influenza vaccines that are directed to viruses with human pandemic potential and increasing the ac- cess to vaccines and other pandemic-related supplies for LMICs. Regulatory support under the PIP framework includes the following (Palkonyay and Fatima, 2016, p. 5418): â¢ âDevelopment of guidelines for non-vaccine-producing countries that will enable them to expedite approval of influenza vaccines used in national immunization programsâ; â¢ Capacity building for LMICs to âregulate influenza products, in- cluding vaccines, with a focus on marketing authorization and pharmacovigilanceâ; and â¢ âDevelopment of a common approach for accelerated regula- tory approval of influenza products in a public health emergency through encouraging 48 target countries to adopt a collaborative procedureâ¦to assess and accelerate national registration of WHO prequalified pharmaceutical products, including vaccines.â REFERENCES Baker, M. G., C. N. Thornley, C. Mills, S. Roberts, S. Perera, J. Peters, A. Kelso, I. Barr, and N. Wilson. 2010. Transmission of pandemic A/H1N1 2009 influenza on passenger aircraft: Retrospective cohort study. British Medical Journal 340:c2424. Barr, I. G., R. O. Donis, J. M. Katz, J. W. McCauley, T. Odagiri, H. Trusheim, T. F. Tsai, and D. E. Wentworth. 2018. Cell culture-derived influenza vaccines in the severe 2017â2018 epidemic season: A step towards improved influenza vaccine effectiveness. Nature Partner Journals Vaccines 3(1):44. Belongia, E. A., M. Z. Levine, O. Olaiya, F. L. Gross, J. P. King, B. Flannery, and H. Q. McLean. 2020. Clinical trial to assess immunogenicity of high-dose, adjuvanted, and recombinant influenza vaccines against cell-grown A(H3N2) viruses in adults 65 to 74 years, 2017â2018. Vaccine 38(15):3121â3128.
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