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Globally Resilient Supply Chains for Seasonal and Pandemic Influenza Vaccines (2021)

Chapter: 4 Vaccine Distribution and Delivery

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Suggested Citation:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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:"4 Vaccine Distribution and Delivery." 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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4 Vaccine Distribution and Delivery Following the Chapter 3 review of issues related to maintaining the supply chains needed to provide the critical components, this chapter turns to the logistical challenges involved in the worldwide distribution of fin- ished vaccines. Those challenges include country preparedness, vaccine characteristics, data systems, and the physical supply chain required for various vaccine types. Given the annual need to update a seasonal influenza vaccine and the limited period of use, poorly managed logistics systems can disrupt vaccina- tion campaigns and lead to inequitable vaccine distribution. Some U.S. re- gions receive more vaccines than needed while others receive an insufficient supply, both of which can increase the costs of a vaccination program (Li et al., 2018). Data are critical to establishing and maintaining a well-managed logistics system, but the currently available tools to gather data and assess the global supply of influenza vaccine fall short of providing those data. In the United States, few states have systems in place that provide the neces- sary visibility into how many doses of vaccine have been administered, how much inventory is left, and where it needs replenishing. The same is true globally, where gaps in countrywide assessments create the same problem regarding visibility. In this chapter the committee discusses how vaccine characteristics and design can affect distribution, the need for diversified portfolios of influenza vaccines, gaps in obtaining supply and demand data, and vaccine information systems and coordination. Table 4-1 summarizes the recommendations in this chapter, delineated by the U.S. and global or regional actors identified for their implementation. 95 PREPUBLICATION COPY—Uncorrected Proofs

96 GLOBALLY RESILIENT SUPPLY CHAINS TABLE 4-1 Summary of Recommendations on Vaccine Distribution and Delivery Global/Regional Actor Recommendation Domestic Actor(s) • World Health Recommendation 4-1: U.S. Department of Health and Organization (WHO) Systems approach to vaccine Human Services, including design and development • Food and Drug Administration • Assistant Secretary for Preparedness and Response • National Institutes of Health (NIH) • WHO, its partners, Recommendation 4-2: and funders Global vaccine portfolio rollout • WHO Recommendation 4-3: • U.S. Centers for Disease Control Commission studies in and Prevention (CDC) • Gavi, The Vaccine forecasting and demand Alliance uptake Recommendation 4-4: • CDC Improved models for vaccine • NIH cost effectiveness • U.S. Agency for International Development • WHO Recommendation 4-5: • Office of Global Affairs Global tools for vaccination • Gavi, The Vaccine planning Alliance • UNICEF DESIGN FOR DISTRIBUTION Looking to the future and the likely development of new types of vac- cines for seasonal and pandemic influenza, it is important to understand that the characteristics of a vaccine have implications for its distribution, acceptance, and appropriate use, particularly in low-resource settings. Vac- cines may have different requirements for cold chain logistics, vial size, shelf life, dose volume and regimen, route of administration (i.e., injec- tion, oral), among others. For example, a vaccine that requires sub-zero cold chain temperatures (<0°C) along with various ancillary supplies will place greater stains on supply chains than a vaccine that can be stored at standard refrigeration temperatures (2°–8°C) or can be administered with fewer ancillary supplies. These considerations have been underscored by the mRNA vaccines developed against SARS-CoV-2. While highly efficacious, the ultra-cold PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 97 temperature requirement is a significant barrier to administration in limited- resource contexts (Crommelin et al., 2021). Manufacturers need encourage- ment to do stability studies to reduce the need for ultra-cold chains and to improve vaccine stability outside of cold chains. However, there are barriers to conducting such studies: since it is in the best interest of manufacturers to have vaccines in the market as quickly as possible, nonessential research, such as stability improvement studies, are not prioritized. A complex array of considerations need to be accounted for when encouraging manufactur- ers to improve existing vaccine platforms. Other specifications have led to a more complicated rollout for some vaccines. For example, the Pfizer mRNA vaccine has a set of unique speci- fications that require additional steps in administration. While the indus- try standard for a vaccine dose is 0.5 mL, the Pfizer vaccine dose is 0.3 mL. This vaccine also requires ultra-cold storage for transportation, along with dilution before administration, which is another nonstandard practice (Pharmacy Today, 2021) that presents challenges in administration. Tim- ing between shots has also caused some confusion, as the recommended interval between doses is 21 days for the Pfizer vaccine and 28 days for the Moderna vaccine (CDC, 2021c). In contrast to these two, the Janssen vac- cine from Johnson & Johnson requires only one dose. Though a one-dose regimen provides significant advantages in reduced needs for supplies, stor- age, and transportation, this vaccine has shown somewhat lower efficacy than the other two. The fact that different vaccines have varying efficacies can lead to con- fusion and the perception that some vaccines are superior to others (Har- vard University, 2021). The development of multiple COVID-19 vaccine candidates demonstrates the tradeoffs between vaccines with high efficacy and those that can be distributed easily and quickly. Though no currently available influenza vaccines require ultra-cold supply chains, these barriers must be considered in the event that mRNA technology is someday used for influenza vaccines. There is a tradeoff between vaccine design and speed and the efficiency of distribution, delivery, and administration. Manufac- turers need to consider mass-scale distribution (especially in low-resources settings) and reverse logistics when developing vaccines, accounting for end-to-end supply chain needs. Desirable vaccine characteristics for dis- tribution, delivery, and administration need to be considered by vaccine manufacturers and public health officials. At a minimum, vaccines must meet criteria for quality, safety, and ef- ficacy (Dellepiane and Wood, 2015). Though available influenza vaccines meet these standards, the World Health Organization (WHO) recognizes the need for improved vaccines that provide longer-lasting protection across a variety of strains (Neuzil et al., 2017). Many low- and middle-income countries (LMICs) do not have national seasonal influenza vaccination PREPUBLICATION COPY—Uncorrected Proofs

98 GLOBALLY RESILIENT SUPPLY CHAINS programs, in part due to the challenges associated with current vaccines, which need to be tailored each year to match the anticipated circulating strains, are generally of moderate efficacy against influenza, and provide limited duration of protection. Improved influenza vaccines that provide broader and longer protection against severe illness endpoints are needed to address public health needs in LMIC settings. Even in the United States, for the 2009–2019 period, effectiveness for seasonal vaccines ranged only from 19 to 60 percent (CDC, 2020a). The committee recognizes that higher vaccine efficacy could increase confidence in influenza vaccines and lead to greater integration into immunization schedules. Beyond vaccine quality and efficacy, there is a need to develop vaccines that account for global logistical constraints. To encourage innovation in influenza vaccine development to address these needs, WHO has developed preferred product characteristics1 for next generation influenza vaccines (WHO, 2017). These characteristics describe preferred parameters of vac- cines that balance efficacy with ease of administration and delivery and result in vaccine formulations for both high-income countries and LMICs. WHO has also published guidance on the programmatic suitability of vaccine candidates, accounting for such considerations as dose volume, dose number, and administration device (WHO, 2012). Improved vaccines should allow for needle-free administration and greater thermostability to reduce requirements on supply chains (Neuzil et al., 2017). The existing WHO prequalification mechanism (see Chapter 3) also contains a descrip- tion of “critical” criteria that, although not required, are “recommended to increase feasibility of administration” (Ortiz and Neuzil, 2019, p. S101). The WHO criteria state that vaccines should be compatible with existing vaccine vial monitors, packaged with materials that can be disposed of at the administration sites, and “have auto-disable needles if prefilled in syringes” (Ortiz and Neuzil, 2019). Until more broadly effective vaccines are available, certain product characteristics can be achieved in the short term to facilitate global access to influenza vaccines (Neuzil et al., 2017). Target Product Profiles and Operational Considerations Target product profiles (TPPs) established by WHO are intended to stimulate improvements to existing vaccines or the development of new products to further expand programmatic suitability. TPPs are documents that contain descriptions of desirable features for future prequalified vac- 1  WHO’s preferred product characteristics are similar to the target product profiles that the pharmaceutical industry develops, except they are tailored to the public health perspective. Industry target product profiles “specify minimally acceptable criteria in addition to preferred criteria” (WHO, 2017, p. 4). PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 99 cines and are targeted at manufacturers and stakeholders to identify needed areas of improvement for vaccines (WHO, 2021b). TPPs are non-obligatory and intended as guidance, but they need to incentivize manufacturers by guiding the development of a more successful product (WHO, 2021a). Con- siderations for program requirements need to be addressed early in vaccine development stages to ensure suitability for LMICs (Zehrung et al., 2017). In addition to TPPs, tools are available to identify operational consider- ations, which are assessed on an implementation level. Operational consid- erations are intended to inform country offices and immunization program partners of factors that affect vaccine rollout, which are separate from the characteristics of the vaccine itself. In the United States, the Centers for Disease Control and Prevention (CDC) established a series of operational considerations for continuing routine immunizations in LMICs during the COVID-19 pandemic (CDC, 2021d). These include recommendations for health care worker engagement with communities and considerations for setting up vaccination sites that reduce risk of SARS-CoV-2 transmission. They also advocate for “catch-up vaccinations”—special efforts to roll out routine immunizations that have been disrupted due to the COVID-19 pandemic. These operational considerations acknowledge that communi- ties with higher risk of vaccine-preventable disease outbreak, such as those experiencing low vaccine coverage, poverty, or displacement, should be prioritized for catch-up efforts (CDC, 2021d). By accounting for local contexts and logistical features, operational considerations can contribute to equitable vaccine rollouts. Operational and programmatic characteris- tics need to be given higher consideration and brought to the attention of manufacturers earlier in the development cycle, especially in low-resource countries, to improve uptake, which will affect forecasting and address hesitancy and can minimize the operational costs. The committee finds that the process of consulting guidance from TPPs and operational considerations is currently disjointed; they need to be aligned for priority vaccines, such as those for seasonal and pandemic influenza. There is a need for additional focus on operational considerations in the TPPs and to upgrade minimum requirements in the TPPs with some preferred vaccine characteristics. Such in-country operational, distribution, and delivery considerations need to be included further upstream in the development process at the policy, manufacturing, and regulatory levels before a vaccine becomes available. Greater integration of operational con- siderations and TPPs can push manufacturers to develop vaccines that are better suited for low-resource contexts, in addition to preparing for mass vaccination and minimizing wastage. As the costs of accounting for all of these considerations is likely to be high, the adoption of a systems approach to product discovery and development, which incorporates the downstream challenges of distribution and delivery as outlined above, may have to be PREPUBLICATION COPY—Uncorrected Proofs

100 GLOBALLY RESILIENT SUPPLY CHAINS incentivized. In addition, countries need to better understand how these various considerations will affect their rollout and uptake. Vaccine Labels During Pandemics Vaccine labeling is an approval task conducted by regulatory agencies, such as the Food and Drug Administration (FDA) in the United States, other national regulatory agencies, and WHO. In a pandemic with ongo- ing assessments, expiration dates may have to be updated, so it is part of a design characteristic. Countries with less robust medical regulatory sys- tems may not understand that new knowledge will develop after labeling, particularly in areas of vaccine stability. During the COVID-19 pandemic, for example, an adenovirus-based recombinant vaccine that received an approval for emergency use was labeled with a particular expiration date based on data available at the time those vials were filled with vaccine. Over time, however, the manufacturer of this vaccine continued assessing vaccine stability, and based on the newer data, regulators extended the expiration date of the vaccine from 3 to 9 months. However, public health authorities in Sudan, the Democratic Republic of the Congo, Malawi, and perhaps other countries rejected and destroyed vials with the original ex- piration date on the label, even after being told about the new, extended expiration date. At least in part, their actions reflect the significant time and effort regulators have taken to ensure vaccinators look at the vial label and discard it if expired. During the unique circumstances of a pandemic, an innovative approach to labeling may be needed to prevent vaccine destruc- tion or the need to recall for relabeling. Currently, regulatory agencies do not authorize relabeling products, but rather issue a letter that the product’s expiration date has been extended or storage requirements have changed (FDA, 2021a). Vaccines, like all medicinal products, have an expiration date and shelf life that is determined by the manufacturer and approved by regulatory authorities (WHO Africa, 2021). During public health crises, approval for emergency use is at times granted by regulators when there is only 6 months of data available for determining an appropriate expiration date (WHO Africa, 2021). Regulators approve the drugs for emergency use with the understanding that more stability data will be forthcoming. This means some profile characteristics, such as the expiration date, will not be fully established at the time the product is being labeled for use. For example, on May 19, 2021, the FDA announced additional information had been obtained from the COVID-19 vaccine manufacturer extending the time undiluted vaccine vials could be stored in the refrigerator from 5 days to up to 1 month (FDA, 2021b). This guidance superseded their previous recommendations, which had been released only a few months earlier, in PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 101 February. An extended shelf life would decrease wasted medicine, which is especially critical when a product is in short supply, as is often the case during a public health crisis. Understandably, however, frontline workers are appropriately trained to carefully review packaging labels and discard any expired drug product that, with additional data, might actually be safe and effective for an extended period. Quick response (QR) codes are one way that manufacturers are pro- viding more up-to-date expiration information to vaccinators rather than printing an expiration date on products (CDC, 2021b). Unlike traditional linear barcodes that require specific scanning engines to be read, QR codes can be read using a smartphone, making the information more accessible to frontline workers in low-resource environments. These codes can be placed on both primary packaging (individual vials) and secondary packaging (cases of vials) (Vander Stichele et al., 2021). The codes can be checked at a district level rather than at individual points of administration. Internet access may be a limiting factor for some areas on an implementation level, but, overall, the use of QR codes could be broadly applicable and provide a pathway to quickly update expiration dates. Despite the value and modest cost to manufacturers, few vaccines supplied to LMICs currently use the technology. While there appear to be discussions that Gavi, The Vaccine Alliance (known as Gavi) and UNICEF will require QR codes in the future to track and trace vaccines, the technology is not currently being used by the vast majority of COVID-19 vaccines (Gavi, 2019b; Vander Stichele et al., 2021). The need for multiple languages on limited label spacing and the use of different expiration date formats on labels are challenges for their adoption (Ramakanth et al., 2021). However, the committee finds that these considerations further strengthen the appeal for greater use of QR codes during public health crises. During a pandemic when there is limited initial stability data for novel vaccines, and potentially even for well-accepted vaccines (i.e., strategic national stockpile), QR codes are the best option for manufacturers to use that provide access to the latest data on vaccine stability, shelf life, and safety. RECOMMENDATION 4-1: The U.S. Department of Health and Hu- man Services (HHS), in partnership with its counterparts in other countries and relevant global stakeholders and funders, should ensure a systems approach to the design and development of vaccines for fea- sible distribution and delivery in various global contexts and support relevant innovations. RECOMMENDATION 4-1(a): HHS, its global counterparts, and rele- vant global funders and stakeholders should encourage attention to op- erational considerations up-front when funding vaccine development. PREPUBLICATION COPY—Uncorrected Proofs

102 GLOBALLY RESILIENT SUPPLY CHAINS RECOMMENDATION 4-1(b): The Food and Drug Administration (FDA), along with the World Health Organization (WHO), should encourage manufacturers to consider including WHO’s preferred char- acteristics in their submissions for clinical trials. The National Institutes of Health (NIH) should prioritize including these preferred character- istics in its influenza vaccine research program. RECOMMENDATION 4-1(c): HHS offices and relevant agencies, in- cluding the Assistant Secretary for Preparedness and Response and NIH, should make sustained global investments in novel vaccine end- to-end technologies, including stabilization and delivery platforms, that will improve equitable access and adaptation for vaccines to be used in various temperature settings. RECOMMENDATION 4-1(d): WHO and FDA, after issuance of a WHO emergency use listing procedure or an FDA emergency use au- thorization, should require digital packaging labels during a pandemic so that changes in vaccine stability and shelf life can be immediately understood and easily accessed by end-users. These labels could also serve as a verification mechanism against counterfeit vaccines. VACCINE PORTFOLIOS The committee notes that a variety of factors, including vaccine char- acteristics and physical supply chain capacity, significantly affect the feasi- bility and efficiency of distribution, which has implications for uptake and administration (Songane, 2018). The committee finds that a lack of capacity of (1) personnel and cold chains, (2) funded national pandemic prepared- ness and response plans, and (3) supplies needed for successful vaccination both internationally and in-country are significant challenges, as well as a lack of personal protective equipment, delivery devices, and waste manage- ment. These challenges also hinder equitable vaccine distribution. Certain vaccines, such as the mRNA COVID-19 vaccines, can strain a country’s vaccine distribution by increasing the need for cold chain maintenance, specific delivery devices, or repeated doses. As a result, researchers and vaccine manufacturers need to consider the effect of these issues on mass- scale distribution. Vaccine “portfolios,” lists of priority vaccine candidates, have previ- ously been funded by institutions that advocate for pandemic preparedness. The Coalition for Epidemic Preparedness Innovations funds 19 vaccine can- didates that use different platforms, targeting a variety of diseases. As it is difficult to determine which technologies will be most successful while vac- cines are in the clinical stages, funding a portfolio increases the likelihood of PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 103 identifying successful candidates (Bernasconi et al., 2020). These portfolios support the development of vaccines that cover a variety of diseases. Before COVID-19 vaccines were widely available, a study developed a model to identify optimal portfolios that allowed users to explore candidates while accounting for research and development and manufacturing timelines (Mc- Donnell et al., 2020). Similar tools could be applied in the future to assist funders and policy makers in preparedness planning. A key initiative, the Vaccine Innovation Prioritization Strategy (VIPS) alliance2 has been recently established to drive priority vaccine product innovations forward and address key roadblocks and gaps to innovation development and uptake. The VIPS alliance is developing a single integrated framework to evaluate and prioritize vaccine product innovations and fo- cus on needs of LMICs, in consultation with wider stakeholders, including end-users from those countries. It is crucial to take stock of the current vaccine innovations implemented in response to COVID-19 vaccines and further support end-to-end vaccine innovations covering the entire product development to simplify logistics, improve equitable access, increase the acceptability and safety of immunization, allow vaccine interchangeability, and facilitate outreach during future pandemic preparedness and response. The committee supports the idea of a new vaccine portfolio specifically for vaccines targeting influenza. A balanced portfolio of vaccines is needed so that different vaccines can be selected for different country contexts to ensure better reach and uptake. Portfolios need to be balanced considering the tradeoff between access and affordability and the additional complexity of managing distribution, management, and administration of multiple vac- cines. The tradeoff of vaccine efficacy and speed of production is another important consideration. If higher efficacy vaccines that, from a total cost perspective, are expensive to purchase, distribute, and administer are un- available to some countries, it could create the perception that LMICs are receiving lower-quality vaccines. To counteract this perception, the commit- tee finds it important to ensure that all vaccines in a portfolio are available to all countries that want them. In developing such a portfolio, agencies should refrain from providing normative guidance to countries about which “approved” vaccines to use.3 The committee recognizes that sources of financing for vaccines may vary. All countries need to have the opportunity to purchase any “approved” vaccine. When there is scarce global funding to buy into a portfolio, interna- 2  The alliance is comprised of the Bill & Melinda Gates Foundation, Gavi, PATH, UNICEF, and WHO. It built on an existing foundation established by WHO’s Immunization Practices Advisory Committee and the Product Development for Vaccines Advisory Committee. 3  For example, the WHO Emergency Use Listing Procedure and WHO prequalification may be used to identify vaccines that meet designated criteria. PREPUBLICATION COPY—Uncorrected Proofs

104 GLOBALLY RESILIENT SUPPLY CHAINS tional agencies could use the lens of program suitability and cost efficiency to determine which vaccines to supply to which regions or countries. Global financing and distribution mechanisms can offer the full portfolio but struc- ture a full or partial subsidy to a country for different vaccines. These mech- anisms could be adjusted as platforms and vaccine characteristics evolve over time. Having country access to a full portfolio of vaccines available is an equity issue to avoid the appearance of some countries receiving subpar vaccines. This approach requires collaboration with regional structures to ensure they can support the use of vaccines. When adopting multiple vac- cines, a country needs to determine its allocation strategy. Choices include allocation of vaccines by geography (based on infrastructure, scale, cold chain and other handling requirements, characteristics of the vaccine) or providing multiple options to every service delivery point. Ethical consider- ations must also play a role in the decision process (WHO, 2020a). RECOMMENDATION 4-2: The World Health Organization, its part- ners, and its funders should facilitate a global vaccine portfolio rollout to ensure the development and access to a broad portfolio of influenza vaccines. DEMAND FORECASTING AND GENERATION Demand Forecasting As governments worldwide increase their focus on initiating large-scale immunization drives to tackle influenza outbreaks, it becomes increasingly important to have tools available to forecast the demand for influenza vaccine, particularly given the long time currently needed for vaccine pro- duction. One estimate projects the influenza vaccines market to rise at a 7.7 percent compounded annual growth rate (Fortune Business Insights, 2020), but this type of projection does not provide the concrete guidance that can help manufacturers or those managing the supply chains for vac- cine production to prepare for an upcoming influenza season or pandemic. Unlike childhood vaccines, whose demand is relatively simple for vaccine manufacturers to predict, seasonal influenza vaccine demand is more un- certain given the seasonality of influenza outbreaks, their changing nature from year to year, varying and uncertain vaccine uptake due to multiple factors, and vaccine spoilage and wastage. The result is that organizations that purchase vaccine are loath to order more than they think they can use in a given season, leaving open the possibility that an unexpected increase in demand by the public can cause shortages. The challenges are different when considering pandemic influenza vac- cines. During the H1N1 pandemic of 2009, demand significantly exceeded PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 105 supply as batches were released. Prioritizing populations to receive the vac- cine was a critical step in allocation (Huang et al., 2017), yet identifying cohort groups based on priority was difficult even in developed nations. There is a tradeoff between risk-based prioritization policies for vaccina- tion and efficiency. Implementing sophisticated prioritization policies is also challenging due to information gaps and cohort group identification. There is a need to better understand how prioritization policies affect demand. The committee agrees that better tools for demand forecasting are needed and that countries need technical assistance in implementing them. Identify- ing priority populations for vaccination will be important when addressing future pandemic scenarios to better match supply and demand. No one factor drives or fully predicts country demand for influenza vaccine. Many factors affect demand, including price elasticity, conve- nience, knowledge of influenza’s impact, severity and timing of the influenza season, demographics, severity of the previous year’s season, providers’ recommendations, and perception of need (Layton et al., 2005). One group has created a model to forecast demand for maternal influenza vaccination in LMICs (Debellut et al., 2018). These investigators assessed potential demand for seasonal influenza vaccine, and the results led them to identify the ways that immunization programs may be affected by availability gaps in supply linked to current vaccine production cycles and shelf life dura- tion. The models projected that demand for seasonal influenza vaccination in pregnant women could increase from 7.7–16.0 million doses in 2020 to 27.0–61.7 million doses in 2029. The reason for this increase is attributed to WHO efforts to expand seasonal influenza immunization in countries that had not yet adopted maternal influenza immunization plans. Although the global capacity for seasonal influenza vaccine production is projected to meet this demand, current vaccine production cycles are likely to leave gaps in vaccine availability and coverage as demand increases (Debellut et al., 2018). Demand forecasting—aggregate as well as disaggregate—is af- fected by many factors and remains a challenge for most countries. Factors affecting forecasts include the challenge of identifying cohorts and access- ing them, operational costs, access to finance, and human behavior. There is a need for better understanding of these factors that affect forecasts and their accuracy. Developing appropriate vaccination strategies also requires information about anticipated demand. Demand forecasting provides decision makers with data on how much vaccine is likely to be taken up in a given region, which informs vaccine ordering and development of allocation procedures. Forecasting models have been successfully implemented in LMIC supply chains to project vaccination needs. An impact assessment in Niger revealed that, when combined with increased transport frequency, use of a demand forecasting system “increased the number of successfully administered vac- PREPUBLICATION COPY—Uncorrected Proofs

106 GLOBALLY RESILIENT SUPPLY CHAINS cine doses and lowered the logistics cost per dose up to 34%” (Mueller et al., 2016, p. 3663). When combined with assessments and improvements in the physical supply chain, demand forecasting can lead to tangible im- provements in supply chain efficiency. Although the importance of demand forecasting is understood at a global level, few tools exist to aid countries in making these assessments. Several challenges that are unique to influenza have to be accounted for to develop accurate and timely estimates for vac- cine demand, which will then inform allocation and distribution strategies. Demand Generation Demand generation and demand forecasting are two distinct gaps affecting vaccine supply chains. Generating demand is a critical consider- ation that is often neglected. Producing vaccines, that is, generating supply, is rightfully a focal point in a pandemic scenario; less focus is placed on building demand for a vaccine among the public. As seen in the COVID-19 vaccine rollout, building demand has become a priority in countries with high vaccine supply, as vaccine hesitancy is a more significant barrier than vaccine availability. In countries such as the United States, most of those who remain unvaccinated are vaccine hesitant. Vaccine hesitancy is also a concern in countries with low vaccine supply, though hesitant populations represent a smaller percentage of the unvaccinated (Evans and French, 2021). As vaccine supplies become more available, hesitancy will likely emerge as a primary factor in influencing demand, and therefore uptake (Evans and French, 2021). When addressing vaccine hesitancy, it is important to iden- tify what factors affect public perception. A meta-analysis of community perceptions of the Ebola vaccine in 2019 revealed that a misunderstand- ing of side effects and limited vaccine information led to hesitancy. Poor engagement of local leaders and low trust in health care workers also con- tributed to hesitancy (Carter et al., 2020). The fact that the Ebola vaccine was investigational (i.e., not fully licensed) and excluded pregnant women and children also contributed to mistrust. Proper communication is criti- cal, and has to be developed with localized contexts to build trust (Hasan, 2019). Vaccine hesitancy will be most effectively addressed with a variety of interventions together with “communication plans, educational efforts, community engagement strategies, and vaccine delivery systems” to address both behavioral and structural drivers of low vaccine uptake (Evans and French, 2021, p. 326). These strategies address not only matters of hesi- tancy, but also matters of information on how to access vaccines. Public outreach and vaccine delivery need to be developed to build confidence and trust in the vaccines while addressing structural issues, such as access to information and vaccination sites. PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 107 In order to generate demand, the root causes of low vaccination cover- age need to be addressed. This has been a challenge in the United States, as demand for COVID-19 vaccines decreased after the initial months of availability to the general public. Surgo Ventures, a U.S.-based research institution, developed the COVID-19 Vaccine Coverage Index, which was designed to reveal underlying barriers to vaccination on a community level. This tool not only identified communities at risk, but also determined causal factors, such as socioeconomic characteristics, vaccine hesitancy, constrained resources, and health care inaccessibility. These results can lead to better-informed policy decisions that address the drivers of low vaccine uptake (Surgo Ventures, 2021). Similar analyses conducted in other coun- tries, particularly LMICs, would be beneficial in revealing drivers of low vaccine coverage in different contexts. Worldwide, vaccine hesitancy has emerged as a significant barrier to vaccine coverage. In countries such as the United States, much of the unvac- cinated population is wary of the COVID-19 vaccine due to perceived risk of severe adverse events. Communication and public education interven- tions are important for increasing public trust, which can, in turn, result in higher uptake, and thereby increase vaccination coverage. There are mul- tiple factors that affect demand uptake including access, hesitancy, supply availability, and prior experience with health systems. Overall, there is a need for better understanding of these factors and development of country- and culture-appropriate mechanisms to address them. RECOMMENDATION 4-3: The Centers for Disease Control and Pre- vention should work with the World Health Organization, Gavi, and global counterparts to commission studies in demand forecasting and demand uptake. The National Vaccine Advisory Committee should be augmented to engage in this task. Seasonal influenza presents a distinct challenge with demand genera- tion, as general acceptance and uptake is low. Especially in LMICs, seasonal influenza is not considered a priority health concern, largely because of a lack of studies that assess the local burden of disease (Bresee et al., 2018) and a lack of local influenza epidemiological data (Bhan and Sinha, 2019). These lacks hinder data-driven decision making to promote influenza vac- cine uptake. Low efficacy of the seasonal vaccine is a poor incentive to increase integration into immunization schedules. The committee distinguishes two factors that affect demand generation for seasonal influenza vaccines: a country’s willingness to include seasonal influenza vaccines in its vaccination programs, and uptake by the public once a vaccine is in the program. Country willingness is largely driven by cost-effectiveness analyses. A lack of cost-effectiveness analyses in LMICs PREPUBLICATION COPY—Uncorrected Proofs

108 GLOBALLY RESILIENT SUPPLY CHAINS is a significant barrier to implementing seasonal influenza vaccination pro- grams (Kraigsley et al., 2021). Though seasonal influenza is often not con- sidered a high-priority disease, the Global Burden of Disease Study revealed that influenza is responsible for a high burden of disease when considering comorbidities, particularly in LMICs. In 2017, lower respiratory tract in- fections resulting from seasonal influenza led to 145,000 deaths and nearly 9.5 million hospitalizations worldwide (GBD 2017 Influenza Collabora- tors, 2019). Seasonal influenza clearly has a significant global health and economic impact. Influenza vaccines remain underutilized because there are relatively few economic evaluations done on seasonal influenza vaccination, leading to poor understanding of the benefits of vaccination to guide deci- sion makers (Newall et al., 2018). A seasonal influenza vaccine program is also crucial in demand gen- eration for both seasonal and pandemic influenza. An evaluation of a program conducted by WHO during the 2009 H1N1 influenza pandemic to increase equitable access through donations found that countries with existing seasonal influenza programs were better prepared for a pandemic. The countries with robust seasonal influenza vaccination programs were more likely to apply for and receive the vaccine. The existence of a program ensured the infrastructure for transportation, storage, and administration of the vaccine, along with trained staff and a population that were familiar with influenza vaccine in the country (Porter et al., 2020). Robust seasonal influenza vaccine programs increase national familiarity with the manage- ment of influenza vaccine and therefore enhance pandemic preparedness. Therefore, investment in seasonal influenza programs can result in broader global health security. RECOMMENDATION 4-4: The Centers for Disease Control and Prevention and the National Institutes of Health should support the development of better models for influenza vaccine cost effectiveness. The U.S. Agency for International Development should support techni- cal assistance to strengthen country systems for vaccine uptake. GLOBAL DISTRIBUTION AND TRANSPORTATION Transporting vaccines to the point of administration is subject to bottle- necks with transport capacity and cold chain requirements at both global and local levels. The cold chain requires significant inputs of energy and resources, along with expensive equipment, to ensure that vaccine integrity is maintained to the point of administration. This section discusses vaccine supply chain and logistics considerations at both the global and country levels. PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 109 Transportation The committee identified transport capacity and cold chain consider- ations as primary logistical constraints in the transportation of vaccines from a manufacturer to the recipient country. Multilateral organizations, such as Gavi and UNICEF, assist in this transport. Transport capacity is often strained during a public health emergency and can delay the delivery to a country’s point of entry. As seen in the COVID-19 pandemic, a drastic reduction of commercial flights significantly reduced the available volume of cargo space, thereby limiting vaccine transport (Kiernan, 2021). In addi- tion, personal protective equipment, ancillary supplies, treatment products, and other materials needed for emergency response all compete for limited space in transport systems. Getting influenza vaccines from manufacturers to recipients while maintaining the cold chain is a logistical challenge. Limited storage capac- ity and inefficient distribution and logistics systems have long been bottle- necks in the supply chain, particularly for LMICs (Zaffran et al., 2013). The development of mRNA vaccines for COVID-19 brought this challenge to the fore, and in response, the manufacturers of those vaccines have de- veloped detailed logistics plans and special insulated containers to ensure that their vaccines get to the intended recipients (Pfizer, 2020). In addition, major logistics companies, including FedEx, UPS, and DHL, invested in new storage facilities for cold chain management that are expected to prove useful after the COVID-19 pandemic is over. Many major cargo handling airports already had extensive temperature-controlled handling facilities with direct apron access. Frankfurt airport, for example, has approxi- mately 12,000 square meters of temperature-controlled handling capacity, including 8,000 square meters at the Lufthansa Cargo Pharma Hub, that meet all international standards (International Airport Review, 2020). Abu Dhabi has also made significant investments for cold chain transportation in its international airport, with the intent to serve as a hub for global pharmaceutical logistics (Etim, 2020). The International Air Transport As- sociation has a program for certifying airports as pharmaceutical freight hubs capable of safely and efficiently handling temperature-sensitive and time-sensitive pharmaceuticals, including vaccines. In June 2021, the asso- ciation updated its guidance for vaccine and pharmaceutical logistics and distribution (IATA, 2021). Various international aid organizations have invested substantial funds in developing global cold chain equipment and services for distribut- ing vaccines. UNICEF, for example, procured close to $100 million worth of cold rooms, refrigerators, cold boxes, and insulated vaccine carriers, pri- marily to deliver vaccines for administration to children. Gavi’s cold chain equipment optimization platform provides funding to procure cold chain PREPUBLICATION COPY—Uncorrected Proofs

110 GLOBALLY RESILIENT SUPPLY CHAINS equipment and also provides market shaping strategies to make equipment more accessible (Gavi, 2019a). The U.N. Environment Program notes, how- ever, that even for countries with effective childhood vaccine distribution, “the sheer scale and urgency of mass . . . vaccination” during a pandemic, such as COVID-19, would be very difficult for “countries with large rural populations” (UNEP, 2020, para. 9). Transportation considerations are also important in planning for reverse logistics, when unused vaccines are returned in order to be redistributed (if appropriate) or destroyed. This process requires supply management and storage at every level of the sup- ply chain (WHO and UNICEF, 2021a). Stringent procedures in place for redistributing or destroying vaccines is important for maintaining public safety. Product and ancillary supplies could follow multiple pathways to a country. Global logistics (from manufacturer to country port of entry) re- quires complex coordination of multiple agencies, receiving countries, man- ufacturers, and logistics providers. A pandemic context places strains on transport capacity that could affect flow of materials and products across the end-to-end supply chain. Better pre-pandemic planning is required to anticipate issues and address them. Trade Barriers As the world rallied around the need to equitably distribute vaccines to fight the COVID-19 pandemic, it became clear that vaccine nationalism was a threat to achieving that goal (Evenett et al., 2021). As the World Bank has noted, vaccine nationalism can take the form of overt export bans or limits that are designed to increase domestic vaccine supplies at the expense of foreign supplies, or it can use more subtle mechanisms, such as delaying promised vaccine shipments (Evenett, 2021; Evenett et al., 2021). Perception of an action’s intent may vary greatly depending on where one sits in relation to the outcome. Some notable examples of perceived vaccine nationalism were the European Union’s move to prohibit export of COVID-19 vaccines and India’s curb of vaccine exports, the latter of which had a severe impact on 91 nations that were depending on vaccines produced in India (Peters and Prabhakar, 2021; Som, 2021). However, both of these export restrictions were implemented after devastating second waves hit each region, and the countries aimed to secure vaccines for their own populations who were in need of vaccines (Kar et al., 2021). The United States leveraged the Defense Production Act, which requires U.S. manufacturers to prioritize fulfilling contracts with the U.S. government (White House, 2021) (see Box 3-1 in Chapter 3). While the United States did not restrict exports of COVID-19 vaccines, it did impose restrictions on the export of key raw materials needed to manufacture COVID-19 vaccines. There are concerns that this could limit PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 111 the supply of these components to global manufacturers (Jain and Rocha, 2021). According to the American Society of International Law, the treaties that form the basis for the multinational trade system—the General Agree- ment on Tariffs and Trade, the General Agreement on Trade in Services, the Agreement on Trade-Related Aspects of Intellectual Property Rights, the Agreement on the Application of Sanitary and Phytosanitary Measures, and the Agreement on Technical Barriers to Trade—provide exceptions that al- low countries to put export restrictions in place when contracts are already signed during a global pandemic (Ibrahim, 2021). However, given the near universal condemnation of these export restrictions, several organizations and authors have called for negotiations to reduce these exceptions to effec- tively address the next pandemic (Pauwelyn, 2020). One specific proposal, for example, calls for importers to eliminate import tariffs in exchange for a guarantee that exporters drop export restrictions and only impose new ones under strict conditions (Evenett and Winters, 2020). This latter approach could be workable given the strong trade interdependencies in the goods needed to produce, distribute, and administer vaccines: see Figure 4-1. The World Trade Organization (WTO) has noted that many LMICs depend on imported vaccines that are either donated or sold at reduced prices, which may increase diversion of these vaccines into higher-priced markets. WTO clearly states that “to ensure that vaccines reach and stay in a destination country, appropriate measures, including but not limited FIGURE 4-1 Nations with the largest share of exports for key vaccine components and sup- plies in 2018. SOURCE: Andrenelli et al. (2021, p. 6). PREPUBLICATION COPY—Uncorrected Proofs

112 GLOBALLY RESILIENT SUPPLY CHAINS to those required under the Agreement on TRIPS [Trade-Related Aspects of Intellectual Property] Rights, need to be taken by the importing country against unlawful diversion to prevent re-exportation of the vaccines, and by all WTO members to prevent the importation and sale of diverted vaccines in their territories” (WTO, 2020, p. 26). The Organisation for Economic Co-operation and Development has noted that “while tariffs on vaccines are unlikely to pose a major challenge” to vaccine distribution, high tariffs on vaccine-related inputs could present a problem (Andrenelli et al., 2021, p. 9). Average world tariffs on vaccine in- gredients, such as preservatives, adjuvants, stabilizers, and antibiotics range between 2.6 and 9.4 percent. Tariffs on materials to administer vaccines, such as syringes and needles, are in the 4.4–4.5 percent range, while tariffs for primary packaging, including vials and stoppers or distribution materi- als, including cold boxes, freezers, and dry ice, can hit 12.7 percent. The need to maximize the availability of vaccines during a pandemic may be considered as justification for reducing or waiving such tariffs (Andrenelli et al., 2021). Absent the ability to drop the tariffs, additional subsidies may be needed from aid donors to cover the additional cost or risk that some countries may be unable to afford to meet their vaccine needs (Gavi, 2021). IN-COUNTRY STORAGE AND DISTRIBUTION The committee finds that the physical supply chain, from cold chain considerations to transport capacity, is already stressed in LMICs. Once vaccines reach a recipient country, it is that country’s responsibility to transport vaccines to points of distribution and administration. Transport capacity in LMICs is highly variable, which has significant effects on speed and efficiency of vaccine rollout. Throughout this process, optimal tempera- tures, which vary depending on the type of vaccine, have to be maintained. Current capacity is already insufficient to cover pediatric immuniza- tion platforms, which, in the committee’s experience, are the most globally developed and reliable vaccine supply chains. Since 2010, the number of vaccines introduced into LMICs has increased due to programs such as the Expanded Program on Immunization (EPI) to increase global access to vac- cines. Despite the efforts to improve vaccination programs in LMICs, many countries have struggled to achieve target levels of vaccine introduction. A primary factor limiting vaccination success is that new vaccines increase logistical complexity, as new vaccines may not fit into established EPI schedules and require additional steps for delivery (Guignard et al., 2019). Concurrently, these introductions often require changes to immunization programs, which may alter other logistical and transport needs in order to achieve vaccination targets. The growing complexity of these systems has to be considered when incorporating new vaccines (Guignard et al., 2019). PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 113 The addition of pandemic vaccines into immunization schedules can re- sult in further burdening of supply chains. COVID-19 vaccination in Africa is predicted to require increased storage capacity at national levels (Ortiz et al., 2021). These dynamics reveal that addition of new vaccines must be implemented with consideration for financial and structural resource constraints, highlighting the importance of careful planning. Failure to ad- dress these dynamics may perpetuate low uptake of influenza vaccines into national vaccine schedules due to the high burden on local supply chains and competition for limited resources with other priority vaccines. Cold Chain Considerations The temperature instability of vaccines can emerge as a key challenge to distributing an approved vaccine for widespread use. Vaccine manufactur- ers attempt to minimize temperature instability using various techniques, but influenza vaccines, like many other vaccines, must be kept within a nar- row temperature range—cold, but not frozen—throughout manufacturing, distribution, storage, and administration. The vaccine cold chain ensures they retain their potency and remain safe for human use. A single transport leg or storage port that is not temperature controlled will break the cold chain and can decrease the potency of the vaccine to the point it is rendered ineffective. Vaccine wastage rates in LMICs are highly variable among countries, and wastage data are not readily available for many countries (Parmar, 2010). A study by Karp et al. (2015) estimated that around 8% of the total cost of immunization programs in LMICs is used on vaccines that are eventually wasted. Wastage is primarily attributed to improper tempera- ture storage and expiration (Songane, 2018). Breaking the cold chain can also mean that patients will need to be revaccinated (Kroger et al., 2021), representing another waste of vaccine and the potential that patients may refuse to be revaccinated, thereby remaining unprotected. According to guidance from the CDC (CDC, 2021f), maintaining an effective cold chain relies on having a well-trained staff, reliable storage and temperature monitoring equipment, and accurate vaccine inventory man- agement. The CDC recommends that every facility that receives, distributes, or administers influenza vaccines maintain clearly written, detailed, and up-to-date storage and handling standard operating procedures and train staff on those procedures. All currently approved influenza vaccines have to be stored between 2℃ and 8℃ and never frozen. Should an mRNA vaccine for influenza be approved for human use in the future, it will likely need to be stored at much lower temperatures: the Pfizer/BioNTech COVID-19 vac- cine, for example, requires storage at –70°C (±10°C) (Pfizer, 2020), while storage of the Moderna mRNA COVID-19 vaccine for longer than 30 days requires a temperature of –20°C (Moderna, 2020). PREPUBLICATION COPY—Uncorrected Proofs

114 GLOBALLY RESILIENT SUPPLY CHAINS While there are pharmaceutical-grade, purpose-built refrigerators de- signed specifically to store vaccines, household-grade refrigerators can be an acceptable option for vaccine refrigeration under the right conditions. The advantage of purpose-built devices is that they include microprocessor- based temperature control with a digital temperature sensor along with fan-forced air circulation using powerful fans or multiple cool air vents that promote uniform temperature and fast temperature recovery from an out-of-range temperature. These specially designed refrigeration units may be cost-prohibitive in LMICs. Temperature monitoring is essential to ensure that proper temperatures have been maintained throughout storage. CDC says that every vaccine storage unit must have a temperature monitoring device. Digital data log- gers are the most accurate of such devices, according to CDC, as they detail how long a unit has been operating outside the recommended temperature range. Simple thermometers only show the highest and lowest temperatures that were reached in a unit, but a digital data logger provides detailed in- formation on all temperatures recorded at preset intervals (CDC, 2021f). Other technologies, such as stickers that change color when exposed to temperatures outside of the recommended range, have also been used with previous vaccine introduction efforts (Zipursky et al., 2014). One of the challenges of distributing influenza vaccines in remote or rural communities in LMICs is the unavailability or unreliability of electric- ity to power refrigeration units. Ultra-cold freezers that reach temperatures of –70°C require high energy inputs and costly equipment to maintain the required temperatures. Cold boxes that are capable of operating at temper- atures from –70°C to –80°C cost from $10,000 to $20,000 each. This was a particular challenge for the mRNA-based COVID-19 vaccines, and experts have assessed that vaccines requiring ultra-cold storage are unlikely to be widespread solutions in some LMICs (Sustainable Energy for All, 2021). To address this challenge, PATH has a program to evaluate and design technologies and systems that can extend the cold chain beyond the power grid, including containers that will prevent vaccines from freezing as they are transported in ice-packed carriers to remote locations (PATH, 2018). Since 2017, UNICEF, partnering with WHO and Gavi, has installed over 40,000 solar-powered cold chain refrigerators, mostly in Africa. UNICEF is also promoting solar technologies to help countries maintain their vaccine supply chains. For example, in South Sudan, the world’s least electrified country, more than 700 health facilities have been equipped by UNICEF with solar power refrigerators, accounting for approximately 50 percent of all facilities nationwide (U.N., 2020). Pfizer has also developed innovative thermal shipping containers for COVID-19 vaccines that ensure tempera- ture control during the transit of vials and can be used as temporary storage units for up to 10 days. For longer shelf life, ultra-low-temperature freez- PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 115 ers are needed, where vaccines can be stored until their expiration dates. Prior to mixing, the Pfizer vaccine can be stored at standard refrigeration temperatures (2°–8°C) for 31 days (CDC, 2021e). Cold chain capacity is a persistent bottleneck, as it requires financing for complexities, such as data loggers and other equipment, and requires accurate reporting. Adding new vaccines without adequate increase in capacity puts a strain on already limited systems, and these strains are magnified for vaccines requiring ultra-cold storage. Good data-logging ability is needed to ensure that vaccines were not compromised in order to move vaccines between different countries. Monitoring temperatures and collecting data needs to be applied to vaccine storage, not just shipment. Up-front investment and increased support for cold chains (including off- grid solutions) need to be highlighted ahead of time during a pandemic preparedness phase. Vaccine Delivery and Rollout Vaccine delivery is the final step in distribution, where vaccines will be administered (CDC, 2021a). Delivery systems vary based on the source of the vaccines and the location of delivery. In the United States, routine vaccines, and recently COVID-19 vaccines, are ordered from the federal government by states, territories, and local jurisdictions, which are fulfilled through a federal system. The Vaccine Tracking System is used to make orders and log data related to vaccine delivery (CDC, 2021a). Even for this system there is an exception, as Pfizer has its own system to deliver vaccines. Global entities, such as UNICEF and COVAX,4 also have their own delivery systems to bring vaccines to countries. Entities that are filling vaccine orders establish allocation criteria for prioritized delivery when demand outpaces supply, such as for COVID-19. Considerations include the number and dis- tribution of at-risk populations, such as health care workers and individuals with compromised immune systems (WTO, 2021). Once vaccines from a multilateral distributor arrive in the target coun- try, the national government becomes responsible for delivery to the final destination. In LMICs, vaccines are often transported from the country point of entry to a distribution center, where vaccines are transported to other local distribution points or to the vaccination site. This “last mile” delivery is subject to several challenges, particularly in limited resource settings. Lack of funding to deliver vaccines is a critical issue. Personnel, cold chain requirements, and transportation costs can all serve as added challenges to vaccine transportation funding, particularly in a pandemic scenario when a significant portion of the population is targeted for vac- 4  COVAX is the acronym for COVID-19 Vaccines Global Access; see fn. 9 in Chapter 2. PREPUBLICATION COPY—Uncorrected Proofs

116 GLOBALLY RESILIENT SUPPLY CHAINS cination. Additional delivery costs for COVID-19 vaccines for the average LMIC are estimated to represent nearly 20 percent “of the entire pre- COVID-19 health budget” (UNICEF, 2021). In addition to the cost, poor infrastructure often serves as a barrier to scale up vaccine rollout efforts. In LMICs, primary care centers often serve as the primary access point for vaccines. Vaccine uptake in these settings may be influenced by the relation- ship between the health care facilities and the local community. Health care workers commonly engage in community outreach activities, such as school programs, which can bolster trust and increase knowledge of vaccines (Guignard et al., 2019). Efforts to increase vaccine access must account for these structural and financial barriers to last-mile delivery. The operational cost of getting influenza vaccines to people is sig- nificant, placing a high burden on some LMIC country budgets. Beyond standard transportation and distribution costs, human resource capacity for distribution and delivery is a major challenge. There are significant gaps in funding of these operational expenses. There is a need to determine effective ways to resource in-country distribution and delivery. Vaccination Strategies Various kinds of locations can serve as pandemic vaccination sites, and there are benefits and drawbacks of different options. Mass vaccination sites, as were established during COVID-19, serve as central points of ad- ministration that can potentially have higher throughput, vaccinating more people per day (Everett et al., 2013). The benefits of this model include easier delivery of vaccines and critical components to one centralized loca- tion, rather than dividing the same volume of resources among multiple, smaller health care settings, which can translate to easier management of the cold chain and less wastage of vaccine doses. It is also easier to sched- ule appointments with one large facility than seeking limited appointment slots from numerous smaller sites. Despite these benefits, access remains a key issue with mass vaccination. Communities that are distant from mass vaccination sites may face challenges in access. Also, establishing a mass vaccination site requires significant investment and time. A lack of health care personnel available to meet the needs of a mass vaccination site is also a limitation, especially in LMICs (He, 2021). Other methods of vaccination may fit more localized contexts. Out- reach strategies often require health care workers to travel to the vaccine recipients. Vaccine dissemination through local clinics and health care cen- ters has the advantage of being more accessible to geographically dispersed communities. In addition, mobile vaccination units have been used effec- tively in settings where local health care access is especially limited, such as rural and remote areas. Mobile vaccination has been found to be effective in PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 117 advancing vaccine coverage in adults living in remote regions in India (Ghia et al., 2021). In LMICs, vaccination occurs mostly in primary care settings, not hospitals. Outreach strategies that involve health care workers travel- ing to the vaccine recipients often require real-time, flexible systems that connect public health, high operational cost, logistics, and medical experts. Various vaccination strategies need to be evaluated and applied based on the localized context, accounting for availability of resources and needs of the community (He, 2021). Guidance documents, such as the WHO Framework for Decision-Making (WHO, 2020b), can assist countries in selecting appropriate methods for vaccination campaigns. The committee finds that these considerations for vaccination methods are generally lack- ing from country vaccination plans: they need to be considered earlier on in the pandemic preparedness process to be fully integrated into preparedness activities. Different types of vaccination strategies (including clinic-based, mass vaccination sites, mobile sites) create different transport, logistics, and operational challenges. Country planning needs to determine the appropri- ate mix of these modalities, perform better cost estimation, seek appropri- ate funding, and solicit private sector expertise for participation in design logistics, distribution, and operational systems. Ancillary Supplies Vaccine delivery strategies are also linked to the supplies required to conduct vaccinations. Ancillary supplies, such as syringes, and workforce capacity are critical components of the vaccination effort (Hatchett et al., 2021). However, these supplies represent additional items and logistical constraints that have to be accounted for when developing vaccine delivery strategies. Procurement of ancillary supplies also varies by country. In Ke- nya, although the national government is responsible for vaccine purchases, counties are responsible for procuring other supplies, such as syringes, and data collection tools. Counties often lack funding to procure these supplies, which puts vaccination programs at risk (VxDel, 2020). Globally, the COVID-19 pandemic has resulted in a syringe short- age, which may have hindered vaccine rollouts. Extracting the maximum number of doses from multi-dose vials, which are used for the Pfizer and Moderna vaccines, requires a specialized “low dead volume” syringe that minimizes the amount of vaccine left in the syringe. These syringes are in short supply even in countries that have greater access to vaccines and supplies, such as the United States. Many of the syringes supplied by the U.S. government during Operation Warp Speed were not low dead volume syringes and were therefore not used. Some vaccination sites were able to procure their own syringes, but others that could not saw vaccine doses go to waste. When standard syringes are used, doses in vials can still be admin- PREPUBLICATION COPY—Uncorrected Proofs

118 GLOBALLY RESILIENT SUPPLY CHAINS istered, but fewer doses can be extracted from each vial due to the amount of vaccine that is retained by the syringe itself (Moutinho, 2021). Both the availability of syringes and the types of syringe used have implications for vaccine wastage and efficacy of vaccination systems. Vaccines that can use novel routes of administration would have signifi- cant impacts on the supply chain. For example, microneedle patch technolo- gies are being developed, in which a patch containing the vaccine is applied to the skin without need for syringes or trained health care personnel for administration (Wedlock et al., 2019). Models of widespread use of patch technologies for some routine vaccinations revealed a significant decrease in vaccine wastage, although specific effects on the supply chain varied depend- ing on context-specific cold chain capacities (Wedlock et al., 2019). It is im- portant to invest in new technologies for administration due to the potential benefits to the supply chain and reduced strain on a limited workforce, even though the variety in ancillary supplies (e.g., different types of syringes and delivery devices) creates complexity in distribution and logistics. MATCHING SUPPLY AND DEMAND In a pandemic scenario, the goal of vaccine rollout should be to have a population that becomes widely immunized. In order to achieve this, deci- sion makers need “evidence-based vaccine delivery strategies that generate demand, allocate and distribute vaccines, and verify coverage” (Weintraub et al., 2021, p. 1). Data on vaccine availability and uptake is foundational for successful policy development. Visibility on the location of the finished product is essential for knowing how much has been administered and how much remains in storage or in transit. As of the 2021 vaccine rollout, there is a lack of end-to-end visibility on the full vaccine supply chain (IATA, 2021). Vaccine management databases in health care facilities track local use and allocation, but these systems are not integrated. As a result, there is a general lack of awareness regarding the location of vaccine batches, which proves challenging for determining where vaccines would be best distributed, and how much should be distrib- uted (Iwu et al., 2019). A study on vaccine inventory visibility revealed that vaccine allocation strategies that account for both population and inventory information were significantly more efficient than strategies based on popu- lation alone. Simulated population and inventory-based models resulted in lower infection rates in a given region and significantly lower inventory leftover (Li et al., 2018). Sending vaccines to areas where they will not be used or failing to distribute vaccines to areas where they are being used will result in wasted efforts in supply chain management and transit. The issue of low visibility for vaccines points to a larger issue of limited data availability for health care in general. Information capture and analytic PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 119 capability is needed to assess visibility and understanding of product move- ment. Lack of visibility is most evident for distribution. There is a need to carefully balance supply with capacity so as not to overwhelm systems. On the demand side, the complicated and rapid vaccine rollout for COVID-19 resulted in confusion among the general public regarding vis- ibility of vaccine access. Appointment systems have not been standardized across districts, resulting in unclear messaging and potentially lower vaccine uptake. When administering vaccines that require two doses, there is the additional challenge of ensuring that each recipient receives both of them for full protection (Sellers, 2020). The lack of data regarding vaccine avail- ability has led to unclear communication and identification of vaccination sites. In the United States during times of high demand for COVID-19 vaccines, complicated online appointment systems led to challenges in vac- cine access among the general public. Appointment websites experienced crashes, and there was a lack of a unified appointment system (Weise, 2021). Individuals with lower technological access or competency struggled to navigate online appointment systems, leading to lower vaccination rates among some populations (Solaiman, 2021). Low visibility on both the global supply and local demand side ultimately leads to lower uptake and improperly distributed resources. In planning and monitoring a vaccination campaign, whether for sea- sonal or pandemic influenza, information systems need to be able to provide data on the uptake of vaccines, both by targeted population groups and by regions, as well as data that public health officials can use to monitor and evaluate the logistical chain that supplies vaccines where they are needed. Currently, “there is no global monitoring system for influenza vaccination coverage,” making it difficult to match vaccine supply and demand (Palache et al., 2021, p. 6082). The International Federation of Pharmaceutical Man- ufacturers and Associations has developed a survey method to assess global distribution of influenza vaccine as a proxy for vaccination coverage rates. This information, while a significant contribution to vaccine monitoring, does not account for vaccination policies or directly measure vaccine uptake (Palache et al., 2021). In the United States, the CDC uses data from two telephone surveys, National Immunization Survey-Flu5 and the Behavioral Risk Factor Surveillance System6 to estimate influenza vaccination coverage for the U.S. population during each influenza season (CDC, 2020b). For COVID-19 vaccinations in the United States, data on administered doses are reported to the CDC by various vaccination providers (CDC, 2021a). 5  NIS-Flu is a national random-digit-dialed cellular telephone survey of households. 6  BRFSS is a state-based random-digit-dialed cellular and landline telephone survey that collects information on a variety of health conditions and risk behaviors from one randomly selected adult ≥18 years in a household. PREPUBLICATION COPY—Uncorrected Proofs

120 GLOBALLY RESILIENT SUPPLY CHAINS WHO and UNICEF, with input from experts and stakeholders, have developed an assessment tool based on WHO’s effective vaccine manage- ment framework that countries can use to generate evidence about bottle- necks in the immunization supply chain (WHO and UNICEF, 2016). This tool can assess primary stores of vaccines—the quantities received directly from manufacturers—as well as at the level of provinces and districts, lo- cal distributors, and health facilities. Based on this assessment, countries can develop and finance comprehensive improvement plans to strengthen immunization supply chains to help ensure that vaccines are available, that vaccines remain potent, and that resources are efficiently used. This tool also assesses information systems and supportive management functions involved in vaccine storage and distribution. Data generated using this tool has shown, for example, that only about a third of LMICs in 2014 were in compliance with WHO-recommended vaccine management policies, which were designed to minimize vaccine waste and increase the odds that supply and demand are in balance (WHO and UNICEF, 2016). The Americas was the only region in which those systems met the WHO standard, with the information systems of every other global region being far from the effective vaccine management standard (WHO and UNICEF, 2021b). Logistics management is another critical component of visibility. The U.N. Development Program developed the Logistic Management Informa- tion System (LMIS) to assist countries in collecting and reporting data related to health systems management, with a focus on maintaining supply chains (UNDP, 2021). In addition to this suite of tools, there are numerous information systems available that can track regional vaccine availability or facilitate vaccine management and ordering for health care and vaccination sites. These systems are critical, as a lack of visibility in vaccine manage- ment can lead to vaccine stockouts in health facilities. A study in Tanzania revealed that implementation of LMIS facilitated vaccine availability better than paper or Excel-based systems, reducing events of vaccine stockouts (Gilbert et al., 2020). Immunization information systems are public health data systems for tracking vaccinations. These tools were developed for public health au- thorities to track and measure the incidence of vaccination within their jurisdiction and assist with distribution and inventory management. A typi- cal system can be used to track immunizations given and collect data on vaccine coverage to inform immunization campaigns. Several immunization information systems tools exist and serve a range of functions, including vaccine planning, delivery and administration, and monitoring. However, these systems operate in silos and lack integration. Also, most immuniza- tion information systems are designed for childhood immunization sched- ules and are not tailored to adults (Gilbert, 2021), and lack the capability PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 121 to identify individuals or population segments that may be particularly at risk or require targeted outreach for vaccination. Immunization information systems can also be used to help monitor vaccine safety and effectiveness, but they have to be used in tandem with other data routinely contained in patients’ individual medical records and health payer claims data (Lenert et al., 2021). In LMICs, the systems have not changed much since they were adopted in the 1970s by the WHO Ex- panded Program on Immunizations. Data are often still collected on paper and compiled into reports to evaluate performance indicators. Data quality is often poor, incomplete, or gathered too late to make timely decisions. The introduction of newer, often more costly vaccines creates additional challenges in tracking and maintenance (PATH and WHO, 2013). Even in developed countries, such the United States, these systems are disparate: for example, there are approximately 60 systems at state and local levels, con- nected only at the national level (CDC) to information national policy. The individual systems are developed to meet national reporting requirements, but they are often built on different platforms that cannot share informa- tion easily. In the absence of a uniform patient identifier, cross-referencing immunization information system data with patient outcomes, including death records, can be extremely difficult (Lenert et al., 2021). During the 2009 H1N1 influenza pandemic, a large-scale U.S. study using health insurance claims and immunization systems data demon- strated the potential for understanding vaccine safety, while also high- lighting some of the major challenges and gaps in the systems (Yih et al., 2012). COVID-19 has further shown the need and potential for more advanced systems that provide real-time dating, incorporate immunization campaigns, offer better capacity to identify and report adverse events, and interact with primary care providers. Greater public awareness of the im- munization process following COVID-19 could be leveraged to develop support for these systems (Atkinson et al., 2020). Though these management systems are useful on local levels, variability in systems across localities leads to limited interoperability and challenges with communication at higher levels (Atkinson et al., 2020). This lack of in- tegration among vaccine data networks leads to low visibility on where vac- cines are sent. Data systems also do not capture demographic information on the vaccine recipients. In the state of Georgia, there was high variability in vaccination rates among counties and demographic groups. Studies re- vealed that people were traveling across county lines in order to receive a COVID-19 vaccine. In addition, white populations were significantly more likely than other groups to have received a vaccine, and vaccine coverage varied significantly on a local level (Wainscott-Sargent, 2021). These find- ings reveal that high-level data on vaccine administration often provides an PREPUBLICATION COPY—Uncorrected Proofs

122 GLOBALLY RESILIENT SUPPLY CHAINS incomplete picture. Data need to be collected on a community level to as- sess vaccine uptake (Wainscott-Sargent, 2021). In these situations, there is a need for additional data on why residents of the counties with low demand are less likely to get the vaccine. Accessibility, time off work, or hesitancy could all be contributing factors. Interventions can be developed, but the primary reasons for low uptake have to be identified and addressed (Surgo Ventures, 2021). Within a country, there is a need to identify areas where inventory is available but demand is weak. In areas with less demand, ef- forts should be made to determine the drivers of low uptake. Resources may need to be allocated to generate demand, which includes advocacy for vaccine uptake and addressing vaccine hesitancy. Immunization information systems for routine immunization are rel- evant to planning, delivery, and administration in supply chain logistics and procurement (delivery, cold chain monitoring). They also facilitate monitoring and evaluation of health information systems, adverse events, and digital vaccine certificates. Integration and interoperability of different information systems (e.g., LMIS and immunization information systems) is needed for efficient flow, combatting vaccine wastage, and informing better allocation in general, and given their scale, especially for influenza and adult immunization programs. The value of globally aggregated data is widely accepted (PATH and WHO, 2013). Organizations need to work with country governments to build trust. A tiered process could work to build trust, where lower-level data are first shared and evolves to more sensitive data. As observed during COVID-19, vaccine distribution has not been ef- ficient. Allocation based solely on population has led to vaccine scarcity in some areas and overabundance in others, as vaccine uptake varies. Both COVID-19 and influenza are best prevented by equitable vaccine distribu- tion and uptake. Distributing influenza vaccines during the COVID-19 pandemic has been hindered by additional strain on health services and a decline in people’s seeking health care. However, developing tools that account for some key factors can facilitate development of equitable distri- bution plans. A study on vaccine allocation in Iran developed a model that accounted for location of vaccine distribution points, cost of transporta- tion to administration sites, distribution center capacity, per-dose holding and transport costs, and the coverage rate of the target population. It also accounted for the priority vaccination groups, including health care work- ers, the elderly, and pregnant women (Rastegar et al., 2021). This model provided insight on the best distribution center in terms of cost, accounting for local budget constraints. Factors affecting allocation and distribution are similar for both influenza and COVID-19 vaccines. Insight into best practices in allocation for one yields valuable insight that can be transferred to the other. PREPUBLICATION COPY—Uncorrected Proofs

VACCINE DISTRIBUTION AND DELIVERY 123 Efficient global distribution of vaccines in a pandemic relies on the existence, coordination, and successful operation of a collection of robust systems. These systems include physical infrastructure for transportation, storage, distribution, and delivery to individuals. They also include infor- mation systems that help to coordinate demand and delivery of products, as well as information systems that provide comprehensive information on populations, vaccine coverage, safety, and effectiveness. Furthermore, the necessary systems include a planning and organization structure at the global and local levels with the principal objective of delivering vaccines. Tools need to be available to assist countries and global institutions with planning vaccination strategies, including selection of sites, supply and logistics, and operational setup of vaccination sites for efficiency. Tools are also needed to bring down the cost of ownership for cold chain equipment, which serves as a bottleneck in vaccine transportation. Enhanced forecast- ing capabilities will also facilitate countries’ abilities to anticipate demand and plan to meet needs for seasonal and pandemic vaccination. Improved models for demand forecasting are also needed that are geographically grounded and account for human behavior. To facilitate each of these com- ponents, tools for more accurate operational distribution and delivery cost estimates to ensure necessary financing cannot be overlooked. RECOMMENDATION 4-5: The Office of Global Affairs, in partner- ship with the World Health Organization, Gavi, UNICEF, and relevant global funders, should facilitate the development of global tools to help countries with better supply planning for vaccines and ancillary sup- plies planning, allocation, and rollout decisions, and with obtaining necessary funding for operations. REFERENCES Andrenelli, A., J. L. Gonzalez, and S. Sorescu. 2021. Using trade to fight COVID-19: Manu- facturing and distributing vaccines. Paris: Organisation for Economic Co-operation and Develompent. Atkinson, K. M., S. S. Mithani, C. Bell, T. Rubens-Augustson, and K. Wilson. 2020. The digi- tal immunization system of the future: Imagining a patient-centric, interoperable immu- nization information system. Therapeutic Advances in Vaccines and Immunotherapy 8. Bernasconi, V., P. A. Kristiansen, M. Whelan, R. G. Román, A. Bettis, S. A. Yimer, C. Gurry, S. R. Andersen, D. Yeskey, H. Mandi, A. Kumar, J. Holst, C. Clark, J. P. Cramer, J. A. Rottingen, R. Hatchett, M. Saville, and G. Norheim. 2020. Developing vaccines against epidemic-prone emerging infectious diseases. Bundesgesundheitsblatt Gesundheitsforsc- hung Gesundheitsschutz 63(1):65-73. Bhan, M. K., and B. Sinha. 2019. Immunisation against influenza in low-income and middle- income countries. Lancet Global Health 7(7):e827-e828. Bresee, J., J. Fitzner, H. Campbell, C. Cohen, V. Cozza, J. Jara, A. Krishnan, V. Lee, and W. H. O. W. G. o. t. B. o. I. Disease. 2018. Progress and remaining gaps in estimating the global disease burden of influenza. Emerging Infectious Diseases 24(7):1173-1177. 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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