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Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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3

Clinical Science

This chapter addresses the second of the four dimensions of vaccine research, development, and manufacturing examined by the committee. It begins by describing the role of clinical science in the development of COVID-19 vaccines. The chapter then considers how lessons learned from the development of COVID-19 vaccines (shown in Box 3-1) can be applied to both seasonal and pandemic influenza vaccines in the dimension of clinical science. The final section presents recommendations drawn from these findings.

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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CLINICAL SCIENCE AND THE DEVELOPMENT OF COVID-19 VACCINES

Lessons can be learned from the experience with developing COVID-19 vaccines in several aspects of clinical science: preclinical and clinical trial design, diversity in clinical trials, evaluation of vaccine effectiveness (VE), and postauthorization safety surveillance.

Preclinical and Clinical Trial Design

During a pandemic, when speed is of the essence, vaccine development through clinical testing in the traditional, sequential order is time consuming. To allow the unprecedented rapid vaccine development for COVID-19, vaccine manufacturers conducted immunogenicity and efficacy trials in parallel, instead of the traditional sequential path of studies (Excler et al., 2021). A data and safety monitoring board (DSMB) was formed to evaluate government-funded trials, coordinate oversight, and share learning pertaining to safety across trials. Additionally, manufacturers liaised with regulatory bodies to clearly define expectations and expedite the process to authorization. Regulatory systems that laid out clear guidelines and worked closely together with industry facilitated these overlapping preclinical and clinical phase studies, while maintaining regulatory standards (see Chapter 5).

The U.S. Food and Drug Administration (FDA) approved Emergency Use Authorization for those vaccines that showed an efficacy of at least 50 percent in placebo-controlled phase III trials and were considered safe (FDA, 2021a). The European Medicines Agency (EMA) had a conditional marketing authorization in place to enable authorization as soon as sufficient data were available regarding efficacy and safety, while requiring monthly safety reports from manufacturers (EMA, 2021a,b). Additionally, regulators allowed for a rolling review of data during the developmental stages of the vaccines to further accelerate the process.

Vaccines should be made available to the most at-risk populations first. Therefore, careful attention should be given to the design and inclusion criteria in trials to allow the vaccine to be available to the most at-risk populations first. In the COVID-19 pandemic, populations at highest risk of disease and death were largely composed of older adults, with 80 percent of deaths occurring in adults over 65 years of age (CDC, 2021a). As a result, vaccine trials—and ultimately vaccine distribution—prioritized these individuals, including first responders, older adults, those with chronic conditions, and marginalized populations that were disproportionately affected by the pandemic (Dooling et al., 2021; Soiza et al., 2021). Especially as it relates to the latter, there was unprecedented advocacy for the engagement of diverse populations, although, as discussed below, most clinical trials

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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ultimately fell short in this regard, and many minority populations were underrepresented (Flores et al., 2021). The goal was three-fold: to learn whether the vaccine candidates were safe, to assess whether they were effective at preventing disease, and to educate these communities about the anticipated benefits of vaccination. While these efforts were generally successful, segments of these communities continue to experience vaccine hesitancy despite the availability of safe and effective vaccines against COVID-19 (Razai et al., 2021).

Diversity in Clinical Trials

Historically, diversity among participants in clinical trials examining vaccine safety and efficacy has not reflected the diversity of the population. In the United States, in a study comparing clinical trial data, it was found that out of 230 trials, only 58.3 percent reported on race and 34.2 percent on ethnicity (Flores et al., 2021). White people were overrepresented in these studies, while Black people were underrepresented. Additionally, the distribution of age groups also does not match their distribution in the population, with those over 65 making up just 12.1 percent of study populations (Flores et al., 2021). Yet, to obtain accurate estimates of efficacy, diversity in enrollment for clinical trials for vaccines is required, including all populations at risk, such as people of all ages and pregnant people.

COVID-19 has disproportionally affected various racial and ethnic groups and is more severe in older adults and those with preexisting conditions (Garg et al., 2020; Webb Hooper et al., 2020). While minorities and the elderly were underrepresented in clinical trials, people who were known to be pregnant were excluded altogether from the phase III efficacy clinical trials for the COVID-19 vaccines (Subbaraman, 2021; Van Spall, 2021). Therefore, limited data were available for recommendations at the time of Emergency Use Authorization. However, given that COVID-19 poses risks for pregnancy outcomes, in most countries, people who were pregnant were offered the vaccine. Monitoring studies are ongoing, and early results suggest the vaccines are safe and effective in this group. Recent data show that in a cohort of 103 women receiving mRNA vaccination, 30 of whom were pregnant and 16 lactating, immunogenicity was similar in all women, and vaccine-induced antibodies were found in their cord blood and breast milk (Collier et al., 2021). Another study among 84 women who received the vaccine during pregnancy showed the vaccine was not associated with placental histopathologic lesions (Shanes et al., 2021).

Children younger than 16 years were also not included in the initial phase III efficacy trials for these vaccines. On the basis of these trial data,

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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the Moderna and Johnson & Johnson vaccines were authorized for ages 18 and older, while the Pfizer-BioNTech vaccine was approved for those 16 and older in most countries (AJMC Staff, 2021a,b). Clinical trials including adolescents followed the successful phase III studies, and Pfizer-BioNTech was authorized for use in children aged 12–15 years in the United States in May 2021 (AJMC Staff, 2021b). Trials for AstraZeneca in children have been halted pending a safety review after rare cases of blood clots in the brain were reported in adult trials (Cunningham and Iati, 2021).

Postauthorization Vaccine Safety Surveillance

A critical component of global vaccination efforts is the ability to monitor vaccine safety in real time. Investment in vaccine safety surveillance systems is crucial to achieve three goals:

  1. Support streamlined vaccine development;
  2. Promote confidence in vaccines; and
  3. Ensure trust in decision making about vaccine use by enabling dynamic benefit–risk assessments.

Clinical trials are typically designed to evaluate efficacy or immunogenicity and are usually sufficient in size to detect common adverse events, such as local or systemic reactogenicity. However, clinical trials are often not powered to detect rare, significant adverse events. A notable exception is the rotavirus vaccine, where pre-licensure trials for subsequent rotavirus vaccines were a priori designed to demonstrate that the risk of intussusception was similar in vaccine versus placebo recipients following observations of intussusception with rotavirus vaccine (Heyse et al., 2008).

Passive surveillance systems, such as the Vaccine Adverse Event Reporting System (VAERS) used in the United States, enable reporting of potential adverse events to a public health authority and can be efficient and timely for detecting rare adverse events (Cashman et al., 2017; Chandler, 2020; Gee et al., 2021; Zanardi et al., 2001). Active monitoring systems, such as the Vaccine Safety Datalink (VSD), are coordinated by the U.S. Centers for Disease Control and Prevention (CDC) and other health systems that assess population-based data with appropriate comparison groups to estimate burden and risk in different populations using electronic medical records and health care encounter data (Lee et al., 2020). Certain population-based surveillance systems include the use of electronic medical records, which is critical for signal validation (FDA, 2021b; Nsubuga et al., 2006; Remmel, 2021). However, these are less commonly available

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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for use as a component of vaccine safety surveillance programs in many countries. Clinical consultation services have also been extremely useful to complement existing safety surveillance systems in the United States and to better support causality assessment of safety signals (Buehler et al., 2004). The vaccine safety review process can also include informal sources, such as social media, watchlists, global and regional databases; formal sources, such as global databases of case safety reports and regional databases; and routine meetings with various regulators—such as the International Coalition of Medicines Regulatory Authorities (ICRMA), FDA, EMA, and low- and middle-income countries (LMICs) having weekly huddles with all six World Health Organization (WHO) regional offices (Helfand and Pal, 2021).

Clinical trials for COVID-19 vaccines were unusual in size, speed, and diverse enrollment practices. To rapidly evaluate the efficacy of newer platforms used for vaccine development, trials contained more than 30,000 participants in the pivotal phase III clinical trials in adult populations (Brothers, 2020; May, 2020; Pfizer, 2020). Given the large size of these initial trials, regulatory agencies in the United States prespecified that a median of 2 months of safety follow-up was sufficient to apply for Emergency Use Authorization, balancing the need for timely availability of vaccines with the ability to detect common vaccine safety events (FDA, 2021a). Subsequent trials, however, are likely to rely on immunobridging rather than efficacy data, deducing efficacy in different populations. This may limit risk–benefit analysis and the availability of safety data in subpopulations such as young children.

As humans are naïve to SARS-CoV-2, potential safety signals for the vaccines were initially unknown. However, efforts have been made to identify and prepare for potential side effects. The Safety Platform for Emergency vACcines (SPEAC) project was formed by the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration in an attempt to create a list of potential adverse events of special interest following COVID-19 vaccination and how to respond appropriately to such adverse events should they occur (Black et al., 2021).

While clinical trials result in a reasonable degree of certainty about the frequency of common adverse events in the overall population such as local and systemic reactogenicity, postauthorization or postapproval safety surveillance systems can affirm that the risk is similar across diverse, real-world populations, meaning by age (teens, elderly), gender, race/ethnicity, presence of comorbidities, and pregnancy. During the COVID-19 pandemic, a novel safety surveillance system called v-safe was implemented using smartphone technology, allowing vaccine recipients to directly report potential adverse events to public health agencies

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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(CDC, 2021b; Gee et al., 2021). Text messaging reminders and links to web surveys enabled vaccine recipients in the United States to record their symptoms following vaccination and report any health impact events. Furthermore, a pregnancy v-safe registry was launched in the United States when it was noted that more pregnant individuals received COVID-19 vaccines early in the pandemic than anticipated (more than 150,000 as of August 2021), in the paucity of clinical trial data (CDC, 2021c). Pregnant individuals had comparable reactogenicity to non-pregnant individuals (Shimabukuro et al., 2021). More than 5,000 of these women have volunteered to provide additional data on their pregnancy and neonatal outcomes (CDC, 2021c). These data could potentially support expanded use of vaccines in different countries where variation in policies or recommendations owing to concerns about safety issues may affect access to vaccines (COMIT, 2021).

Similar survey-based approaches to monitoring postauthorization or postapproval vaccine safety can provide data complementary to those obtained from clinical trials. For example, during COVID-19 vaccine trials, self-reported surveys were used to measure safety and reactogenicity. The study showed that more severe adverse events were more likely in participants who had previously been infected with SARS-CoV-2 (Mathioudakis et al., 2021). Similar results have been demonstrated in influenza vaccine studies, such as a short-term reactogenicity study after receiving a two-dose H5N1 vaccine (Standaert et al., 2019), and a study that sent participants a daily SMS link to collect reactogenicity data after vaccination (Stuurman et al., 2017).

In contrast to local and systemic reactogenicity, rare adverse events are difficult to detect in clinical trials. Instead, it is necessary to rely almost entirely on postauthorization or postapproval safety surveillance systems to capture rare adverse events. The importance of these systems during a pandemic cannot be overemphasized given our experience with observations of Guillain-Barré syndrome during the 1976 swine flu and 2009 H1N1 pandemics (Salmon et al., 2011; Sencer and Millar, 2006). During the vaccine rollout for COVID-19, some very rare adverse events have been detected, including anaphylaxis and myocarditis following receipt of the mRNA vaccines (Blumenthal et al., 2021; Kim et al., 2021) and thrombosis with thrombocytopenia syndrome (TTS) following receipt of the adenoviral vector-based vaccines (Meredith, 2021). These events have mainly been detected in countries with well-developed surveillance mechanisms and ongoing real-time monitoring and coordination between regulatory bodies within and across countries to ensure the rapid detection and management of these rare events. However, these surveillance systems may not accurately measure the experience of diverse populations receiving vaccines.

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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CLINICAL SCIENCE: APPLYING LESSONS FROM THE DEVELOPMENT OF COVID-19 VACCINES TO VACCINES FOR INFLUENZA

Diversity in Clinical Trials

When faced with an influenza pandemic, it is likely that the same diverse populations sought for COVID-19 vaccine trials, as well as the immunocompromised, children, and pregnant individuals, would benefit from vaccination at the earliest opportunity (Rasmussen et al., 2008; Ruf and Knuf, 2014). Therefore, diversity in clinical trials for influenza vaccines is critical as was the case with COVID-19 vaccines. Given the relatively low vaccination rates against seasonal influenza in pregnant individuals and children, it is reasonable to assume that there may be similar challenges in pandemic conditions (CDC, 2016, 2020).

Until recently, influenza vaccines have been implemented using a one-size-fits-all approach. However, the response to vaccines can vary with age. For instance, older individuals often have reduced responses to vaccines and might benefit from a higher vaccine dose or an adjuvanted vaccine to improve effectiveness in this population (Derhovanessian and Pawelec, 2012). Children who are naïve to influenza need to be primed suitably, which might be achieved with a live-attenuated vaccine that exposes them to all components of the influenza virus (Sridhar et al., 2015). Therefore, clinical vaccine platform development needs to consider the different needs of subsets of the population and incorporate them into the design of subsequent efficacy trials.

Clinical Trials for Influenza in Low- and Middle-Income Countries

The issue of clinical trials in LMICs is an important concern in the development of seasonal and pandemic influenza vaccines. The conduct of clinical trials and participation may be more problematic in LMICs where there are limited seasonal influenza programs due to lack of funds and a lack of urgency, as other health-related issues may take priority (Kraigsley et al., 2021; Ortiz and Neuzil, 2019; Williams et al., 2021). There may be limited surveillance data to support the need for vaccination in these areas. Moreover, even after the need is established, vaccine hesitancy may persist in the absence of local efficacy and safety data; limited capacity to distribute vaccines can also hamper efforts to increase vaccine coverage (Ortiz and Neuzil, 2019).

Conclusion 3-1: In LMICs that have performed disease burden studies, vaccination rates have improved (Bresee et al., 2018). Moreover, local surveillance data may convince local governments to invest in access to

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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a seasonal vaccine and aid in increasing acceptability by the population. These strategies to increase seasonal influenza vaccine uptake would create a foundation for later introduction of pandemic influenza vaccines when they are needed.

Multiple factors may challenge the conduct of clinical trials in LMICs. First, clinical trial protocols need to be reviewed locally, which requires local expert committees. In outbreak situations, there is a risk that such committees may have limited capacity and can become overwhelmed. A lack of resources and expertise may limit the conduct of a prompt and complete review to assess the risks of the research and balance it with the risk of disease. Second, obtaining informed consent can be challenging in regions with low literacy levels, as there might be limited comprehension of the research principles, requiring witnesses and a more extensive consent process to explain the multitude of factors involved in the research (Minnies et al., 2008). Additionally, in many cultures, women are not the primary decision makers and might have lower levels of literacy (NBAC, 2001). Therefore, it can be challenging to include women or their children in trials. Third, specimen banking is often needed for clinical trials, which might not be possible in LMIC regions (Alemayehu et al., 2018). Additionally, certain levels of expertise might be needed to conduct assays on such samples, which might not be available in LMICs. Shipping specimen abroad to high-income countries for storage and analyses may also result in ownership issues.

Conclusion 3-2: The highest priority regions for vaccines are those where they are needed the most, the population at risk is willing to accept them, and local authorities can see their benefit. To achieve this goal, it is necessary to conduct clinical trials that include particularly at-risk populations. Local research centers in LMICs can conduct these trials, but the present model of providing temporary funding for specific projects for a limited amount of time makes it difficult to maintain them. As a result, it is challenging to quickly ramp up research efforts when there is a pandemic. During the COVID-19 pandemic, setting up and running trials of candidate vaccines has been slower in some areas of the world and is affecting uptake of these vaccines (COVID Clinical Research Coalition, 2020; Hall et al., 2021).

Monitoring Vaccine Effectiveness

For existing vaccine platforms, licensure of seasonal or pandemic influenza vaccines can be obtained either through a traditional approval pathway or by the accelerated approval mechanism (Weir and Gruber, 2016).

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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Typically, new vaccine platforms would use the traditional pathway and provide information on efficacy against influenza illness in clinical trials; however efficacy trials can be challenging to implement in a pandemic scenario where timeliness matters. Under the accelerated pathway, immunogenicity endpoints may be used for licensure as a mechanism for streamlining the vaccine approval process, with a requirement for postmarketing First Occurrence VE studies (Weir and Gruber, 2016).

While the appropriate pathway for regulatory approval for a pandemic influenza vaccine cannot be predicted, postmarket vaccine effectiveness evaluations are clearly needed for pandemic planning. Furthermore, ensuring that diverse populations are captured by these data systems is essential for a thorough assessment of the effectiveness of different vaccine platforms, adjuvants, doses, and schedules for different subpopulations, as well as effectiveness among emerging variants in the case of COVID-19.

VE studies are necessary for validating clinical trial data that may rely on immunogenicity or efficacy in well-defined populations. Real-world effectiveness may differ from prelicensure expectations, which in turn may affect benefit–risk balance and decision making about use of a vaccine in different populations (Hodgson et al., 2021). Efficiency in surveillance efforts is also essential for feasibility and sustainability. Previous work has provided some good models for VE studies, which can be applied to improving vaccines that target seasonal and pandemic influenza. The test-negative study design has been found to be an accurate way to monitor VE (Sullivan et al., 2014). This study design is a variant of the case-control study and is relatively easy to conduct, allowing its widespread use. It corrects for bias in health care–seeking behavior, as it studies those seeking health care for influenza-like symptoms (Jackson et al., 2006; Sullivan et al., 2014). Those who test positive for influenza infection are considered cases, and those who test negative serve as the controls. The vaccination status between the two groups is compared to determine the VE. This VE is estimated from the adjusted odds ratio and adjusts for potential confounders (Sullivan et al., 2014). The test-negative study design can be used to establish accurate VE for influenza vaccines.

Like clinical trials, VE studies need to include a representative mix of varying demographics (age, comorbidities, race/ethnicity); necessary as well is the standardization of age bands to provide accurate age estimates that can be applied to the population as a whole. Note that age affects VE for influenza and may bias VE assessment if not explicitly considered (Feng et al., 2021). Therefore, it may be preferable and more accurate to establish an age-weighted average VE to determine overall VE, instead of using the average without taking age into account.

Once a vaccine is licensed for use, yearly updates for strain changes can be submitted as a supplement to an existing license, without postmarket

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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requirements for inactivated and recombinant protein vaccines (Wei et al., 2020). For example, 2009 monovalent H1N1 influenza vaccines were approved as a supplement to seasonal influenza vaccine licenses. Clinical trials to assess efficacy were not required prior to approval, shortening the time to an available H1N1 vaccine (Weir and Gruber, 2016). A similar approach to ensure timely access could be used for pandemic vaccines that are already licensed for use, with a supplement submitted for a strain change. In the absence of clinical efficacy data for a pandemic vaccine before authorization or approval, however, it becomes crucial to monitor vaccine effectiveness to support vaccine confidence and dynamic assessments of the benefit–risk balance.

The COVID-19 vaccine development story is remarkable. Novel platforms were evaluated for efficacy and safety in large-scale clinical trials prior to submission for Emergency Use Authorization, and the scope and speed of these clinical trials and the rapid regulatory response were unprecedented. In tandem with vaccine research, potential treatments for COVID-19 are also being explored. The WHO-designed Solidarity Trial monitors the effects of potential COVID-19 drug treatments in more than 14,000 participants across 52 countries (WHO, 2021a). While interim results found only corticosteroids to be effective at treating severe COVID-19, trials are still ongoing.

Conclusion 3-3: A priority for the development of seasonal and pandemic influenza vaccines in the dimension of clinical science is the design of surveillance activities that would support the demonstration of vaccine effectiveness and safety postauthorization.

Conclusion 3-4: Population-based studies of VE also need to capture the racial/ethnic, socioeconomic, age, and medical conditions diversity within and across countries, in order to ensure confidence in vaccine effectiveness.

Conclusion 3-5: To control for other variables that may bias VE, electronic medical records can be used to provide context on comorbidities that may affect VE, such as immunosuppression. Additional factors that may affect influenza vaccine VE include exposure risk, infection and vaccination history, and more indirect effects like herd immunity (Hollingsworth et al., 2021). These factors are more challenging to include in studies; their inclusion would allow better VE assessment and guide vaccine development.

Conclusion 3-6: Existing networks collaborating to monitor influenza VE could be leveraged to provide the infrastructure to enable VE monitoring worldwide during a pandemic.

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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Conclusion 3-7: An approach similar to the Solidarity Trial for COVID-19 treatments could provide opportunities to evaluate VE of multiple vaccine candidates simultaneously across a broad range of settings and populations (WHO, 2021a). Such international studies could support broad engagement, facilitate robust worldwide comparisons, and allow us to more quickly understand optimal use and allocation of vaccine candidates with differing profiles.

Postauthorization Vaccine Safety Surveillance

The COVID-19 pandemic has highlighted the critical role vaccine safety surveillance systems play in both detection of rare adverse events not identified in clinical trials and the effect of vaccine safety on decision making about use of vaccines in different countries. Some adverse events are so rare that they are not detected until millions of people have been vaccinated (Remmel, 2021). The ability to rapidly scale-up existing safety surveillance systems and implement novel approaches to surveillance is essential for real-time decision making during a pandemic.

Postmarket vaccine safety surveillance enables dynamic assessment of the benefit–risk balance. However, the assessment of benefit–risk balance may vary by country, as it depends on local burden of disease, type of populations prioritized, types of vaccines available for use, vaccine effectiveness of various vaccine candidates, values and preferences, and feasibility of implementation (Greenberg et al., 2016). Given the contextual variability, global benefit–risk assessments may not be useful to support uniform decision making.

Enhancing collaboration on vaccine safety is a critically important issue. Experience with COVID-19 vaccine safety highlights the need for such collaboration. For example, TTS was noted with the AstraZeneca COVID-19 vaccine in March 2021, which is an adenoviral vector vaccine (Meredith, 2021). In April 2021, the United States temporarily paused vaccination with the Janssen/J&J vaccine after six cases of TTS were identified, in part owing to similarities in the platform (Kupferschmidt and Vogel, 2021). In contrast, rare adverse events were detected more infrequently in LMICs, such as India that used many of the AstraZeneca vaccines for their population (Das and Mehta, 2021). On the other hand, data sharing increases the importance of data integrity, as incorrect information has the potential to spread further. One Canadian study showing excessive heart inflammation after COVID-19 vaccines was retracted after it was discovered to be a computation error (Miller, 2021). In addition, each vaccine safety surveillance system has unique strengths and limitations, particularly with regard to population coverage, types of vaccines used in these populations, timing of availability of vaccines for the population based on distribution

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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efforts, and timing of availability of data for review and analysis. Standardization and harmonization between monitoring systems are essential for detecting rare adverse events and gathering accurate safety data (Li et al., 2021). Systems that can conduct signal evaluation activities in response to detected events are needed to support dynamic decision making about vaccine use (Remmel, 2021). Additional capabilities to support vaccine safety include the ability to generate background rates for rare events, to conduct rapid signal evaluations that incorporate chart validation, and to run formal epidemiologic studies to evaluate the risk of adverse events following vaccination in subpopulations. In the first two pandemic years, no vaccine-enhanced adverse reactions have been observed. However, what should happen and who should cover associated costs of such vaccine-associated events induced by novel COVID-19 or influenza vaccines is an area that should be explored in future reports.

Conclusion 3-8: As a core component of tailored benefit–risk assessments, countries need access to all available data relevant for decision making in their populations (WHO, 2019). Transparency in decision-making regarding key domains that influence recommendations for use and clear communication about the rationale for decisions is vital to support vaccine confidence, particularly if different decisions are made about authorization or use of vaccines in different countries.

Conclusion 3-9: Since postauthorization vaccine safety surveillance is crucial for vaccine confidence, timely and transparent vaccine communication may be just as important as the science and data on vaccine safety.

Conclusion 3-10: Harmonization between organizations is key. EMA and the European Centre for Disease Prevention and Control have initiated a program to jointly monitor postmarket safety monitoring and vaccine effectiveness (Balfour, 2021). WHO can play an important role in this, as its global advisory committee on vaccine safety, the Strategic Advisory Group of Experts, can make recommendations (WHO, 2021b).

RECOMMENDATIONS

Recommendation 3-1: The World Health Organization, in collaboration with national public health agencies (e.g., the U.S. Centers for Disease Control and Prevention, the European Centre for Disease Prevention and Control, the China Center for Disease Control and Prevention, and the Africa Centres for Disease Control and Prevention) should

Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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conduct burden-of-disease studies in low- and middle-income countries to understand factors such as the health and economic burden of influenza illness and barriers to immunization in adult, pregnant, and pediatric populations to ensure development of infrastructure and capacity needed for pandemic vaccine development and implementation. Cost–benefit analyses should include additional economic productivity losses caused by delayed access to a vaccine in a pandemic.

Recommendation 3-2: The International Coalition of Medicines Regulatory Authorities and the World Health Organization, in partnership with national regulatory (e.g., the U.S. Food and Drug Administration and the European Medicines Agency) and public health agencies (e.g., the U.S. Centers for Disease Control and Prevention, the European Centre for Disease Prevention and Control, the China Center for Disease Control and Prevention, and the Africa Centres for Disease Control and Prevention) should invest, on a global level, in data infrastructure and capacity building to conduct real-time sentinel site surveillance of vaccine safety and effectiveness of different vaccine products deployed for use in epidemics and pandemics in diverse populations (e.g., age group, gender, race/ethnicity, geographic, presence of comorbidities, pregnancy, and socioeconomics), including a plan to ensure coordination, collaboration, and data sharing across these sentinel surveillance sites.

Recommendation 3-3: The International Coalition of Medicines Regulatory Authorities and the World Health Organization (Global Advisory Committee on Vaccine Safety) should ensure international coordination and collaboration on the timely and transparent review of vaccine safety data during epidemics and pandemics to support real-time decision making about the use of vaccines. Safety data should be made available to support country-level benefit–risk assessments, particularly for low- and middle-income countries relying on regional data from sentinel sites conducting safety surveillance.

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Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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Suggested Citation:"3 Clinical Science." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2022. Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response: Lessons from COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26282.
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The global response to COVID-19 has demonstrated the importance of vigilance and preparedness for infectious diseases, particularly influenza. There is a need for more effective influenza vaccines and modern manufacturing technologies that are adaptable and scalable to meet demand during a pandemic. The rapid development of COVID-19 vaccines has demonstrated what is possible with extensive data sharing, researchers who have the necessary resources and novel technologies to conduct and apply their research, rolling review by regulators, and public-private partnerships. As demonstrated throughout the response to COVID-19, the process of research and development of novel vaccines can be significantly optimized when stakeholders are provided with the resources and technologies needed to support their response.

Vaccine Research and Development to Advance Pandemic and Seasonal Influenza Preparedness and Response focuses on how to leverage the knowledge gained from the COVID-19 pandemic to optimize vaccine research and development (R&D) to support the prevention and control of seasonal and pandemic influenza. The committee's findings address four dimensions of vaccine R&D: (1) basic and translational science, (2) clinical science, (3) manufacturing science, and (4) regulatory science.

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