key: cord-0908638-6crputzl authors: Anderson, Evan J; Campbell, James D; Creech, C Buddy; Frenck, Robert; Kamidani, Satoshi; Munoz, Flor M; Nachman, Sharon; Spearman, Paul title: Warp Speed for COVID-19 Vaccines: Why are Children Stuck in Neutral? date: 2020-09-18 journal: Clin Infect Dis DOI: 10.1093/cid/ciaa1425 sha: c45a4213e6a37d21a9db8e1172886bf68a4bcf64 doc_id: 908638 cord_uid: 6crputzl While adult clinical trials of COVID-19 vaccines have moved quickly into Phase 3 clinical trials, clinical trials have not started in children in the US. The direct COVID-19 impact upon children is greater than that observed for a number of other pathogens for which we now have effective pediatric vaccines. Additionally, the role of children in SARS-CoV-2 transmission has clearly been underappreciated. Carefully conducted Phase II clinical trials can adequately address potential COVID-19 vaccine safety concerns. Delaying Phase II vaccine clinical trials in children will delay our recovery from COVID-19 and unnecessarily prolong its impact upon children’s education, health and emotional well-being, and equitable access to opportunities for development and social success. Given the potential direct and indirect benefits of pediatric vaccination, implementation of Phase II clinical trials for COVID-19 vaccines should begin now. A c c e p t e d M a n u s c r i p t 4 of hospitalized SARS-CoV-2 PCR-positive children and up to 80% of those with Multisystem Inflammatory Syndrome in Children (MIS-C) are admitted to the ICU [8, 9] . The risk of serious COVID- Hispanics and Blacks as compared to Whites [8] [9] [10] . A pediatric COVID-19 vaccine could dramatically reduce hospitalization and racial disparities from COVID-19. Children in the US are dying of COVID-19-related complications; in the first 5 months of the pandemic, 103 children have died in the US from COVID-19 through September 9, 2020 [11] . It is important to recognize that other vaccine-preventable diseases for which vaccination is recommended today, resulted in similar or fewer annual pediatric deaths before vaccines became widely utilized (e.g., hepatitis A, varicella, rubella, rotavirus) ( Table 1 ) [12] [13] [14] [15] . Additionally, pediatric COVID-19 deaths are rapidly approaching the 110-188 influenza-associated pediatric deaths per season from the past 4 seasons (2016 -2020) [16] . The anticipated persistence of SARS-CoV-2 circulation and the burden of COVID-19 hospitalizations and deaths in children justify development of a pediatric indication for COVID-19 vaccines. In addition to direct medical benefits, a COVID-19 vaccine could provide direct benefits on childhood education by allowing a safer return to school, a critical factor in children maximizing their potential. The intermittent or complete closure of schools to onsite education threatens to adversely impact that opportunity across all households that cannot provide direct educational oversight and is worse among households without adequate access to online learning -an issue disproportionately affecting racial minorities. In addition to the altered learning environment, social distancing and the lack of extracurricular activities (e.g., sports, drama, music, art, social events) impacts the emotional and psychological development of children. Thus, an approved COVID-19 vaccine for children could have far-reaching positive ramifications on health and educational equity. A c c e p t e d M a n u s c r i p t 5 Vaccinated children would receive potential direct impact from a COVID-19 vaccine, but substantial potential for indirect effects of implementing a vaccine in children should also be recognized, as has been observed with hepatitis A, rotavirus, pneumococcus, rubella, and potentially influenza [17] [18] [19] [20] [21] [22] [23] [24] . Marked declines in adult pneumococcal disease occurred after implementation of 7-valent pediatric pneumococcal conjugate vaccine (PCV) [21] . Additional pronounced impact occurred after implementation of PCV-13 [20] such that routine PCV-13 vaccination is no longer routinely recommended in adults ≥65 years of age [25] . The potential for an indirect impact depends upon the ability of the vaccine to prevent transmission of a pathogen to unvaccinated populations. Although it is unknown whether this will be the case for COVID-19, recent nonhuman primate data in which animals received COVID-19 vaccination followed by SARS-CoV-2 challenge demonstrated declines in both disease and viral titers in the nose [26] . These nonhuman primate challenge data in conjunction with high neutralizing antibodies achieved in early human trials provide strong support for the potential of a direct and indirect impact of vaccination. Vaccination of children against COVID-19 may mimic the indirect benefits previously identified with other vaccines [17, 18] . Data from a study of close contacts of SARS-CoV-2 infected patients suggest that while children were less likely to have severe symptoms, they were just as likely to be infected as adults (rate of about 7% in both) [27] . Several studies suggest that the viral titers in the respiratory tracts of children are greater than those of adults [28, 29] . A large contact tracing study of COVID-19 cases, conducted while schools were closed in South Korea, supports the concept that older children can transmit COVID-19, as the highest COVID-19 rate (18.6%) occurred in household contacts of those 10 -19 years of age [30] . An outbreak at a summer camp reported an attack rate of 44%, demonstrating that children of all ages were susceptible for SARS-CoV-2 infection and that they may play a role in transmission [31] . Recent modeling demonstrated that US school closures were temporally associated with overall decreased COVID-19 incidence and mortality [32] . A c c e p t e d M a n u s c r i p t 6 Approximately 3.8 million children are born in the US annually; all are naïve to COVID-19. Without a COVID-19 vaccine, children will likely serve as a reservoir, which would undermine efforts to end the pandemic. Until all children can more safely return to school and parents can return to fulltime work, it is difficult to imagine that the economy can completely recover. Ensuring the safety of potential vaccine candidates is paramount, particularly in children. Data in adults show that all COVID-19 vaccines evaluated thus far have local (e.g., pain, redness, swelling, induration) and systemic (e.g., fever, chills, myalgia) reactogenicity [2-4, 6, 33, 34] . Reactogenicity is self-limited, treatable, and reflects a typical innate immune response to antigen exposure. More important is vaccine safety. Uncommon, unexpected safety events can occur after vaccination, such as thrombocytopenia after the measles, mumps and rubella (MMR) vaccination; febrile seizures with certain vaccines; and intussusception associated with the original tetravalent rotavirus vaccine [35] [36] [37] . All vaccines have the potential for unknown and uncommon safety problems. The potential benefit and risks of new vaccines should be considered. A carefully designed clinical development plan can ensure that potential benefits outweigh risks. This approach has been successful in moving vaccines against RSV, CMV, and other pathogens into clinical trials. The vaccine safety network within the US includes several post-marketing surveillance systems for all vaccines to detect rare adverse events that were not detected pre-licensure [38] . Importantly, withdrawal for safety has only occurred once, with the tetravalent rotavirus vaccine [39] . Thus, the process of obtaining FDA licensure and post-licensure safety surveillance should remain rigorous and robust in ensuring safe vaccines. Statements by the FDA to date suggest that this will remain the case for COVID-19 vaccines [40] . A c c e p t e d M a n u s c r i p t 7 Vaccine-associated immune-mediated enhanced disease (VAED), while a theoretical concern, is a process that is considered unlikely to occur with SARS-CoV-2. VAED may be associated with two different mechanisms of action [41] . Antibody-dependent enhancement (ADE), as has been observed with dengue, occurs when a vaccine-induced antibody paradoxically mediates increased viral entry [41] , particularly with exposure to a different strain of virus. Although minor mutations have occurred in circulating SARS-CoV-2, including the D614G [42] , available data do not suggest that major mutations have emerged. Vaccine-associated enhancement of respiratory disease (VAERD) occurred in association with use of a formalin-inactivated respiratory syncytial virus (RSV) vaccine in the 1960s. Investigations into the pathophysiology suggest that this was due to nonneutralizing antibodies and a predominantly Th2-biased response. [41] Importantly, all COVID-19 vaccines with available data induce high levels of neutralizing antibodies, and some also generate a Th1 response [2-4, 6, 34, 43] . The final safety issue that has been raised is the potential for induction of MIS-C associated with COVID-19. The timing of MIS-C (frequently weeks after infection) and the detection of neutralizing and receptor-binding-domain antibodies at the time of illness suggest that this might be an immunemediated injury triggered by SARS-CoV-2 infection [9, 44] . Given the viremia that is known to occur with COVID-19 [45] and the response of most patients to brief courses of immunomodulators (e.g., steroids), it may be due to immunological recognition of viral antigens (or live virus) rather than triggering of an autoimmune condition. Although not powered to detect rare events, data from early clinical studies in humans have not yet identified any cases of ADE, or VAERD [2-4, 33, 34] . A vaccine that prevents infection could also prevent MIS-C; available data suggest that vaccines prevent COVID-19 in a nonhuman primate challenge model without enhancement of disease [26, 46, 47] . Large Phase III efficacy trials conducted in adults may provide additional insights into vaccineelicited immunity and enhanced disease and such data would be anticipated to be available during the Phase II pediatric clinical trials. Given the rarity of MIS-C with natural infection, any risk is A c c e p t e d M a n u s c r i p t 8 unlikely to be resolved even with carefully conducted large pediatric clinical trials and ongoing surveillance for MIS-C will be necessary even after a vaccine approval. The current default position, waiting until data from adult efficacy studies are available, will unduly delay Phase II clinical trials of leading COVID-19 vaccines in children resulting in additional pediatric hospitalizations and deaths. Data are now available from early phase adult clinical trials [2] [3] [4] [5] [6] . Pediatric clinical trials of leading vaccine candidates can safely be initiated now. To establish safety, trials should start with adolescents and older children before expanding to younger children. The strategy of age de-escalating trials to bridge vaccines from adult studies to children is one that has been commonly used in the past to ensure early identification of safety signals while minimizing risks, establishing dosing, and evaluating immune responses. Similar to adult studies, it will take time to conduct these studies safely in children. Moving forward now with pediatric COVID-19 vaccine trials will help prevent delays in obtaining a pediatric indication from the US Food and Drug Administration (FDA). The Pediatric Research Equity Act (PREA, section 505B of the FD&C Act (21 U.S.C. 355c)) requires manufacturers to conduct vaccine studies of safety and effectiveness in children. Although the timing of pediatric studies is not delineated in the Act, we believe the FDA, funding agencies, investigators, and manufacturers should join to initiate these studies now. The FDA clarified that to ensure compliance with 21 CFR Part 50 Subpart D, considerations of the prospect of direct benefit and acceptable risk to support initiation of pediatric studies and the appropriate design and endpoints for pediatric studies should be discussed in the context of specific vaccine development programs [48] . vaccine protocol template. The template is adaptable to multiple vaccines currently under evaluation in adults and could standardize the approach and endpoints across vaccine manufacturers. It features an age de-escalation strategy, incorporating multiple provisions that will allow these vaccines to be safely evaluated in adolescents, young children, and infants. Children are at substantial risk of COVID-19. Delays in starting Phase II vaccine clinical trials in children will delay our recovery from COVID-19 and unnecessarily prolong its impact upon children's health and emotional well-being, their education, and equitable access to opportunities for development and social success, as well as the country's economy. Understanding the safety, immunogenicity, and efficacy of COVID-19 vaccines in children is critical to protect children and adults. For children, a vaccine has the added benefit of returning them safely to school and extracurricular activities, and allowing them to engage with their world face-to-face once again. Ensuring acceleration of vaccine clinical trials to warp speed for children will be critical in making this our future reality. All other authors have no potential conflicts to disclose. 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Data about the impact of other vaccines have previously been summarized [50] . †Hepatitis A hospitalization data after implementation of routine vaccination in those ≥2 years of age in 11 states with elevated rates of disease, but before routine hepatitis A vaccination was implemented in all children. ‡Data are not available, to our knowledge, about this outcome before vaccine implementation.