Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes coronavirus disease 2019 (COVID-19), was first reported in Wuhan, China on December 31, 2019 [1,2]. SARS-CoV-2 spread rapidly worldwide, and the WHO declared COVID-19 a global pandemic on March 11, 2020 . By early October 2020, about 7,400,000 cases had been reported to the Centers for Disease Control and Prevention (CDC), including about 210,000 deaths . Although physical control measures, including sheltering at home, social distancing and wearing facemasks, have been critical to delaying the spread of COVID-19, these have come at enormous economic, social and educational costs. Although much of the mortality has occurred in older adults, substantial morbidity and mortality also occur in children.
Based on the current estimates of SARS-CoV-2 transmissibility, more than 2/3 of the population must have immunity to SARS-CoV-2 before sustained transmission will cease [5,6]. As of July 2020, the estimated seroprevalence of SARS-CoV-2 in U.S. adults was only 9% . The development of a safe and effective vaccine against COVID-19 is imperative to mitigate morbidity and mortality. Vaccination benefits both the individual who receives it through direct protection and the greater society through community protection (also known as indirect or herd protection).
Operation Warp Speed (OWS), a partnership between the U.S. Department of Health and Human Services, the Department of Defense, and the private sector, was established in May 2020 to accelerate the development, manufacturing and distribution of SARS-CoV-2 countermeasures [8▪]. OWS set the ambitious goal of advancing eight SARS-CoV-2 vaccine candidates in parallel and delivering 300 million vaccines by January 2021. Although multiple vaccine candidates have demonstrated safety and efficacy in phase 1 and 2 clinical trials in adults, pediatric trials are not yet underway. The objectives of this article are, therefore, to update pediatricians about COVID-19 in children, to describe the status of SARS-CoV-2 U.S. vaccine clinical trials, to discuss the need for initiation of pediatric clinical trials and to instill confidence in the process of vaccine licensure.
BURDEN OF COVID-19 IN CHILDREN AND POTENTIAL BENEFITS OF COVID-19 VACCINES
Children of all ages are susceptible to SARS-CoV-2 infection  and severe disease manifestations . Although the majority of cases of COVID-19 in children are asymptomatic or mild, 18.4/100,000 children 0–4 years of age and 10.6/100,000 children 5–17 years of age require hospitalization , of which one-third require intensive care . Extremes of ages, including infancy and late adolescence, are risk factors for hospitalization . Underlying medical comorbidities, including medical complexity, immunocompromising conditions and obesity, are risk factors for admission to intensive care . Although preexisting medical conditions clearly predispose children to severe disease, previously healthy children are also at risk for severe COVID-19 and multisystem inflammatory syndrome in children (MIS-C) [15,16]. MIS-C complications include myocardial dysfunction, shock and respiratory failure requiring intensive care . Similar to adults, black and Hispanic white children are disproportionately affected by both severe COVID-19 disease manifestations [10,12] and MIS-C [15,16]. Thus, SARS-CoV-2 vaccination could mitigate health disparities among children belonging to racial and ethnic minority groups, as has previously been demonstrated for other routinely administered pediatric vaccines [18,19].
In addition to the direct health benefits of active immunity to SARS-CoV-2, a safe and effective pediatric vaccine could dramatically mitigate the marked social impact of COVID-19 upon children. Following declaration of the COVID-19 pandemic in March 2020, K-12 schools closed in all 50 U.S. states, affecting more than 57 million students . The consequences of such unprecedented school closures include interrupted learning, nutrition impact for children reliant upon federally funded meals, gaps in childcare and supervision, and economic impacts on families because of parents missing work. Pediatric COVID-19 vaccines could also restore other experiences that have intangible benefits upon children (e.g. extracurricular activities) [21,22].
Furthermore, pediatric vaccines will likely be needed to achieve the control of SARS-CoV-2 transmission. Children transmit numerous respiratory and enteric pathogens, including influenza, pneumococcus, rotavirus and hepatitis A. Following the implementation of routine pediatric vaccination with PCV7 in 2000 and PCV13 in 2010, dramatic declines in invasive pneumococcal disease occurred in both children and adults [23,24]. Thus, there is a strong precedent for pediatric vaccination reducing community transmission and preventing adult disease [25▪]. Although some early studies suggested that children are less likely to transmit SARS-CoV-2 than adults , recent studies have demonstrated transmission among children in childcare facilities , schools, summer camps  and at the population level . U.S. school closures were temporally associated with significant declines in the incidence of COVID-19 and associated mortality . Thus, children likely play a significant role in SARS-CoV-2 transmission that has been underestimated because of early school closures, frequent asymptomatic infections and less frequent pediatric testing.
Critical questions remain regarding the benefits of a pediatric vaccine, including the magnitude of protective immunity, and whether a vaccine could decrease infection and transmission, in addition to symptomatic disease. Encouraging results from nonhuman primate studies demonstrated that the SARS-CoV-2 vaccines may not only prevent infection but may also reduce the viral load in both the nasopharynx and bronchoalveolar lavage samples [31▪,32], implying that they may reduce transmission. To address these questions, pediatric COVID-19 vaccine clinical trials are needed to establish the dose, safety, reactogenicity and immunogenicity of vaccines in children.
COVID-19 VACCINE PLATFORMS
As of October 2020, over 200 vaccines were in development with over 40 vaccines in adult clinical trials . To accelerate and harmonize U.S. vaccine development efforts, OWS adopted a strategy to advance eight vaccine candidates in parallel based on one of four vaccine platforms deemed most likely to be safe and effective. These platforms include mRNA, replication-defective live-viral vectors, attenuated replicating live-viral vectors and adjuvanted protein subunit vaccines. In this manner, OWS sought a diverse portfolio of vaccine candidates to mitigate risk of failure and to maximize the likelihood of developing and distributing 300 million doses of a successful vaccine candidate by mid-2021 [8▪].
All of these leading vaccine candidates are focused on generating an immune response to the immunodominant SARS-CoV-2 spike (S) protein and are summarized below (Table 1) [8▪,31▪,32,34▪▪,35,36,37▪▪,38▪▪,39,40▪▪,41▪▪,42]. Notably, the phase 3 clinical trial of the Pfizer candidate mRNA vaccine recently was expanded down to include children 12–17 years of age.
Table 1 -
Vaccines moving rapidly into phase 3 clinical trials in adults through Operation Warp Speed Funding
||Status early October
||Other vaccines using technology
||Nearly 30,000 enrolled in phase 3 study
||Greater with the second than the first dose
||Rapid manufacturing and scale-up2 doses
||Nearly 40,000 enrolled in phase 3 study, enrollment expanded to include 12–17 year olds
||Greater with the second than the first dose
||Rapid manufacturing and scale-up2 doses
|Replication-defective live-viral vector
||Chimpanzee adenovirus-Spike protein
||Phase 3 on hold in the United States because of a case of transverse myelitis
||Greater with the first than the second dose
||Rapid manufacturing and scale-up2 dosesPreexisting immunity to the viral vector may attenuate immunogenicity
||Zabdeno (Ad26.ZEBOV) for Zaire Ebola (licensed in Europe)
||Adenovirus 26-Spike protein
||Recently began enrolling phase 3 study
||Rapid manufacturing and scale-up1 dosePreexisting immunity to the viral vector may attenuate immunogenicity
||Zabdeno (Ad26.ZEBOV) for Zaire Ebola (Iicensed in Europe)
|Recombinant-subunit-adjuvanted protein vaccines
||Phase 3 anticipated to begin in the last quarter of 2020
||Greater with the second than the first dose.
||Slower manufacturing2 dosesProtein platform is established but with adjuvant
||Multiple pediatric vaccines use protein based (e.g. DTaP and PCV13)
||Phase 3 anticipated to begin in the last quarter of 2020
||No data available
||Slower manufacturing2 dosesProtein platform is established but with adjuvant
||Multiple pediatric vaccines use protein based (e.g. DTaP and PCV13)
||No published data available
Note: Attenuated replicating live-vector platform vaccines have not been announced.
VACCINE DEVELOPMENT DURING THE COVID-19 PANDEMIC
Traditionally, each stage of vaccine development, including the exploratory stage, preclinical trials, clinical trials, regulatory review and approval, and manufacturing, occurs in sequential order. For COVID-19, the phases of vaccine development have occurred in parallel with simultaneous manufacturing scale-up owing to financial support by OWS (at risk). Similar to the development and licensure of new drugs, vaccines must progress through a series of three clinical trial phases before licensure (Fig. 1). During phase I trials, small numbers of healthy participants are enrolled to evaluate the initial safety and reactogenicity of the vaccine and to begin to determine the dose. Phase II trials evaluate safety and immunogenicity in hundreds of participants, and determine the final dose and schedule. In phase III trials, vaccine is given to thousands of participants and is tested for efficacy (e.g. does it work?) and safety. These are typically randomized, controlled, double-blind studies. Ensuring safety of participants is paramount, and strict halting criteria are in place at each phase of vaccine trials.
Despite the promising safety and immunogenicity data reported in adults, clinical trials have not been initiated in U.S. children. Given the potential direct and indirect benefits of pediatric COVID-19 vaccination, pediatric clinical trials are acutely needed [43▪,44]. Critical features of these trials will include determining the safety, reactogenicity and immunogenicity of the vaccine in children, which may differ from adults. Children have differences in their size, fat distribution, muscle mass and other factors that could all impact dosing. Such trials would start with small numbers of older children at a low dose. As data about safety and reactogenicity in children are established, the age of children able to enroll in the trial would decrease and dose of vaccine would increase toward the adult dose. Ensuring informed consent about the potential risks of joining the study is critical, and safety data from the large phase 3 adult studies would need to continuously inform and potentially modify initial pediatric studies.
POTENTIAL COVID-19 VACCINE SAFETY CONCERNS IN CHILDREN
Any SARS-CoV-2 vaccine must meet high safety standards, as a vaccine would be administered to healthy individuals. Vaccine safety is commonly confused with vaccine reactogenicity, but they are usually different. Reactogenicity is self-limited, treatable and reflects a normal innate immune response to antigen exposure that generates an adaptive immune response. As expected, published data show that COVID-19 vaccines have transient local (e.g. pain, redness, swelling and induration) and systemic (e.g. fever, chills, myalgia and headache) reactogenicity [34▪▪,37▪▪,40▪▪]. In contrast, safety events carry with them risk of long-term implications. One potential important safety event has occurred to date, a case of suspected transverse myelitis that occurred in a recipient of AstraZeneca's nonreplicating chimpanzee adenovirus vectored vaccine. Although the AstraZeneca trial resumed in the United Kingdom following assessment of the event, the U.S. study remains on hold pending FDA review at the time of this article being written.
Another potential safety concern that has been raised regarding SARS-CoV-2 vaccines in general is the potential for vaccine-enhanced disease, as was observed in animal models of some SARS-CoV-1, MERS and other respiratory viral vaccine candidates . Vaccine-enhanced disease is associated with two different syndromes: vaccine-associated enhancement of respiratory disease (VAERD) and antibody-dependent enhancement (ADE) of infection . VAERD was first observed in vaccine trials of a formalin-inactivated respiratory syncytial virus vaccine in the 1960s . This enhanced respiratory illness was likely associated with nonneutralizing antibodies and a predominantly Th2-biased immune response resulting in allergic inflammation [46,48]. ADE has been best described following natural dengue virus infection or dengue vaccination because of the generation of nonneutralizing antibodies to heterologous dengue strains, mediating increased viral entry into host cells . To minimize the risk of vaccine-enhanced disease, it is thought that candidate vaccines will need to induce high levels of neutralizing antibodies and generate a Th1-biased response (instead of Th2) to avoid allergic inflammation. These criteria are now benchmarks in the safety evaluation of COVID-19 vaccine candidates advancing through development and COVID-19 vaccines entering phase 3 clinical trials meet these requirements [34▪▪,37▪▪,40▪▪,45]. In addition, available data suggest that vaccines prevent COVID-19 in a nonhuman primate challenge model without enhancement of disease [31▪,32]. Although VAERD has not been observed in early clinical trials, safety data from large phase III trials and postlicensure vaccine safety monitoring will be needed to evaluate for small increases in risk [34▪▪,37▪▪,40▪▪,45].
Finally, some speculate that MIS-C could occur in children receiving COVID-19 vaccines because of the hypothesis of aberrant immune-mediated pathogenesis of MIS-C associated with natural SARS-CoV-2 infection [15,50]. An effective COVID-19 vaccine would likely prevent SARS-CoV-2 infection, and thereby prevent MIS-C. It will be important to evaluate MIS-C as a potential COVID-19 vaccine safety outcome through established postlicensure vaccine safety monitoring systems.
VACCINE SAFETY MONITORING SURVEILLANCE
Even with the very large phase 3 clinical trials that are being conducted (e.g. 30,000 enrolled in the adult trials), it is not possible to exclude the risk of very rare safety events (e.g. those observed less frequently than 1/10,000). Postmarket vaccine safety monitoring surveillance can detect and evaluate rare adverse events not identified in prelicensure clinical trials. In the United States, the CDC has three long-standing vaccine safety programs: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD) and the Clinical Immunization Safety Assessment (CISA). VAERS, a national early warning system designed to detect possible safety problems, is a passive reporting system allowing anyone to report a potential adverse event . Although VAERS can rapidly detect very rare adverse events (e.g. a 1/10,000 risk of intussusception after RotaShield), it generally cannot assess causality because of its limitations (e.g. no comparison groups and no denominators) [52,53]. The VSD is a collaborative active surveillance project between the CDC and nine healthcare organizations which have extensive experience in conducting population-based vaccine safety studies on new vaccines for emerging public health problems. VSD's strengths include flexibility in study design, highly accurate vaccination data and the capacity for manual review of electronic records. CISA serves as a resource for U.S. healthcare providers with specific vaccine safety questions to assist with immunization decision making .
FDA VACCINE LICENSURE
Vaccines are licensed based on Food and Drug Administration (FDA) review of Biologic License Applications submitted by vaccine manufacturers with a full risk-benefit analysis. In addition, the FDA's Center for Biologics Evaluation and Research (CBER) makes decisions regarding approvals and emergency use authorizations (EUAs) for COVID-19 vaccines. This process has been supported by the Vaccines and Related Biological Products Advisory Committee (VRBPAC), consisting of nongovernment experts, which provides transparent discussion . Review of all phases of vaccine clinical trial data by the FDA is ongoing. Although an EUA could be made by the FDA without efficacy data, prominent vaccine manufacturers recently released a joint statement that they will only seek FDA approval for data ‘…demonstrating safety and efficacy through a phase 3 clinical study that is designed and conducted to meet requirements of expert regulatory authorities such as FDA .’
THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES AND CENTERS FOR DISEASE CONTROL AND PREVENTION RESPONSES
The Advisory Committee on Immunization Practices (ACIP) is a federal advisory committee that provides expert advice and guidance to the CDC in the form of recommendations on use of FDA licensed vaccines for the control of vaccine-preventable diseases [57,58]. The ACIP consists of 15 voting members that hold regular meetings to review scientific data and vote on vaccine recommendations. ACIP has discussed key issues related to COVID-19 vaccines, including the epidemiology of COVID-19, vaccine safety and immunogenicity, enhanced postlicensure vaccine safety surveillance, vaccine prioritization and distribution. Implementation issues may vary depending on each type of vaccines (e.g. one vs. two-dose series, vaccine efficacy and safety profile in different populations, cold-chain requirements), and include prioritization of high-risk populations, allocation of vaccine, vaccine distribution and vaccine administration. ACIP is developing recommendations on vaccine prioritization, as vaccine availability will initially be limited. Currently proposed groups to receive early-phase vaccination include healthcare personnel, essential workers, persons with high-risk medical conditions and adults above 65 years of age. The Vaccines for Children (VFC) program provides all routine vaccines recommended by the ACIP at no cost to eligible children through enrolled healthcare providers . Children ages 18 years or younger who meet at least one of the following requirements are eligible: American Indian or Alaska Native, Medicaid-eligible, uninsured or underinsured. VFC substantially increased access to pediatric vaccinations across the country and has reduced racial and ethnic disparities in vaccine uptake among children . Because of established programs such as the VFC and because of pediatricians’ longitudinal relationships and pivotal role in child and community health, pediatricians are positioned to distribute and administer any SARS-CoV-2 vaccine that is found to be safe and effective.
THE PUBLIC VACCINATION ACCEPTANCE
Although the clinical development of COVID-19 vaccines has progressed at warp speed, a vaccine dose that remains in its vial does not provide benefit. Public vaccination acceptance is closely associated with vaccination confidence and hesitancy. Transparency and consistency of vaccine recommendations are paramount for the public confidence. The CDC's ACIP provides evidence-based recommendations of vaccinations using a consistent and transparent framework . ACIP's discussion and materials are publicly available. On the basis of evidence-based knowledge and information on disease burden and vaccine safety and efficacy, the individual recommendations of vaccination by pediatricians and other healthcare providers are critical . The American Academy of Pediatrics called upon the U.S. Department of Health and Human Services and FDA to discuss the need for COVID-19 vaccine trials in children and to ensure that a transparent approach is taken to maintain public confidence in vaccines .
Children of all ages are at risk for SARS-CoV-2 infection and severe disease manifestations. A pediatric COVID-19 vaccine could confer both medical and nonmedical benefits to children and interrupt community transmission. In light of the positive safety and immunogenicity results of recent adult COVID-19 vaccine clinical trials, we discuss the need for initial pediatric clinical trials to begin in parallel with ongoing adult phase 3 clinical trials. The support and recommendations of pediatricians will be integral for the success of any COVID-19 vaccine that is ultimately licensed.
Financial support and sponsorship
Conflicts of interest
All three investigators have received federal funding from NIAID to their institution to conduct phase I and III clinical trials in adults.
EJA has received personal fees from AbbVie, Pfizer and Sanofi Pasteur for consulting, and his institution receives funds to conduct clinical research unrelated to this article from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Novavax, Sanofi-Pasteur, Janssen and Micron. He also serves on a safety monitoring board for Kentucky BioProcessing, Inc.
CAR's institution has received funds to conduct clinical research unrelated to this article from BioFire Inc, MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Novavax, Sanofi-Pasteur, Janssen and Micron. She is also coinventor on patented RSV vaccine technology unrelated to this article, which has been licensed to Meissa Vaccines, Inc.
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