The Importance of Advancing Severe Acute Respiratory Syndrome Coronavirus 2 Vaccines in Children

Abstract

While the role of children in the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains to be defined, children likely play an important role based on our knowledge of other respiratory viruses. Children are more likely to be asymptomatic or have milder symptoms and less likely to present for healthcare and be tested for SARS-CoV-2. Thus, our current estimates are likely under-representative of the true burden of SARS-CoV-2 in children. Given the potential direct benefit of a SARS-CoV-2 vaccine in children and the substantial indirect benefit through community protection, or “herd immunity,” we argue that planning and implementation of SARS-CoV-2 vaccines should include children. Furthermore, community protection occurred after widespread implementation of prior childhood vaccines against Streptococcus pneumoniae, rubella, and rotavirus. We detail considerations for vaccine clinical trials, potential barriers to the implementation of widespread vaccination and argue why children would be an ideal target population for vaccination.

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes coronavirus disease 2019 (COVID-19), first emerged in Wuhan, China, there have been more than 5.5 million cases of SARS-CoV-2 worldwide, including more than 1.6 million in the United States [1]. SARS-CoV-2 is highly transmissible between humans. Once community distancing measures are relaxed, recrudescence of SARS-CoV-2 can be expected until infection rates induce population immunity levels in excess of herd immunity thresholds, probably more than two thirds of the population infected based on the estimated basic reproduction number (R₀) [2–4]. This underscores the urgent need for a safe and effective SARS-CoV-2 vaccine. An astounding number of vaccine candidates are in various stages of development [5]. As of 22 May 2020, there were 114 vaccines in development and 10 vaccines in phase 1 or 2 clinical trials, including an mRNA-based SARS-CoV-2 vaccine (ClinicalTrials.gov Identifier NCT04283461) that went into clinical trials less than 10 weeks after the genetic sequence of the virus was released and is enrolling adults of any age [6].

Given the epidemiology of severe cases and deaths from COVID-19, it is tempting to focus vaccine development and implementation strategies on high-risk populations (eg, elderly, immunocompromised). There is a lack of discussion about moving vaccine clinical trials to children. We believe that this approach is shortsighted and fails to consider the critical importance of children in contributing to adult infectious diseases.

ILL-DEFINED BURDEN OF SARS-CoV-2 IN CHILDREN

Although pediatric cases were not reported initially during the SARS-CoV-2 pandemic, retrospective data demonstrate that children were indeed infected early on [7]. As of 26 May 2020, children aged <18 years comprised 3.5% (42 810 of 1 211 030) of all laboratory-confirmed COVID-19 cases in the United States [8] and 5.2% of COVID-19–associated hospitalizations [9]. Data from COVID-NET show that children aged <4 years account for the highest percentage of hospitalizations among pediatric patients, and the majority have at least 1 underlying medical condition [9]. Thus, similar to other respiratory pathogens (eg, influenza, respiratory syncytial virus), SARS-CoV-2 disproportionately affects the very young and old.

In general, children with COVID-19 are asymptomatic or have mild to moderate symptoms. However, there has been a recent increase in the number of children worldwide presenting with a severe inflammatory syndrome that has Kawasaki disease–like features, now termed multisystem inflammatory syndrome in children (MIS-C), in the setting of recent or past infection [10–14]. The full clinical spectrum of SARS-CoV-2 disease in children continues to evolve as more information becomes available. In a retrospective cohort study, children aged <10 years were as likely to be infected (7.4%) as the population average (6.6%) but less likely to have fever or severe symptoms [15]. Thus, children are less likely to be seen by a healthcare provider [10] and less likely to be tested. In addition, early school and daycare closures may have temporarily mitigated the disease burden in children. Until large-scale population studies are completed, the true burden of SARS-CoV-2 in children will remain unknown. As schools are considering reopening, data regarding SARS-CoV-2 seroprevalence and transmission in children are urgently needed to further the understanding of the role of children in the chain of transmission [15].

THE ROLE OF CHILDREN IN COMMUNITY TRANSMISSION AND COMMUNITY PROTECTION

Although the SARS-CoV-2 symptomatic burden is limited in children, there is likely direct benefit of a vaccine in children and substantial indirect benefit through community protection as observed with other respiratory and gastrointestinal pathogens [16]. Epidemiologic studies of other common community human coronaviruses (HCoV; eg, HKU1, NL63, 229E, OC43) and novel coronaviruses (severe acute respiratory syndrome coronavirus 1 [SARS-CoV-1], Middle East respiratory syndrome coronavirus [MERS-CoV]) may inform our understanding of SARS-CoV-2 in children. Similar to the current pandemic, children were less affected and had lower mortality during the SARS-CoV-1 and MERS-CoV outbreaks [17–19]. The BIG-LoVE study, conducted prior to emergence of SARS-CoV-2 that looked at weekly viral surveillance in Utah households, found that young children had the highest number of positive total viral episodes and longest duration of viral shedding with an average of 2 weeks [20]. Children have also been shown to have higher rates of HCoV compared with adults, and there is a higher likelihood of HCoV viral detection in households that contain young children [20, 21]. HCoV is more often asymptomatic in children compared with other viruses such as influenza. In addition, relying on hospitalization or testing rates alone underestimates the true community disease burden [20].

In addition to HCoV, children have been linked to the community spread of other respiratory and gastrointestinal pathogens. Community protection, or “herd immunity,” has been clearly demonstrated after implementation of new childhood vaccines against Streptococcus pneumoniae, rubella, influenza, rotavirus, and hepatitis A [16]. Dramatic declines in invasive pneumococcal disease (IPD) and hospitalization for IPD occurred after the introduction of 7 valent heptavalent pneumococcal conjugate vaccine in children in 2000 and again after the 13-valent pneumococcal conjugate vaccine (PCV13) in children in 2010 but before adult PCV13 vaccination [22]. Rubella and congenital rubella syndrome (CRS) were eliminated in the United States following introduction of rubella-containing vaccines into the childhood immunization schedule for both girls and boys to interrupt transmission to pregnant women [16]. In comparison, ongoing cases of CRS occurred in the United Kingdom where prepubertal girls were initially prioritized for rubella vaccination until a universal pediatric vaccination policy was adopted. Targeted vaccination of school children in Tecumseh, Michigan, during an influenza outbreak in 1968 resulted in substantial decreased community transmission compared with surrounding neighborhoods where similar strategies were not implemented [16]. Unvaccinated household contacts of influenza-vaccinated daycare children benefit, with fewer febrile respiratory illnesses, missed school days, physician visits, missed work, and physician-prescribed antibiotics [23]. After implementation of infant rotavirus vaccination in 2006, substantial decreases in both pediatric and adult hospitalizations for gastroenteritis occurred [16, 24], although unvaccinated children subsequently spread rotavirus to adults [25]. Similarly, marked declines in symptomatic adult hepatitis A infections and mortality occurred with widespread pediatric vaccination [16]. Importantly, the burden of disease and the critical role of children in transmitting each of these pathogens to adults was underappreciated until implementation of pediatric vaccination.

The impact of childhood vaccines is not surprising to those who care for children. Children are less able to control their secretions and maintain social distancing. Children have prolonged viral shedding of HCoV up to 18 days. In Italy, half of the children with SARS-CoV-2 at the Bambino Gesu Pediatric Hospital continued to have a positive SARS-CoV-2 nasopharyngeal swab at day 14, although it is unclear if this represents viable virus [20, 26, 27]. Importantly, detection of viral RNA in stool raises the possibility of SARS-CoV-2 fecal–oral transmission, particularly to caregivers [27–29]. Obviously, substantial risk exists for family and household members, but the risk is also substantial for other critical adult members of society such as grocery workers, teachers, daycare providers, and healthcare providers who have frequent contact with children.

CONSIDERATIONS FOR SARS-CoV-2 VACCINE CLINICAL TRIALS IN CHILDREN

We advocate that planning for SARS-CoV-2 vaccine clinical trials in children should begin now and studies should be implemented as soon as preliminary data are available about safety in adults from phase 2 trials. Given the potential of direct benefit to children, we believe that a phase 2 clinical trial in children would fall under a 46.405 designation by the Office for Human Research Protections. We suggest an age de-escalation approach to pediatric vaccination in order to minimize safety concerns. Based on experience with prior US Food and Drug Administration (FDA)–approved vaccines, it is likely that children can receive the same dose established for adults. Multiple clinical trials are ongoing in adults, and it is unknown at this time whether a single dose or multiple doses will be needed to generate an immune response. Preliminary results from a phase 1 study of a nonreplicating Ad5 vectored COVID-19 vaccine showed that a single dose was immunogenic 28 days postvaccination, particularly in individuals in the high-dose group [30]. In children, this may differ between younger and older children. For example, children aged <9 years who receive seasonal influenza vaccine for the first time require a booster dose [31]. Finally, we argue for the use of a placebo control, as there currently is no standard vaccine for SARS-CoV-2 to be used as a comparator. In such trials, it would be critical to determine not only whether children were protected from COVID-19 disease but also protected from infection and shedding virus. For example, inactivated polio vaccine is highly effective in protecting the central nervous system from paralytic disease but has very limited impact on fecal shedding following exposure to polio viruses, thus permitting transmission via that route in populations where fecal–oral transmission is common [32, 33].

In subsequent phase 3 trials, long-term safety will need to be established in large cohorts of children. It may be necessary to expand to non-US sites given the large number of participants required to meet study end points and also to increase the generalizability of findings to ethnically diverse populations. It may also be necessary to make the primary end point immunogenicity (eg, seroconversion defined by 4-fold change in antibody titer from baseline to the vaccine structural protein target) rather than vaccine efficacy to facilitate FDA licensure, as it is unlikely any pediatric clinical trial can be powered to demonstrate protection against symptomatic COVID-19 or hospitalization. We are presuming that a correlate of protection will be identified from adult vaccination or natural history data, allowing us the ability to determine the percentage of children who reach the “protective threshold” as a measure of protective immunity. Preliminary studies on COVID-19 hospitalized adults have shown universal antibody response within 2–3 weeks after infection, and adults vaccinated with an Ad5 vectored COVID-19 vaccine developed SARS-CoV-2–specific humoral and T-cell responses [30, 34, 35]. A critical secondary end point would include determining whether children are protected from COVID-19 infections and viral shedding (eg, microbiological detection of virus from the respiratory tract by polymerase chain reaction, immune response to nontargeted viral structural proteins), as these impact transmission.

SARS-CoV-2 VACCINE IMPLEMENTATION CHALLENGES AND THE IMPORTANCE OF PEDIATRIC VACCINATION

Widespread implementation of a SARS-CoV-2 vaccine program will be challenging. Early after licensure, there may be a limited supply of vaccine, begging the question, which individuals should be vaccinated first? Counterintuitively, it may be wisest to focus initial vaccination efforts not on the highest-risk adults (eg, elderly, immunocompromised). In general, their responses to vaccines are impaired, sometimes relying on adjuvants or higher doses of vaccine to improve efficacy (eg, high-dose influenza vaccine) [36, 37]. Additionally, due to impaired responses of the immunocompromised (eg, leukemia patients, solid organ transplant and stem cell transplant recipients), studies have been completed and are underway in these populations to improve responses through use of higher doses of vaccines for S. pneumoniae and influenza (eg, NCT01216332, NCT01525004, NCT02860039, NCT01215734, NCT03179761). In the setting of a very limited initial supply of vaccine, it may be better to focus vaccination efforts using a standard dose of vaccine on the close contacts of high-risk individuals assuming such contacts will make a more effective immune response to SARS-CoV-2 vaccines and particularly if further evidence supports the role of children in community transmission. These individuals may be better candidates for novel approaches such as long-acting monoclonal antibodies (if available).

Ultimately, postlicensure studies will be needed to understand the safety and effectiveness of a licensed vaccine. Multiple platforms can monitor vaccine safety postlicensure through passive and active surveillance systems such as Vaccine Adverse Events Reporting System, World Health Organization Uppsala Monitoring Centre, Vaccine Safety Datalink, Clinical Immunization Safety Assessment Project, and the New Vaccine Surveillance Network. Although unlikely, should children suffer a vaccine-related adverse event after licensure, they may be covered under the National Vaccine Injury Compensation Program.

POTENTIAL ISSUES THAT NEED TO BE ADDRESSED ABOUT IMPLEMENTING COVID-19 VACCINATION IN CHILDREN

Prior to implementing a SARS-CoV-2 vaccine in children, outstanding obstacles will need to be addressed. Additional information regarding current SARS-CoV-2 transmission is needed to optimize vaccine implementation strategies. It will be important to conduct serosurveys in communities impacted by COVID-19 to see what the true seroprevalence is in children. In addition, families can be surveyed to see which age groups are first affected to inform whether vaccination should first target the youngest children or school-age children.

Despite these potential barriers, we believe that widespread vaccination in children will be feasible and likely successful. There already exists a “medical home” for children to receive routine checkups (eg, at least yearly checkups in all children and more frequent visits in those aged <2 years) [31]. In addition, pediatricians’ offices have existing infrastructure for distributing and handling large quantities of vaccines (eg, freezers, refrigerators for vaccine storage, experienced staff members). Any licensed and Advisory Committee on Immunization Practices–recommended vaccine would need to be available to all children regardless of insurance or socioeconomic status, which could be achieved through the US Vaccines for Children program. Unfortunately, no similar structure exists for adults, particularly for the socioeconomic disadvantaged who are at highest risk for disease. Although controversial, there is historical precedent to mandate vaccination in children as a precursor to school attendance (eg, measles vaccination) [38].

CONCLUSIONS

Children likely play an important role in the spread of SARS-CoV-2 based on available data and by our experience with other respiratory tract infections. Additional studies could establish this link and help guide future vaccination strategies, but the extent of this link will likely remain uncertain until after vaccine implementation. In addition to clear direct benefits to children, vaccinating children would likely provide community protection. Because of these features, children should be included early in SARS-CoV-2 vaccine clinical trials. If determined to be safe and immunogenic, such vaccines should be integrated into childhood immunization programs.

Notes

Financial support. E. J.A has received personal fees from AbbVie and Pfizer 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, and Micron.

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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