key: cord-0852520-1wjvxov3
authors: L’Huillier, Arnaud G.; Ardura, Monica I.; Chaudhuri, Abanti; Danziger‐Isakov, Lara; Dulek, Daniel; Green, Michael; Michaels, Marian G.; Posfay‐Barbe, Klara M.; Vàsquez, Luciola; Benden, Christian
title: COVID‐19 vaccination in pediatric solid organ transplant recipients—Current state and future directions
date: 2021-06-02
journal: Pediatr Transplant
DOI: 10.1111/petr.14031
sha: f334955d4743d2ac70ee68c4c20c860221f31cfb
doc_id: 852520
cord_uid: 1wjvxov3

BACKGROUND: Population‐level COVID‐19 immunization will play a key role in slowing down the SARS‐CoV‐2 pandemic on a global scale and protect the most at‐risk individuals. Thanks to a formidable universal effort, several SARS‐CoV‐2 vaccines have been marketed less than a year since the first documented COVID‐19 case, with promising safety, efficacy, and immunogenicity results in adults. As children were not included in the initial trials, no vaccine is currently approved for individuals <16 years of age. Similarly, immunosuppressed individuals, such as solid organ transplant recipients, were excluded from initial vaccine trials, limiting the understanding of vaccine immunogenicity and safety in this at‐risk population. Thus, data regarding COVID‐19 vaccination in pediatric solid organ transplantation recipients are currently lacking. METHODS: Members of the International Pediatric Transplant Association review the current general status of COVID‐19 vaccines focusing on pediatric‐specific issues. RESULTS: This review provides an overview of COVID‐19 vaccines in pediatric SOT recipients and highlights the current paucity of data in both pediatric and transplant settings in terms of safety, immunogenicity, and clinical efficacy. CONCLUSIONS: Vaccine trials including children and transplant recipients are underway and will be necessary to characterize COVID‐19 vaccine safety, immunogenicity, and efficacy, which will determine potential future research directions.

in the United Kingdom (UK); an astonishing feat due to collaboration between governments, industry, and academia. However, so far, no vaccine has been approved for use in individuals <16 years old (yo) as children were not included in the initial clinical trials. Further, immu- vaccines focusing on pediatric-specific issues and provide an outlook on COVID-19 vaccination after pediatric SOT and potential future vaccine research directions. As an international group of pediatric transplant specialists from across different continents, we emphasize the overall importance of a collaborative international effort to tackle this global pandemic for the benefit of our patients across the globe. 5 For the purpose of this commentary, pediatric patients refer to individuals <18 years. As additional data emerge in pediatric immunocompromised patients, recommendations may change.

Current vaccines employ a range of strategies and include mRNAbased, subunit with or without adjuvants, replication-deficient viral vectors, inactivated or live virus, and DNA platforms. Broad variability exists across the globe in the assessment, approval, and availability of potential vaccines ( 16 Additional studies are under consideration including children as young as 6 months old, but these are in the planning stages. Pediatric immunocompromised patients and SOT recipients were not included in these studies.

So far, only the Pfizer vaccine is approved in patients <18 yo, with a lower age limit of 16 yo. In the large-scale phase 3 placebocontrolled trial, adverse events (AEs) in vaccinees were mostly mild to moderate, with serious AEs only rarely reported. 8 Local AEs mainly consisted of pain at injection site, whereas systemic AEs mainly consisted of fatigue, headache, and muscle pain, with respective rates of 78-83%, 47-59%, 42-52%, and 21-37% in participants 16-55 yo. 8 In general, local and systemic AEs were more frequent in patients <55 yo than in older patients. 8 Regarding anaphylaxis, early reports suggested an incidence of 1/100 000 doses; however, with expanded administration, it appears to be similar to other vaccinations with 2-3 events per 1 000 000 doses. 17, 18 Although SOT recipients have been excluded from recently published COVID-19 vaccine trials, very early data indicate that mRNAbased COVID-19 vaccines are safe in adult SOT recipients. 19 This agrees with the generally similar safety profile of inactivated vaccines in immunocompromised and immunocompetent individuals. 20 As with any recently marketed vaccine, concerns about vaccineinduced allograft rejection or induction of donor-specific antibodies arise although no currently marketed vaccine has been clearly associated with allograft rejection. 21, 22 Indeed, among 187 SOT patients who received the mRNA-based COVID-19 vaccine, none developed acute cellular rejection. 19 Altogether, the overall safety profile as well as the potential associations with allograft rejection will have to be carefully evaluated in SOT recipients receiving COVID-19 vaccines.

Based on experience with other inactivated vaccines, mRNAbased vaccines are anticipated to be as safe in children as in individuals ≥16-18 yo.

Based on experience with other inactivated vaccines, the mRNAbased vaccines are expected to be as immunogenic in children as in individuals ≥16 yo. COVID-19 vaccines have been successful at both eliciting a robust SARS-CoV-2-specific immune response and preventing overall and severe COVID-19, 8, 9, 23, 24 but data on healthy children, pediatric SOT recipients, or otherwise immunocompromised children are lacking. 25 Importantly, transplanted children demonstrate decreased immunogenicity to various vaccines compared with healthy children. 26 Therefore, it is very likely that transplanted children will have diminished immune responses to COVID-19 vaccines, although the extent of this impairment is currently unknown.

Impaired antibody development following confirmed COVID-19 illness in one study of adult SOT recipients highlights the concern that SOT-associated COVID-19 vaccine immunogenicity impairment will be a challenge. 27 Determining correlates of protection after both acute COVID-19

or vaccination and threshold values for these correlates will be useful for reliably evaluating COVID-19 vaccine immunogenicity in future studies of transplanted children. 28 It will also facilitate the design and completion of vaccine clinical trials in pediatric SOT recipients given the challenges of enrolling sufficient participants to perform efficacy trial(s). In addition, initial immunobridging data from adult SOT cohorts may provide additional context for pediatric recommendations.

With the high concentrations of neutralizing antibodies gener- though extent and duration of protection are unknown. 40, 41 Currently 

In the near future, studies in pediatric candidates and SOT recipients are needed to guide preventive strategies for these vulnerable While awareness of the presence of these variants has been increasingly recognized recently, it is worth noting that the emergence of the D614G variant identified in early 2020 was thought to account for a substantial increase in spread through increased replication efficiency and transmissibility. 44 To date, three major SARS-CoV-2 variants have drawn attention. In August 2020, the so-called UK variant, also known as B.1.1.7 (N501Y), was initially recognized and has been associated with increased transmissibility. 45 While there has been speculation of increased virulence, this has not been confirmed at this time. 46 Moreover, this variant does not appear at present to "escape" antibody-mediated immunity from prior COVID-19 infection or immunization. 47 With continued global SARS-CoV-2 circulation in association with high rates of infection, additional variants will continue to emerge, evolve, and spread. 55, 56 Of major concern is the ongoing potential for the development of escape mutations against immunity derived from prior infection with older strains or from vaccine. In addition, immunocompromised hosts, potentially including SOT recipients, may serve as source for development of SARS-CoV-2 variants. 57 Areas of uncertainty include the relative contribution of T-cell responses to conserved peptide epitopes amongst SARS-CoV-2 variants and whether these conserved responses could mitigate the loss of antibody responsiveness described above. 58 Increased vigilance and use of molecular sequencing to fully characterize these mutations combined with the ability of newer vaccine platforms to rapidly generate updated vaccines for use as boosters for those previously vaccinated or in combination with the initial vaccines for those not yet vaccinated, does provide hope to minimize the impact of these variants. In the meantime, prevention strategies are the best way to limit the spread of these variants and to slow the emergence of new ones.

So far, data are still lacking about safety, efficacy, and immunogenicity of COVID-19 vaccine in pediatric SOT candidates and recipients.

However, excellent efficacy data, associated with robust vaccineassociated immune responses and a good vaccine safety profile in healthy adults, are promising signals that the currently available vaccines will be safe and effective in the pediatric transplant population.

Pediatric-and transplant-specific vaccine trials are rapidly needed to confirm the findings generated in the general population.

Paragraphs were divided between authors, with at least two authors contributing to one paragraph. Each author group performed at least one nonsystematic review of the available literature and drafted the paragraph(s) accordingly. All authors critically reviewed the final version of the manuscript.

No original data in this manuscript. 

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