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Cited by 55SARS-CoV-2 and COVID-19 ResearchVaccine Coverage and HesitancyCOVID-19 Clinical Research Studies

The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index; none of the 42 sources its claims cite is checked for support yet.

SARS-CoV-2 vaccine testing and trials in the pediatric population: biologic, ethical, research, and implementation challenges

Open access
Cooper, Dan M., Afghani, Behnoush, Byington, Carrie L., Cunningham, Coleen K., Golub, Sidney, Lu, Kim D., Radom-Aizik, Shlomit, Ross, Lainie Friedman, Singh, Jasjit, Smoyer, William E., Lucas, Candice Taylor, Tunney, Jessica, Zaldivar, Frank, Ulloa, Erlinda R.·2021·Pediatric Research
DOI 10.1038/s41390-021-01402-zPMC PMC7903864
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Abstract

As the nation implements SARS-CoV-2 vaccination in adults at an unprecedented scale, it is now essential to focus on the prospect of SARS-CoV-2 vaccinations in pediatric populations. To date, no children younger than 12 years have been enrolled in clinical trials. Key challenges and knowledge gaps that must be addressed include (1) rationale for vaccines in children, (2) possible effects of immune maturation during childhood, (3) ethical concerns, (4) unique needs of children with developmental disorders and chronic conditions, (5) health inequities, and (6) vaccine hesitancy. Because COVID-19 is minimally symptomatic in the vast majority of children, a higher acceptable risk threshold is required when evaluating pediatric clinical trials. Profound differences in innate and adaptive immunity during childhood and adolescence are known to affect vaccine responsiveness for a variety of childhood diseases. COVID-19 and the accompanying social disruption, such as the school shutdowns, has been disproportionately damaging to minority and low-income children. In this commentary, we briefly address each of these key issues, specify research gaps, and suggest a broader learning health system approach to accelerate testing and clinical trial development for an ethical and effective strategy to implement a pediatric SARS-CoV-2 vaccine as rapidly and safely as possible. As the US begins an unprecedented implementation of SARS-CoV-2 vaccination, substantial knowledge gaps have yet to be addressed regarding vaccinations in the pediatric population. Maturational changes in the immune system during childhood have influenced the effectiveness of pediatric vaccines for other diseases and conditions, and could affect SARS-CoV-2 vaccine responsiveness in children. Given that COVID-19 disease is far milder in the majority of children than in adults, the risk–benefit of a pediatric SARS-CoV-2 vaccine must be carefully weighed. The needs of children with developmental disabilities and with chronic disease must be addressed. Minority and low-income children have been disproportionately adversely affected by the COVID-19 pandemic; care must be taken to address issues of health equity regarding pediatric SARS-CoV-2 vaccine trials and allocation. Research and strategies to address general vaccine hesitancy in communities must be addressed in the context of pediatric SARS-CoV-2 vaccines. As the US begins an unprecedented implementation of SARS-CoV-2 vaccination, substantial knowledge gaps have yet to be addressed regarding vaccinations in the pediatric population. Maturational changes in the immune system during childhood have influenced the effectiveness of pediatric vaccines for other diseases and conditions, and could affect SARS-CoV-2 vaccine responsiveness in children. Given that COVID-19 disease is far milder in the majority of children than in adults, the risk–benefit of a pediatric SARS-CoV-2 vaccine must be carefully weighed. The needs of children with developmental disabilities and with chronic disease must be addressed. Minority and low-income children have been disproportionately adversely affected by the COVID-19 pandemic; care must be taken to address issues of health equity regarding pediatric SARS-CoV-2 vaccine trials and allocation. Research and strategies to address general vaccine hesitancy in communities must be addressed in the context of pediatric SARS-CoV-2 vaccines.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This commentary identifies biologic, ethical, research, and implementation challenges for SARS-CoV-2 vaccine testing and trials in children, noting that no children younger than 12 years had been enrolled in clinical trials as of early 2021. It argues for phased pediatric trials and vaccination, attention to equity and special-needs populations, and a learning health system approach to accelerate ethical and effective implementation.

Key findings

  • As of 7 January 2021, more than 2.3 million children in the USA had been infected with SARS-CoV-2; pediatric hospitalization rates are similar to influenza, and influenza vaccination reduces influenza-associated death by 50–66%. Because COVID-19 is minimally symptomatic in most children, a higher acceptable risk threshold is required for pediatric trials.
  • More than 180 SARS-CoV-2 candidate vaccines were in development, with 48 in clinical evaluation as of 12 November 2020; the two furthest-along candidates used an mRNA platform and reported >94% efficacy. Immune maturation and environmental factors such as childhood obesity and physical inactivity may affect vaccine responsiveness.
  • Children under 12 years had not been enrolled in COVID-19 vaccine trials; minority and low-income children were disproportionately affected by the pandemic. One in 5 US children has a vaccine-hesitant parent, with an 11.9 percentage point higher prevalence of hesitancy about childhood shots and 9.9 percentage point higher concern about serious long-term side effects among parents of black compared with white children.
  • The authors propose a phased pediatric vaccination program starting with ages 12–17 years, addressing special-needs and chronic-disease populations, and establishing regional/national learning health systems for pediatric vaccine trials and implementation.

Methods

  • Commentary/position paper by a group of frontline healthcare providers, ethicists, community representatives, and translational researchers; no primary data collection or systematic review.
  • Synthesizes published literature, public data, and expert discussion around seven issues: rationale for pediatric vaccination, immune maturation, ethics, special needs, health inequities, vaccine hesitancy, and research/outreach strategies.
  • Includes Table 1 listing key knowledge gaps and proposes a learning health system model for pediatric SARS-CoV-2 vaccine testing and implementation.

Limitations

  • No formal limitations section is stated in the paper.
  • As a commentary, it does not report original data, a systematic search, or quantitative synthesis; its recommendations are expert opinion rather than empirically tested in this paper.
  • Evident from the text: the analysis reflects the vaccine landscape and evidence available in early 2021, and some cited sources are news reports, agency data, and preprints/publications that may be time-sensitive.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41390-021-01402-z

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 42 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The hospitalization rate in children infected with COVID-19 is similar to that for influenza.

    “The hospitalization rate in children infected with COVID-19 is similar to that for influenza,5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Song, X. et al. Comparison of clinical features of COVID-19 vs seasonal influenza A and B in US children. JAMA Netw. Open 3, e2020495 (2020). source
  • Premisecitation

    Pediatric COVID-19 hospitalization rates have increased dramatically in recent months in many states.

    “pediatric COVID-19 hospitalization rates have increased dramatically in recent months in many states, raising concerns that medical resources suited for children may not be available as needed.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Levin, Z., Choyke, K., Georgiou, A., Sen, S. & Karaca-Mandic, P. Trends in pediatric hospitalizations for coronavirus disease 2019. JAMA Pediatr. https://doi.org/10.1001/jamapediatrics.2020.5535 (2021). source
  • Premisecitation

    Development of effective vaccines in newborns and young children for respiratory syncytial virus, diarrheal diseases, and tuberculosis has proved challenging.

    “the development of effective vaccines in newborns and young children for a variety of diseases [e.g., respiratory syncytial virus,19 diarrheal diseases,20 tuberculosis21] has proved challenging.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Rossey, I., Saelens, X. Vaccines against human respiratory syncytial virus in clinical trials, where are we now? Expert Rev. Vaccines 18, 1053–1067 (2019). source
    • cites [20] Mokomane, M., Kasvosve, I., de Melo, E., Pernica, J. M. & Goldfarb, D. M. The global problem of childhood diarrhoeal diseases: emerging strategies in prevention and management. Ther. Adv. Infect. Dis. 5, 29–43 (2018). source
    • cites [21] Schrager, L. K., Vekemens, J., Drager, N., Lewinsohn, D. M. & Olesen, O. F. The status of tuberculosis vaccine development. Lancet Infect. Dis. 20, e28–37 (2020). source
  • Premisenone given

    The immune system of children differs from that of adults in many ways.

    “The immune system of children differs from adults in many ways.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Non-pharmaceutical interventions are effective in children.

    “Non-pharmaceutical interventions (NPI) are effective in children with evidence mounting from schools and summer camps.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Blaisdell, L. L., Cohn, W., Pavell, J. R., Rubin, D. S. & Vergales, J. E. Preventing and mitigating SARS-CoV-2 transmission—four overnight camps, Maine, June–August 2020. MMWR Morb. Mortal. Wkly Rep. 69, 1216–20 (2020). source
  • The quote only partly states this claim. 1
  • It may state two separate claims as one. 7
  • Probably not a substantial claim. 8

  • The quote only partly states this claim.

    Interpretationreasoning

    Childhood vaccination protects adults by reducing transmission from children.

    “Childhood vaccination not only protects young children and adolescents from disease but also protects adults.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Children can be a source of transmission of SARS-CoV-2 to each other and to adult family members.

    “children can be a source of transmission of SARS-CoV-2 to each other and to adult family members.9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Laxminarayan, R. et al. Epidemiology and transmission dynamics of COVID-19 in two Indian states. Science 370, 691–697 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The scientific community has demonstrated no link between receiving vaccines and autism spectrum disorder.

    “Although the scientific community has demonstrated no link between receiving vaccines and ASD, questions about the safety of vaccines persist.36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Davidson, M. Vaccination as a cause of autism-myths and controversies. Dialogues Clin. Neurosci. 19, 403–407 (2017). source

  • It may state two separate claims as one.

    Premisecitation

    Altered immunity in obesity is associated with reduced responses to Hepatitis B and tetanus vaccines and increased susceptibility to influenza.

    “This altered immunity has been associated with suboptimal (reduced) responses to vaccines, including Hepatitis B26 and tetanus,27 and increased susceptibility to influenza.28”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] Weber, D. J., Rutala, W. A., Samsa, G. P., Santimaw, J. E. & Lemon S. M. Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine. JAMA 254, 3187–3189 (1985). source
    • cites [27] Eliakim A., Swindt C., Zaldivar F., Casali P. & Cooper D. M. Reduced tetanus antibody titers in overweight children. Autoimmunity 39, 137–141 (2006). source
    • cites [28] Green, W. D. & Beck, M. A. Obesity impairs the adaptive immune response to influenza virus. Ann. Am. Thorac. Soc. 14, S406–S409 (2017). source

  • It may state two separate claims as one.

    Premisecitation

    Obesity, irrespective of age, is associated with severe COVID-19 and may predispose to the disease.

    “There is increasing evidence that obesity, irrespective of age, is associated with severe COVID‐19, and may predispose to the disease.29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Hernández-Garduño, E. Obesity is the comorbidity more strongly associated for Covid-19 in Mexico. A case-control study. Obes. Res. Clin. Pract. 14, 375–379 (2020). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Childhood obesity is linked to physical inactivity, which is increasing in children as a result of pandemic shutdown and shelter-at-home policies.

    “Childhood obesity is linked to physical inactivity, which is increasing in children as a result of the pandemic shutdown and shelter-at-home policies.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Dunton, G. F., Do, B. & Wang, S. D. Early effects of the COVID-19 pandemic on physical activity and sedentary behavior in children living in the U.S. BMC Public Health. 20, 1351 (2020). source

  • It may state two separate claims as one.

    Premisecitation

    The mechanisms for these difficulties include the effect of maternally transferred immune factors and the immaturity of innate and adaptive immune cells.

    “The mechanisms for these difficulties include the effect of maternally transferred immune factors and the immaturity of innate and adaptive immune cells.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Basha, S., Surendran, N. & Pichichero, M. Immune responses in neonates Expert Rev. Clin. Immunol. 10, 1171–1184 (2014). source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Premisecitation

    Coalitions of community stakeholders, caregivers, parents, children, academic health centers, and data managers are core elements of successful learning health systems.

    “Coalitions of community stakeholders (e.g., local healthcare agencies and school personnel), caregivers, parents, children, academic health centers, and data managers are the core elements of successful LHS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Friedman, C. et al. Toward a science of learning systems: a research agenda for the high-functioning learning health system. J. Am. Med. Informatics Assoc. 22, 43–50 (2014). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    One in 5 children in the United States has a parent who is vaccine hesitant, and hesitancy is negatively associated with childhood influenza vaccination.

    ““One in 5 children in the United States has a parent who is vaccine hesitant, and hesitancy is negatively associated with childhood influenza vaccination.””
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Santibanez, T. A. et al. Parental vaccine hesitancy and childhood influenza vaccination. Pediatrics 146, e2020007609 (2020). source

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisenone given

    Many fundamental knowledge gaps exist that will affect the testing and implementation of SARS-CoV-2 vaccines for children.

    “Many fundamental knowledge gaps exist that will affect the testing and implementation of SARS-CoV-2 vaccines for children (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Interpretationcitation

    School mandated vaccination and exemptions from vaccination will emerge as contentious issues as pediatric COVID-19 vaccines become available.

    “School mandated vaccination and exemptions from vaccination will surely emerge as contentious issues as pediatric COVID-19 vaccines become available.3, 49”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Opel, D. J., Diekema, D. S. & Ross L. F. Should we mandate a COVID-19 vaccine for children? JAMA Pediatr. 175, 125–126 (2021). source
    • cites [49] Simon, G. R. et al. Medical versus nonmedical immunization exemptions for child care and school attendance. Pediatrics 138, e20162145 (2016). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Parents of black children have an 11.9 percentage point higher prevalence of hesitancy about childhood shots and a 9.9 percentage point higher prevalence of concerns about serious, long-term side effects compared with parents of white children.

    ““an 11.9 percentage point higher prevalence of ‘hesitant about childhood shots’ and 9.9 percentage point higher prevalence of concerns about serious, long-term side effects among parents of black compared with white children.””
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Santibanez, T. A. et al. Parental vaccine hesitancy and childhood influenza vaccination. Pediatrics 146, e2020007609 (2020). source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationcitation

    The learning health system model is well-suited for pediatric vaccine trials and implementation.

    “The LHS model50 is well-suited for this challenge.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Friedman, C. et al. Toward a science of learning systems: a research agenda for the high-functioning learning health system. J. Am. Med. Informatics Assoc. 22, 43–50 (2014). source
13 of 13

  • The paper relies on this without support.

    Hospitalization and mortality in children due to COVID-19 are lower than in adults.

    “Hospitalization and mortality in children due to COVID-19 are lower than in adults.”

  • The paper relies on this without support.

    New strains of SARS-CoV-2 are emerging which may be more infective for children and possibly more virulent.

    “Finally, new strains of SARS-CoV-2 are emerging which may be more infective for children and possibly more virulent.”

  • The paper relies on this without support.

    The current frontrunner SARS-CoV-2 vaccines require two doses given 21–28 days apart and must be stored at low temperatures.

    “This will be complicated by the need for two doses for the current frontrunner vaccines, which must be given 21–28 days apart and the vaccines must be stored at low temperatures.”

  • The paper relies on this without support.

    The infection rate and hospitalization rate of adolescents over age 12 years is at least double that of younger children.

    “the infection rate and hospitalization rate of adolescents over age 12 years is at least double that of younger children”

  • The paper relies on this without support.

    NPI mitigation and prevention behaviors are not natural behaviors, particularly in children and adolescents, who tend to be physically close in their social interactions.

    “the NPI mitigation and prevention behaviors (face covering, physical distancing, hand hygiene, cohorting children in schools) are not natural behaviors, particularly in children and adolescents, who tend to be physically close in their social interactions.”

  • The paper relies on this without support.

    Reasons for under-vaccination of special groups include awareness of the need for vaccination, fear of adverse outcomes or illness caused by the vaccine, and in some settings, cost.

    “Reasons for under-vaccination of special groups include awareness of the need for vaccination, fear of adverse outcomes or illness caused by the vaccine, and in some settings, cost.”

  • The paper relies on this without support.

    Healthcare providers can also contribute to attitudes through their own hesitancy to vaccinate children with special needs or chronic disease.

    “Healthcare providers can also contribute to attitudes through their own hesitancy to vaccinate children with special needs or chronic disease.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Vaccination of adolescents will allow them to reintegrate into society and resume in-person learning safely.

    “Vaccination of adolescents will allow them to reintegrate into society and resume in-person learning safely, which are especially important outcomes given the severe mental health effects of the Covid-19 pandemic on this group.18,22,26”

    From Safety, immunogenicity, and efficacy of the BNT162b2 covid-19 vaccine in adolescents (2021) · cites this paper as [22]

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Metadata

Authors
Cooper, D. M., Afghani, B., Byington, C. L., Cunningham, C. K., Golub, S., Lu, K. D., Radom-Aizik, S., Ross, L. F., Singh, J., Smoyer, W. E., Lucas, C. T., Tunney, J., Zaldivar, F., & Ulloa, E. R.
Affiliations
  • University of California, Irvine (US)
  • University of California System (US)
  • Duke University (US)
  • University of Chicago (US)
  • Children's Hospital of Orange County (US)
  • Nationwide Children's Hospital (US)
  • Florida Department of Health in Orange County (US)
Corresponding author
Ulloa, Erlinda R.
ORCID
Venue
Pediatric Research
Publisher
Springer Science and Business Media LLC
Published
2021-02-24
Volume
90
Issue
5
Pages
966-970
ISSN
  • 0031-3998 (ISSN-L)
  • 1530-0447
DOI
10.1038/s41390-021-01402-z
PMC
PMC7903864
OpenAlex
W3129888978
Semantic Scholar
b6c42609b5808da964571383c8049e27bc8937f9
Cited by
55
References
45
Citations by year
2026: 2 · 2024: 3 · 2023: 24 · 2022: 10 · 2021: 16
FWCI
4.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Pediatric Research (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Robert Wood Johnson Foundation
  • National Institutes of Health (UL1TR001414, KL2TR001416)
  • National Institute of Allergy and Infectious Diseases (K08AI151253)
  • National Center for Advancing Translational Sciences (TR001414)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Social Sciences › Health › Vaccine Coverage and Hesitancy
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
COVID-19 vaccines, COVID-19 vaccination, pediatric clinical trials, children under 12, immune system maturation, vaccine hesitancy, health equity, children with developmental disabilities, children with chronic illness, research ethics, learning health systems, risk-benefit assessment, vaccine allocation
MeSH terms
Immunogenicity, Vaccine, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Vaccine Efficacy, Vaccination Hesitancy, Age Factors, Clinical Trials as Topic, Humans, Pediatrics, Public Opinion, Research Design, Risk Factors, Vaccination, Treatment Outcome, Risk Assessment, Host-Pathogen Interactions, Patient Safety

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