[Skip to Content]
[Skip to Content Landing]

Long-term Immune Response to SARS-CoV-2 Infection Among Children and Adults After Mild Infection

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What are the long-term features of the immune response to SARS-CoV-2 in children compared with adults?

Findings  In this cohort study of 252 family clusters with COVID-19, anti–SARS-CoV-2 spike receptor-binding domain IgG persisted until 12 months after infection in all age groups, showing significant higher antibody peaks for younger individuals at every follow-up time point. Children younger than 3 years were found to develop higher levels of binding antibodies compared with adults older than 18 years.

Meaning  This study provided novel insights into the long-term features of the immune response to COVID-19 for different age classes, which could help in optimizing future COVID-19 vaccination strategies and prevention policies.


Importance  Understanding the long-term immune response against SARS-CoV-2 infection in children is crucial to optimize vaccination strategies. Although it is known that SARS-CoV-2 antibodies may persist in adults 12 months after infection, data are limited in the pediatric population.

Objective  To examine long-term anti–SARS-CoV-2 spike receptor-binding domain (S-RBD) IgG kinetics in children after SARS-CoV-2 infection.

Design, Setting, and Participants  In this single-center, prospective cohort study, patients were enrolled consecutively from April 1, 2020, to August 31, 2021, at the COVID-19 Family Cluster Follow-up Clinic, Department of Women's and Children's Health, University Hospital of Padua. A cohort of 252 COVID-19 family clusters underwent serologic follow-up at 1 to 4, 5 to 10, and more than 10 months after infection with quantification of anti–S-RBD IgG by chemiluminescent immunoassay.

Exposures  SARS-CoV-2 infection.

Results  Among 902 study participants, 697 had confirmed SARS-CoV-2 infection, including 351 children or older siblings (mean [SD] age, 8.6 [5.1] years) and 346 parents (mean [SD] age, 42.5 [7.1] years). Among 697 cases, 674 (96.7%) were asymptomatic or mild. Children had significantly higher S-RBD IgG titers than older patients across all follow-up time points, with an overall median S-RBD IgG titer in patients younger than 3 years 5-fold higher than adults (304.8 [IQR, 139.0-516.6] kBAU/L vs 55.6 [24.2-136.0] kBAU/L, P < .001). Longitudinal analysis of 56 study participants sampled at least twice during follow-up demonstrated the persistence of antibodies up to 10 months from infection in all age classes, despite a progressive decline over time.

Conclusions and Relevance  In this cohort study of Italian children and adults following SARS-CoV-2 infection different kinetics of SARS-CoV-2 antibodies were found across several age classes of individuals with asymptomatic or mild COVID-19, which could help in optimizing COVID-19 vaccination strategies and prevention policies. This work provides further evidence of sustained immune response in children up to 1 year after primary SARS-CoV-2 infection.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: May 17, 2022.

Published: July 13, 2022. doi:10.1001/jamanetworkopen.2022.21616

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Di Chiara C et al. JAMA Network Open.

Corresponding Author: Costanza Di Chiara, MD, Division of Pediatric Infectious Diseases, Department for Women’s and Children’s Health, University of Padua, Via Giustiniani 3, Padua, Italy (costanza.dichiara@phd.unipd.it).

Author Contributions: Drs Giaquinto and Di Chiara had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Padoan and Prof Giaquinto contributed as co–last authors.

Concept and design: Di Chiara, Cantarutti, Costenaro, Donà, Palma, Di Salvo, De Rossi, Giaquinto.

Acquisition, analysis, or interpretation of data: Di Chiara, Cantarutti, Costenaro, Bonfante, Cosma, Ferrarese, Cozzani, Petrara, Carmona, Liberati, Palma, Plebani, Padoan.

Drafting of the manuscript: Di Chiara, Cantarutti, Costenaro, Cosma, Ferrarese, Liberati, Padoan.

Critical revision of the manuscript for important intellectual content: Cantarutti, Costenaro, Donà, Bonfante, Cozzani, Petrara, Carmona, Palma, Di Salvo, De Rossi, Plebani, Padoan, Giaquinto.

Statistical analysis: Cantarutti, Costenaro, Padoan.

Obtained funding: Palma, Giaquinto.

Administrative, technical, or material support: Di Chiara, Bonfante, Cosma, Cozzani, Petrara, Carmona, Liberati, Palma.

Supervision: Costenaro, Donà, Palma, Di Salvo, De Rossi, Plebani, Padoan, Giaquinto.

Conflict of Interest Disclosures: Dr Palma reported receiving grants from the Chiesi Foundation to support research about immunologic aspects of long-term COVID-19 in children outside the submitted work. No other disclosures were reported.

Funding/Support: This work was partially supported by ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic). ORCHESTRA has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement 101016167.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The submission for publication was discussed with the funder.

Li  L , Zhang  W , Hu  Y ,  et al.  Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.  [published correction appears in JAMA. 2020 Aug 4;324(5):519].  JAMA. 2020;324(5):460-470. doi:10.1001/jama.2020.10044 PubMedGoogle ScholarCrossref
Suthar  MS , Zimmerman  MG , Kauffman  RC ,  et al.  Rapid generation of neutralizing antibody responses in COVID-19 patients.   Cell Rep Med. 2020;1(3):100040. doi:10.1016/j.xcrm.2020.100040 PubMedGoogle ScholarCrossref
Premkumar  L , Segovia-Chumbez  B , Jadi  R ,  et al.  The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients.   Sci Immunol. 2020;5(48):eabc8413. doi:10.1126/sciimmunol.abc8413 PubMedGoogle ScholarCrossref
Peterhoff  D , Glück  V , Vogel  M ,  et al.  A highly specific and sensitive serological assay detects SARS-CoV-2 antibody levels in COVID-19 patients that correlate with neutralization.   Infection. 2021;49(1):75-82. doi:10.1007/s15010-020-01503-7 PubMedGoogle ScholarCrossref
Padoan  A , Bonfante  F , Cosma  C ,  et al.  Analytical and clinical performances of a SARS-CoV-2 S-RBD IgG assay: comparison with neutralization titers.   Clin Chem Lab Med. 2021;59(8):1444-1452. doi:10.1515/cclm-2021-0313PubMedGoogle ScholarCrossref
Yin  Q , Zhang  Y , Lian  L ,  et al.  Chemiluminescence immunoassay based serological immunoassays for detection of SARS-CoV-2 neutralizing antibodies in COVID-19 convalescent patients and vaccinated population.   Viruses. 2021;13(8):13. doi:10.3390/v13081508 PubMedGoogle ScholarCrossref
Petersen  MS , Hansen  CB , Kristiansen  MF ,  et al.  SARS-CoV-2 natural antibody response persists for at least 12 months in a nationwide study from the Faroe Islands.   Open Forum Infect Dis. 2021;8(8):ofab378. doi:10.1093/ofid/ofab378 PubMedGoogle ScholarCrossref
Li  C , Yu  D , Wu  X ,  et al.  Author Correction: Twelve-month specific IgG response to SARS-CoV-2 receptor-binding domain among COVID-19 convalescent plasma donors in Wuhan.   Nat Commun. 2021;12(1):4846. doi:10.1038/s41467-021-25109-1 PubMedGoogle ScholarCrossref
Turner  JS , Kim  W , Kalaidina  E ,  et al.  SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans.   Nature. 2021;595(7867):421-425. doi:10.1038/s41586-021-03647-4 PubMedGoogle ScholarCrossref
Wang  Z , Muecksch  F , Schaefer-Babajew  D ,  et al.  Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection.   Nature. 2021;595(7867):426-431. doi:10.1038/s41586-021-03696-9 PubMedGoogle ScholarCrossref
Haveri  A , Ekström  N , Solastie  A ,  et al.  Persistence of neutralizing antibodies a year after SARS-CoV-2 infection in humans.   Eur J Immunol. 2021;51(12):3202-3213. doi:10.1002/eji.202149535 PubMedGoogle ScholarCrossref
Gallais  F , Gantner  P , Bruel  T ,  et al.  Evolution of antibody responses up to 13 months after SARS-CoV-2 infection and risk of reinfection.   EBioMedicine. 2021;71:103561. doi:10.1016/j.ebiom.2021.103561 PubMedGoogle ScholarCrossref
Choe  PG , Kang  CK , Kim  KH ,  et al.  Persistence of neutralizing antibody response up to 1 Year After asymptomatic or symptomatic SARS-CoV-2 infection.   J Infect Dis. 2021;224(6):1097-1099. doi:10.1093/infdis/jiab339 PubMedGoogle ScholarCrossref
Vacharathit  V , Srichatrapimuk  S , Manopwisedjaroen  S ,  et al.  SARS-CoV-2 neutralizing antibodies decline over one year and patients with severe COVID-19 pneumonia display a unique cytokine profile.   Int J Infect Dis. 2021;112:227-234. doi:10.1016/j.ijid.2021.09.021 PubMedGoogle ScholarCrossref
Dan  JM , Mateus  J , Kato  Y ,  et al.  Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.   Science. 2021;371(6529):eabf4063. doi:10.1126/science.abf4063 PubMedGoogle ScholarCrossref
Paul  LA , Daneman  N , Schwartz  KL ,  et al.  Association of age and pediatric household transmission of SARS-CoV-2 infection.   JAMA Pediatr. 2021;175(11):1151-1158. doi:10.1001/jamapediatrics.2021.2770 PubMedGoogle ScholarCrossref
Li  X , Xu  W , Dozier  M , He  Y , Kirolos  A , Theodoratou  E ; UNCOVER.  The role of children in transmission of SARS-CoV-2: A rapid review.   J Glob Health. 2020;10(1):011101. doi:10.7189/jogh.10.011101 PubMedGoogle ScholarCrossref
Yang  HS , Costa  V , Racine-Brzostek  SE ,  et al.  Association of age with SARS-CoV-2 antibody response.   JAMA Netw Open. 2021;4(3):e214302. doi:10.1001/jamanetworkopen.2021.4302 PubMedGoogle ScholarCrossref
Bonfante  F , Costenaro  P , Cantarutti  A ,  et al.  Mild SARS-CoV-2 infections and neutralizing antibody titers.   Pediatrics. 2021;148(3):e2021052173. doi:10.1542/peds.2021-052173 PubMedGoogle ScholarCrossref
Renk  H , Dulovic  A , Seidel  A ,  et al.  Robust and durable serological response following pediatric SARS-CoV-2 infection.   Nat Commun. 2022;13(1):128. doi:10.1038/s41467-021-27595-9 PubMedGoogle ScholarCrossref
Padoan  A , Bonfante  F , Pagliari  M ,  et al.  Analytical and clinical performances of five immunoassays for the detection of SARS-CoV-2 antibodies in comparison with neutralization activity.   EBioMedicine. 2020;62:103101. doi:10.1016/j.ebiom.2020.103101 PubMedGoogle ScholarCrossref
European Centre for Disease Prevention and Control.  Reinfection With SARS-CoV-2: Implementation of a Surveillance Case Definition Within the EU/EEA. ECDC; 2021.
World Health Organization. Clinical management. 2021. Accessed June 2, 2022. https://apps.who.int/iris/bitstream/handle/10665/338871/WHO-2019-nCoV-clinical-web_annex-2021.1-eng.pdf
Ireland  G , Jeffery-Smith  A , Zambon  M ,  et al.  Antibody persistence and neutralising activity in primary school students and staff: prospective active surveillance, June to December 2020, England.   EClinicalMedicine. 2021;41:101150. doi:10.1016/j.eclinm.2021.101150 PubMedGoogle ScholarCrossref
Bloise  S , Marcellino  A , Testa  A ,  et al.  Serum IgG levels in children 6 months after SARS-CoV-2 infection and comparison with adults.   Eur J Pediatr. 2021;180(11):3335-3342. doi:10.1007/s00431-021-04124-w PubMedGoogle ScholarCrossref
Röltgen  K , Powell  AE , Wirz  OF ,  et al.  Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome.   Sci Immunol. 2020;5(54):eabe0240. doi:10.1126/sciimmunol.abe0240 PubMedGoogle ScholarCrossref
Cotugno  N , Ruggiero  A , Bonfante  F ,  et al; CACTUS Study Team.  Virological and immunological features of SARS-CoV-2-infected children who develop neutralizing antibodies.   Cell Rep. 2021;34(11):108852. doi:10.1016/j.celrep.2021.108852 PubMedGoogle ScholarCrossref
Yang  F , Nielsen  SCA , Hoh  RA ,  et al.  Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues.   Science. 2021;372(6543):738-741. doi:10.1126/science.abf6648 PubMedGoogle ScholarCrossref
Ng  KW , Faulkner  N , Cornish  GH ,  et al.  Preexisting and de novo humoral immunity to SARS-CoV-2 in humans.   Science. 2020;370(6522):1339-1343. doi:10.1126/science.abe1107 PubMedGoogle ScholarCrossref
Scepanovic  P , Alanio  C , Hammer  C ,  et al; Milieu Intérieur Consortium.  Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines.   Genome Med. 2018;10(1):59. doi:10.1186/s13073-018-0568-8 PubMedGoogle ScholarCrossref
Márquez-González  H , López-Martínez  B , Parra-Ortega  I ,  et al.  Analysis of the behaviour of immunoglobulin G antibodies in children and adults convalescing from severe acute respiratory syndrome-coronavirus-2 infection.   Front Pediatr. 2021;9(9):671831. doi:10.3389/fped.2021.671831 PubMedGoogle ScholarCrossref
Weisberg  SP , Connors  TJ , Zhu  Y ,  et al.  Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum.   Nat Immunol. 2021;22(1):25-31. doi:10.1038/s41590-020-00826-9 PubMedGoogle ScholarCrossref
Rosati  M , Terpos  E , Ntanasis-Stathopoulos  I ,  et al.  Sequential analysis of binding and neutralizing antibody in COVID-19 convalescent patients at 14 months after SARS-CoV-2 infection.   Front Immunol. 2021;12:793953. doi:10.3389/fimmu.2021.793953 PubMedGoogle ScholarCrossref
Xiao  K , Yang  H , Liu  B ,  et al.  Antibodies can last for more than 1 year after SARS-CoV-2 infection: a follow-up study from survivors of COVID-19.   Front Med (Lausanne). 2021;8:684864. doi:10.3389/fmed.2021.684864 PubMedGoogle ScholarCrossref
Li  K , Huang  B , Wu  M ,  et al.  Dynamic changes in anti-SARS-CoV-2 antibodies during SARS-CoV-2 infection and recovery from COVID-19.   Nat Commun. 2020;11(1):6044. doi:10.1038/s41467-020-19943-y PubMedGoogle ScholarCrossref
Luo  H , Camilleri  D , Garitaonandia  I ,  et al.  Kinetics of anti-SARS-CoV-2 IgG antibody levels and potential influential factors in subjects with COVID-19: a 11-month follow-up study.   Diagn Microbiol Infect Dis. 2021;101(4):115537. doi:10.1016/j.diagmicrobio.2021.115537 PubMedGoogle ScholarCrossref
Choe  PG , Kim  KH , Kang  CK ,  et al.  Antibody responses one year after mild SARS-CoV-2 infection.   J Korean Med Sci. 2021;36(21):e157. doi:10.3346/jkms.2021.36.e157 PubMedGoogle ScholarCrossref
Lau  EH , Hui  DS , Tsang  OT ,  et al.  Long-term persistence of SARS-CoV-2 neutralizing antibody responses after infection and estimates of the duration of protection.   EClinicalMedicine. 2021;41:101174. doi:10.1016/j.eclinm.2021.101174 PubMedGoogle ScholarCrossref
Khoury  DS , Cromer  D , Reynaldi  A ,  et al.  Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.   Nat Med. 2021;27(7):1205-1211. doi:10.1038/s41591-021-01377-8 PubMedGoogle ScholarCrossref
Petrara  MR , Bonfante  F , Costenaro  P ,  et al.  Asymptomatic and mild SARS-CoV-2 infections elicit lower immune activation and higher specific neutralizing antibodies in children than in adults.   Front Immunol. 2021;12:741796. doi:10.3389/fimmu.2021.741796 PubMedGoogle ScholarCrossref
Zuo  J , Dowell  AC , Pearce  H ,  et al.  Robust SARS-CoV-2-specific T cell immunity is maintained at 6 months following primary infection.  [published correction appears in Nat Immunol. 2021 Jul;22(7):928].  Nat Immunol. 2021;22(5):620-626. doi:10.1038/s41590-021-00902-8 PubMedGoogle ScholarCrossref
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.


My Saved Courses

You currently have no courses saved.