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Association Between Immune Dysfunction and COVID-19 Breakthrough Infection After SARS-CoV-2 Vaccination in the US

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Key Points

Question  Is immune dysfunction associated with an increased risk for COVID-19 breakthrough infection after SARS-CoV-2 vaccination?

Findings  In this cohort study of 664 722 patients who received at least 1 dose of a SARS-CoV-2 vaccine, those with immune dysfunction, such as HIV infection, rheumatoid arthritis, and solid organ transplant, had a higher rate for COVID-19 breakthrough infection and worse outcomes after full or partial vaccination, compared with persons without immune dysfunction.

Meaning  The findings suggest that persons with immune dysfunction are at much higher risk for contracting a breakthrough infection and thus should use nonpharmaceutical interventions (eg, mask wearing) and alternative vaccination approaches (eg, additional dose or immunogenicity testing) even after full vaccination.


Importance  Persons with immune dysfunction have a higher risk for severe COVID-19 outcomes. However, these patients were largely excluded from SARS-CoV-2 vaccine clinical trials, creating a large evidence gap.

Objective  To identify the incidence rate and incidence rate ratio (IRR) for COVID-19 breakthrough infection after SARS-CoV-2 vaccination among persons with or without immune dysfunction.

Design, Setting, and Participants  This retrospective cohort study analyzed data from the National COVID Cohort Collaborative (N3C), a partnership that developed a secure, centralized electronic medical record–based repository of COVID-19 clinical data from academic medical centers across the US. Persons who received at least 1 dose of a SARS-CoV-2 vaccine between December 10, 2020, and September 16, 2021, were included in the sample.

Main Outcomes and Measures  Vaccination, COVID-19 diagnosis, immune dysfunction diagnoses (ie, HIV infection, multiple sclerosis, rheumatoid arthritis, solid organ transplant, and bone marrow transplantation), other comorbid conditions, and demographic data were accessed through the N3C Data Enclave. Breakthrough infection was defined as a COVID-19 infection that was contracted on or after the 14th day of vaccination, and the risk after full or partial vaccination was assessed for patients with or without immune dysfunction using Poisson regression with robust SEs. Poisson regression models were controlled for a study period (before or after [pre– or post–Delta variant] June 20, 2021), full vaccination status, COVID-19 infection before vaccination, demographic characteristics, geographic location, and comorbidity burden.

Results  A total of 664 722 patients in the N3C sample were included. These patients had a median (IQR) age of 51 (34-66) years and were predominantly women (n = 378 307 [56.9%]). Overall, the incidence rate for COVID-19 breakthrough infection was 5.0 per 1000 person-months among fully vaccinated persons but was higher after the Delta variant became the dominant SARS-CoV-2 strain (incidence rate before vs after June 20, 2021, 2.2 [95% CI, 2.2-2.2] vs 7.3 [95% CI, 7.3-7.4] per 1000 person-months). Compared with partial vaccination, full vaccination was associated with a 28% reduced risk for breakthrough infection (adjusted IRR [AIRR], 0.72; 95% CI, 0.68-0.76). People with a breakthrough infection after full vaccination were more likely to be older and women. People with HIV infection (AIRR, 1.33; 95% CI, 1.18-1.49), rheumatoid arthritis (AIRR, 1.20; 95% CI, 1.09-1.32), and solid organ transplant (AIRR, 2.16; 95% CI, 1.96-2.38) had a higher rate of breakthrough infection.

Conclusions and Relevance  This cohort study found that full vaccination was associated with reduced risk of COVID-19 breakthrough infection, regardless of the immune status of patients. Despite full vaccination, persons with immune dysfunction had substantially higher risk for COVID-19 breakthrough infection than those without such a condition. For persons with immune dysfunction, continued use of nonpharmaceutical interventions (eg, mask wearing) and alternative vaccine strategies (eg, additional doses or immunogenicity testing) are recommended even after full vaccination.

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Article Information

Accepted for Publication: October 9, 2021.

Published Online: December 28, 2021. doi:10.1001/jamainternmed.2021.7024

Corresponding Authors: Jing Sun, MD, MPH, PhD, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 2213 McElderry St, Baltimore, MD 21205 (; Rena C. Patel, MD, MPH, Division of Allergy and Infectious Diseases, Departments of Medicine and Global Health, University of Washington, 325 Ninth Ave, Seattle, WA 98104 (

Author Contributions: Dr Sun had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Kirk and Patel contributed equally.

Concept and design: Sun, J.A. Singh, Agarwal, N. Singh, Mannon, Kirk, Patel.

Acquisition, analysis, or interpretation of data: Sun, Zheng, Madhira, Olex, Anzalone, Vinson, J.A. Singh, French, Abraham, Mathew, Safdar, Fitzgerald, N. Singh, Topaloglu, Chute, Mannon, Kirk, Patel.

Drafting of the manuscript: Sun, J.A. Singh, Mathew, Patel.

Critical revision of the manuscript for important intellectual content: Zheng, Madhira, Olex, Anzalone, Vinson, J.A. Singh, French, Abraham, Safdar, Agarwal, Fitzgerald, N. Singh, Topaloglu, Chute, Mannon, Kirk, Patel.

Statistical analysis: Sun, Zheng, Madhira, Anzalone, Vinson, Abraham, Fitzgerald, Patel.

Obtained funding: Chute.

Administrative, technical, or material support: Madhira, Olex, Anzalone, French, N. Singh, Topaloglu, Chute, Mannon, Kirk, Patel.

Supervision: Sun, Safdar, N. Singh, Kirk, Patel.

Conflict of Interest Disclosures: Dr Vinson reported receiving grants from Paladin Labs Inc and personal fees from Paladin Labs Inc advisory board outside the submitted work. Dr J.A. Singh reported receiving personal fees from Crealta/Horizon, Medisys, Fidia, PK Med, Two Labs Inc, Adept Field Solutions, Clinical Care Options, ClearView Healthcare Partners, Putnam Associates, Focus Forward, Navigant, Spherix, MedIQ, Jupiter Life Science, UBM LLC, Trio Health, Medscape, WebMD, Practice Point Communications, National Institutes of Health (NIH), American College of Rheumatology, and Simply Speaking; holding stock options from TPT Global Tech, Vaxart Pharmaceuticals, Atyu Biopharma, and Charlotte's Web Holdings Inc outside the submitted work. Dr Abraham reported receiving grants from NIH and personal fees from Implementation Group Inc outside the submitted work. Dr Topaloglu reported being a stockholder of CareDirections LLC. Dr Chute reported receiving grants from NIH outside the submitted work. Dr Mannon reported serving as a steering committee member for IMAGINE trial from Vitaeris; receiving honorarium as deputy editor of American Journal of Transplantation; grants from Mallinckrodt Pharmaceuticals, and grants to institution for clinical trial from CSL Behring, Transplant Genomics, and Quark Pharmaceuticals outside the submitted work; and serving as chair of Policy and Advocacy Committee of American Society of Nephrology and co-chair of review committee of Scientific Registry of Transplant Recipients. No other disclosures were reported.

Funding/Support: This study accessed data and tools through the N3C Data Enclave (, which is supported by grant U24 TR002306 from National Center for Advancing Translational Sciences (NCATS). National COVID Cohort Collaborative (N3C) is funded by grant U24 TR002306 from NCATS. Ms Olex and Mr French were supported by Clinical and Translational Science Awards UL1TR002649 from NCATS. Mr Anzalone was supported by grants U54GM104942-05S2 and U54GM115458 from National Institute of General Medical Sciences, which funds the West Virginia Clinical & Translational Science Institute and the Great Plains IDeA Clinical and Translational Research Network. Dr Safdar was supported by grant DP2AI144244 from National Institute of Allergy and Infectious Diseases (NIAID) and by a grant from the US Department of Veterans Affairs. Dr N. Singh was supported in part by grant DP2AI144244 from NIAID. Dr Kirk was supported in part by grant K24AI118591 from NIAID. Dr Patel was supported by grant K23AI120855 from NIAID.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NCATS and N3C had a role in the review and approval of all results reported in the manuscript for public review.

Group Information: N3C Consortium members are listed in Supplement 2.

Additional Contributions: The following N3C core teams contributed to this study: Melissa A. Haendel (principal investigator [PI]), Christopher G. Chute (PI), Kenneth R. Gersing, Anita Walden; Workstream, subgroup and administrative leaders: Melissa A. Haendel (PI), Tellen D. Bennett, Christopher G. Chute, David A. Eichmann, Justin Guinney, Warren A. Kibbe, Hongfang Liu, Philip R.O. Payne, Emily R. Pfaff, Peter N. Robinson, Joel H. Saltz, Heidi Spratt, Justin Starren, Christine Suver, Adam B. Wilcox, Andrew E. Williams, Chunlei Wu; key liaisons at data partner sites; regulatory staff at data partner sites; individuals at the sites who are responsible for creating the data sets and submitting data to N3C; Data Ingest and Harmonization team: Christopher G. Chute (PI), Emily R. Pfaff (PI), Davera Gabriel, Stephanie S. Hong, Kristin Kostka, Harold P. Lehmann, Richard A. Moffitt, Michele Morris, Matvey B. Palchuk, Xiaohan Tanner Zhang, Richard L. Zhu; Phenotype team (individuals who create the scripts that the sites use to submit their data, based on the COVID and long COVID definitions): Emily R. Pfaff (PI), Benjamin Amor, Mark M. Bissell, Marshall Clark, Andrew T. Girvin, Stephanie S. Hong, Kristin Kostka, Adam M. Lee, Robert T. Miller, Michele Morris, Matvey B. Palchuk, Kellie M. Walters; Project management and operations team: Anita Walden (PI), Yooree Chae, Connor Cook, Alexandra Dest, Racquel R. Dietz, Thomas Dillon, Patricia A. Francis, Rafael Fuentes, Alexis Graves, Julie A. McMurry, Andrew J. Neumann, Shawn T. O’Neil, Usman Sheikh, Andréa M. Volz, Elizabeth Zampino; Partners from NIH and other federal agencies: Christopher P. Austin (PI), Kenneth R. Gersing (PI), Samuel Bozzette, Mariam Deacy, Nicole Garbarini, Michael G. Kurilla, Sam G. Michael, Joni L. Rutter, Meredith Temple-O’Connor; Analytics team (individuals who build the Data Enclave infrastructure, help create code sets and variables, and help domain teams and project teams with their data sets): Benjamin Amor (PI), Mark M. Bissell, Katie Rebecca Bradwell, Andrew T. Girvin, Amin Manna, Nabeel Qureshi; Publication committee management team: Mary Morrison Saltz (PI), Christine Suver (PI), Christopher G. Chute, Melissa A. Haendel, Julie A. McMurry, Andréa M. Volz, Anita Walden; Publication committee review team: Carolyn Bramante, Jeremy Richard Harper, Wenndy Hernandez, Farrukh M. Koraishy, Federico Mariona, Saidulu Mattapally, Amit Saha, Satyanarayana Vedula.

Additional Information: This research was possible because of the patients whose information is included in the data from participating organizations ( and the organizations and scientists ( who have contributed to the ongoing development of this community resource (

Polack  FP , Thomas  SJ , Kitchin  N ,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577 PubMedGoogle ScholarCrossref
Jackson  LA , Anderson  EJ , Rouphael  NG ,  et al.  An mRNA vaccine against SARS-CoV-2—preliminary report.   N Engl J Med. 2020;383:1920-1931.Google ScholarCrossref
Walsh  EE , Frenck  RW  Jr , Falsey  AR ,  et al.  Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates.   N Engl J Med. 2020;383(25):2439-2450. doi:10.1056/NEJMoa2027906 PubMedGoogle ScholarCrossref
Abu Jabal  K , Ben-Amram  H , Beiruti  K ,  et al.  Impact of age, ethnicity, sex and prior infection status on immunogenicity following a single dose of the BNT162b2 mRNA COVID-19 vaccine: real-world evidence from healthcare workers, Israel, December 2020 to January 2021.   Euro Surveill. 2021;26(6):2100096. doi:10.2807/1560-7917.ES.2021.26.6.2100096PubMedGoogle Scholar
Haas  EJ , Angulo  FJ , McLaughlin  JM ,  et al.  Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.   Lancet. 2021;397(10287):1819-1829. doi:10.1016/S0140-6736(21)00947-8 PubMedGoogle ScholarCrossref
Butt  AA , Omer  SB , Yan  P , Shaikh  OS , Mayr  FB .  SARS-CoV-2 vaccine effectiveness in a high-risk national population in a real-world setting.   Ann Intern Med. 2021;174(10):1404-1408. doi:10.7326/M21-1577 PubMedGoogle ScholarCrossref
Tenforde  MW , Patel  MM , Ginde  AA ,  et al; Influenza and Other Viruses in the Acutely Ill (IVY) Network.  Effectiveness of SARS-CoV-2 mRNA vaccines for preventing Covid-19 hospitalizations in the United States.   medRxiv. Preprint posted online July 8, 2021. doi:10.1101/2021.07.08.21259776Google Scholar
Brosh-Nissimov  T , Orenbuch-Harroch  E , Chowers  M ,  et al.  BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel.   Clin Microbiol Infect. 2021;27(11):1652-1657. doi:10.1016/j.cmi.2021.06.036PubMedGoogle ScholarCrossref
Centers for Disease Control and Prevention. COVID-19 vaccine breakthrough infections reported to CDC–United States, January 1-April 30, 2021. Accessed May 28, 2021.
Centers for Disease Control and Prevention. COVID-19 vaccine breakthrough case investigation and reporting. Accessed September 30, 2021.
Sun  J , Patel  RC , Zheng  Q ,  et al; National COVID Cohort Collaborative (N3C) Consortium.  COVID-19 disease severity among people with HIV infection or solid organ transplant in the United States: a nationally-representative, multicenter, observational cohort study.   medRxiv. Preprint posted online July 28, 2021. doi:10.1101/2021.07.26.21261028Google Scholar
Nicolini  LA , Magne  F , Signori  A ,  et al.  Hepatitis B virus vaccination in HIV: immunogenicity and persistence of seroprotection up to 7 years following a primary immunization course.   AIDS Res Hum Retroviruses. 2018;34(11):922-928. doi:10.1089/aid.2017.0070 PubMedGoogle ScholarCrossref
Abzug  MJ , Warshaw  M , Rosenblatt  HM ,  et al; International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1024 and P1061s Protocol Teams.  Immunogenicity and immunologic memory after hepatitis B virus booster vaccination in HIV-infected children receiving highly active antiretroviral therapy.   J Infect Dis. 2009;200(6):935-946. doi:10.1086/605448 PubMedGoogle ScholarCrossref
Eckerle  I , Rosenberger  KD , Zwahlen  M , Junghanss  T .  Serologic vaccination response after solid organ transplantation: a systematic review.   PLoS One. 2013;8(2):e56974. doi:10.1371/journal.pone.0056974 PubMedGoogle Scholar
Gangappa  S , Kokko  KE , Carlson  LM ,  et al.  Immune responsiveness and protective immunity after transplantation.   Transpl Int. 2008;21(4):293-303. doi:10.1111/j.1432-2277.2007.00631.x PubMedGoogle ScholarCrossref
Dhodapkar  MV , Dhodapkar  KM , Ahmed  R .  Viral immunity and vaccines in hematologic malignancies: implications for COVID-19.   Blood Cancer Discov. 2021;2(1):9-12. doi:10.1158/2643-3230.BCD-20-0177PubMedGoogle ScholarCrossref
Rozans  MK , Smith  BR , Burakoff  SJ , Miller  RA .  Long-lasting deficit of functional T cell precursors in human bone marrow transplant recipients revealed by limiting dilution methods.   J Immunol. 1986;136(11):4040-4048.PubMedGoogle Scholar
Haidar  G , Agha  M , Lukanski  A ,  et al.  Immunogenicity of COVID-19 vaccination in immunocompromised patients: an observational, prospective cohort study interim analysis.   medRxiv. Preprint posted online June 30, 2021. doi:10.1101/2021.06.28.21259576Google Scholar
Bertrand  D , Hamzaoui  M , Lemée  V ,  et al.  Antibody and T cell response to SARS-CoV-2 messenger RNA BNT162b2 vaccine in kidney transplant recipients and hemodialysis patients.   J Am Soc Nephrol. 2021;32(9):2147-2152. doi:10.1681/ASN.2021040480 PubMedGoogle ScholarCrossref
Kamar  N , Abravanel  F , Marion  O , Couat  C , Izopet  J , Del Bello  A .  Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients.   N Engl J Med. 2021;385(7):661-662. doi:10.1056/NEJMc2108861 PubMedGoogle ScholarCrossref
Boyarsky  BJ , Werbel  WA , Avery  RK ,  et al.  Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.   JAMA. 2021;325(21):2204-2206. doi:10.1001/jama.2021.7489 PubMedGoogle ScholarCrossref
Marion  O , Del Bello  A , Abravanel  F ,  et al.  Safety and immunogenicity of anti-SARS-CoV-2 messenger RNA vaccines in recipients of solid organ transplants.   Ann Intern Med. 2021;174(9):1336-1338. doi:10.7326/M21-1341 PubMedGoogle ScholarCrossref
Georgery  H , Devresse  A , Yombi  J-C ,  et al.  Very low immunization rate in kidney transplant recipients after one dose of the BNT162b2 vaccine: beware not to lower the guard!   Transplantation. 2021;105(10):e148-e149. doi:10.1097/TP.0000000000003818 PubMedGoogle ScholarCrossref
Haendel  MA , Chute  CG , Bennett  TD ,  et al; N3C Consortium.  The National COVID Cohort Collaborative (N3C): rationale, design, infrastructure, and deployment.   J Am Med Inform Assoc. 2021;28(3):427-443. doi:10.1093/jamia/ocaa196 PubMedGoogle ScholarCrossref
Bennett  TD , Moffitt  RA , Hajagos  JG ,  et al; National COVID Cohort Collaborative (N3C) Consortium.  Clinical characterization and prediction of clinical severity of SARS-CoV-2 infection among US adults using data from the US National COVID Cohort Collaborative.   JAMA Netw Open. 2021;4(7):e2116901. doi:10.1001/jamanetworkopen.2021.16901 PubMedGoogle Scholar
von Elm  E , Altman  DG , Egger  M , Pocock  SJ , Gøtzsche  PC , Vandenbroucke  JP ; STROBE Initiative.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.   Ann Intern Med. 2007;147(8):573-577. doi:10.7326/0003-4819-147-8-200710160-00010 PubMedGoogle ScholarCrossref
Browne  SK , Beeler  JA , Roberts  JN .  Summary of the Vaccines and Related Biological Products Advisory Committee meeting held to consider evaluation of vaccine candidates for the prevention of respiratory syncytial virus disease in RSV-naïve infants.   Vaccine. 2020;38(2):101-106. doi:10.1016/j.vaccine.2019.10.048 PubMedGoogle ScholarCrossref
Centers for Disease Control and Prevention. COVID data tracker: monitoring variant proportions. Accessed September 30, 2021.
GitHub. National COVID Cohort Collaborative Phenotype Data Acquisition. Accessed September 30, 2021.
Bennett  TD , Moffitt  RA , Hajagos  JG ,  et al.  The National COVID Cohort Collaborative: clinical characterization and early severity prediction.   medRxiv. Preprint posted online January 23, 2021. doi:10.1101/2021.01.12.21249511Google Scholar
Marshall  JC , Murthy  S , Diaz  J ,  et al; WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection.  A minimal common outcome measure set for COVID-19 clinical research.   Lancet Infect Dis. 2020;20(8):e192-e197. doi:10.1016/S1473-3099(20)30483-7 PubMedGoogle ScholarCrossref
Harpaz  R , Dahl  RM , Dooling  KL .  Prevalence of immunosuppression among US adults, 2013.   JAMA. 2016;316(23):2547-2548. doi:10.1001/jama.2016.16477 PubMedGoogle ScholarCrossref
Bernal  JL , Andrews  N , Gower  C ,  et al  Effectiveness of COVID-19 vaccines against the B.1.617.2 variant.   medRxiv. Preprint posted online May 24, 2021. doi:10.1101/2021.05.22.21257658Google Scholar
Werbel  WA , Boyarsky  BJ , Ou  MT ,  et al.  Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series.   Ann Intern Med. 2021;174(9):1330-1332. doi:10.7326/L21-0282 PubMedGoogle ScholarCrossref
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