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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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To identify the key insights or developments described in this article
1 Credit CME
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.

Abstract

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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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: 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 (jsun54@jhu.edu); 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 (rcpatel@uw.edu).

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 (ncats.nih.gov/n3c/about), 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 (covid.cd2h.org/dtas) and the organizations and scientists (covid.cd2h.org/duas) who have contributed to the ongoing development of this community resource (https://doi.org/10.1093/jamia/ocaa196).

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