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. 2022 Feb 1;182(2):153-162.
doi: 10.1001/jamainternmed.2021.7024.

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

Jing Sun  1 , Qulu Zheng  1 , Vithal Madhira  2 , Amy L Olex  3 , Alfred J Anzalone  4 , Amanda Vinson  5 , Jasvinder A Singh  6   7 , Evan French  3 , Alison G Abraham  8 , Jomol Mathew  9 , Nasia Safdar  10 , Gaurav Agarwal  11 , Kathryn C Fitzgerald  1   12 , Namrata Singh  13 , Umit Topaloglu  14 , Christopher G Chute  1   15 , Roslyn B Mannon  16 , Gregory D Kirk  1   17 , Rena C Patel  18 ; National COVID Cohort Collaborative (N3C) Consortium
Collaborators, Affiliations

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

Jing Sun et al. JAMA Intern Med. .

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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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Time to COVID-19 Breakthrough Infection by Immune Dysfunction Condition
All breakthrough infections that occurred from 0 to 14 days after full SARS-CoV-2 vaccination were excluded. BMT indicates bone marrow transplantation; MS, multiple sclerosis; RA, rheumatoid arthritis; and SOT, solid organ transplant.
Figure 2.
Figure 2.. COVID-19 Disease Severity in Prevaccination vs Breakthrough Infection Cases
Prevaccination cases were defined as those with a COVID-19 diagnosis before the first dose of a vaccine. Breakthrough infection cases were defined as those who contracted a COVID-19 infection on or after the 14th day of vaccination. Disease severity was assigned as the highest level of health care utilization within 45 days of breakthrough infection. Severe outcomes included inpatient hospitalization with invasive ventilation, extracorporeal membrane oxygenation, or death. Data are given in eTable 4 in Supplement 1.
See this image and copyright information in PMC

Comment in

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