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Randomized Controlled Trial

Risk of COVID-19 after natural infection or vaccination

Anne-Marie Rick et al. EBioMedicine. 2023 Oct.

Abstract

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection.

Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7-15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures.

Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05-0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01-0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease.

Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection.

Funding: National Institutes of Health.

Keywords: COVID-19; Hybrid immunity; Natural infection; Vaccination.

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Conflict of interest statement

Declaration of interests YiH, CY, TCSM, RMM, HMES, BG, GEG, PBG, JGK, LC, and DF declare no conflicts of interest. AMR declares unrelated grants or contracts from NIAID, I4kids, Society to Improve Diagnosis in Medicine, Beckwith Clinical Innovation Award, CTSI COVID-19 Pilot Award; unrelated consulting fees from Pfizer; unrelated support for attending meetings/travel from IDweek (2023); and an unrelated unpaid leadership role as the medical director of Human Milk Science Institute and Biobank. MBL declares unrelated grants or contracts from NIH VTEU paid to their institution. CaAR declares unrelated grants or contracts paid to their institution from Novavax and Moderna. ChAR declares unrelated grants or contracts paid to their institution from BioFire, Inc, GSK, Merck, Micron, MedImmune, Novavax, PaxVax, Regeneron, Pfizer, Sanofi-Pasteur, Janssen, Moderna, NIH, and CDC; unrelated royalties or licenses from Meissa Vaccines, Inc; and unrelated patent interests for “RSV Live-Attenuated Vaccine Candidates with Deleted G-Protein Mucin Domains” and “Chimeric RSV, Immunogenic, Compositions, and Methods of Use”. LRB declares unrelated grants or contracts paid to their institution from NIH/Harvard Medical School and Wellcome Trust/Gates Foundation; unrelated participation on a Data Safety Monitoring Board or Advisory Board for NIAID and FDA; and unrelated involvement in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), Covid Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), the Gates Foundation, and Harvard Medical School. CLG declares unrelated grants or contracts paid to their institution from NIH. HEJ declares unrelated grants or contracts paid to their institution from NIH; and unrelated participation in multiple NIH-convened DSMBs. YuH declares unrelated grants or contracts paid to their institution from WHO and unrelated participation (with payment) on a Data Safety Monitoring Board or Advisory Board for WHV. BL is an employee of Moderna, Inc. IH is an employee of AstraZeneca and declares unrelated stock options held in AstraZeneca. FS is an employee of Janssen and declares unrelated stock received as compensation for past employment with GlaxoSmithKline. LMD is an employee of Novavax, Inc. KMN declares unrelated grants or contracts from Pfizer (no salary support) and NIH. PAG declares unrelated grants or contracts from NIH and patent interests for “Human monoclonal antibodies to SARS-COV-2 and use thereof”. SRW declares unrelated grants or contracts from Sanofi Pasteur, Moderna, Vir Biotechnology, Worcester HIV Vaccine, Pfizer, and Janssen Vaccines/Johnson & Johnson paid to their institution; unrelated support for attending meetings and/or travel from Sasnofi Pasteur; unrelated participation on a Data Safety Monitoring Board or Advisory Board for Janssen Vaccines/Johnson & Johnson; and that their spouse is an employee that holds stock/stock options at Regeneron Pharmaceuticals. KLK declares unrelated grants or contracts from NIAID. The CoVPN was funded by the NIH.

Figures

Fig. 1
Fig. 1
Population-level circulating SARS-CoV-2 strains during enrolment and follow-up of participants in included trials. Proportion of SARS-CoV-2 variants of concern (VOC) and variants of interest (VOI) relative to total circulating SARS-CoV-2 by vaccine trial and geographic location over trial enrolment and follow-up period. Data obtained from GISAID (https://gisaid.org) (A). Proportion of enrolled participants from each geographic location by vaccine trial (B).
Fig. 2
Fig. 2
Cumulative incidence of COVID-19 by trials and groups in the per-protocol cohorts. Cumulative incidence of COVID-19 during the follow-up period in days for the Janssen trial (A), the Moderna trial (B), the AstraZeneca trial (C), and the Novavax trial (D) by SARS-CoV-2 exposure status at enrolment and vaccination status (placebo/no previous infection (NPI); placebo/previous infection (PI); vaccine/NPI; vaccine/PI).
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