Risk of COVID-19 after Natural Infection or Vaccination

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 enrollment 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 93% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall adjusted risk [aRR] ratio: 0·07; 95% CI: 0·04-0·12). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (aRR: 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: This work was supported by National Institutes of Health [UM1 AI068614 to LC, GEG for CoVPN Operational Infrastructure]; [UM1 AI068635 to PBG, YuH, HEJ for CoVPN cross-protocol statistical analyses]; [K23AI159399 to AMR]; [UM1 AI069412 to LRB, SRW], [P30 AI50410 to CLG].Declaration of Interest: MBL, YiH, CY, ChAR, RMM, BG, GEG, YuH, and, DF have nothing to disclose. AMR, PBG, HEJ, JGK, LRB, PG, KLK, KMN, LC, HME have grant/contract support provided by the National Institutes of Health. TCSM has received clinical trial funding from Gilead Sciences. CaAR conducted clinical trials funded by Novavax and Moderna, Inc. LRB has grant/contract support provided by the Ragon Institute, Bill and Melinda Gates Foundation, and Wellcome Trust, and is a Deputy Editor at the New England Journal of Medicine. PG serves as a consultant for Johnson & Johnson. CLG was a co-chair on the Novavax trial but did not receive funding from the company. BL is an employee of Moderna, Inc. IH is an employee of AstraZeneca and may hold share stock. FS is an employee of Janssen; Jansen has a contract with BARDA. LMD is an employee of Novavax, Inc. KMN has grant/contract support provided by Pfizer. PAG has conducted clinical trials funded by Sanofi Pasteur and Janssen Vaccines. He has also served as a consultant for Janssen Vaccines in the past. SRW has conducted clinical trials funded by Sanofi Pasteur, Janssen Vaccines, and Moderna, Inc. and chairs an Independent Data Monitoring Committee for Janssen Vaccines; SRW’s spouse is an employee of Regeneron Therapeutics and may hold stock and stock/options.Ethical Approval Statement: The series of trials included in this analysis obtained ethical approval from the required regulatory bodies prior to activation and individual informed consent was provided by all trial participants.