- Rick, Anne-Marie;
- Laurens, Matthew;
- Huang, Ying;
- Yu, Chenchen;
- Martin, Thomas;
- Rodriguez, Carina;
- Rostad, Christina;
- Maboa, Rebone;
- Baden, Lindsey;
- El Sahly, Hana;
- Grinsztejn, Beatriz;
- Gray, Glenda;
- Gay, Cynthia;
- Gilbert, Peter;
- Janes, Holly;
- Kublin, James;
- Huang, Yunda;
- Leav, Brett;
- Hirsch, Ian;
- Struyf, Frank;
- Dunkle, Lisa;
- Neuzil, Kathleen;
- Corey, Lawrence;
- Goepfert, Paul;
- Walsh, Stephen;
- Follmann, Dean;
- Kotloff, Karen
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.