Effectiveness of COVID-19 mRNA Vaccination in Preventing COVID-19–Associated Hospitalization Among Adults With Previous SARS-CoV-2 Infection

United States, June 2021-February 2022

Ian D. Plumb, MBBS; Leora R. Feldstein, PhD; Eric Barkley; Alexander B. Posner, MPH; Howard S. Bregman, MD; Melissa Briggs Hagen, MD; Jacqueline L. Gerhart, MD


Morbidity and Mortality Weekly Report. 2022;71(15):549-555. 

In This Article


Among persons with previous SARS-CoV-2 infection or COVID-19 diagnosis, receipt of a COVID-19 mRNA vaccine provided protection against subsequent COVID-19 hospitalization. The highest level of protection was conferred by a booster vaccine dose, with similar VE during the Delta- and Omicron-predominant periods (approximately 60%–70%). In contrast, VE of 1 or 2 doses declined from 50%–60% during the Delta-predominant to approximately 35% during the Omicron-predominant period. Receiving a booster dose conferred protection even if the previous infection occurred after receipt of the second vaccine dose. Findings from this report indicate that SARS-CoV-2 reinfections leading to COVID-19–associated hospitalizations are preventable by COVID-19 vaccination.

Benefit of vaccination after previous SARS-CoV-2 infection was also indicated by an analysis of surveillance data from New York City that estimated approximately 50%–70% protection against hospitalization from reinfection.[5] A case-control analysis using surveillance data from Brazil estimated 90% protection by 2 doses of Pfizer-BioNTech vaccine against hospitalization or death after reinfection;[6] the high estimated VE might partly reflect recent vaccination in the context of potential decreased infection-induced immunity. The similar estimated benefit from 1 or 2 vaccine doses in preventing reinfection leading to hospitalization in the current study is consistent with evidence that vaccination elicits a more rapid immunologic response if preceded by a SARS-CoV-2 infection¶¶¶.[7] In the current analysis, a booster dose offered superior protection against reinfection leading to hospitalization.

Immunity from previous SARS-CoV-2 infection wanes over time[1,8] and was lower against the Omicron variant compared with immunity against other virus variants.[2] However, protection is estimated to have remained stable against SARS-CoV-2 reinfection leading to hospitalization or death.[2] Previous studies have indicated that, in general, protection by a hybrid of infection-induced and vaccination-induced immunity is superior to that from either alone and is less likely to wane over time.[1,8] Compared with unvaccinated persons without previous infection, persons with a booster dose of mRNA vaccine have been estimated to have 90% protection against hospitalization with COVID-19 during the Omicron period; the highest estimated protection was among vaccinated persons with previous infection.****

The findings in this report are subject to at least five limitations. First, underascertainment of vaccination status from available information would likely lead to an underestimation of VE, particularly if vaccinated control-patients were misclassified as unvaccinated; this might have led to lower estimated VE compared with similar analyses.[5,6,9] Second, generalizability might be limited by incomplete data or by missing data from persons who do not seek health care; however, Cosmos data are broadly representative of the U.S. population.[4] Third, several VE estimates were imprecise, with broad CIs; estimates should be interpreted with caution. Fourth, underascertainment of previous infection might have occurred because of dependence on EHR data; however, findings were similar when restricting analyses to case-patients with positive initial NAAT results, and the test-negative design for an endpoint of severe illness mitigates the risk for selection bias. Finally, there might be residual or unmeasured confounding by characteristics associated with exposure, vaccination, or hospitalization that were not recorded in the data set.

An increasing proportion of the U.S. population has had SARS-CoV-2 infection†††† and might be at risk for SARS-CoV-2 reinfection leading to hospitalization. In the current analysis, approximately 50% of these reinfections occurred during the Omicron-predominant period. Vaccination remains the safest strategy for preventing complications of SARS-CoV-2 infection. COVID-19 vaccination offers additional protection against reinfection leading to hospitalization, with a booster dose offering the highest level of protection. To prevent COVID-19–associated hospitalization, all eligible persons should stay up to date with vaccination, including those with previous SARS-CoV-2 infection.