Is COVID-19 vaccination beneficial in persons with past infection?

Since the first COVID-19 vaccine received authorization for emergency use in December 2020, physicians and the public have vigorously debated whether infection-acquired ("natural") or vaccine-mediated immunity provides better protection against future infection and severe illness. The answer may never be known for certain, as observational studies are limited by confounding and it's hard to imagine a research ethics committee approving a trial that randomizes one group to intentional exposure to a potentially lethal infection. A more important clinical question is: does getting vaccinated after recovery from COVID-19 provide additional benefits? Currently, the Centers for Disease Control and Prevention recommends routine vaccination in all persons aged 5 years or older, regardless of their history of past infection.

Two large cohort studies published last week provided the strongest evidence to date that the answer is yes. The first study used electronic medical records from a health care organization covering more than half of the population of Israel to identify 149,000 patients age 16 years or older who had recovered from documented SARS-CoV-2 infection at least 100 days earlier and had not yet received COVID-19 vaccination as of March 1, 2021. 56% of these persons received at least one dose of BNT162b2 (Pfizer-BioNTech) vaccine by November 26, 2021. 2,168 of those who remained unvaccinated (3.3%) were reinfected during the study, compared to 354 of the vaccinated patients (0.4%). After adjustment for sociodemographic factors and coexisting illnesses, the estimated vaccine effectiveness was 82% for patients aged 64 years or younger and 60% for patients aged 65 years or older. A secondary analysis showed no difference in protection between one or two vaccine doses.

A second study in a highly vaccinated cohort of 35,768 health care workers in the United Kingdom tracked primary infections and reinfections between December 7, 2020 and September 21, 2021. Most participants received two doses of BNT162b2 (Pfizer-BioNTech) vaccine; 8% received the single-dose ChAdOx1 nCoV-19 vaccine (AstraZeneca). In previously uninfected participants who received the second dose of BNT162b2 six weeks or more after the first dose, adjusted vaccine effectiveness was 85% up to 73 days after the second dose but declined to 51% after 200 days. In comparison, adjusted effectiveness of the ChAdOx1 nCoV-19 vaccine was only 58% up to 73 days. In 6,169 participants who had COVID-19 prior to the study, long-term (>1 year) protection against re-infection was 69% in unvaccinated persons but remained high at 94% in persons who received one or two doses of BNT162b2.

Acknowledging some differences between the populations and the predominant variants circulating during the respective study periods, the results support the following conclusions. First, re-infection in unvaccinated persons is relatively uncommon during the first 9 months after a primary infection (1 in 30 in the Israeli study) but becomes more likely after 1 year (per the U.K. study). Similarly, the effectiveness of the initial two doses of BNT162b2 vaccine in preventing COVID-19 declines after 6-7 months, supporting booster doses. However, patients with past infections who subsequently receive one or two doses of BNT162b2 have sustained high levels of protection ("hybrid immunity") against re-infection for at least one year. In an editorial in The Guardian, Dr. Eric Topol recently argued that these and other data support re-defining "fully vaccinated" to include recovery from past infection plus a single dose of an mRNA vaccine.