Relative effectiveness of booster vs. 2-dose mRNA Covid-19 vaccination in the Veterans Health Administration: Self-controlled risk interval analysis.

Objective: To estimate relative effectiveness of the booster mRNA Covid-19 vaccination versus the 2-dose primary series for both Delta and Omicron variants with self-controlled study design.

Methods: We used the Veterans Health Administration (VHA) Corporate Data Warehouse to identify U.S. Veterans who received the 2-dose primary mRNA Covid-19 vaccine series and a mRNA Covid-19 booster, and who had a positive SARS-CoV-2 test during the Delta (9/23/2021-11/30/2021) or Omicron (1/1/22-3/19/22) predominant period. Among them, we conducted a self-controlled risk interval (SCRI) analysis to compare odds of SARS-CoV-2 infection during a booster exposure interval versus a control interval. Exposures were a control interval (days 4-6 post-booster vaccination, presumably prior to gain of booster immunity), and booster exposure interval (days 14-16 post-booster vaccination, presumably following gain of booster immunity). Cases had a positive PCR or antigen SARS-CoV-2 test. Separately for Delta and Omicron periods, we used conditional logistic regression to calculate odds ratios (OR) of a positive test for the booster versus control interval and calculated relative effectiveness of booster versus 2-dose primary series as (1-OR)*100. The SCRI approach implicitly controlled for time-fixed confounders.

Results: We found 42 individuals with a positive SARS-CoV-2 test in the control interval and 14 in the booster exposure interval during the Delta period, and 141 and 70, respectively, in the Omicron period. For the booster versus 2-dose primary series, the odds of infection were 70% (95 %CI: 42%, 84%) lower during the Delta period and 54% (95 %CI: 38%, 66%) lower during Omicron. In sensitivity analyses among those with prior Covid-19 history, and age stratification, ORs were similar to the main analysis.

Conclusions: Booster vaccination was more effective relative to a 2-dose primary series during the Delta and Omicron predominant periods, and the relative effectiveness was consistent across age groups.