A recent study published in the BMJ investigated the associations between coronavirus disease 2019 (COVID-19) vaccination or non-vaccination and adverse outcomes during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron waves.

Study: Adverse outcomes of SARS-CoV-2 infection with delta and omicron variants in vaccinated versus unvaccinated US veterans: retrospective cohort study. Image Credit: MeekoMedia/Shutterstock.comStudy: Adverse outcomes of SARS-CoV-2 infection with delta and omicron variants in vaccinated versus unvaccinated US veterans: retrospective cohort study. Image Credit: MeekoMedia/Shutterstock.com


Studies suggest a decrease in vaccine effectiveness and a surge in vaccine breakthrough infections during the Delta period. However, SARS-CoV-2 Omicron caused an even more significant increase in cases and breakthrough infections in the United States (US).

Evidence suggests that severe illness with SARS-CoV-2 infection is less common in vaccinated individuals than in non-vaccinated persons.

Nonetheless, the difference in clinical severity of COVID-19 outcomes by vaccination status is minimally characterized.

Furthermore, only a few studies have addressed the impact of third and fourth vaccination on COVID-19 outcomes, with only slight adjustment for potential confounders, which drive vaccination decisions and are also COVID-19 severity risk factors.

About the study

The present study examined the associations between COVID-19 vaccination status and severe clinical outcomes among US Veterans Health Administration patients.

Adult patients were included on the sampling date (index date) of the first SARS-CoV-2-positive test when their 30-day outcome assessment commenced.

Only those who tested positive between July and November 2021 (Delta period) or January and June 2022 (Omicron period) were included.

Patients without primary care and inpatient/outpatient encounters within 18 and 12 months before the index date, respectively, were excluded. Reinfections were not considered for analysis.

The primary exposure variable was SARS-CoV-2 vaccination status. Subjects were stratified by vaccine type and the number of doses received.

The primary outcomes were hospitalization, admission to the intensive care unit (ICU), mechanical ventilation use, and all-cause mortality. The researchers evaluated patients’ clinical and demographic characteristics at baseline.

They applied multivariable logistic regression to examine associations between vaccination status and individual outcomes, adjusted for patients’ characteristics. Models were separately built for the SARS-CoV-2 Delta and Omicron periods.

Additionally, the team tested whether outcomes varied by mRNA vaccine manufacturer and the time since the last vaccination.


95,336 and 184,653 patients had a positive SARS-CoV-2 test during the Delta and Omicron periods, respectively. They were disproportionately older, male, and non-Hispanic White, and more likely to be vaccinated if infected during the Omicron period.

The proportion of patients receiving three vaccine doses increased to 30.4% by the Omicron period compared to 1.8% in the Delta period.

The proportion of patients with adverse COVID-19 outcomes (hospital or ICU admission, mechanical ventilation, and death) was lower during the Omicron period compared to the Delta period. Regardless of the number of doses, vaccination was associated with a lower risk of adverse outcomes than no vaccination.

During the Delta period, there was an association between partial mRNA vaccination and an increased risk of hospitalization, mechanical ventilation use, and death relative to receiving two mRNA vaccine doses after correcting for multiple comparisons.

Receiving Janssen’s vaccine (Ad26.COV2.S) was associated with elevated odds of hospitalization, ICU admission, and death relative to receiving two mRNA vaccine doses.

A third vaccine dose did not produce consistent association patterns with outcomes in the Delta period. During the Omicron period, estimates were similar to those in the Delta period.

However, a third vaccination was associated with a reduced risk of hospitalization, ICU admission, mechanical ventilation use, and death relative to double vaccination.

Two doses of Pfizer’s BNT162b2 vaccine were associated with increased odds of hospital or ICU admission and mechanical ventilation use during both periods than receiving two doses of Moderna’s mRNA-1273 vaccine.

Further, receiving three BNT162b2 doses was associated with an elevated risk of hospital or ICU admission in the Omicron period relative to receiving three mRNA-1273 doses.

A more extended period since vaccination was not associated with adverse outcomes among recipients of the two doses of the mRNA vaccine, even when the interval between vaccination and infection was 271 to 365 days.

However, increasing the time since vaccination to 91 to 150 days after the third mRNA dose was associated with an increased risk of hospitalization and death.


The study demonstrated a significant reduction in the risk of severe and fatal COVID-19 outcomes with vaccination during SARS-CoV-2 Delta- and Omicron-predominant periods among US veterans.

Overall, data from the Omicron period indicated that a third mRNA vaccination conferred the highest benefit, especially the mRNA-1273 vaccine.

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