The SARS-CoV-2 Omicron variant is associated with less severe disease in a high-risk cohort of Veterans

Globally, reports have shown that the COVID-19 Omicron variant results in less severe disease compared to previous variants, including Delta. The extent to which disease severity differs based on vaccination status and in high-risk populations is poorly characterized.

Studying the SARS-CoV-2 virus and COVID-19 disease throughout the pandemic has been defined by a rapidly developing landscape of variants, treatments, and vaccines. Characterizing how these variables interact and affect disease course and outcomes remains critical in understanding the evolving pandemic and ensuring appropriate public health, policy, and clinical medicine responses. In November 2021, the SARS-CoV-2 Omicron variant quickly became the predominant global SARS-CoV-2 strain as a more infectious variant, reported to cause less severe disease and with less susceptibility to vaccination. Evidence from studies around the globe has supported these claims, but these findings have not been replicated among patients in the United States. 

The Veterans Health Administration (VA) proved to be an ideal system for this study as a single-payer entity with centers across the country and access to the VA’s COVID-19 Shared Data Resource, which carries extensive demographic, clinical, and vaccine-related information on VA patients. With this in mind, we set out to compare the disease severity of patients infected with Omicron and Delta variants in the United States. We first included patients with at least two primary care visits at the VA in the 18 months preceding our end point to select patients more likely to receive care and vaccinations through the VA. We included patients with confirmed SARS-CoV-2 infection via positive RT-PCR from October 1st, 2021, to January 15th, 2022, excluding those with prior infection and non-mRNA vaccination. Our cohort of VA patients was predominantly male (91.9%), White (82.4%), older (mean age of 61), and with an increased burden of preexisting comorbidities, making this a high-risk population. 

These criteria resulted in 108,340 Veterans available for matching. After identifying Delta and Omicron predominant periods and patients infected during these timeframes, we constructed a 1:1 matched cohort of patients infected with Omicron and Delta variants, with 22,841 patients in each group. We matched patients on age, sex, race, comorbidity burden, socioeconomic status, period of vaccine series completion, and type of vaccine administered. When examining disease severity in the 14 days after a positive test, we found those infected with the Omicron variant were less than half as likely to experience severe disease (i.e., requiring ICU admission) as compared to those infected with the Delta variant and those infected with Omicron were much less likely to require respiratory support (including supplemental oxygen and mechanical ventilation). Vaccination was a key mediator in disease severity, with most moderate and severe disease events occurring in individuals who had not received a booster. These results persisted after additional analyses accounting for individuals who had received monoclonal antibody treatment or nirmatrelvir/ritonavir (paxlovid), as well as when accounting for hospital bed capacity during Omicron and Delta-predominant periods.  

Our findings support the notion that the Omicron variant is associated with less severe infection compared to the Delta variant within a large, multicenter health system in the United States. Importantly, these results held in the face of matching and additional analyses, in which we attempted to account for the large variety of factors that may alter disease severity. While the baseline health and demographics of the VA are not particularly generalizable to the average health and demographics of the U.S. population, our results nonetheless highlight the importance of vaccination as a means to reduce disease severity, especially in high-risk patients. 

While the VA has been particularly forward-thinking in ensuring access to vaccines for their patient population, inequity in vaccine access remains a significant barrier to a large proportion of patients both in the United States and worldwide. At this moment, Omicron subvariants (primarily BA.4 and BA.5) are responsible for the vast majority of new COVID-19 cases, with evidence of waning immunity and/or immune escape after both prior infection and vaccination for those infected with these subvariants. As we progress into the fall and winter of 2022, these subvariants will continue to evolve and will likely bring unique challenges with them as they spread. The role that vaccine development including Omicron-targeted boosters, access, and administration will play during this time will certainly be crucial factors in minimizing viral spread and preventing severe disease, particularly in those at high risk.