Effectiveness of mRNA COVID-19 Booster Vaccines against Omicron and Delta Variants among US Veterans (preprint)

Background We estimated vaccine effectiveness (VE) of mRNA vaccines among US Veterans during periods of Delta and Omicron variant dominance. Patients included in this study were largely 65 years or older (62,834, 55%), male (101,259, 88%), and non-Hispanic white (66,986, 58%). Methods We used SARS-CoV-2 laboratory test results to conduct a matched test-negative case-control study to estimate VE of three and two doses of mRNA vaccines against infection (regardless of symptoms), and a matched case-control study to estimate VE against COVID-19-related hospitalization and death. We estimated VE as (1-odds ratio) x 100%. Severity of disease was measured using hospital length of stay (LOS) and admission to an intensive care unit (ICU). Results Against infection, booster doses had 7-times higher VE - 59% (95% confidence interval [CI], 57 to 61) - than 2-dose VE (7%; 95% CI, 3 to 10) during the Omicron period. For the Delta period, estimated VE against infection was 90% (95% CI, 88 to 92) among boosted vaccinees, 64% higher than VE among 2-dose vaccinees [55% (95% CI, 51 to 58)]. Against hospitalization, booster dose VE was 87% (95% CI, 80 to 91) during Omicron and 95% (95% CI, 91 to 97) during Delta; the 2-dose VE was 44% (95% CI, 26 to 58) during Omicron and 75% (95% CI, 70 to 80) during Delta. Against death, estimated VE with a booster dose was 94% (95% CI, 85 to 98) during Omicron and 96% (95% CI, 88 to 99) during Delta, while the 2-dose VE was 75% (95% CI, 52 to 87) during Omicron and 93% (95% CI, 85 to 97) during Delta. During the Omicron period, average hospital LOS was 4 days shorter [3 days (95%CI, 3 to 4 days)] than during the Delta period. Conclusions A mRNA vaccine booster is more effective against infection, hospitalization, and death than 2-dose vaccination among an older male population with comorbidities.

Utilization of a SARS-CoV-2 Variant Assay for the Rapid Differentiation of Omicron and Delta (preprint)

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529), creates a diagnostic vacuum, since differentiation of Omicron from Delta relies on relatively slow next generation sequencing (NGS) technology delaying epidemiologic understanding and therapeutic intervention. The RUO SARS-CoV-2 Variant Set 1 Test (RSCov2V1) RT-PCR for detection of spike gene N501Y, E484K and del69-70 was designed to differentiate Alpha from Beta and Gamma variants. While Delta lacks these three variants, Omicron has the N501Y and del69-70 mutation. We submitted 88 samples for RSCov2V1 identifying 9 samples with the N501Y and del69-70 mutations while all other samples (79) were negative for all three variants. 9/9 samples with the del69-70 and N501Y were identified by NGS to be Omicron while 47/47 other samples assessed by NGS were confirmed to be Delta family variants. We demonstrate here that an immediately available RT-PCR assay for detection of spike gene N501Y and del69-70 can be utilized to rapidly differentiate Omicron from Delta variants in the proper epidemiologic context

Effectiveness of a third dose of BNT162b2 or mRNA-1273 vaccine for preventing post-vaccination COVID-19 infection: an observational study (preprint)

Background BNT162b2 and mRNA-1273 vaccines are highly protective against COVID-19. Concern about waning immunity and reduced effectiveness against SARS-COV-2 variants led to use of a third dose six months after completing the primary series. We used data from the Veterans Health Administration to evaluate the effectiveness of a third dose of BNT162b2 or mRNA-1273 compared to the primary series in preventing post-vaccination COVID-19. Methods During January 1 - November 22, 2020, third dose recipients were matched (1:1) to demographically similar controls who did not receive a third dose. Eligible participants had completed the primary series at least six months (180 days) before recruitment date. Long-term care residents were excluded. Primary outcomes were documented SARS-CoV-2 infection and COVID-19 hospitalization. Effectiveness was estimated as 1-incidence rate ratio. Findings Following matching, the BNT162b2 group included 99,856 pairs and the mRNA-1273 group included 74,116 pairs. In BNT162b2 and mRNA-1273 groups, median age was 72 (interquartile range [IQR]: 65-75) and 72 (IQR: 67-76) years, 94,990 (95.1%) and 71,213 (96.1%) were male, and 61,261 (61.3%) and 52,170 (70.4%) were non-Hispanic White, respectively. Effectiveness of a third dose of BNT162b2 or mRNA-1273 compared to the primary series was 49.4% (95% confidence interval [CI]: 41.2-56.5%) and 46.0% (95% CI: 33.5-56.2%) for documented SARS-CoV-2 infection and 52.3% (95% CI: 33.8-65.6%) and 44.7% (95% CI: 10.7-65.7%) for COVID-19 hospitalization, respectively. Interpretation A third dose of BNT162b2 or mRNA-1273 is moderately effective against post-vaccination COVID-19 infection compared to the primary series.

COVID-19 Vaccine Breakthrough Infections in the Veterans Health Administration. (preprint)

BackgroundVaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been accompanied by rising concern of vaccine breakthrough due to SARS-CoV-2 variants, waning protection over time, differential vaccine effectiveness, and regional resurgence of Coronavirus 2019 (COVID-19). Characterizing the frequency and drivers of vaccine breakthrough is necessary to inform COVID-19 control efforts. MethodsWe performed a retrospective cohort study of vaccine breakthrough infections in fully vaccinated persons in Veterans Health Administration. We applied Cox proportional hazard models to estimate cumulative incidence, assess differences in outcomes by vaccine, and identify associations with individual characteristics as well as time-dependent geographic variation in COVID-19 incidence, proportion of delta variant, and vaccine coverage. ResultsAmong 3,032,561 fully vaccinated persons, documented SARS-CoV-2 infection occurred in 11,197 (0.37%) and COVID-19 hospitalization occurred in 2,080 (0.07%). Compared to Ad26.COV2.S, BNT162b2 and mRNA-1273 had lower occurrence of documented SARS-CoV-2 infection (aHR 0.54, 95% confidence interval (CI) 0.51-0.58; aHR 0.36; 95% CI 0.33-0.38; respectively) and COVID-19 hospitalization (aHR 0.56, 95% CI 0.47-0.66; aHR 0.30; 0.25-0.35; respectively). Documented SARS-CoV-2 infection and COVID-19 hospitalization were associated with younger age, Hispanic or Latino ethnicity, number of comorbidities, and previous SARS-CoV-2 infection. Regional proportion of delta variant and county-level COVID-19 incidence were predictors of vaccine breakthrough events; county-level vaccine coverage was inversely associated. ConclusionsVaccine breakthrough was rare among fully vaccinated persons. mRNA-1273 and BNT162b2 were more protective against documented SARS-CoV-2 infection and COVID-19 hospitalization compared to Ad26.COV2.S. Efforts to limit COVID-19 transmission and bolster vaccine coverage would also curtail vaccine breakthrough.

Covid-19 by Race and Ethnicity: A National Cohort Study of 6 Million United States Veterans (preprint)

Background: There is growing concern that racial and ethnic minority communities around the world are experiencing a disproportionate burden of morbidity and mortality from symptomatic SARS-Cov-2 infection or coronavirus disease 2019 (Covid-19). Most studies investigating racial and ethnic disparities to date have focused on hospitalized patients or have not characterized who received testing or those who tested positive for Covid-19. Objective: To compare patterns of testing and test results for coronavirus 2019 (Covid-19) and subsequent mortality by race and ethnicity in the largest integrated healthcare system in the United States. Design: Retrospective cohort study. Setting: United States Department of Veterans Affairs (VA). Participants: 5,834,543 individuals in care, among whom 62,098 were tested and 5,630 tested positive for Covid-19 between February 8 and May 4, 2020. Exposures: Self-reported race/ethnicity. Main outcome measures: We evaluated associations between race/ethnicity and receipt of Covid-19 testing, a positive test result, and 30-day mortality, accounting for a wide range of demographic and clinical risk factors including comorbid conditions, site of care, and urban versus rural residence. Results: Among all individuals in care, 74% were non-Hispanic white (white), 19% non-Hispanic black (black), and 7% Hispanic. Compared with white individuals, black and Hispanic individuals were more likely to be tested for Covid-19 (tests per 1000: white=9.0, [95% CI 8.9 to 9.1]; black=16.4, [16.2 to 16.7]; and Hispanic=12.2, [11.9 to 12.5]). While individuals from minority backgrounds were more likely to test positive (black vs white: OR 1.96, 95% CI 1.81 to 2.12; Hispanic vs white: OR 1.73, 95% CI 1.53 to 1.96), 30-day mortality did not differ by race/ethnicity (black vs white: OR 0.93, 95% CI 0.64 to 1.33; Hispanic vs white: OR 1.07, 95% CI 0.61 to 1.87). Conclusions: Black and Hispanic individuals are experiencing an excess burden of Covid-19 not entirely explained by underlying medical conditions or where they live or receive care. While there was no observed difference in mortality by race or ethnicity, our findings may underestimate risk in the broader US population as health disparities tend to be reduced in VA.

Covid-19 Testing, Hospital Admission, and Intensive Care Among 2,026,227 United States Veterans Aged 54-75 Years (preprint)

Importance: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (Covid-19), an evolving pandemic. Limited data are available characterizing SARS-Cov-2 infection in the United States. Objective: To determine associations between demographic and clinical factors and testing positive for coronavirus 2019 (Covid-19+), and among Covid-19+ subsequent hospitalization and intensive care. Design, Setting, and Participants: Retrospective cohort study including all patients tested for Covid-19 between February 8 and March 30, 2020, inclusive. We extracted electronic health record data from the national Veterans Affairs Healthcare System, the largest integrated healthcare system in the United States, on 2,026,227 patients born between 1945 and 1965 and active in care. Exposures: Demographic data, comorbidities, medication history, substance use, vital signs, and laboratory measures. Laboratory tests were analyzed first individually and then grouped into a validated summary measure of physiologic injury (VACS Index). Main Outcomes and Measures: We evaluated which factors were associated with Covid-19+ among all who tested. Among Covid-19+ we identified factors associated with hospitalization or intensive care. We identified independent associations using multivariable and conditional multivariable logistic regression with multiple imputation of missing values. Results: Among Veterans aged 54-75 years, 585/3,789 (15.4%) tested Covid-19+. In adjusted analysis (C-statistic=0.806) black race was associated with Covid-19+ (OR 4.68, 95% CI 3.79-5.78) and the association remained in analyses conditional on site (OR 2.56, 95% CI 1.89-3.46). In adjusted models, laboratory abnormalities (especially fibrosis-4 score [FIB-4] >3.25 OR 8.73, 95% CI 4.11-18.56), and VACS Index (per 5-point increase OR 1.62, 95% CI 1.43-1.84) were strongly associated with hospitalization. Associations were similar for intensive care. Although significant in unadjusted analyses, associations with comorbid conditions and medications were substantially reduced and, in most cases, no longer significant after adjustment. Conclusions and Relevance: Black race was strongly associated with Covid-19+, but not with hospitalization or intensive care. Among Covid-19+, risk of hospitalization and intensive care may be better characterized by laboratory measures and vital signs than by comorbid conditions or prior medication exposure.