ABSTRACT
Background: The decline in COVID-19 mRNA vaccine effectiveness (VE) is well established, however the impact of variant-specific immune evasion and waning protection remains unclear. Here, we use whole-genome-sequencing (WGS) to tease apart the contribution of these factors on the decline observed following the introduction of the Delta variant. Further, we evaluate the utility of calendar-period-based variant classification as an alternative to WGS. Methods: We conducted a test-negative-case-control study among people who received SARS-CoV-2 RT-PCR testing in the Yale New Haven Health System between April 1 and August 24, 2021. Variant classification was performed using WGS and secondarily by calendar-period. We estimated VE as one minus the ratio comparing the odds of infection among vaccinated and unvaccinated people. Results: Overall, 2,029 cases (RT-PCR positive, sequenced samples) and 343,985 controls (negative RT-PCRs) were included. VE 14-89 days after 2nd dose was significantly higher against WGS-classified Alpha infection (84.4%, 95% confidence interval: 75.6-90.0%) than Delta infection (68.9%, CI: 58.0-77.1%, p-value: 0.013). The odds of WGS-classified Delta infection were significantly higher 90-149 than 14-89 days after 2nd dose (Odds ratio: 1.6, CI: 1.2-2.3). While estimates of VE against calendar-period-classified infections approximated estimates against WGS-classified infections, calendar-period-based classification was subject to outcome misclassification (35% during Alpha period, 4% during Delta period). Conclusions: These findings suggest that both waning protection and variant-specific immune evasion contributed to the lower effectiveness. While estimates of VE against calendar-period-classified infections mirrored that against WGS-classified infections, our analysis highlights the need for WGS when variants are co-circulating and misclassification is likely.
Subject(s)
COVID-19 , Genomic Instability , Hepatitis DABSTRACT
Background. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes Coronavirus disease-19 (COVID-19), a respiratory illness with influenza-like symptoms that can result in hospitalization or death. We investigated human genetic determinants of COVID-19 risk and severity in 455,838 UK Biobank participants, including 2,003 with COVID-19. Methods. We defined eight COVID-19 phenotypes (including risks of infection, hospitalization and severe disease) and tested these for association with imputed and exome sequencing variants. Results. We replicated prior COVID-19 genetic associations with common variants in the 3p21.31 (in LZTFL1) and 9q34.2 (in ABO) loci. The 3p21.31 locus (rs11385942) was associated with disease severity amongst COVID-19 cases (OR=2.2, P=3x10-5), but not risk of SARS-CoV-2 infection without hospitalization (OR=0.89, P=0.25). We identified two loci associated with risk of infection at P<5x10-8, including a missense variant that tags the epsilon 4 haplotype in APOE (rs429358; OR=1.29, P=9x10-9). The association with rs429358 was attenuated after adjusting for cardiovascular disease and Alzheimer's disease status (OR=1.15, P=0.005). Analyses of rare coding variants identified no significant associations overall, either exome-wide or with (i) 14 genes related to interferon signaling and reported to contain rare deleterious variants in severe COVID-19 patients; (ii) 36 genes located in the 3p21.31 and 9q34.2 GWAS risk loci; and (iii) 31 additional genes of immunologic relevance and/or therapeutic potential. Conclusions. Our analyses corroborate the association with the 3p21.31 locus and highlight that there are no rare protein-coding variant associations with effect sizes detectable at current sample sizes. Our full analysis results are publicly available, providing a substrate for meta-analysis with results from other sequenced COVID-19 cases as they become available. Association results are available at https://rgc-covid19.regeneron.com