Use of whole genome sequencing to estimate the contribution of immune evasion and waning immunity to decreasing COVID-19 vaccine effectiveness during alpha and delta variant waves (preprint)

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.

In vitro and in vivo preclinical studies predict REGEN-COV protection against emergence of viral escape in humans (preprint)

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in nature or identified from preclinical in vitro and in vivo studies and in the clinic. This study demonstrates that a combination of non-competing antibodies not only provides full coverage against currently circulating variants but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.

Genetic association analysis of SARS-CoV-2 infection in 455,838 UK Biobank participants (preprint)

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