Spike Mutation Profiles Associated With SARS-CoV-2 Breakthrough Infections in Delta Emerging and Predominant Time Periods in British Columbia, Canada

Abstract

BackgroundCOVID-19 vaccination is a key public health measure in the pandemic response. The rapid evolution of SARS-CoV-2 variants introduce new groups of spike protein mutations. These new mutations are thought to aid in the evasion of vaccine-induced immunity and render vaccines less effective. However, not all spike mutations contribute equally to vaccine escape. Previous studies associate mutations with vaccine breakthrough infections (BTI), but information at the population level remains scarce. We aimed to identify spike mutations associated with SARS-CoV-2 vaccine BTI in a community setting during the emergence and predominance of the Delta-variant.MethodsThis case-control study used both genomic, and epidemiological data from a provincial COVID-19 surveillance program. Analyses were stratified into two periods approximating the emergence and predominance of the Delta-variant, and restricted to primary SARS-CoV-2 infections from either unvaccinated individuals, or those infected ≥14 days after their second vaccination dose in a community setting. Each sample's spike mutations were concatenated into a unique spike mutation profile (SMP). Penalized logistic regression was used to identify spike mutations and SMPs associated with SARS-CoV-2 vaccine BTI in both time periods.Results and DiscussionThis study reports population level relative risk estimates, between 2 and 4-folds, of spike mutation profiles associated with BTI during the emergence and predominance of the Delta-variant, which comprised 19,624 and 17,331 observations, respectively. The identified mutations cover multiple spike domains including the N-terminal domain (NTD), receptor binding domain (RBD), S1/S2 cleavage region, fusion peptide and heptad regions. Mutations in these different regions imply various mechanisms contribute to vaccine escape. Our profiling method identifies naturally occurring spike mutations associated with BTI, and can be applied to emerging SARS-CoV-2 variants with novel groups of spike mutations.

Bridging Computational Predictions and Empirical Data: Insights into SARS-CoV-2 Mutational Impacts and Evolution

“…The presence of this mutation in such a key location suggests its potential impact on the fusion ability of the spike protein 18 . This observation is particularly relevant considering the notable association of this mutation with breakthrough infections (BTIs) during the emergence of the Delta variant 19 . According to pre-clinical evidence, the presence of both D614G and S939F mutations in the spike protein of SARS-CoV-2 resulted in a higher infection rate than other mutations 20 .…”

RCoV19: A One-Stop Hub for SARS-CoV-2 Genome Data Integration, Variant Monitoring, and Risk Pre-Warning

“…Moreover, several novel mutations with high frequencies, such as S371F, T376A, and S477N (frequency > 0.89), in S gene, have emerged in XBB.1 and XBB.1.5. Additionally, well-known mutations, such as D614G (known to enhance SARS-CoV-2 infectivity in human lung cells) and N501Y (associated with reduced vaccine protection in Delta), may explain the prevalence of ongoing XBB variants [24] . In addition to the extensively studied S gene, N gene mutations like R203K and G204R, implicated in increased transmission [25] , are commonly observed in the top 3 ongoing lineages ( Figure 6 B).…”

RCoV19: A One-stop Hub for SARS-CoV-2 Genome Data Integration, Variants Monitoring, and Risk Pre-warning

“…Moreover, several novel mutations with high frequencies, such as S371F, T376A, and S477N (frequency > 0.89), have emerged in XBB.1 and XBB.1.5. Additionally, well-known mutations like D614G, known to enhance SARS-CoV-2 infectivity in human lung cells, and N501Y, associated with reduced vaccine protection in Delta, may explain the prevalence of ongoing XBB variants [19]. In addition to the extensively studied S protein, N protein mutations like R203K and G204R, implicated in increased transmission [20], are commonly observed in the top three ongoing lineages ( Figure 6B ).…”