ABSTRACT
Background COVID-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. Methods This 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 Discussion This 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.