Large scale analysis of the SARS-CoV-2 main protease reveals marginal presence of nirmatrelvir-resistant SARS-CoV-2 Omicron mutants in Ontario, Canada, December 2021-September 2023.

BACKGROUND

In response to the COVID-19 pandemic, a new oral antiviral called nirmatrelvir-ritonavir (Paxlovid) was authorized for use in Canada in January 2022. studies have reported mutations in M protein that may be associated with the development of nirmatrelvir resistance.

OBJECTIVES

To survey the prevalence, relevance and temporal patterns of M mutations among SARS-CoV-2 Omicron lineages in Ontario, Canada.

METHODS

A total of 93,082 M gene sequences from December 2021 to September 2023 were analyzed. Reported M mutations were screened against our database using in-house data science pipelines to determine the nirmatrelvir resistance. Negative binomial regression was conducted to analyze the temporal trends in M mutation counts over the study time period.

RESULTS

A declining trend was observed in non-synonymous mutations of M sequences, showing a 7.9% reduction (95% CI: 6.5%-‬9.4%; <0.001) every 30 days. The P132H was the most prevalent mutation (higher than 95%) in all Omicron lineages. nirmatrelvir-resistant mutations were found in 3.12% (n=29/929) Omicron lineages with very low counts, ranging from one to 19. Only two mutations, A7T (n=19) and M82I (n=9), showed temporal presence among the BA.1.1 in 2022 and the BQ.1.2.3 in 2022, respectively.

CONCLUSION

The observations suggest that, as of September 2023, no significant or widespread resistance to nirmatrelvir has developed among SARS-CoV-2 Omicron variants in Ontario. This study highlights the importance of creating automated monitoring systems to track the emergence of nirmatrelvir-resistant mutations within the SARS-CoV-2 virus, utilizing genomic data generated in real-time.