Immunogenicity of Convalescent and Vaccinated Sera Against Clinical Isolates of Ancestral SARS-CoV-2, Beta, Delta, and Omicron Variants

The omicron variant of concern (VOC) of SARS-CoV-2 was first reported in November 2021 in Botswana and South Africa. Omicron has evolved multiple mutations within the spike protein and the receptor binding domain (RBD), raising concerns of increased antibody evasion. Here, we isolated infectious omicron from a clinical specimen obtained in Canada. The neutralizing activity of sera from 65 coronavirus disease (COVID-19) vaccine recipients and convalescent individuals against clinical isolates of ancestral SARS-CoV-2, beta, delta, and omicron VOCs was assessed. Convalescent sera from unvaccinated individuals infected by the ancestral virus during the first wave of COVID-19 in Canada (July, 2020) demonstrated reduced neutralization against beta and omicron VOCs. Convalescent sera from unvaccinated individuals infected by the delta variant (May-June, 2021) neutralized omicron to significantly lower levels compared to the delta variant. Sera from individuals that received three doses of the Pfizer or Moderna vaccines demonstrated reduced neutralization of the omicron variant relative to ancestral SARS-CoV-2. Sera from individuals that were naturally infected with ancestral SARS-CoV-2 and subsequently received two doses of the Pfizer vaccine induced significantly higher neutralizing antibody levels against ancestral virus and all VOCs. Importantly, infection alone, either with ancestral SARS-CoV-2 or the delta variant was not sufficient to induce high neutralizing antibody titers against omicron. This data will inform current booster vaccination strategies, and we highlight the need for additional studies to identify longevity of immunity against SARS-CoV-2 and optimal neutralizing antibody levels that are necessary to prevent infection and/or severe COVID-19.Funding: SARS-CoV-2 research is supported in the laboratory of D.F. by the Canadian Institutes of Health Research (CIHR; OV5-170349, VRI-173022 and VS1-175531). A.B. receives funding from VIDO. VIDO receives operational funding from the Government of Saskatchewan through Innovation Saskatchewan and the Ministry of Agriculture and from the Canada Foundation for Innovation through the Major Science Initiatives for its CL3 facility. Studies from which clinical samples were collected were funded by CIHR grants to A.J.M and S.M. (#439999, #465038); from the Canadian COVID-19 Immunity Task Force to S.E.S and A.J.M.; and from the Toronto COVID Action Initiative Fund from the University of Toronto to J.L.W. and T.M. A.B., A-.C.G., J.L.W., S.M. and D.F. are members of the CIHR-funded Coronavirus Variants Rapid Response Network (CoVaRR-Net). R.K. is supported by an Ontario Together grant.Declaration of Interests: The authors declare no competing interests or conflicts of interest.Ethics Approval Statement: Use of clinical specimen for virus isolation and use of human serum samples for micro-neutralization assays were approved by the University of Saskatchewan’s Biomedical Research Ethics Board (REB# 2591). Cohort participants provided informed consent for sharing of serum, and studies were approved by the Sunnybrook Research Institute (REB# 149-1994) and/or the Mount Sinai Hospital (REB# 02-0118-U, 20-0339-E, and 21-0069-E) Research Ethics Board.