mRNA vaccines and hybrid immunity use different B cell germlines against Omicron BA.4 and BA.5

Omicron strains of SARS-CoV-2 have displayed high transmissibility and immunological escape to antibody responses derived from natural infection and vaccination. Here the authors compare the antibody response to vaccination and natural infection, assessing neutralisation after vaccine doses and analyse the repertoire of such responses. Severe acute respiratory syndrome 2 Omicron BA.4 and BA.5 are characterized by high transmissibility and ability to escape natural and vaccine induced immunity. Here we test the neutralizing activity of 482 human monoclonal antibodies isolated from people who received two or three mRNA vaccine doses or from people vaccinated after infection. The BA.4 and BA.5 variants are neutralized only by approximately 15% of antibodies. Remarkably, the antibodies isolated after three vaccine doses target mainly the receptor binding domain Class 1/2, while antibodies isolated after infection recognize mostly the receptor binding domain Class 3 epitope region and the N-terminal domain. Different B cell germlines are used by the analyzed cohorts. The observation that mRNA vaccination and hybrid immunity elicit a different immunity against the same antigen is intriguing and its understanding may help to design the next generation of therapeutics and vaccines against coronavirus disease 2019.

Automated summary

Omicron strains of SARS-CoV-2 exhibit high transmissibility and immune evasion against antibodies generated from natural infection and vaccination. This study compares the antibody response to vaccination and natural infection, evaluates neutralization after vaccine doses, and analyzes the diversity of these responses. The BA.4 and BA.5 variants of SARS-CoV-2 are only neutralized by approximately 15% of antibodies, with different antibody targeting preferences observed between vaccinated individuals and those who have been infected. Understanding the distinct immune responses elicited by mRNA vaccination and hybrid immunity can inform the development of future therapeutics and vaccines against COVID-19.