RESUMO
The SARS-CoV-2 Omicron BA.1 variant, which exhibits high level neutralization resistance, has since evolved into several sub-lineages including BA.4 and BA.5, which have dominated the fifth wave of infection in South Africa. Here we assessed the sensitivity of BA.4 to neutralization and antibody dependent cellular cytotoxicity (ADCC) in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections (BTIs) caused by Delta or BA.1. We confirm that BA.4 shows high level resistance to neutralization, regardless of the infecting variant. However, breakthrough infections, which trigger potent neutralization, retained activity against BA.4, albeit at reduced titers. Fold reduction of neutralization in BTIs was lower than that seen in unvaccinated convalescent donors, suggesting maturation of neutralizing responses to become more resilient against VOCs in hybrid immunity. BA.4 sensitivity to ADCC was reduced but remained detectable in both convalescent donors and in BTIs. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infections, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC activity against BA.4 was reduced, residual activity may nonetheless contribute to the protection from disease.
RESUMO
SARS-CoV-2 variants of concern (VOCs) differentially trigger neutralizing antibodies with variable cross-neutralizing capacity. Here we show that unlike SARS-CoV-2 Omicron BA.1, which triggered neutralizing antibodies with limited cross-reactivity, BA.4/5 infection triggers highly cross-reactive neutralizing antibodies. Cross-reactivity was observed both in the absence of prior vaccination and also in breakthrough infections following vaccination. This suggests that next-generation vaccines incorporating BA.4, which is spreading globally, might result in enhanced neutralization breadth.
