Primary SARS-CoV-2 variant of concern infections elicit broad antibody Fc-mediated effector functions and memory B cell responses

Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by human sera is a strong correlate of protection against symptomatic and severe Coronavirus Disease 2019 (COVID-19). The emergence of antigenically distinct SARS-CoV-2 variants of concern (VOCs) and the relatively rapid waning of serum antibody titers, however, raises questions about the sustainability of serum protection. In addition to serum neutralization, other antibody functionalities and the memory B cell (MBC) response are suggested to help maintaining this protection. In this study, we investigate the breadth of spike (S) protein-specific serum antibodies that mediate effector functions by interacting with Fc-gamma receptor IIa (Fc gamma RIIa) and Fc gamma RIIIa, and of the receptor binding domain (RBD)-specific MBCs, following a primary SARS-CoV-2 infection with the D614G, Alpha, Beta, Gamma, Delta, Omicron BA.1 or BA.2 variant. Irrespectively of the variant causing the infection, the breadth of S protein-specific serum antibodies that interact with Fc gamma RIIa and Fc gamma RIIIa and the RBD-specific MBC responses exceeded the breadth of serum neutralization, although the Alpha-induced B cell response seemed more strain-specific. Between VOC groups, both quantitative and qualitative differences in the immune responses were observed, suggesting differences in immunogenicity. Overall, this study contributes to the understanding of protective humoral and B cell responses in the light of emerging antigenically distinct VOCs, and highlights the need to study the immune system beyond serum neutralization to gain a better understanding of the protection against emerging variants. The SARS-CoV-2 virus, first identified in 2019, swiftly led to a global pandemic. Crucial for the protection against re-infections are sufficient levels of neutralizing antibodies in the blood. However, SARS-CoV-2 have evolved into antigenically distinct variants of concern (VOC) that escape protection by these neutralizing antibodies. In addition, the relatively rapid waning of serum antibody titers raises questions about the sustainability of protection. In this study, we investigated the ability of antibodies and memory B cells to recognize the emerging variants after primary SARS-CoV-2 infection with different variants of concern. Compared with neutralizing antibodies, antibodies that can mediate Fc-mediated effector functions as well as memory B cells were, in general, more cross-reactive to other variants, irrespectively of the variant causing the infection. However, we found variations in the level of immune responses depending on the infecting variant, indicating differences in the immunogenicity of SARS-CoV-2 VOC. These results highlight the need to study the immune system beyond serum neutralization to gain a better understanding of the protection against emerging variants.