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 (FcγRIIa) and FcγRIIIa, 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 FcγRIIa and FcγRIIIa 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.

A Robust SARS-CoV-2-specific T and B Cell Response is Associated with Early Viral Clearance in SARS-CoV-2 Omicron-Infected Immunocompromised Individuals.

BACKGROUND: The immunological determinants of delayed viral clearance and intra-host viral evolution that drive the development of new pathogenic virus strains in immunocompromised individuals are unknown. Therefore, we longitudinally studied SARS-CoV-2-specific immune responses in relation to viral-clearance and evolution in immunocompromised individuals. METHODS: Among Omicron-infected immunocompromised individuals, we determined SARS-CoV-2-specific T- and B-cell responses, anti-spike IgG(3) titers, neutralization titers, and monoclonal antibody (mAb)-resistance-associated mutations. The 28-day post-enrollment nasopharyngeal specimen defined early (RT-PCR negative ≤28 days) or late (RT-PCR- positive >28 days) viral-clearance. RESULTS: Of 30 patients included (median age 61.9 years [IQR 47.4-72.3], 50% females), 20 (66.7%) received mAb-therapy. Thirteen (43.3%) demonstrated early and 17 (56.7%) late viral-clearance. Early viral-clearance patients and patients without resistance-associated mutations had significantly higher baseline IFN-γ release and early viral-clearance patients had a higher frequency of SARS-CoV-2-specific B-cells at baseline. In non-mAb-treated patients, day 7 IgG and neutralization titers were significantly higher in those with early versus late viral-clearance. CONCLUSION: An early robust adaptive immune response is vital for efficient viral-clearance and associated with less emergence of mAb-resistance-associated mutations in Omicron-infected immunocompromised patients. This emphasizes the importance of early SARS-CoV-2-specific T- and B-cell responses and thereby provides a rationale for development of novel therapeutic approaches.