Distinct Features and Functions of Systemic and Mucosal Humoral Immunity Among SARS-CoV-2 Convalescent Individuals

Abstract

Understanding humoral immune responses to SARS-CoV-2 infection will play a critical role in the development of vaccines and antibody-based interventions. We report systemic and mucosal antibody responses in convalescent individuals who experienced varying severity of disease. Whereas assessment of neutralization and antibody-mediated effector functions revealed polyfunctional antibody responses in serum, only robust neutralization and phagocytosis were apparent in nasal wash samples. Serum neutralization and effector functions correlated with systemic SARS-CoV-2-specific IgG response magnitude, while mucosal neutralization was associated with nasal SARS-CoV-2-specific IgA. Antibody depletion experiments support the mechanistic relevance of these correlations. Associations between nasal IgA responses, virus neutralization at the mucosa, and less severe disease suggest the importance of assessing mucosal immunity in larger natural infection cohorts. Further characterization of antibody responses at the portal of entry may define their ability to contribute to protection from infection or reduced risk of hospitalization, informing public health assessment strategies and vaccine development efforts.

Diverse immunoglobulin gene usage and convergent epitope targeting in neutralizing antibody responses to SARS-CoV-2

“…While some of the potent neutralizing antibodies could mediate ADE, they are still able to protect animals from virus challenge (Kam et al, 2007;Li et al, 2021). Studies have shown that both neutralization and other effector functions of antibody contribute to optimal protection against SARS-CoV-2 challenge in vivo (Butler et al, 2021;Chan et al, 2020;Schä fer et al, 2021). We show in this study that 47D1 is able to protect hamsters from SARS-CoV-2 challenge.…”

Decay of Fc-dependent antibody functions after mild to moderate COVID-19

“…At present, analyses of Fc-mediated functions of SARS-CoV-2 antibodies within COVID-19 convalescent subjects have focused upon cross-sectional analyses or short-term longitudinal studies up to 1 to 2 months post-symptom onset. 16,19,20 We extend these findings and analyze Fc effector functions mediated by S-specific antibodies in a cohort of 53 convalescent individuals up to 149 days postsymptom onset. We developed functional assays using SARS-CoV-2 S-expressing cells to comprehensively analyze plasma ADCC and ADP activity against SARS-CoV-2 S. Our results show that plasma ADCC and ADP activity decays over the first 4 months post-infection, mirroring the decline in S-specific IgG titers.…”

“…Fc effector functions contribute to the prevention and control of other viral infections, including HIV-1, influenza, and Ebola. [13][14][15] Butler et al 16 recently showed that SARS-CoV-2 RBD-specific antibodies within plasma could crosslink Fcg receptors and mediate ADP and antibody-dependent complement deposition. Importantly, two recent challenge studies demonstrated that certain RBD-specific mAbs rely on Fc effector functions to mediate protection against SARS-CoV-2 in mice.…”

Anti-spike S1 IgA, anti-spike trimeric IgG, and anti-spike RBD IgG response after BNT162b2 COVID-19 mRNA vaccination in healthcare workers

“…Although it is virtually undeniable that cellular immunity and circulating anti-SARS-CoV-2 IgG antibodies would act in synergy to neutralize the virus either within or outside the host cells (9), mucosal immune response is expected to play a major role in preventing or limiting viral infection, as SARS-CoV-2 initially penetrates the cells of upper and lower respiratory tracts (10). To this end, the associations between nasal anti-SARS-CoV-2 IgA antibodies responses, virus neutralization at the mucosal surface, and lower risk of developing severe COVID-19 illness provide further support to the clinical significance of assessing and monitoring mucosal immunity in patients with natural SARS-CoV-2 infection and/or in COVID-19 vaccine recipients (17,18).…”