ABSTRACT
It is becoming increasingly clear that individuals recovered from acute coronavirus disease 2019 (COVID-19) can develop into long-term sequelae (post-acute sequala of SARS-CoV-2 infection, PACS). While antibody response kinetics against viral particles is well studied in natural infection and vaccine, the molecular mechanisms governing disease formation remain elusive. We investigated plasma and saliva samples from COVID-19 and healthy control subjects to understand early immune responses globally after exposure to the virus. Antibody analyses showed robust IgA and IgG responses, neutralizing functions to the SARS-CoV-2, and positive correlations between matched plasma and saliva fluids. Shotgun proteomics revealed persistent inflammatory patterns in convalescent samples including dysfunction of neutrophil-fibrinogen axis, and dysregulated immune and clotting functions. Our study suggests saliva as fluid to monitor serology and immune functions to detect early and chronic signs of disease development. Further delineation of the pathophysiology in saliva may lead to discovery of novel biomarkers and therapeutic targets to patients at risk to develop PASC and chronic conditions.
Subject(s)
COVID-19ABSTRACT
Multiple SARS-CoV-2 variants that possess mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. While the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.529) spike appear to diminish the efficacy of pre-existing immunity. Using pseudoparticles expressing the spike of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in naturally infected and in mRNA-vaccinated individuals. We observed that while boosting increases the magnitude of the antibody response to wildtype (D614), Beta, Delta and Omicron variants, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses while responses were relatively reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.
Subject(s)
COVID-19ABSTRACT
Serologic markers that predict severe COVID-19 disease trajectories could enable early medical interventions and reduce morbidity and mortality. We found that distinct features of IgG Fab and Fc domain structures were present within three days of a positive test that predicted two separate disease trajectories in a prospective cohort of patients with COVID-19. One trajectory was defined by early production of neutralizing antibodies and led to mild disease. A distinct trajectory, characterized by an initial period of mild symptoms followed by rapid progression to more severe outcomes, was predicted by the absence of early neutralizing antibody responses with concomitant production of afucosylated IgGs. Elevated frequencies of monocytes expressing the receptor for afucosylated IgGs, Fc{gamma}RIIIa (CD16a), were an additional antecedent in patients with the more severe outcomes. In mechanistic studies, afucosylated immune complexes in the lung triggered an inflammatory infiltrate and cytokine production that was dependent on CD16a. Finally, in healthy subjects, mRNA SARS-CoV-2 vaccination elicited neutralizing antibodies that were enriched for Fc fucosylation and sialylation and distinct from both infection-induced trajectories. These data show the importance of combined Fab and Fc domain functions in the antiviral response, define an early antibody signature in people who progressed to more severe COVID-19 outcomes and have implications for novel therapeutic strategies targeting Fc{gamma}RIIIa pathways.