Early cross-coronavirus reactive signatures of protective humoral immunity against COVID-19

Abstract

The introduction of vaccines has inspired new hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against COVID-19, thus we profiled the earliest humoral signatures in a large cohort of severe and asymptomatic COVID-19 individuals. While a SARS-CoV-2-specific immune response evolved rapidly in survivors of COVID-19, non-survivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibody evolution. Given the conservation of S2 across β-coronaviruses, we found the early development of SARS-CoV-2-specific immunity occurred in tandem with pre-existing common β-coronavirus OC43 humoral immunity in survivors, which was selectively also expanded in individuals that develop paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19.

Boosting of cross-reactive antibodies to endemic coronaviruses by SARS-CoV-2 infection but not vaccination with stabilized spike

“…To date, antibody cross-reactivity has been inferred from indirect evidence in the form of boosted responses to endemic CoV ( Guo et al, 2021 ; Morgenlander et al, 2021 ; Wang et al, 2021 ; Kaplonek et al, 2021 ; Ortega et al, 2021 ), and more conclusively observed for select monoclonal antibodies that have been cloned and cross-tested ( Sakharkar et al, 2021 ; Dugan et al, 2021 ). To better generalize the more definitive monoclonal studies, we sought to directly define the cross-reactivity of polyclonal antibodies raised following SARS-CoV-2 infection.…”

“…The extent to which preexisting responses to prior endemic CoV exposures may influence responses to SARS-CoV-2 infection and vaccination is not yet clear, but has been suggested from studies relating recent endemic CoV infection with reduced severity of COVID-19 ( Sagar et al, 2021 ; Aran et al, 2020 ). Numerous studies have observed elevated responses to endemic CoV following SARS-CoV-2 infection ( Guo et al, 2021 ; Morgenlander et al, 2021 ; Wang et al, 2021 ; Kaplonek et al, 2021 ; Ortega et al, 2021 ), and more recent work has shown that the magnitude of this ‘back-boosting’ effect is inversely correlated with the induction of IgG and IgM against SARS-CoV-2 spike (S) protein ( Aydillo et al, 2021 ). Given differential degrees of homology between the receptor-binding domain (RBD) in S1 that is the target of the majority of neutralizing antibodies, and the better-conserved S2 domain that may be the target of antibodies with diverse effector functions but which are rarely neutralizing, the original antigenic sin hypothesis suggests that lower titers of neutralizing antibodies against SARS-CoV-2 may result from boosting of preexisting cross-reactive lineages.…”

Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike

“…To date, antibody cross-reactivity has been inferred from indirect evidence in the form of boosted responses to endemic CoV [23][24][25][26][27] , and more conclusively observed for select monoclonal antibodies that have been cloned and cross tested 33,34 . To better generalize the more definitive monoclonal studies, we sought to directly define the cross-reactivity of polyclonal antibodies raised following SARS-CoV-2 infection.…”

“…Numerous studies have observed elevated responses to endemic CoV following SARS-CoV-2 infection [23][24][25][26][27] , and more recent work has shown that the magnitude of this "back-boosting" effect is inversely correlated with the induction of IgG and IgM against to SARS-CoV-2 spike (S) protein 28 . Given differential degrees of homology between the receptor binding domain (RBD) in S1 that is the target of the majority of neutralizing antibodies, and the better conserved S2 domain that may be the target of antibodies with diverse effector functions but which are rarely neutralizing, the original antigenic sin hypothesis suggests that lower titers of neutralizing antibodies against SARS-CoV-2 may result from boosting of pre-existing cross-reactive lineages.…”

Detailed Analysis of Immune Tolerance Mechanisms to SARS-CoV-2 in Children Is Needed

“…This humoral immunity selectively expanded in asymptomatic SARS-CoV-2 infected individuals, leading to a more robust containment of the infection. Especially, considering conservation of S2 across β-coronaviruses, presence of S2-specific antibodies with Fc-receptor binding capabilities strongly predicted the protective immunity against mortality ( 15 ).…”