Antibody Attributes that Predict the Neutralization and Effector Function of Polyclonal Responses to SARS-CoV-2

Abstract

While antibodies provide significant protection from SARS-CoV-2 infection and disease sequelae, the specific attributes of the humoral response that contribute to immunity are incompletely defined. In this study, we employ machine learning to relate characteristics of the polyclonal antibody response raised by natural infection to diverse antibody effector functions and neutralization potency with the goal of generating both accurate predictions of each activity based on antibody response profiles as well as insights into antibody mechanisms of action. To this end, antibody-mediated phagocytosis, cytotoxicity, complement deposition, and neutralization were accurately predicted from biophysical antibody profiles in both discovery and validation cohorts. These predictive models identified SARS-CoV-2-specific IgM as a key predictor of neutralization activity whose mechanistic relevance was supported experimentally by depletion. Validated models of how different aspects of the humoral response relate to antiviral antibody activities suggest desirable attributes to recapitulate by vaccination or other antibody-based interventions.

Heterologous SARS-CoV-2 IgA neutralising antibody responses in convalescent plasma

“…However, purified IgG mediated higher RBD-ACE2 inhibition compared to purified IgA for most convalescent donors. While IgG and IgA contribute to convalescent plasma neutralisation, depletion of IgG and IgA did not abolish neutralisation in many individuals, supporting the role of IgM in the convalescent plasma neutralising response to SARS-CoV-2 (Gasser et al, 2021;Natarajan, Xu, et al, 2021). Our data further supports the finding that IgA is capable of neutralising SARS-CoV-2 WT, although this response is heterogenous with in this cohort, likely due to heterogeneity in IgA titres against RBD.…”

“…A strong correlate of protection for most viral vaccines, including SARS-CoV-2 vaccines, are neutralising antibodies (Khoury et al, 2021;Plotkin, 2010). IgM and IgG have been widely implicated in effective neutralisation of SARS-CoV-2 (Gasser et al, 2021;Lopez et al, 2021;Natarajan, Xu, et al, 2021;Wheatley et al, 2021). However, throughout the COVID-19 pandemic, the study of anti-SARS-CoV-2 IgA responses have been relatively neglected (Verkerke et al, 2021).…”

“…Neutralising and non-neutralising antibodies, including IgG and IgA, can engage Fc receptors (FcγR and FcαR respectively) on immune cells and activate Fc effector functions to clear viral infection (Asokan et al, 2020; Blutt et al, 2012; Davis et al, 2020). Effector functions including complement activation, phagocytosis, and antibody dependent cellular cytotoxicity (ADCC) have been implicated in clearance and control of SARS-CoV-2 infection (Dufloo et al, 2021; Lee et al, 2021; Natarajan et al, 2021). Importantly, compromised Fc effector function and reduced neutralising potency have been linked to poorer disease outcomes in humans (Garcia-Beltran et al, 2021; Zohar et al, 2020).…”

Heterologous SARS‐CoV‐2 IgA neutralising antibody responses in convalescent plasma

“…While we show that IgG and IgA contribute to convalescent plasma neutralisation, depletion of IgG and IgA did not abolish this response in most individuals, further reinforcing the importance of IgM in the convalescent plasma neutralising response to SARS-CoV-2. 17,42 Our data further support the finding that IgA is capable of neutralising SARS-CoV-2 WT. However, this response is highly heterogenous and is likely to be due to variability in IgA titres generated against RBD.…”

Protein-protein conjugation enhances the immunogenicity of SARS-CoV-2 receptor-binding domain (RBD) vaccines

“…AS01, which incorporates two immune potentiators (the TLR4 agonist MPL and the saponin QS-21), gave a mixed IgG subclass distribution with larger contributions from IgG2a and IgG2b compared to IgG1, indicating a Th1-biased immune response (Coccia et al, 2017). A mixed immune response inducing multiple antibody subclasses may be beneficial for an effective antiviral activity involving receptor-binding inhibition as well as other antibody-mediated effector functions such as complementdependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) (Natarajan et al, 2020;Tay et al, 2019).…”