Abstract

Miroslava Cuperlovic-Culf, Yannick Galipeau, Pauline S. McCluskie, Corey Arnold, Salman Bagheri, Jörg Fritz, Ciriaco A. Piccirillo, Curtis L. Cooper, Marc-André Langlois, Angela M. Crawley, Steffany A.L. Bennett

Sex differences in anti-viral responses, vaccination and long-term recovery are increasingly recognized. Early in the Covid-19 pandemic it was observed that infection prevalence is sex independent or possibly higher in females. In contrast, males are more likely to experience severe disease, combined with increased hospitalization rates and higher mortality particularly significant in men over 60 years of age. In an effort to better understand the observed sex and age differences in SARS-CoV2 infection risk and immunization performance we have extensively analyzed a large longitudinal cohort: Stop the Spread Ottawa (SSO) (Collins, et al., 2022). The effects of sex and age on serum antibodies and ACE2 neutralization are investigated using a variety of novel data mining tools. This work demonstrates a novel approach for determining time changes in the response to infection and vaccination. It also provides insight into the neutralization differences observed by sex and age.
Specifically, the main objective of this work is to identify sex effects in integrated antibody and neutralization following SARS-CoV-2 infection and immunization. The Stop the Spread Ottawa (SSO) cohort has followed  1000 participants during SARS-CoV-2 pandemic including uninfected and convalescent infected participants. This longitudinal study has started in Oct 2020, continuing through infection and vaccinations for 10 months (n=1000) with ongoing follow-up (n=300). A comprehensive quantification of antibody responses to relevant SARS-CoV-2 viral antigens, seasonal coronaviruses across immunoglobulin isotypes and neutralization of SARS-CoV-2 (RBD) has been conducted. Serial collection of serum samples finally provided 3666 samples. In this analysis, samples are divided by the vaccination period, age or sex of the participant or SARS-CoV-2 natural immunity status. Nine antibodies were measured from each serum sample corresponding to IgG, IgA and IgM titers specific for SARS-CoV-2 receptor binding domain (R), spike (S) and nucleoprotein (N) as well as ACE2 protein neutralization values. These data have been combined with accompanying extensive clinical data, generating a unique dataset for detailed analyses of sex differences following COVID-19 vaccination and/or infection using integrative machine learning approaches.

Through machine learning unsupervised and supervised analysis and distance correlation we have described major changes in the role of individual immunoglobulins in neutralization of ACE2. Contribution program changes over time and is strongly dissimilar between sex and age groups. Major impact of this work is in understanding that the contribution of the antibodies to neutralization is a more significant change in immunization and between subjects groups then their concentration. Thus, alterations in contributions of individual immunoglobulins, in an attempts to improve immunization strategy or reduce effects of imprinting requires analysis and alteration of the complete network of immunoglobulins in humoral response rather than change of only individual factors. Characterization of SARS-CoV-2 antibody responses by age and sex offer an opportunity to direct future studies to integrate associated cell mediated responses in search of defining correlates of protection that will inform future vaccine design.