Demystifying the antiviral activity of the IgG3+ antibody response

Since 2002, several coronaviruses have emerged able to cause severe respiratory disease, however no vaccineis available to prevent these rapidly spreading pathogens. Vaccine design has specifically lagged due to our lackof understanding of the correlates of immunity against these pathogens. Both cellular and humoral immuneresponses have been implicated in resolution of disease, but to date only the passive transfer of antibodies hasbeen shown to confer complete protection in mice. Interestingly, the transfer of both "neutralizing" and non-neutralizing antibodies have shown protective efficacy, highlighting the role of multiple humoral mechanisms inlimiting viral infection/spread. The precise mechanism of action of these antibodies that have the most profoundimpact on limiting disease is currently unclear, but if elucidated could provide critical insights for the developmentof effective vaccines against COVID-19 and other coronaviruses. Thus, here we aim to take a systematicapproach to dissect and define both the polyclonal and monoclonal mechanisms by which antibodies conferprotection against COVID-19. Specifically, samples from DNA- and adenovirus 26 (Ad26)- COVID-19 Spikeprotein (S) immunized animals, that will be challenged with COVID-19, will be comprehensively profiled usingSystems Serology, to define the functional humoral immune responses linked to protection from infection/diseasein mice, ferrets, and macaques. Machine learning modeling will be employed to discern key immune responsefeatures that translate usefully across these diverse animal contexts. Coupled to a novel systems-Fc-engineeringapproach, the COVID-19 CR3022 monoclonal antibody will be engineered to specifically define the Fc-effectorfunctions that provide the greatest impact on limiting disease. Collectively, these studies will not only definecorrelates of immunity across vaccines and species, but also provide mechanistic insights into the precisemechanisms by which antibodies may confer protection in the context of future vaccines.