Subtle immunological differences in mRNA-1273 and BNT162b2 COVID-19 vaccine induced Fc-functional profiles (preprint)

The successful development of several COVID-19 vaccines has substantially reduced morbidity and mortality in regions of the world where the vaccines have been deployed. However, in the wake of the emergence of viral variants, able to evade vaccine induced neutralizing antibodies, real world vaccine efficacy has begun to show differences across the mRNA platforms, suggesting that subtle variation in immune responses induced by the BNT162b2 and mRNA1273 vaccines may provide differential protection. Given our emerging appreciation for the importance of additional antibody functions, beyond neutralization, here we profiled the postboost binding and functional capacity of the humoral response induced by the BNT162b2 and mRNA-1273 in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to WT SARS-CoV-2 and VOCs. However, differences emerged across epitopespecific responses, with higher RBD- and NTD-specific IgA, as well as functional antibodies (ADNP and ADNK) in mRNA-1273 vaccine recipients. Additionally, RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector function induced across the mRNA vaccines, providing novel insights into potential differences in protective immunity generated across these vaccines in the setting of newly emerging VOCs.

Therapeutic Potential of SARS-CoV-2-Specific Monoclonal Antibody CR3022 (preprint)

The spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics or vaccines, has paralyzed the globe. While significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc-interactions may be vital to eliminate the virus. However, Fc-engineering efforts have largely been blind, using limited data to select Fc-modifications. To explore the role of Fc-activity in SARS-CoV-2 immunity, the functional potential of a cross-SARS-reactive antibody, CR3022, was assessed. CR3022 was able to broadly drive antibody effector functions, providing critical immune clearance at entry and upon egress. Using selectively engineered Fc-variants, enhanced disease was observed after administration of wildtype IgG. Conversely, the functionally enhanced Fc-variant provided protection when administered therapeutically. Surprisingly, the Fc-silenced variant showed significant protection. These data point to the need for strategic Fc-engineering for the prevention and treatment of SARS-CoV-2 infection.Funding: We acknowledge support from the Ragon Institute of MGH, MIT, the Massachusetts Consortium on Pathogen Readiness (MassCPR), and the Bill & Melinda Gates Foundation (235730).Conflict of Interest: Galit Alter is a founder of SeromYx Systems. All other authors declare no conflicts of interest.