Sustained Humoral Activation through self-amplifying mRNA Vaccination Enhances Longitudinal Antibody Function in a Phase III Trial 2305471

Abstract Introduction The development and deployment of mRNA vaccines during the COVID-19 pandemic was a landmark achievement in modern medicine and ushered in a new age of vaccine innovation. The vaccines strongly elicited both neutralizing and non-neutralizing antibody responses against the viral Spike protein, but these waned over time. Self-amplifying mRNA (sa-mRNA) vaccines such as ARCT-154 can prolong antigen production and durability of humoral immune response post-immunization and can thus be administered at a lower dose. How this translates into the overall humoral architecture compared to that shaped by conventional mRNA vaccinations is unclear. Methods We analyzed serum antibody responses from a Phase III trial comparing humoral responses elicited by ARCT-154 and mRNA BNT162B2 by systems serology. All participants had received three doses of mRNA COVID-19 vaccines and were randomized to receive a booster dose of ARCT-154 or BNT162B2. Primary outcomes were to quantify waning responses against ancestral SARS-CoV-2 Spike and a panel of antigenically drifted SARS-CoV-2 variant Spikes. Results We identified that the sa-mRNA vaccine ARCT-154 elicited a unique antibody response compared to BNT162B2 defined by a sustained, activating profile to the vaccine-encoded Spike protein and a broad spectrum of drifted Spikes. Notably, potently activating FcgRIIIA-binding antibodies showed a sustained stimulation in the ARCT-154-treatment arm, and this translated to enhanced antibody-dependent natural killer cell activation (ADNKA) to both target WT Spike and the antigenically drifted BA.5 Spike, which was the predominant form of SARS-CoV-2 during the observation period. Conclusion Recipients of the sa-mRNA booster showed a temporally sustained humoral activation and an overall antibody architecture that favored pro-activating phenotypes. Our results support a model whereby prolonged antigen expression and presentation moves immune profiles towards activating phenotypes with broad antigenic coverage. Funding Source Bill and Melinda Gates Foundation INV-080712 Topic Categories Vaccines and Immunotherapy (VAC)