Self-amplifying COVID-19 mRNA vaccination induces longitudinally enhanced antibody function in a Phase 3 trial

Sustained and functional antibody responses to respiratory pathogens through vaccination is critical for global public health. The development and deployment of mRNA vaccines during the coronavirus disease 2019 (COVID-19) pandemic was a landmark achievement in modern medicine and ushered in a new age of vaccine innovation. The mRNA-based vaccines elicited strong antibody responses, both neutralizing and extra-neutralizing, against the viral Spike protein. The antibody levels waned with time since vaccination, and that coupled with the antigenic drift of the virus prompted updates to the mRNA vaccine composition and evaluation of other mRNA modalities. 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, however, is unclear. Here, we analyze serum-based antibody responses in a subset of participants from a recent Phase III trial comparing neutralizing immune responses elicited by ARCT-154 and mRNA BNT162B2 as a post-hoc research. 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 of this research were to quantify waning responses against ancestral/wild type SARS-CoV-2 Spike (WT Spike) and a panel of diverse SARS-CoV-2 variant Spikes. Through a systems serology approach, 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 FcγRIIIA-binding antibodies showed a sustained stimulation in the ARCT-154-treatment arm, and this translated to an enhanced natural killer (NK) cell activation. The NK-activation through ARCT-154 was present for both target WT Spike and the antigenically drifted BA.5 Spike, which was the predominant form of SARS-CoV-2 during the observation period. Our results support a model whereby prolonged antigen expression and presentation moves immune profiles towards activating phenotypes with broad antigenic coverage.