Durability of next-generation self-replicating RNA vaccine RBI-4000: a phase 1, randomized open label clinical trial.

Abstract

Background: The benefits of mRNA-based platforms, such as rapid response and simplified manufacturing, may be overshadowed by lack of durable protective immunity compared to traditional vaccine technologies targeting certain pathogens. Self-replicating RNA has the potential to induce durable immune responses at lower doses than traditional mRNA. A recent Phase 1 clinical trial showed that a self-replicating RNA vaccine encoding rabies, RBI-4000, was able to show de novo immunogenicity at all doses tested, specifically 0.1, 1, and 10 micrograms in a prime-boost regimen or a single 10 microgram dose (NCT06048770).

Methods: Here, we report the secondary outcome of the Phase 1 study, durability of immune responses elicited by RBI-4000, as assessed by the presence of the rabies virus neutralizing antibody response, up to 8 months post immunization. We compare long term immunogenicity of RBI-4000 to a commercial comparator, an inactivated viral vaccine RabAvert, using several statistical models with a post-hoc analysis. The trial was performed at two sites in the United States enrolling 89 healthy volunteers aged 18-45.

Results: Individual rabies virus neutralizing antibody titers, above the benchmark seropositivity, were detected out to 8 months in all study cohorts. Statistical decay modeling showed that RBI-4000 induces rabies virus neutralizing antibodies with similar or improved durability compared to RabAvert.

Conclusions: We report the first durability data from a head-to-head study of an optimized self-replicating RNA vaccine for rabies that elicits sustained immune responses compared to a commercial comparator that uses a traditional vaccine technology.