Self-replicating RNA rabies vaccine clears early test, boosting Replicate's plans for platform

Replicate Bioscience has early evidence its self-replicating RNA technology works in humans. The Apple Tree Partners biotech showed all doses of its rabies vaccine triggered protective responses, providing an initial sign of the potential of a platform with applications in infectious diseases and cancer.

Self-replicating RNA works as the name suggests. The molecules copy themselves inside the body, creating more and more instructions that tell cells to produce a particular protein. Because the RNA replicates itself, the modality may be effective at lower doses than mRNA, a similar technology that lacks the ability to make more copies. Lower doses potentially mean more shots and fewer side effects. 

Replicate, which raised a $40 million series A round in 2021, is using rabies as a proving ground for the technology. The phase 1 trial is comparing three doses of its vaccine candidate, RBI-4000, to Bavarian Nordic’s approved product RabAvert in healthy volunteers. 

In “most subjects,” all three RBI-4000 doses generated antibody titers of at least 0.5 IU/ml, the level that the World Health Organization considers to be protective. Replicate said the 0.1-mcg dose is the smallest amount of any RNA technology reported to achieve the surrogate of protection in humans.

The biotech said a single shot of RBI-4000 met the surrogate protection metric “for a majority of subjects in multiple cohorts.” Replicate tested single shots at all dose levels, plus a two-administration regimen at the highest, 10 mcg, dose. GSK studied one- and two-dose regimens of its self-amplifying mRNA rabies vaccine in a phase 1 study that finished in 2022.

More details of the effect of RBI-4000 will emerge once Replicate presents the data at upcoming scientific conferences. For now, points such as the antibody titers seen at each dose and the comparison to RabAvert remain unknown. Replicate saw “favorable tolerability across all dose levels tested, with no severe adverse events,” but is yet to share safety data.

Bavarian Nordic and Sanofi sell inactivated rabies vaccines in the U.S. Both vaccines cleared the bar for protection in their trials, although they require people to receive multiple shots and titers fall over time—from 12.9 IU/mL at Day 49 to 5.1 IU/mL at Day 90 in the case of Sanofi’s Imovax. Replicate began working on rabies because it spied an opportunity to improve immunogenicity and simplify manufacturing. 

Beyond rabies, Replicate CEO Nathaniel Wang, Ph.D., believes the results de-risk the srRNA platform, manufacturing processes and pipeline, boosting the biotech’s prospects as it pursues diseases including breast and lung cancers. CSL Seqirus and Arcturus Therapeutics won approval for a self-amplifying vaccine that uses similar technology last year, but Replicate is still validating its platform.