Evaluation of the minipig as an alternative model based on cross-study comparisons with rabbit in mRNA vaccine safety assessment

Robust non-clinical safety models are crucial to the development and evaluation of messenger ribonucleic acid (mRNA)-based drugs and vaccines. In this study, we leveraged cross-study data to explore whether the Göttingen minipig could serve as an alternative to the rabbit, a commonly used species in vaccine safety assessment.

Results from two independent toxicity studies of lipid nanoparticle-encapsulated mRNA encoding the hemagglutinin H3 antigen, administered at equivalent dose levels, were qualitatively compared. Clinical observations, local reactions, body weight, food consumption, body temperature, clinical pathology, immunogenicity, inflammatory biomarkers, and anatomical pathology endpoints were evaluated.

Both species exhibited expected vaccine responses, with minor differences in local reactogenicity and body temperature. The vaccine candidate was well tolerated at the injection site in both species. However, mild and transient vaccine-related effects (i.e., injection site induration and increased body temperature) were observed only in minipigs. Transient increases in neutrophil, fibrinogen, and C-reactive protein levels were observed in both species following vaccination, consistent with an inflammatory response. Microscopic findings (i.e., inflammation at the injection site and increased germinal center cellularity in the draining lymph nodes) were comparable between species and aligned with expected immune activation following vaccination.

This qualitative comparison provides preliminary, supportive evidence for the potential use of the minipig as an alternative to the rabbit in non-clinical safety evaluation of mRNA vaccines, with the added benefit of larger blood volume for sampling and availability of validated key inflammatory markers.