Phase 1 Assessment of the Safety and Immunogenicity of an mRNA- Lipid Nanoparticle Vaccine Candidate Against SARS-CoV-2 in Human Volunteers

Oostvogels, L.; Kremsner, P.; Kreidenweiss, A.; Leroux-Roels, I.; Leroux-Roels, G.; Kroidl, A.; Schunk, M.; Schindler, C.; Bosch, J.; Fendel, R.; Gabor, J. J.; Velavan, T. P.; Mann, P.; Walz, L.; Mueller, S.; Schoenborn-Kellenberger, O.; Verstraeten, T.; Fotin-Mleczek, M.; Vahrenhorst, D.; Quintini, G.; Wolz, O.-O.

There is an urgent need for vaccines to counter the COVID-19 pandemic due to infections with severe acute respiratory syndrome coronavirus (SARS-CoV-2). Evidence from convalescent sera and preclinical studies has identified the viral Spike (S) protein as a key antigenic target for protective immune responses. We have applied an mRNA-based technology platform, RNActive, to develop CVnCoV which contains sequence optimized mRNA coding for a stabilized form of S protein encapsulated in lipid nanoparticles (LNP). Following demonstration of protective immune responses against SARS-CoV-2 in animal models we performed a dose-escalation phase 1 study in healthy 18-60 year-old volunteers. This interim analysis shows that two doses of CVnCoV ranging from 2 g to 12 g per dose, administered 28 days apart were safe. No vaccine-related serious adverse events were reported. There were dose-dependent increases in frequency and severity of solicited systemic adverse events, and to a lesser extent of local reactions, but the majority were mild or moderate and transient in duration. Immune responses when measured as IgG antibodies against S protein or its receptor-binding domain (RBD) by ELISA, and SARS-CoV-2-virus neutralizing antibodies measured by micro-neutralization, displayed dose-dependent increases. Median titers measured in these assays two weeks after the second 12 g dose were comparable to the median titers observed in convalescent sera from COVID-19 patients. Seroconversion (defined as a 4-fold increase over baseline titer) of virus neutralizing antibodies two weeks after the second vaccination occurred in all participants who received 12 g doses. Preliminary results in the subset of subjects who were enrolled with known SARS-CoV-2 seropositivity at baseline show that CVnCoV is also safe and well tolerated in this population, and is able to boost the pre-existing immune response even at low dose levels. Based on these results, the 12 g dose is selected for further clinical investigation, including a phase 2b/3 study that will investigate the efficacy, safety, and immunogenicity of the candidate vaccine CVnCoV.