Safety, Tolerability, and Immunogenicity of NeomiVac, a Next-Generation mRNA–Lipid Nanoparticle Vaccine Comprising a Novel Ionisable Lipid: A First-In-Human, Phase 1, Dose-Escalation Trial

Background: Lipid nanoparticle (LNP)-based mRNA vaccines demonstrated high efficacy and a favourable safety profile during the COVID-19 pandemic. Beyond SARS-CoV-2, this platform holds considerable promise for the prevention of infectious diseases and for broader therapeutic applications. However, further optimisation of mRNA-LNP formulations is required to minimise reactogenicity and toxicity, while maintaining immunogenicity and clinical efficacy. Method: Healthy adults aged 18-64 years were recruited to a dose escalation phase I study to evaluate safety, tolerability and immunogenicity of a candidate next generation LNP mRNA vaccine against SARS-CoV-2 (NeomiVac). Thirty-six participants received a single intramuscular dose of either 25 µg, 50 µg or 100 µg of an mRNA-LNP encoding the SARS-CoV-2 spike protein from the B.1.1.529 (Omicron) variant. Study endpoints included solicited, unsolicited, and serious adverse events (AEs), biochemical/haematological parameters, binding and neutralising antibody responses to Omicron, and cell-mediated immunogenicity assessed by IFN-γ ELISpot. Findings: A single dose of NeomiVac was safe and well tolerated across all dose levels, including the highest dose of 100 µg. Most adverse reactions were mild to moderate and spontaneously resolved within a few days. The most frequently reported solicited AEs were pain at the injection site (26 of 36 participants [72%]), headache (16 of 36 [44%]) and fatigue (12 of 36 [33%]). No clinically significant abnormalities in liver function were observed. Both the 50 ug and 100 µg dose induced robust binding and neutralising antibody responses, increased binding and neutralising titres persisted until 182 days post-vaccination in participants receiving the 100 µg dose. Interpretation: The favourable low reactogenicity profile and demonstrable immunogenicity observed in this study provides a compelling basis for further clinical development of low reactogenic LNPs for vaccines against infectious diseases or other preventive or therapeutic interventions.