Safety and immunogenicity of an mRNA COVID-19 vaccine administered to adults: A phase 2, randomized, active-controlled trial.

We conducted a phase 2, randomized, active-controlled, observer-blind study (NCT05960097) among healthy adults ≥18 y of age who completed a primary COVID-19 mRNA vaccination series, with or without a booster, ≥3 months earlier. Participants were randomized (1:1:1:1:1) to either receive an investigational bivalent mRNA COVID-19 vaccine encoding ancestral D614G and Omicron BA.4-5 spike proteins (CV0701 mRNA vaccine) at one of three dose levels, an investigational monovalent mRNA COVID-19 vaccine encoding the Omicron BA.4-5 spike protein (CV0601 mRNA vaccine), or a licensed Original Wuhan/Omicron BA.4-5 bivalent mRNA COVID-19 vaccine. The primary objectives were to evaluate reactogenicity, safety and immunogenicity post-vaccination. Secondary and tertiary objectives were to further evaluate humoral and cell-mediated immunity post-vaccination. In total, 425 participants were vaccinated and 381 were included in the Day 29 per-protocol immunogenicity analysis. Most solicited events were mild to moderate. No vaccine-related serious adverse events or myocarditis/pericarditis cases were reported. For the CV0701 mRNA vaccine, a dose-dependent increase in Day 29 neutralizing titers against ancestral D614G and Omicron BA.4-5 was observed. Neutralizing titers against ancestral D614G and Omicron BA.4-5 declined by Days 91 and 181, but remained above baseline. Similar immune responses were observed for the CV0601 mRNA vaccine. At Day 8, CD4+ T cells (Th1 profile) increased in all study groups and CD8+ T cells increased in all study groups, except the lowest CV0701 dose group. The CV0701 and CV0601 mRNA vaccines elicited robust humoral and cellular immunity with an acceptable safety profile, comparable to a licensed, bivalent mRNA vaccine. Clinical Trial Registration EU CT number: 2023-504596-25-00 ClinicalTrials.gov: NCT05960097. What is the context?Vaccination is recommended to protect against severe COVID-19. In this study, we tested two investigational COVID-19 vaccines and compared them to an existing, approved COVID-19 vaccine.What is new?We included healthy adults aged 18y or older at 13 healthcare sites in Australia. All study participants had completed their primary COVID-19 vaccination series, with or without a booster, at least three months before this study started. We randomly assigned the participants to one of five groups. One group received an investigational vaccine that targets the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron BA.4–5 variant, three groups received different doses of another investigational vaccine that targets both the Omicron BA.4–5 and the ancestral D614G variants, and one group received an approved vaccine that targets the Original Wuhan and the Omicron BA.4–5 variants and was already in use in Australia.The safety profile of both investigational vaccines was comparable to the approved vaccine. Most side effects were mild to moderate and transient. No serious side effects were considered related to the investigational vaccines, and no deaths occurred.All but the lowest dose of the second investigational vaccine induced immune responses that were comparable to the approved vaccine.What is the impact?The investigational vaccines showed an acceptable safety profile, which was comparable to the vaccine that is already used. The immune response was also comparable. These results can help inform future vaccine development.