SARS-CoV-2 booster vaccination needs to enhance protection against existing and future variants and minimise immune imprinting from earlier vaccinations. Previous studies have shown that the beta variant drove broad immunity against other SARS-CoV-2 variants, including omicron. In collaboration, Doherty Institute and Monash Institute of Pharmaceutical Sciences have developed 2 vaccines targeting the SARS-CoV-2 beta variant receptor-binding domain (RBD): a recombinant dimeric RBD-human IgG1 Fc-fusion protein, and an mRNA encoding a membrane-anchored RBD. In a Phase I clinical trial (ClinicalTrials.gov NCT05272605), 76 healthy adults aged 18–64 years, previously vaccinated with 3 doses of licensed SARS-CoV-2 ancestral strain vaccines, were randomised to receive a 4th dose in sequential, sentinel-stepped dose escalation of either an adjuvanted (MF59®, CSL Seqirus) recombinant protein vaccine, or a lipid nanoparticle-formulated mRNA vaccine, or placebo, administered as a 0.5mL IM injection, at least 90 days after 3rd booster immunisation or a prior COVID infection. All participants received one dose of study vaccine or placebo on Day 1, in double-blind manner. Results from an interim analysis based on Day 28 post-vaccination data will be presented.