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UB-612 pan-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine targets the monomeric Spike S1-receptor binding domain (RBD) subunit protein along with five sequence-conserved T cell epitopes found on Spike S2 and non-Spike M and N proteins. UB-612 vaccination safely induces potent, broad, and long-lasting immunity against SARS-CoV-2. A phase-2 trial-extended observational study during the Omicron BA.2-/BA.5-dominated outbreak was conducted to investigate UB-612's protective effect against COVID-19 hospitalization and intensive care unit (ICU) admission (H-ICU). Additionally, memory viral-neutralizing titer and T cell immunity behind disease protection were explored. No cases of H-ICU were reported beyond 14 months post-second dose or beyond 10 months post-booster (third dose). The positive outcome correlates with strong cytotoxic CD8 T cell immunity, in line with the results of an ongoing phase-3 heterologous booster trial showing that UB-612 can enhance anti-BA.5 seroconversion rate and viral-neutralizing titer for mRNA, adeno-vectored, and virus-inactivated vaccine platforms. The UB-612 multitope vaccine may serve as an effective primer and booster for those at risk of SARS-CoV-2 infection., Competing Interests: C.Y.W. is a co-founder and board member of UBI, United BioPharma, and UBI Asia and named as an inventor on several patent applications filed covering COVID vaccine development. W.-J.P. is also named as a co-inventor on related patent applications. C.Y.W., W.-J.P., B.-S.K., Y.-H.L., Y.-H.H., Y.-H.P., Y.-T.Y., H.-C.C., and L.-F.F. are employees within the UBI group., (© 2024 The Author(s).)