UB-612 Multitope Vaccine targeting both Spike and Non-Spike Proteins of SARS-CoV-2 Provides Broad and Durable Immune Responses

The SARS-CoV-2 non-Spike (S) structural protein targets of nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, have been grossly overlooked since the inception of COVID vaccine development. To pursue a universal (pan-sarbecovirus) vaccine against ever-emergent future mutants, we explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved rationally designed promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-γ+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). Booster vaccination is safe and well tolerated without SAEs. By recognition against epitopes on Spike (S1-RBD and S2) and non-Spike (N and M) structure proteins, UB-612 provides potent, broad and long-lasting B-cell and T-cell memory immunity and offers a potential as a universal vaccine to fend off Omicrons and new VoCs.