A multitope SARS-CoV-2 vaccine provides long-lasting B cell and T cell immunity against Delta and Omicron variants

Abstract

Background The Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins. Method We conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 μg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 μg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 μg of UB-612 ( n = 3,875, 18–85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose. Results No vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs. Conclusion UB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines. Trial Registration ClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742. Funding UBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.

High neutralizing antibody levels against SARS-CoV-2 Omicron BA.1 and BA.2 after UB-612 vaccine booster

“…The estimated decrease in neutralization titers against Omicron BA.1 and BA.2 in 15 sera obtained 2 weeks after UB-612 booster, was 9.2- and 12.7-fold, respectively, compared with the ancestral Victoria strain. Previously, only a 5.5-fold decrease against BA.1 was reported when 20 sera from UB-612 vaccinated participants were tested in a pseudovirus-based neutralization assay (GMT pVNT 50 of 12,778 against the Wuhan strain, vs. 2,325 against the BA.1 strain) [9]. These data support the breadth of UB-612−elicited neutralizing antibodies across multiple SARS-CoV-2 variants after the booster, a differentiation property of UB-612 primarily attributed to its subunit protein RBD antigenic component [10].…”

“…The magnitude and extent of reactivity of the humoral response after the UB-612 booster match those reported for the authorized vaccines, including mRNA-1273. Additionally, UB-612 immunization has been shown to stimulate T-cell responses against conserved S, N, and M Th/CTL peptides, included in the UB-612 vaccine formulation ( 13,14, 22 ), and may provide long-lasting antibody responses ( 15 ) which further differentiates UB-612 from many authorized vaccines. As SARS-CoV-2 continues to evolve, several strategies are being explored to effectively prevent COVID-19 caused by newly emerging SARS-CoV-2 variants, including monovalent variant antigen matching, multivalent, or universal vaccine approaches.…”

“…In contrast to most of the approved COVID-19 vaccines that encode the full-length S protein, the UB-612 vaccine candidate is composed of Wuhan-Hu S1-RBD-sFc fusion protein and is enriched with 5 rationally designed peptides representing Sarbecovirus conserved Th and CTL epitopes on the S2 subunit, Membrane (M), and Nucleocapsid (N) proteins ( 13 ). A favorable safety and tolerability profile for UB-612 was demonstrated in ∼4000 participants in a Phase 1 trial and its extension and a Phase 2 trial conducted in Taiwan ( 14 ). In both Phase 1 and Phase 2 trials, the UB-612 vaccine was found to have a favorable safety profile and low reactogenicity after every injected dose.…”

“…1) . Notably, the estimated loss in neutralization titer against Omicron in sera obtained 2 weeks after the booster was only 1.4-fold compared to the ancestral strain in a live virus assay and 5.5-fold in a pseudovirus assay ( 14 ). In contrast, after the third booster dose, the neutralizing antibody GMT against Omicron and ancestral strain were 106 and 763 (6.3-fold loss) for BNT162b2 ( 11 ), or 850 and 2423 (2.9-fold loss) for mRNA-1273-50 μg ( 7 ).…”

“…Two immunizations with UB-612 led to a >90% seroconversion rate of neutralizing antibodies in vaccine recipients. In these same studies, UB-612 was shown to elicit long-lasting neutralizing antibody titers similar to levels detected in convalescent patients [10], that were cross-reactive against Delta and Omicron variants [9].…”