UB-612, a Multitope Universal Vaccine Eliciting a Balanced B and T Cell Immunity against SARS-CoV-2 Variants of Concern
Abstract
Importance
The SARS-CoV-2 non-spike structural proteins of nucleocapsid (N), membrane (M) and envelope (E) are critical in the host cell interferon response and memory T-cell immunity and have been grossly overlooked in the development of COVID vaccines.
Objective
To determine the safety and immunogenicity of UB-612, a multitope vaccine containing S1-RBD-sFc protein and rationally-designed promiscuous peptides representing sequence-conserved Th and CTL epitopes on the Sarbecovirus nucleocapsid (N), membrane (M) and spike (S2) proteins.
Design, setting and participants
UB-612 booster vaccination was conducted in Taiwan. A UB-612 booster dose was administered 6-8 months post-2 nd dose in 1,478 vaccinees from 3,844 healthy participants (aged 18-85 years) who completed a prior placebo (saline)-controlled, randomized, observer-blind, multi-center Phase-2 primary 2-dose series (100-μg per dose; 28-day apart) of UB-612. The interim safety and immunogenicity were evaluated until 14 days post-booster.
Exposure
Vaccination with a booster 3 rd -dose (100-μg) of UB-612 vaccine.
Main outcomes and measures
Solicited local and systemic AEs were recorded for seven days in the e-diaries of study participants, while skin allergic reactions were recorded for fourteen days. The primary immunogenicity endpoints included viral-neutralizing antibodies against live SARS-CoV-2 wild-type (WT, Wuhan strain) and live Delta variant (VNT 50 ), and against pseudovirus WT and Omicron variant (pVNT 50 ). The secondary immunogenicity endpoints included anti-S1-RBD IgG antibody, S1-RBD:ACE2 binding inhibition, and T-cell responses by ELISpot and Intracellular Staining.
Results
No post-booster vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. The UB-612 booster prompted a striking upsurge of neutralizing antibodies against live WT Wuhan strain (VNT 50 , 1,711) associated with unusually high cross-neutralization against Delta variant (VNT 50 , 1,282); and similarly with a strong effect against pseudovirus WT (pVNT 50, 6,245) and Omicron variant (pVNT 50 , 1,196). Upon boosting, the lower VNT 50 and pVNT 50 titers of the elderly in the primary series were uplifted to the same levels as those of the young adults. The UB-612 also induced robust, durable VoC antigen-specific Th1-oriented (IFN-γ + -) responses along with CD8 + T-cell (CD107a + -Granzyme B + ) cytotoxicity.
Conclusions and relevance
With a pronounced cross-reactive booster effect on B- and T-cell immunity, UB-612 may serve as a universal vaccine booster for comprehensive immunity enhancement against emergent VoCs.
Trial registration
[ClinicalTrials.gov: <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT04773067">NCT04773067</ext-link> ]
KEY POINTS
Question
Facing ever-emergent SARS-CoV-2 variants and long-haul COVID, can composition-updated new vaccines be constructed capable of inducing striking, durable booster-recalled B/T-immunity to prevent infection by VoCs?
Findings
In a Phase-2 extension study, a booster dose of UB-612 multitope protein-peptide vaccine prompted high viral-neutralizing titers against live wild-type virus (VNT 50 , 1,711), Delta variant (VNT 50 , 1,282); pseudovirus wild-type (pVNT 50 , 6,245) and Omicron variant (pVNT 50 , 1,196). Robust, durable Th1-IFNγ + responses and CD8 + T cell-(CD107a + -Granzyme B + ) cytotoxic activity were both observed.
Meaning
UB-612 RBD-sFc vaccine armed with T cell immunity-promoting conserved N, M and S2 Th/CTL epitope peptides may serve as a universal vaccine to fend off new VoCs.
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