UB-612 Multitope Vaccine Targeting SARS-CoV-2 Spike and Non-Spike Proteins 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-{gamma}+-) 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. SIGNIFICANCE STATEMENTThe Omicron has swept the globe with a rapid succession of dominating sublineages from BA.1, BA.2, to the current BA.5 with increasing infectivity and antibody evasion. Concerningly, the non-Spike structure proteins that promote T-cell immunity are grossly overlooked in vaccine development. Looking beyond short-interval booster jabs and omicron-updated vaccines, a pragmatic approach to curbing ever-emergent new mutants would be "universal (pan-Sarbecovirus) vaccines" targeting conserved nonmutable epitopes on coronavirus. UB-612, a multitope-vaccine armed with Spike (S1-RBD and S2) and non-Spike targets (Nucleocapsid N and Membrane M), allows booster vaccination to elicit potent, broadly-recognizing, durable B- and T-cell memory immunity. Sequence-conserved epitope peptides were rationally-designed from S2, N and M proteins to synergistically enhance memory helper and cytotoxic T-cell immunity and B-cell immunity.

UB-612, a Multitope Universal Vaccine Eliciting a Balanced B and T Cell Immunity against SARS-CoV-2 Variants of Concern

ImportanceThe 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. ObjectiveTo 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 participantsUB-612 booster vaccination was conducted in Taiwan. A UB-612 booster dose was administered 6-8 months post-2nd 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-g per dose; 28-day apart) of UB-612. The interim safety and immunogenicity were evaluated until 14 days post-booster. ExposureVaccination with a booster 3rd-dose (100-g) of UB-612 vaccine. Main outcomes and measuresSolicited 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 (VNT50), and against pseudovirus WT and Omicron variant (pVNT50). The secondary immunogenicity endpoints included anti-S1-RBD IgG antibody, S1-RBD:ACE2 binding inhibition, and T-cell responses by ELISpot and Intracellular Staining. ResultsNo 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 (VNT50, 1,711) associated with unusually high cross-neutralization against Delta variant (VNT50, 1,282); and similarly with a strong effect against pseudovirus WT (pVNT50, 6,245) and Omicron variant (pVNT50, 1,196). Upon boosting, the lower VNT50 and pVNT50 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-{gamma}+-) responses along with CD8+ T-cell (CD107a+-Granzyme B+) cytotoxicity. Conclusions and relevanceWith 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: NCT04773067] KEY POINTSO_ST_ABSQuestionC_ST_ABSFacing 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? FindingsIn 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 (VNT50, 1,711), Delta variant (VNT50, 1,282); pseudovirus wild-type (pVNT50, 6,245) and Omicron variant (pVNT50, 1,196). Robust, durable Th1-IFN{gamma}+ responses and CD8+ T cell-(CD107a+-Granzyme B+) cytotoxic activity were both observed. MeaningUB-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.

Safety and Immunogenicity of CpG 1018 and Aluminium Hydroxide-Adjuvanted SARS-CoV-2 S-2P Protein Vaccine MVC-COV1901: A Large-Scale Double-Blinded, Randomised, Placebo-Controlled Phase 2 Trial

BackgroundWe have assessed the safety and immunogenicity of the COVID-19 vaccine MVC-COV1901, a recombinant protein vaccine containing prefusion-stabilized spike protein S-2P adjuvanted with CpG 1018 and aluminium hydroxide. MethodsThis is a phase 2, prospective, randomised, double-blind, placebo-controlled, and multi-centre study to evaluate the safety, tolerability, and immunogenicity of the SARS-CoV-2 vaccine candidate MVC-COV1901. The study comprised 3,844 participants of [≥] 20 years who were generally healthy or with stable pre-existing medical conditions. The study participants were randomly assigned in a 6:1 ratio to receive either MVC-COV1901 containing 15 g of S-2P protein or placebo containing saline. Participants received two doses of MVC-COV1901 or placebo, administered 28 days apart via intramuscular injection. The primary outcomes were to evaluate the safety, tolerability, and immunogenicity of MVC-COV1901 from Day 1 (the day of first vaccination) to Day 57 (28 days after the second dose). Immunogenicity of MVC-COV1901 was assessed through geometric mean titres (GMT) and seroconversion rates (SCR) of neutralising antibody and antigen-specific immunoglobulin. This clinical trial is registered at ClinicalTrials.gov: NCT04695652. FindingsFrom the start of this phase 2 trial to the time of interim analysis, no vaccine-related Serious Adverse Events (SAEs) were recorded. The most common solicited adverse events across all study participants were pain at the injection site (64%), and malaise/fatigue (35%). Fever was rarely reported (<1%). For all participants in the MVC-COV1901 group, at 28 days after the second dose against wild type SARS-CoV-2 virus, the GMT was 662{middle dot}3 (408 IU/mL), the GMT ratio was 163{middle dot}2, and the seroconversion rate was 99{middle dot}8%. InterpretationMVC-COV1901 shows good safety profiles and promising immunogenicity responses. The current data supports MVC-COV1901 to enter phase 3 efficacy trials and could enable regulatory considerations for Emergency Use Authorisation (EUA). FundingMedigen Vaccine Biologics Corporation and Taiwan Centres for Disease Control.