Targeting Multiple Conserved T-Cell Epitopes for Protection against COVID-19 Moderate-Severe Disease by a Pan-Sarbecovirus Vaccine

Abstract

ABSTRACTBackgroundMost of current approved vaccines, based on a Spike-only as single immunogen, fall short of producing a full-blown T-cell immunity. SARS-CoV-2 continues to evolve with ever-emergent higher-contagious mutants that may take a turn going beyond Omicron to bring about a new pandemic outbreak. New recombinant SARS-CoV-2 species could be man-made through genetic manipulation to infect systemically. Development of composition-innovated, pan-variant COVID-19 vaccines to prevent from hospitalization and severe disease, and to forestall the next pandemic catastrophe, is an urgent global objective.Methods and findingsIn a retrospective, e-questionnaire Observational Study, extended from a clinical Phase-2 trial conducted in Taiwan, during the prime time of Omicron outbreak dominated by BA.2 and BA.5 variants, we investigated the preventive effects against COVID-19 moderate-severe disease (hospitalization and ICU admission) by a pan-Sarbecovirus vaccine UB-612 that targets monomeric S1-RBD-focused subunit protein and five designer peptides comprising sequence-conserved, non-mutable helper and cytotoxic T lymphocyte (Th/CTL) epitopes derived from Spike (S2), Membrane (M) and Nucleocapsid (N) proteins. Per UB-612 vaccination, there were no hospitalization and ICU admission cases (0% rate, 6 months after Omicron outbreak) reported ≥14 months post-2nddose of primary series, and ≥10 months post-booster (3rddose), to which the potent memory cytotoxic CD8 T cell immunity may be the pivotal in control of the infection disease severity. Six months post-booster, the infection rate (asymptomatic and symptomatic mild) was only 1.2%, which increased to 27.8% observed ≥10 months post-booster. The notable protection effects are in good alignment with a preliminary Phase-3 heterologous booster trial report showing that UB-612 can serve as a competent booster substitute for other EUA-approved vaccine platforms to enhance their seroconversion rate and viral-neutralizing titer against Omicron BA.5.ConclusionsUB-612, a universal multitope vaccine promoting full-blown T cell immunity, may work as a competent primer and booster for persons vulnerable to Sarbecovirus infection.Trial RegistrationClinicalTrials.govID:NCT04773067.AUTHOR SUMMARYA COVID-19 vaccine based on a Spike-only single immunogen would fall short of producing a full-blown, escape-proof T cell immunity. In Omicron era plagued with ever-evolving and higher-contagious SARS-CoV-2 mutants, immune antibodies against variants beyond BA.5 are seen on a cliff drop, rendering the viral-neutralizing titer strength an increasingly less relevant immunity parameter. The true, urgent issue at heart in vaccine development has not been updating variant component to increase antibody titer for prevention of infection, but to validate universal vaccines that would have a potential to head off hospitalization, severe disease and ultimately reinfection altogether, and so to forestall a new catastrophe of pandemic outbreak. To reach the ideal goals, a universal vaccine able to produce potent, broadly recognizing and durable memory T cell immunity would be essential. UB-612, a pan-Sarbecovirus T cell immunity-promoting mutitope vaccine, has been shown to provide strong and long-lasting ≥10 month protective effect against COVID-19 moderate-severe disease (0% cases of hospitalization and ICU admission). UB-612 is a unique S1-RBD subunit protein vaccine armed with five designer peptides comprising sequence-conserved helper and cytotoxic T lymphocyte (Th/CTL) epitopes derived from Spike (S2×3), Membrane (M) and Nucleocapsid (N) proteins across Sarbecovirus species.