Significance This work demonstrates the feasibility of rationally designing and synthesizing vaccine candidates for testing in response to an emerging disease in real world conditions. Furthermore, using a live attenuated codon-pair–deoptimized virus approach ensures that all components of the host immune system will be engaged, and potential effects from the vector sequences from hybrid live viruses are avoided. Evidence from other codon-deoptimized viruses suggests that COVI-VAC will be resistant to reversion and loss of potency due to antigenic drift. The ease of large-scale virus growth under permissive conditions coupled with the potential for single-dose intranasal administration make COVI-VAC an appealing candidate for clinical testing for possible use in mass immunization programs. Successfully combating the COVID-19 pandemic depends on mass vaccination with suitable vaccines to achieve herd immunity. Here, we describe COVI-VAC, the only live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine currently in clinical development. COVI-VAC was developed by recoding a segment of the viral spike protein with synonymous suboptimal codon pairs (codon-pair deoptimization), thereby introducing 283 silent (point) mutations. In addition, the furin cleavage site within the spike protein was deleted from the viral genome for added safety of the vaccine strain. Except for the furin cleavage site deletion, the COVI-VAC and parental SARS-CoV-2 amino acid sequences are identical, ensuring that all viral proteins can engage with the host immune system of vaccine recipients. COVI-VAC was temperature sensitive in vitro yet grew robustly (>10 7 plaque forming units/mL) at the permissive temperature. Tissue viral loads were consistently lower, lung pathology milder, and weight loss reduced in Syrian golden hamsters ( Mesocricetus auratus ) vaccinated intranasally with COVI-VAC compared to those inoculated with wild-type (WT) virus. COVI-VAC inoculation generated spike IgG antibody levels and plaque reduction neutralization titers similar to those in hamsters inoculated with WT virus. Upon challenge with WT virus, COVI-VAC vaccination reduced lung challenge viral titers, resulted in undetectable virus in the brain, and protected hamsters from almost all SARS-CoV-2–associated weight loss. Highly attenuated COVI-VAC is protective at a single intranasal dose in a relevant in vivo model. This, coupled with its large-scale manufacturing potential, supports its potential use in mass vaccination programs.
【저자키워드】 COVID-19, Vaccine, live attenuated, codon deoptimization, 【초록키워드】 SARS-CoV-2, coronavirus, vaccination, Immunity, furin, antibody, feasibility, hamsters, COVID-19 pandemic, mutations, lung, Viral proteins, in vitro, virus, immunization, Brain, Spike protein, IgG antibody, Viral load, furin cleavage site, herd immunity, vaccine candidate, emerging disease, temperature, hamster, intranasal, Protective, spike IgG, antigenic drift, Lung pathology, Amino acid, administration, dose, viral genome, Syrian golden hamster, amino acid sequence, mass vaccination, mass immunization, Support, weight loss, viral spike protein, acute respiratory syndrome, Viral protein, acute respiratory syndrome coronavirus, recipients, antigenic, sequence, clinical development, potency, host immune system, wild-type, vaccine candidates, clinical testing, viral titers, component, reversion, vaccine strain, segment, plaque reduction neutralization, Syrian Golden hamsters, virus growth, WT virus, Effect, approach, synonymous, combating, furin cleavage site deletion, temperature sensitive, virus, intranasally, inoculated, addition, reduced, condition, added, the spike protein, the vaccine, deleted, conditions, parental, engage, silent, in vivo model, live virus, Mesocricetus, Significance, undetectable, 【제목키워드】 Efficacy, SARS-CoV-2 vaccine,