Abstract
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 (>107 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.
Highlights
Combating the COVID-19 pandemic depends on mass vaccination with suitable vaccines to achieve herd immunity
We have conducted preclinical testing of a SARS-CoV-2 Live attenuated vaccines (LAVs), designed by the “synthetic attenuated virus engineering” (SAVE) strategy, which we propose has led to a live COVID-19 vaccine candidate (COVI-VAC)
The WT WA1 virus was deposited by the US Centers for Disease Control and Prevention (CDC) and was obtained from BEI Resources
Summary
Combating the COVID-19 pandemic depends on mass vaccination with suitable vaccines to achieve herd immunity. 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. 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. 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. SAVE replaces efficient WT codon pairs in the reading frame of a viral genome with synonymous suboptimal codon pairs leading to reduced protein production in human cells due to slowed translation and/or other mechanisms [9]. A vaccine that can present all SARS-CoV-2 antigens to the host is optimal because it can both induce a broad immune response and is less likely to lose significant potency due to the antigenic drift that we are already witnessing [4,5,6]
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