Abstract
The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has high transmissibility and recently swept the globe. Due to the extensive number of mutations, this variant has high level of immune evasion, which drastically reduced the efficacy of existing antibodies and vaccines. Thus, it is important to test an Omicron-specific vaccine, evaluate its immune response against Omicron and other variants, and compare its immunogenicity as boosters with existing vaccine designed against the reference wildtype virus (WT). Here, we generated an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and tested its activity in animals, both alone and as a heterologous booster to existing WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicited strong and specific antibody response in vaccination-naïve mice. Mice that received two-dose WT LNP-mRNA, the one mimicking the commonly used Pfizer/Moderna mRNA vaccine, showed a >40-fold reduction in neutralization potency against Omicron variant than that against WT two weeks post second dose, which further reduced to background level >3 months post second dose. As a booster shot for two-dose WT mRNA vaccinated mice, a single dose of either a homologous booster with WT LNP-mRNA or a heterologous booster with Omicron LNP-mRNA restored the waning antibody response against Omicron, with over 40-fold increase at two weeks post injection as compared to right before booster. Interestingly, the heterologous Omicron LNP-mRNA booster elicited neutralizing titers 10-20 fold higher than the homologous WT booster against the Omicron variant, with comparable titers against the Delta variant. All three types of vaccination, including Omicron mRNA alone, WT mRNA homologous booster, and Omicron heterologous booster, elicited broad binding antibody responses against SARS-CoV-2 WA-1, Beta, and Delta variants, as well as other Betacoronavirus species such as SARS-CoV, but not Middle East respiratory syndrome coronavirus (MERS-CoV). These data provided direct proof-of-concept assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to the existing widely-used WT mRNA vaccine form.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* Co-first authors.
↵# Lead contact: SC (sidi.chen{at}yale.edu), +1-203-737-3825 (office), +1-203-737-4952 (lab)
-(1) Performed parallel WT- and Omicron-specific vaccine booster comparison, to test the effect of homologous booster (WT x2+1) and heterologous booster (WT x2 + Omicron x1). Results showed that both WT- and Omicron-specific vaccine boosters enhanced the waning immunity, however, the effect of homologous Omicron-specific vaccine booster is stronger against the Omicron variant. -(2) Omicron vaccine vs Delta: Omicron-specific vaccine booster has comparable antibody response against Delta variant, i.e. it does not lose potency against Delta as compared to WT vaccine. -(3) Performed BL3 live virus (authentic virus) neutralization experiment, further validating the findings above. -(4) Performed broad antibody activity testing against VoCs (WT, Beta, Delta) and different Betacoronavirus species (SARS2, SARS, MERS), revealing that both Omicron alone and WT + Omicron vaccination showed broadly reactive antibody responses. -(5) Performed antibody characterization experiment in the context of other known clinical mAbs, showing that Omicron-mRNA induced antibody pool covering portions of antibodies contains Class I-III (overlapped with hACE2 epitopes), IV antibodies. -(6) Performed repeat experiments that increased sample sizes, e.g. numbers of animals used, experimental replicates, and improved statistics.