Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2

Abstract

The Omicron variant of SARS-CoV-2 has high transmissibility and recently been sweeping the globe, dominating new infection cases in the US and many regions in the world. Due to its 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 develop an Omicron-specific vaccine and test if it can induce immune responses against Omicron and broadly against other variants. Here, we generated an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and tested its potency of antibody induction in animals, both alone and as a booster to existing mRNA vaccine designed against the ancestral reference virus (WA-1). This Omicron-specific LNP-mRNA vaccine elicited strong and specific antibody response in vaccination-naïve mice. Consistent with recent reports, mice that received two-dose WA-1 LNP-mRNA, the one mimicking the commonly used Pfizer/Moderna mRNA vaccine administered in the general population, showed a 41-fold reduction in neutralization potency against Omicron variant as compared to WA-1 two weeks post second dose, which further reduced to background level 3.5 months post second dose. As a booster for WA-1 mRNA vaccination, a single dose Omicron LNP-mRNA induced potent antibody response against the Omicron variant, with over 1,000-fold increase at two weeks post injection as compared to the blood samples right before booster. The Omicron-specific antibody level of the Omicron-boosted samples is numerically similar to WA-1 vaccine against WA-1 variant. This boost also elicited broader antibody responses against WA-1 and Delta variants, restoring these activities of the WA-1 vaccinated animals that also dropped over time. A consecutive second dose of Omicron LNP-mRNA 2 weeks following the first dose did not significantly increased the level of antibodies. These in vivo animal data provided a timely proof-of-concept for Omicron-specific mRNA vaccination, alone and as a booster to the existing widely-used mRNA vaccine form.

Heterotypic vaccination responses against SARS-CoV-2 Omicron BA.2

“…Animal immunization were performed previously on 6-8 weeks female C57BL/6Ncr mice purchased from Charles River in two sets of experiments: 1) sequential vaccination with two doses of 1μg WT LNP-mRNA followed by 10μg Omicron BA.1 or WT boosters 7 ; 2) vaccination with two doses of 1μg WT, B.1.351, B.1.617 LNP-mRNA 8 . Retro-orbital blood were collected two weeks post boost (2 nd dose, day 35), right before boosters (day 166), and two weeks post boosters (3 rd dose, day 180).…”

“…The lipid nanoparticle mRNA were prepared as previously described 7,8 . In brief, lipid mixture was dissolved in ethanol and mixed with mRNA in pH 5.2 sodium acetate.…”

“…The binding and neutralizing antibody titers were determined by ELISA and pseudovirus neutralization assay as previously described 7,8 . The Omicron BA.1 RBD and BA.2 RBD used in ELISA were purchased from Sino Biological (Cat.…”

“…We generated several COVID variant-specific mRNA vaccine candidates (including BA.1 subvariant) 7,8 which were designed based on variants’ spike stabilized by six proline mutations 9 . Variant-specific vaccine candidates, or lipid nanoparticle (LNP)- mRNAs, unequivocally exhibited varying degrees of advantage over WT LNP-mRNA in terms of eliciting neutralizing antibody against cognate variant antigens 7,8 . Moreover, immune profiling of Omicron BA.1 LNP-mRNA showed a significant boosting effect on waning immune response of WT LNP-mRNA vaccinated mice to both Delta and Omicron BA.1 variants.…”

“…The substantial differences between WT and Omicron spike lead to extensive immune escape of Omicron from WT mRNA vaccine 6 , which prompt the idea of developing Omicron-specific vaccines. We generated several COVID variant-specific mRNA vaccine candidates (including BA.1 subvariant) 7,8 which were designed based on variants’ spike stabilized by six proline mutations 9 . Variant-specific vaccine candidates, or lipid nanoparticle (LNP)- mRNAs, unequivocally exhibited varying degrees of advantage over WT LNP-mRNA in terms of eliciting neutralizing antibody against cognate variant antigens 7,8 .…”