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

Abstract

The Omicron variant of SARS-CoV-2 recently swept the globe and showed high level of immune evasion. Here, we generate an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and test its activity in animals, both alone and as a heterologous booster to WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicits strong antibody response in vaccination-naïve mice. Mice that received two-dose WT LNP-mRNA show a > 40-fold reduction in neutralization potency against Omicron than WT two weeks post boost, which further reduce to background level after 3 months. The WT or Omicron LNP-mRNA booster increases the waning antibody response of WT LNP-mRNA vaccinated mice against Omicron by 40 fold at two weeks post injection. Interestingly, the heterologous Omicron booster elicits neutralizing titers 10-20 fold higher than the homologous WT booster against Omicron variant, with comparable titers against Delta variant. All three types of vaccination, including Omicron alone, WT booster and Omicron booster, elicit broad binding antibody responses against SARS-CoV-2 WA-1, Beta, Delta variants and SARS-CoV. These data provide direct assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to WT mRNA vaccine.

Efficacy of Parainfluenza Virus 5 (PIV5)-vectored Intranasal COVID-19 Vaccine as a Single Dose Vaccine and as a Booster against SARS-CoV-2 Variants

“…However, WA1-neutralizing antibody levels were highest in the 2X CVXGA1 group and lowest in the 2X mRNA group, indicating that CVXGA1 immunization maintains neutralizing antibody levels better than 2X mRNA immunization. The rapid reduction of neutralizing antibody titers in hamster following 2X mRNA vaccine immunization (Figure 3C) is consistent with reports of rapid reduction of neutralizing antibody titers after two doses of mRNA vaccine immunization [30]. The long-lasting neutralizing antibody levels from CVXGA1 immunization (Figure 6B and Figure 6C) may be attributed to the intranasally-expressed S antigen delivered by the live replicating PIV5 vector.…”

Pre-Omicron Vaccine Breakthrough Infection Induces Superior Cross-Neutralization against SARS-CoV-2 Omicron BA.1 Compared to Infection Alone

“…The fact that booster strategies based on pre-Omicron VOCs Beta or Delta did not neutralize Omicron BA.1 better than the wild-type booster [ 80 ] lends further support to this view. In contrast, heterologous Omicron BA.1-based booster vaccines [ 130 ] and bivalent booster vaccines based on wild-type + Omicron BA.1, Delta + Omicron BA.1 or hybrid Omicron BA.1/Delta determinants induce higher neutralizing humoral responses and T-cell responses against all Omicron sublineages as well as against pre-Omicron VOCs than homologous (wild-type) or pre-Omicron (Beta or Delta) booster vaccines in humans and mice [ 80 , 117 , 131 , 132 , 133 ]. Our results also indirectly confirm the serologic similarities between B.1 and Delta ( Figure 1 B,D and Figure 3 A,D,E) on one hand and the serotypic specificity of the Omicron lineage and sublineages on the other.…”

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

“…The substantial differences between WT and Omicron spikes lead to extensive immune escape of Omicron from WT mRNA vaccine 4 , which prompted the idea of developing Omicron-specific vaccines. We generated several COVID-19 variant-specific mRNA vaccine candidates (including Omicron BA.1) 5 , 6 which were designed based on variants’ spike stabilized by six proline mutations 7 . Variant-specific vaccine candidates, or lipid nanoparticle (LNP)-mRNAs, unequivocally exhibited advantage over WT LNP-mRNA in terms of eliciting neutralizing antibody against cognate antigens 5 , 6 .…”

“…We generated several COVID-19 variant-specific mRNA vaccine candidates (including Omicron BA.1) 5 , 6 which were designed based on variants’ spike stabilized by six proline mutations 7 . Variant-specific vaccine candidates, or lipid nanoparticle (LNP)-mRNAs, unequivocally exhibited advantage over WT LNP-mRNA in terms of eliciting neutralizing antibody against cognate antigens 5 , 6 . Moreover, immune profiling of Omicron BA.1 LNP-mRNA showed a significant boosting effect on waning immunity of WT LNP-mRNA-vaccinated mice to both Delta and Omicron BA.1 variants.…”