SARS-CoV-2 Omicron-specific mRNA vaccine induces potent and broad antibody responses in vivo (preprint)

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-naive mice. Consistent with recent reports, mice that received two-dose WA-1 LNP-mRNA, the one mimicking the commonly used Pfizer or 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.

Systems immune profiling of variant-specific vaccination against SARS-CoV-2 (preprint)

Lipid-nanoparticle(LNP)-mRNA vaccines offer protection against COVID-19. However, multiple variant lineages caused widespread breakthrough infections. There is no report on variant-specific vaccines to date. Here, we generated LNP-mRNAs specifically encoding wildtype, B.1.351 and B.1.617 SARS-CoV-2 spikes, and systematically studied their immune responses in animal models. All three LNP-mRNAs induced potent antibody responses in mice. However, WT-LNP-mRNA vaccination showed reduced neutralization against B.1.351 and B.1.617; and B.1.617-specific vaccination showed differential neutralization. All three vaccine candidates elicited antigen-specific CD8 and CD4 T cell responses. Single cell transcriptomics of B.1.351-LNP-mRNA and B.1.617-LNP-mRNA vaccinated animals revealed a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induced a systemic increase in reactive CD8 T cell population, with a strong signature of transcriptional and translational machineries in lymphocytes. BCR-seq and TCR-seq unveiled repertoire diversity and clonal expansions in vaccinated animals. These data provide direct systems immune profiling of variant-specific LNP-mRNA vaccination in vivo.