SARS-CoV-2 RBD dimers elicit response comparable to VLPs in mice (preprint)

We report the direct comparison of monomeric, dimeric and trimeric RBD protein subunit vaccines to a virus-like particle (VLP) displaying RBD. After two and three doses, a RBD dimer and trimer elicited antibody levels in mice comparable to an RBD-VLP. Furthermore, an Omicron (BA.1) RBD hetero-dimer induced neutralizing activity similar to the RBD-VLP. A RBD hetero-dimer and RBD-VLP also shows comparable breadth to other SARS-CoV-2 variants-of-concern (VOCs).

Comparable Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 Variants (preprint)

The SARS-CoV-2 Omicron variant (B.1.1.529) has three major lineages BA.1, BA.2, and BA.3. BA.1 rapidly became dominant and has demonstrated substantial escape from neutralizing antibodies (NAbs) induced by vaccination. BA.2 has recently increased in frequency in multiple regions of the world, suggesting that BA.2 has a selective advantage over BA.1. BA.1 and BA.2 share multiple common mutations, but both also have unique mutations. The ability of BA.2 to evade NAbs induced by vaccination or infection has not yet been reported. We evaluated WA1/2020, Omicron BA.1, and BA.2 NAbs in 24 individuals who were vaccinated and boosted with the mRNA BNT162b2 vaccine5 and in 8 individuals who were infected with SARS-CoV-2.

Vaccine Protection Against the SARS-CoV-2 Omicron Variant in Macaques (preprint)

Background: The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. Immune correlates of vaccine protection against Omicron are not known. Methods: 30 cynomolgus macaques were immunized with homologous and heterologous prime-boost regimens with the mRNA-based BNT162b2 vaccine and the adenovirus vector-based Ad26.COV2.S vaccine. Following vaccination, animals were challenged with the SARS-CoV-2 Omicron variant by the intranasal and intratracheal routes. Results: Omicron neutralizing antibodies were observed following the boost immunization and were higher in animals that received BNT162b2, whereas Omicron CD8+ T cell responses were higher in animals that received Ad26.COV2.S. Following Omicron challenge, sham controls showed more prolonged virus in nasal swabs than in bronchoalveolar lavage. Vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs, showing that current vaccines provide substantial protection against Omicron in this model. However, vaccinated animals that had moderate levels of Omicron neutralizing antibodies but negligible Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Virologic control correlated with both antibody and T cell responses. Conclusions: BNT162b2 and Ad26.COV2.S provided robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in macaques. Protection against this highly mutated SARS-CoV-2 variant correlated with both humoral and cellular immune responses.

Reduced Pathogenicity of the SARS-CoV-2 Omicron Variant in Hamsters (preprint)

The SARS-CoV-2 Omicron (B.1.1.529) variant has proven highly transmissible and has outcompeted the Delta variant in many regions of the world. Early reports have also suggested that Omicron may result in less severe clinical disease in humans. Here we show that Omicron is less pathogenic than prior SARS-CoV-2 variants in Syrian golden hamsters. Infection of hamsters with the SARS-CoV-2 WA1/2020, Alpha, Beta, or Delta strains led to 4-10% weight loss by day 4 and 10-17% weight loss by day 6, as expected. In contrast, infection of hamsters with two different Omicron challenge stocks did not result in any detectable weight loss, even at high challenge doses. Omicron infection still led to substantial viral replication in both the upper and lower respiratory tracts and pulmonary pathology, but with a trend towards higher viral loads in nasal turbinates and lower viral loads in lung parenchyma compared with WA1/2020 infection. These data suggest that the SARS-CoV-2 Omicron variant may result in more robust upper respiratory tract infection but less severe lower respiratory tract clinical disease compared with prior SARS-CoV-2 variants.

Immune Responses in Fully Vaccinated Individuals Following Breakthrough Infection with the SARS-CoV-2 Delta Variant in Provincetown, Massachusetts (preprint)

Background A cluster of over a thousand infections with the SARS-CoV-2 delta variant was identified in a predominantly fully vaccinated population in Provincetown, Massachusetts in July 2021. Immune responses in breakthrough infections with the SARS-CoV-2 delta variant remain to be defined. Methods Humoral and cellular immune responses were assessed in 35 vaccinated individuals who were tested for SARS-CoV-2 in the Massachusetts Department of Public Health outbreak investigation. Results Vaccinated individuals who tested positive for SARS-CoV-2 demonstrated substantially higher antibody responses than vaccinated individuals who tested negative for SARS-CoV-2, including 28-fold higher binding antibody titers and 34-fold higher neutralizing antibody titers against the SARS-CoV-2 delta variant. Vaccinated individuals who tested positive also showed 4.4-fold higher Spike-specific CD8+ T cell responses against the SARS-CoV-2 delta variant than vaccinated individuals who tested negative. Conclusions Fully vaccinated individuals developed robust anamnestic antibody and T cell responses following infection with the SARS-CoV-2 delta variant. These data suggest important immunologic benefits of vaccination in the context of breakthrough infections.