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

The SARS-CoV-2 Omicron variant (B.1.1.529) has three major lineages BA.1, BA.2, and BA.31. BA.1 rapidly became dominant and has demonstrated substantial escape from neutralizing antibodies (NAbs) induced by vaccination2-4. 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 mutations1 (Fig. 1A). 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 (Table S1). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/22270533v1_fig1.gif" ALT="Figure 1"> O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/22270533v1_fig1a.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1b39fc8org.highwire.dtl.DTLVardef@1bf16ceorg.highwire.dtl.DTLVardef@7248ecorg.highwire.dtl.DTLVardef@111a215_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Neutralizing antibody responses to Omicron BA.1 and BA.2. A. Cartoon showing BA.1 and BA.2 mutations in the SARS-CoV-2 Spike. NTD, N-terminal domain; RBD, receptor binding domain; RBM, receptor binding motif; SD1, subdomain 1; SD2, subdomain 2; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2. B. Neutralizing antibody (NAb) titers by a luciferase-based pseudovirus neutralization assay in individuals two weeks following initial BNT162b2 vaccination (Prime), prior to boost (Pre-Boost), and two weeks following the third boost with BNT162b2 (Boost). C. NAb titers in 8 individuals following infection with SARS-CoV-2 Omicron BA.1, of whom 7 were vaccinated. The individual with negative NAb titers was unvaccinated and was sampled 4 days following diagnosis and hospitalization with severe COVID-19 pneumonia. Responses were measured against the SARS-CoV-2 WA1/2020, Omicron BA.1, and BA.2 variants. Medians (red bars) are depicted and shown numerically with fold differences. C_FIG O_TBL View this table: org.highwire.dtl.DTLVardef@a84ecborg.highwire.dtl.DTLVardef@1cd2d42org.highwire.dtl.DTLVardef@1567410org.highwire.dtl.DTLVardef@ddcf54org.highwire.dtl.DTLVardef@56b617_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable S1.C_FLOATNO O_TABLECAPTIONStudy population. C_TABLECAPTION C_TBL

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

BackgroundThe 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. Methods30 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. ResultsOmicron 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. ConclusionsBNT162b2 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

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 world1. 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 expected2,3. 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.

Ad26.COV2.S or BNT162b2 Boosting of BNT162b2 Vaccinated Individuals

The rapid spread of the highly mutated SARS-CoV-2 Omicron variant has raised substantial concerns about the protective efficacy of currently available vaccines. We assessed Omicron-specific humoral and cellular immune responses in 65 individuals who were vaccinated with two immunizations of BNT162b2 and were boosted after at least 6 months with either Ad26.COV2.S (Johnson & Johnson; N=41) or BNT162b2 (Pfizer; N=24) (Table S1). O_TBL View this table: org.highwire.dtl.DTLVardef@41c8baorg.highwire.dtl.DTLVardef@e14f5forg.highwire.dtl.DTLVardef@21ea87org.highwire.dtl.DTLVardef@ac4522org.highwire.dtl.DTLVardef@1eed52b_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable S1.C_FLOATNO O_TABLECAPTIONCharacteristics of the study population C_TABLECAPTION C_TBL

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

BackgroundA 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. MethodsHumoral 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. ResultsVaccinated 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. ConclusionsFully 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.