Substantial Neutralization Escape by the SARS-CoV-2 Omicron Variant BQ.1.1

Omicron BA.5 has been the globally dominant SARS-CoV-2 variant and has demonstrated substantial neutralization escape compared with prior variants. Additional Omicron variants have recently emerged, including BA.4.6, BF.7, BA.2.75.2, and BQ.1.1, all of which have the Spike R346T mutation. In particular, BQ.1.1 has rapidly increased in frequency, and BA.5 has recently declined to less than half of viruses in the United States. Our data demonstrate that BA.2.75.2 and BQ.1.1 escape NAbs induced by infection and vaccination more effectively than BA.5. BQ.1.1 NAb titers were lower than BA.5 NAb titers by a factor of 7 in two cohorts of individuals who received the monovalent or bivalent mRNA vaccine boosters. These findings provide the immunologic context for the rapid increase in BQ.1.1 prevalence in regions where BA.5 is dominant and have implications for both vaccine immunity and natural immunity.

Immunogenicity of the BA.5 Bivalent mRNA Vaccine Boosters

Waning immunity following mRNA vaccination and the emergence of SARS-CoV-2 variants has led to reduced mRNA vaccine efficacy against both symptomatic infection and severe disease. Bivalent mRNA boosters expressing the Omicron BA.5 and ancestral WA1/2020 Spike proteins have been developed and approved, because BA.5 is currently the dominant SARS-CoV-2 variant and substantially evades neutralizing antibodies (NAbs). Our data show that BA.5 NAb titers were comparable following monovalent and bivalent mRNA boosters.

Neutralization Escape by the SARS-CoV-2 Omicron Variants BA.2.12.1 and BA.4/BA.5

Multiple lineages of the SARS-CoV-2 Omicron variant (B.1.1.529) have emerged, and BA.1 and BA.2 have demonstrated substantial escape from neutralizing antibodies (NAbs). BA.2.12.1 has now become dominant in the United States, and BA.4 and BA.5 have become dominant in South Africa. Our data show that BA.2.12.1 and BA.4/BA.5 substantially escape NAbs induced by both vaccination and infection. Moreover, BA.4/BA.5 NAb titers, and to lesser extent BA.2.12.1 NAb titers, were lower than BA.1 and BA.2 NAb titers, suggesting that the SARS-CoV-2 Omicron variant has continued to evolve with increasing neutralization escape. These findings have important public health implications and provide immunologic context for the current surges with BA.2.12.1 and BA.4/BA.5 in populations with high rates of vaccination and BA.1/BA.2 infection.

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.

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