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

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

AUG-3387, a Human-Derived Monoclonal Antibody Neutralizes SARS-CoV-2 Variants and Reduces Viral Load from Therapeutic Treatment of Hamsters In Vivo

Infections from the SARS-CoV-2 virus have killed over 4.6 million people since it began spreading through human populations in late 2019. In order to develop a therapeutic or prophylactic antibody to help mitigate the effects of the pandemic, a human monoclonal antibody (mAb) that binds to the SARS-CoV-2 spike protein was isolated from a convalescent patient following recovery from COVID-19 disease. This mAb, designated AUG-3387, demonstrates a high affinity for the spike protein of the original viral strains and all variants tested to date. In vitro pseudovirus neutralization and SARS-CoV-2 neutralization activity has been demonstrated in vitro. In addition, a dry powder formulation has been prepared using a Thin-Film Freezing (TFF) process that exhibited a fine particle fraction (FPF) of 50.95 {+/-} 7.69% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 3.74 {+/-} 0.73 {micro}m and 2.73 {+/-} 0.20, respectively. The dry powder is suitable for delivery directly to the lungs of infected patients using a dry powder inhaler device. Importantly, AUG-3387, administered as a liquid by intraperitoneal injection or the dry powder formulation delivered intratracheally into Syrian hamsters 24 hours after intranasal SARS-CoV-2 infection, demonstrated a dose-dependent reduction in the lung viral load of the virus. These data suggest that AUG-3387 formulated as a dry powder demonstrates potential to treat COVID-19.