Preclinical Characterization of the Omicron XBB.1.5-Adapted BNT162b2 COVID-19 Vaccine

Author:

Modjarrad KayvonORCID,Che Ye,Chen Wei,Wu Huixian,Cadima Carla I.,Muik Alexander,Maddur Mohan S.,Tompkins Kristin R.,Martinez Lyndsey T.,Cai Hui,Hong Minah,Mensah Sonia,Cumbia Brittney,Falcao Larissa,Chang Jeanne S.,Fennell Kimberly F.,Huynh Kevin,McLellan Thomas J.,Sahasrabudhe Parag V.,Chen Wei,Cerswell Michael,Garcia Miguel A.,Li Shilong,Sharma Rahul,Li Weiqiang,Dizon Kristianne P.,Duarte Stacy,Gillett Frank,Smith Rachel,Illenberger Deanne M.,Sweeney Kari E.,Vogel Annette B.,Anderson Annaliesa S.,Sahin Ugur,Swanson Kena A.

Abstract

ABSTRACTAs SARS-CoV-2 continues to evolve, increasing in its potential for greater transmissibility and immune escape, updated vaccines are needed to boost adaptive immunity to protect against COVID-19 caused by circulating strains. Here, we report features of the monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine, which contains the same mRNA backbone as the original BNT162b2 vaccine, modified by the incorporation of XBB.1.5-specific sequence changes in the encoded prefusion-stabilized SARS-CoV-2 spike protein (S(P2)). Biophysical characterization of Omicron XBB.1.5 S(P2) demonstrated that it maintains a prefusion conformation that adopts a flexible and predominantly open one-RBD-up state, with high affinity binding to the human ACE-2 receptor. When administered as a 4thdose in BNT162b2-experienced mice, the monovalent Omicron XBB.1.5 vaccine elicited substantially higher serum neutralizing titers against pseudotyped viruses of Omicron XBB.1.5, XBB.1.16, XBB.1.16.1, XBB.2.3, EG.5.1 and HV.1 sublineages and the phylogenetically distant BA.2.86 lineage than the bivalent Wild Type + Omicron BA.4/5 vaccine. Similar trends were observed against Omicron XBB sublineage pseudoviruses when the vaccine was administered as a 2-dose primary series in naïve mice. Strong S-specific Th1 CD4+and IFNγ+CD8+T cell responses were also observed. These findings, together with prior experience with variant-adapted vaccine responses in preclinical and clinical studies, suggest that the monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine is anticipated to confer protective immunity against dominant SARS-CoV-2 strains.ONE-SENTENCE SUMMARYThe monovalent Omicron XBB.1.5-adapted BNT162b2 mRNA vaccine encodes a prefusion-stabilized spike immunogen that elicits more potent neutralizing antibody responses against homologous XBB.1.5 and other circulating sublineage pseudoviruses compared to the bivalent Wild Type + Omicron BA.4/5 BNT162b2 vaccine, thus demonstrating the importance of annual strain changes to the COVID-19 vaccine.

Publisher

Cold Spring Harbor Laboratory

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