XBB.1.16-RBD-based trimeric protein vaccine can effectively inhibit XBB.1.16-included XBB subvariant infection

Abstract

The newly identified XBB.1.16-containing sublineages, including XBB.1.5, have become the prevailing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant in circulation. Unlike previous Omicron XBB variants (e.g., XBB.1.5 and XBB.1.9) harboring the F486P substitution, XBB.1.16 also carries a T478R substitution in the receptor-binding domain (RBD). Numerous researchers have delved into the high transmissibility and immune evasion of XBB.1.16 subvariant. Therefore, developing a new vaccine targeting XBB.1.16, including variants of concern (VOCs), is paramount. In our study, we engineered a recombinant protein by directly linking the S-RBD sequence of the XBB.1.16 strain of SARS-CoV-2 to the sequences of two heptad repeat sequences (HR1 and HR2) from the SARS-CoV-2 S2 subunit. Named the recombinant RBD_XBB.1.16-HR/trimeric protein, this fusion protein autonomously assembles into a trimer. Combined with an MF59-like adjuvant, the RBD_XBB.1.16-HR vaccine induces a robust humoral immune response characterized by high titers of neutralizing antibodies against variant pseudovirus and authentic VOCs and cellular immune responses. Additionally, a fourth heterologous RBD_XBB.1.16-HR vaccine enhances both humoral and cellular immune response elicited by three-dose mRNA vaccines. These findings demonstrate that the recombinant RBD_XBB.1.16-HR protein, featuring the new T478R mutation, effectively induces solid neutralizing antibodies to combat newly emerged XBB variants.

Keywords

heterologous booster / recombinant RBD-HR protein / XBB.1.16 variant

References

[1] Umar TP. Arcturus (XBB.1.16) COVID-19 subvariant emergence in Indonesia. Lancet. 2023; 402(10408): 1127-1128.

[2] WHO. Tracking SARS-CoV-2 variants. 2023. Accessed October 11, 2023. https://www.who.int/en/activities/tracking-SARS-CoV-2-variants

[3] Nehlmeier I, Kempf A, Arora P, et al. Host cell entry and neutralisation sensitivity of the SARS-CoV-2 XBB.1.16 lineage. Cell Mol Immunol. 2023; 20(8): 969-971.

[4] Yamasoba D, Uriu K, Plianchaisuk A, et al. Virological characteristics of the SARS-CoV-2 omicron XBB.1.16 variant. Lancet Infect Dis. 2023; 23(6): 655-656.

[5] European Medicines Agency. EMA and ECDC statement on updating COVID-19 vaccines to target new SARS-CoV-2 virus variants. Accessed June 6, 2023. https://www.ema.europa.eu/en/news/ema-and-ecdc-statement-updating-covid-19-vaccines-target-new-sars-cov-2-virus-variants

[6] Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. New Engl J Med. 2021; 384(5): 403-416.

[7] Haas EJ, Angulo FJ, McLaughlin JM, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet (Lond, Engl). 2021; 397(10287): 1819-1829.

[8] Sun P, Balinsky CA, Jiang L, et al. Antibody responses to the SARS-CoV-2 ancestral strain and Omicron variants in Moderna mRNA-1273 vaccinated active-duty US navy sailors and marines. J Infect Dis. 2023; 228(2): 149-159.

[9] Scheaffer SM, Lee D, Whitener B, et al. Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice. Nat Med. 2023; 29(1): 247-257.

[10] Andersson NW, Thiesson EM, Baum U, et al. Comparative effectiveness of bivalent BA.4-5 and BA.1 mRNA booster vaccines among adults aged ≥50 years in Nordic countries: nationwide cohort study. BMJ (Clin Res Ed). 2023; 382: e075286.

[11] Mateo-Urdiales A, Sacco C, Fotakis EA, et al. Relative effectiveness of monovalent and bivalent mRNA boosters in preventing severe COVID-19 due to omicron BA.5 infection up to 4 months post-administration in people aged 60 years or older in Italy: a retrospective matched cohort study. Lancet Infect Dis. 2023; 23(12): 1349-1359.

[12] Kurhade C, Zou J, Xia H, et al. Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster. Nat Med. 2023; 29(2): 344-347.

[13] Kopel H, Nguyen VH, Boileau C, et al. Comparative effectiveness of bivalent (original/Omicron BA.4/BA.5) COVID-19 vaccines in adults. Vaccines (Basel). 2023; 11(11): 1711.

[14] He C, Yang J, Hong W, et al. A self-assembled trimeric protein vaccine induces protective immunity against Omicron variant. Nat Commun. 2022; 13(1): 5459.

[15] Yang J, Wang W, Chen Z, et al. A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature. 2020; 586(7830): 572-577.

[16] Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020; 581(7807): 215-220.

[17] Yang J, Wang W, Chen Z, et al. Publisher correction: a vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature. 2021; 590(7844): E23.

[18] Flurkey K, Currer JM, Leiter EH, Witham B. The Jackson Laboratory Handbook on Genetically Standardized Mice. The Jackson Laboratory; 2009.

[19] Fernández-Ciriza L, González Á, Del Pozo JL, et al. Humoral and cellular immune response over 9 months of mRNA-1273, BNT162b2 and ChAdOx1 vaccination in a University Hospital in Spain. Sci Rep. 2022; 12(1): 15606.

[20] Milligan EC, Olstad K, Williams CA, et al. Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge 1 year later. Sci Transl Med. 2023; 15(685): eadd6383.

[21] Park YJ, Pinto D, Walls AC, et al. Imprinted antibody responses against SARS-CoV-2 Omicron sublineages. Science. 2022; 378(6620): 619-627.

[22] Peng D, Zhao T, Hong W, et al. Heterologous vaccination with subunit protein vaccine induces a superior neutralizing capacity against BA.4/5-included SARS-CoV-2 variants than homologous vaccination of mRNA vaccine. MedComm. 2023; 4(2): e238.

[23] Wang Q, Guo Y, Iketani S, et al. Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5. Nature. 2022; 608(7923): 603-608.

[24] He C, Yang J, Hong W, et al. A self-assembled trimeric protein vaccine induces protective immunity against Omicron variant. Nat Commun. 2022; 13(1): 5459.

[25] Ye F, Lin X, Chen Z, et al. S19W, T27W, and N330Y mutations in ACE2 enhance SARS-CoV-2 S-RBD binding toward both wild-type and antibody-resistant viruses and its molecular basis. Signal Transduct Target Ther. 2021; 6(1): 343.

[26] Rohou A, Grigorieff N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J Struct Biol. 2015; 192(2): 216-221.

[27] Tang G, Peng L, Baldwin PR, et al. EMAN2: an extensible image processing suite for electron microscopy. J Struct Biol. 2007; 157(1): 38-46.

[28] Kimanius D, Dong L, Sharov G, Nakane T, Scheres SHW. New tools for automated cryo-EM single-particle analysis in RELION-4.0. Biochem J. 2021; 478(24): 4169-4185.

[29] Punjani A, Rubinstein JL, Fleet DJ, Brubaker MA. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat Methods. 2017; 14(3): 290-296.

[30] Badoual C, Hans S, Rodriguez J, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006; 12(2): 465-472.

[31] Ren Z, Shi Q, Xu S, et al. Elicitation of T-cell-derived IFN-γ-dependent immunity by highly conserved Plasmodium ovale curtisi Duffy binding protein domain region II (PocDBP-RII). Parasites Vectors. 2023; 16(1): 269.

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.