The omicron BA.2.86 subvariant as a new serotype of SARS-CoV-2

The evolution of SARS-CoV-2 has resulted in the emergence of multiple serotypes1Hu S Wu C Wu X et al.Classification of five SARS-CoV-2 serotypes based on RBD antigenicities.Sci Bull (Beijing). 2023; 68: 3003-3012Crossref PubMed Scopus (0) Google Scholar,2Tan CW Zhu F Chia WN et al.Distinctive serotypes of SARS-related coronaviruses defined by convalescent sera from unvaccinated individuals.hLife. 2023; 1: 26-34Crossref Google Scholar capable of evading vaccines based on the SARS-CoV-2 prototype.3Xu K Fan C Han Y Dai L Gao GF Immunogenicity, efficacy and safety of COVID-19 vaccines: an update of data published by 31 December 2021.Int Immunol. 2022; 34: 595-607Crossref PubMed Scopus (12) Google Scholar Classifying SARS-CoV-2 serotypes can guide antigen selection for development of broad-spectrum vaccines and neutralising antibodies. Previously, we classified five SARS-CoV-2 serotypes (I to V) on the basis of the receptor binding domain (RBD) antigenicity of 23 variants, encompassing the pre-omicron variants and omicron and its subvariants.1Hu S Wu C Wu X et al.Classification of five SARS-CoV-2 serotypes based on RBD antigenicities.Sci Bull (Beijing). 2023; 68: 3003-3012Crossref PubMed Scopus (0) Google Scholar Serotype I includes all selected pre-omicron variants, whereas omicron and its subvariants are distributed across serotypes II to V on the basis of their evolutionary stages. In recent months, several novel omicron subvariants—XBB.1.16, EG.5, FL.1.5.1, and BA.2.86—have been circulating. Of these, BA.2.86 harbours 36 amino acid changes in its spike protein compared with the spike protein amino acid sequence of XBB.1.5, which has raised concerns about the emergence of a subvariant that might cause an impact similar to that of omicron.4Wang Q Guo Y Liu L et al.Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike.Nature. 2023; 624: 639-644Crossref PubMed Scopus (12) Google Scholar Using the same strategy as that in our previous investigation, we can further classify the serotypes of these new variants.1Hu S Wu C Wu X et al.Classification of five SARS-CoV-2 serotypes based on RBD antigenicities.Sci Bull (Beijing). 2023; 68: 3003-3012Crossref PubMed Scopus (0) Google Scholar We inoculated mice with the RBD of XBB.1.16, EG.5, FL.1.5.1, or BA.2.86 and chose two vaccines—one containing gamma variant to represent serotype I and another containing omicron XBB subvariant to represent serotype V (appendix p 1). We then performed cross-neutralisation assays using the antisera of these mice and pseudotyped viruses of the 27 variants, comprising the 23 variants in our previous study and the four new omicron subvariants (appendix p 1). We found potent cross-reactivity between the antisera of XBB, XBB.1.16, EG.5, and FL.1.5.1 and their corresponding pseudotyped viruses. In comparison, neutralisation by the antisera of these four subvariants against the BA.2.86 pseudotyped virus was substantially reduced, and the BA.2.86 antisera showed diminished neutralisation capacity against the pseudotyped viruses of these four subvariants by 1–2 orders of magnitude (appendix p 1). We next calculated the homologous-to-heterologous titre ratios of these variants to indicate the level of reduced cross-neutralising activities compared with those against their homologous pseudotyped viruses. With a cutoff homologous-to-heterologous titre ratio of 5, XBB.1.16, EG.5, and FL.1.5.1 could be classified as serotype V alongside XBB and XBB.1.5 (appendix p 1, yellow box), whereas BA.2.86 qualified as a new SARS-CoV-2 serotype, namely, serotype VI, as it showed severely reduced bidirectional cross-reactivity with other serotypes (appendix p 1). Classifying BA.2.86 as a new serotype was consistent with the previously reported divergence in BA.2.86 antigenicity.4Wang Q Guo Y Liu L et al.Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike.Nature. 2023; 624: 639-644Crossref PubMed Scopus (12) Google Scholar,5Yang S Yu Y Jian F et al.Antigenicity and infectivity characterisation of SARS-CoV-2 BA.2.86.Lancet Infect Dis. 2023; 23: e457-e459Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar Despite their classification as serotype V, EG.5 and FL.1.5.1 appeared to have undergone further antigenic drift compared with XBB and XBB.1.16. EG.5 and FL.1.5.1 showed higher homologous-to-heterologous titre ratios than XBB or XBB.1.16 across serotypes II, III, IV, and VI and XBB in serotype V as well (appendix p 1, blue and red boxes). This effect could be attributed to the Phe456Leu mutation in the RBD of EG.5 and FL.1.5.1 compared with the XBB.1.16 RBD (appendix p 2), as this change contributes to further immune escape, resulting in evasion from or dampening of neutralisation by many XBB.1.5-neutralising antibodies.6Yisimayi A Song W Wang J et al.Repeated omicron exposures override ancestral SARS-CoV-2 immune imprinting.Nature. 2024; 625: 148-156Crossref PubMed Scopus (1) Google Scholar XBB-based vaccines remain effective against BA.2.86;4Wang Q Guo Y Liu L et al.Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike.Nature. 2023; 624: 639-644Crossref PubMed Scopus (12) Google Scholar however, the pronounced antigenic differences have raised concerns. Given the widespread vaccination with XBB monovalent vaccines, BA.2.86-derived omicron subvariants might gain a growth advantage, leading to a surge in breakthrough infections. As a preventive measure, vaccines should offer broad-spectrum protection against XBB-derived subvariants and variants before XBB. This serotype classification could guide the development of broad-spectrum vaccines against COVID-19. We declare no competing interests. PD, CW, and SH contributed equally to this work. This work was supported by the National Key R&D Program of China (2022YFC2303403), the National Natural Science Foundation of China (82225021, 92269203, and 32171428), and Chinese Academy of Sciences (CAS) Young Scientists in Basic Research (YSBR-010). We thank Prof Xin Zhao for sharing the plasmids used to prepare the pseudotyped viruses. We thank the Laboratory Animal Center at the Institute of Zoology, CAS, and the Institutional Center for Shared Technology and Facilities at the Institute of Microbiology, CAS. QW and GFG initiated and coordinated the project. GFG, QW, and PD designed the experiments. CW and SH constructed the plasmids, prepared the mRNA vaccines, and performed neutralisation assays with RF to prepare the pseudotyped viruses. SH performed animal experiments. PD, CW, and SH analysed the data. PD wrote the manuscript. QW and GFG revised the manuscript. Download .pdf (.45 MB) Help with pdf files Supplementary appendix