Transmissibility, infectivity, and immune evasion of the SARS-CoV-2 BA.2.86 variant.

In September, 2023, the SARS-CoV-2 XBB descendants, such as XBB.1.5 and EG.5.1 (originally XBB.1.9.2.5.1), are the predominant variants circulating worldwide.1NextstrainGenomic epidemiology of SARS-CoV-2 with subsampling focused globally over the past 6 months.https://nextstrain.org/ncov/gisaid/global/6mDate accessed: September 4, 2023Google Scholar Unexpectedly, however, a lineage distinct from XBB was identified and named BA.2.86 on Aug 14, 2023.2GitHub2nd-Generation BA.2 Saltation Lineage, >30 spike mutations (3 seq, 2 countries, Aug 14).https://github.com/cov-lineages/pango-designation/issues/2183#issue-1849123156Date accessed: September 4, 2023Google Scholar Notably, BA.2.86 bears more than 30 mutations in the spike (S) protein when compared with XBB and the parental BA.2, and many of these mutations are assumed to be associated with immune evasion (appendix p 10).2GitHub2nd-Generation BA.2 Saltation Lineage, >30 spike mutations (3 seq, 2 countries, Aug 14).https://github.com/cov-lineages/pango-designation/issues/2183#issue-1849123156Date accessed: September 4, 2023Google Scholar Although the number of reported cases is low (68 sequences have been reported as of Sept 7, 2023), BA.2.86 has been detected in several continents (Europe, North America, and Africa), suggesting that this variant might be spreading silently worldwide. On Aug 17, 2023, WHO designated BA.2.86 as a variant under monitoring.3WHOTracking SARS-CoV-2 variants.https://www.who.int/en/activities/tracking-SARS-CoV-2-variantsDate accessed: September 4, 2023Google Scholar We first estimated the effective reproduction number (Re) of BA.2.86 based on genome surveillance data until Sept 4, 2023, in Denmark, where multiple XBB subvariants including EG.5.1 are currently co-circulating, and 12 BA.2.86 sequences were reported (appendix p 10). Although there was considerable uncertainty in this estimation due to a smaller number of available BA.2.86 sequences, the Re of BA.2.86 was 1·29-fold greater than that of XBB.1.5 (95% Bayesian confidence interval 1·17–1·47; appendix p 10). Importantly, the Re of BA.2.86 was comparable to or even greater than that of EG.5.1, one of the most rapidly expanding XBB subvariants (appendix p 10), and the estimated posterior probability that the Re of BA.2.86 exceeds that of EG.5.1 was 0·901 (appendix p 10). These findings suggest that BA.2.86 potentially has greater fitness than current circulating XBB variants including EG.5.1. To assess the possibility that the enhanced infectivity of BA.2.86 contributes to its augmented Re, we prepared lentivirus-based pseudoviruses with the S proteins of BA.2.86, EG.5.1, parental BA.2, and ancestral D614G-bearing B.1.1. The pseudovirus assay showed that the infectivity of BA.2.86 pseudoviruses in HOS-ACE2/TMPRSS2 cells was significantly lower than that of B.1.1 and EG.5.1 (appendix p 10), suggesting that the increased Re of BA.2.86 is not due to the increased infectivity. The fact that the lower infectivity of BA.2.86 does not translate into its lower Re is reminiscent of the findings for omicron BA.1 and BA.2: although BA.1 and BA.2 are less infectious than other variants such as delta in cell culture, these omicron variants exhibited greater immune escape capacity.4Suzuki R Yamasoba D Kimura I et al.Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant.Nature. 2022; 603: 700-705Crossref PubMed Scopus (246) Google Scholar, 5Yamasoba D Kimura I Nasser H et al.Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike.Cell. 2022; 185 (15.e19): 2103Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar These observations suggest that Re can be determined by multiple factors such as infectivity and immune evasive potential. We then performed neutralisation assays using vaccine sera to assess the possibility that BA.2.86 evades the antiviral effect of vaccine-induced humoral immunity. The sera obtained from individuals vaccinated with third-dose monovalent, fourth-dose monovalent, BA.1 bivalent, and BA.5 bivalent mRNA vaccines exhibited very little or no antiviral effects against BA.2.86 (appendix p 10). Additionally, the three monoclonal antibodies (bebtelovimab, sotrovimab, and cilgavimab), which worked against the parental BA.2,6Yamasoba D Kosugi Y Kimura I et al.Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to therapeutic monoclonal antibodies.Lancet Infect Dis. 2022; 22: 942-943Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar did not exhibit antiviral effects against BA.2.86 (appendix p 10). Finally, a neutralisation assay using XBB breakthrough infection sera showed that the 50% neutralisation titre of XBB breakthrough infection sera against BA.2.86 was significantly (1·6-fold) lower than that against EG.5.1 (p<0·0001; appendix p 10). Altogether, these results suggest that BA.2.86 is one of the most highly immune evasive variants so far. This work was supported in part by the Japan Agency for Medical Research and Development (AMED) Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response (SCARDA) Japan Initiative for World-leading Vaccine Research and Development Centers UTOPIA programme (JP223fa627001 to KS); AMED SCARDA Program on R&D of New Generation Vaccine Including New Modality Application (JP223fa727002 to KS); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP22fk0108146 to KS; JP21fk0108494 to G2P-Japan Consortium, TI, and KS; JP21fk0108425 to KS; JP21fk0108432 to KS; JP22fk0108511 to G2P-Japan Consortium, AS, TI, and KS; JP22fk0108516 to KS; JP22fk0108506 to AS and KS; JP22fk0108534 to TI and KS); AMED Research Program on HIV/AIDS (JP23fk0410047 to AS; JP23fk0410056 to AS; JP23fk0410058 to AS; JP22fk0410055 to TI; JP22fk0410039 to KS); JST PRESTO (JPMJPR22R1 to JI); JST CREST (JPMJCR20H4 to KS); JSPS KAKENHI Grant-in-Aid for Scientific Research C (22K07103 to TI); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (23K14526 to JI); JSPS Leading Initiative for Excellent Young Researchers (LEADER; to TI); JSPS Core-to-Core Program (A. Advanced Research Networks; JPJSCCA20190008 to KS); JSPS Research Fellow DC2 (22J11578 to KU); JSPS Research Fellow DC1 (23KJ0710 to YKo); The Tokyo Biochemical Research Foundation (to KS); The Mitsubishi Foundation (to KS); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to TI); The Naito Foundation (to TI); International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to TI and AS). JI has received consulting fees and honoraria for lectures from Takeda Pharmaceutical. KS has received consulting fees from Moderna Japan and Takeda Pharmaceutical and honoraria for lectures from Gilead Sciences, Moderna Japan, and Shionogi & Co. All other authors declare no competing interests. KU and JI contributed equally to this study. Members of The Genotype to Phenotype Japan (G2P-Japan) Consortium are listed in the appendix (p 12). Download .pdf (.67 MB) Help with pdf files Supplementary appendix