BA.2.86 variant is highly immune evasive and antigenically distinct from XBB.1.5 and previous Omicron variants

On August 14, 2023, a lineage distinct from XBB was identified and named BA.2.86. BA.2.86 bears 33 mutations in the spike (S) protein and 14 mutations in the receptor binding domain (RBD) compared with the parental BA.2, as well as 35 S mutations and 12 RBD mutations compared with XBB.1.5. Also, many unusual mutations on the N-terminal domain (NTD), may change the antigenicity of the BA.2.86 variant. The studies conducted by authors from China and Japan have shown that BA.2.86 variant is highly immune evasive and antigenically distinct from XBB.1.5 and previous Omicron variants.

The first study

The authors from China conducted an antigenicity and infectivity analysis of the SARS-CoV-2 BA.2.86 variant. Initially, the authors generated the pseudovirus of BA.2.86 and established its antigenic distance from B.1 (D614G), BA.5, BQ.1.1, and XBB using serum samples from mice that had received two doses of spike mRNA vaccines. The findings revealed that BA.2.86 exhibited antigenically distinct characteristics from the wild-type, BA.2, BA.5, and XBB.1.5, indicating a significant antigenic drift.

In order to assess the immune-evasion capabilities of BA.2.86, the researchers conducted a neutralization assays using XBB breakthrough infection sera from people who received three doses of inactivated vaccines before having a XBB (XBB subvariants with S486P substitution) breakthrough infection. The first cohort (n=27) included convalescents who had a single XBB breakthrough infection after vaccination, and the second cohort (n=54) comprised convalescents who got a XBB reinfection after BA.5 or BF.7 breakthrough infection. The results showed that BA.2.86 has high immune evasion capability of XBB-stimulated plasma. BA.2.86’s immune evasion capability even exceeded EG.5.

It is noteworthy that the E554K mutation, carried by BA.2.86 and located on the binding interface of spike subdomain 1 (SD1), escaped SD1-targeting neutralizing antibodies, represented by S3H3, an antibody effective against many evasive mutants. The E554K mutation added to XBB.1.5 was also capable to enhance plasma evasion, suggesting that neutralizing antibodies targeting SD1 compose a substantial proportion of XBB-stimulated convalescent plasma.

The results also showed that by switching the RBD part of BA.2.86 to XBB.1.5, the pseudovirus still had a higher capability of immune evasion than XBB.1.5 or XBB.1.5 plus E554K. This suggests that mutations on the BA.2.86 NTD could cause significant neutralizing evasion. The authors also tested a panel of XBB.1.5-effective neutralizing antibodies against XBB.1.5-based pseudoviruses carrying single BA.2.86 RBD mutations in order to delineate which are the key RBD mutations involved in BA.2.86’s enhanced immune evasion compared with XBB.1.5.

The infectivity of BA.2.86 was evaluated by testing the efficiency of its pseudovirus form in infecting Vero cells and human ACE2- HEK293T cells. Compared with XBB.1.5, EG.5, and HK.3, BA.2.86 had the lowest infectivity. Researchers then constructed and expressed BA.2.86 recombinant RBD and tested its affinity for human ACE2 using surface plasmon resonance to determine whether the compromised infectivity could be attributed to binding affinity for ACE2. BA.2.86 had higher binding to human ACE2 compared with XBB.1.5 and EG.5, so, the low infectivity observed in vitro could be due to other factors.

The authors, however, emphasized, the necessity of confirming these findings through tests employing authentic BA.2.86 isolates, given that the infectivity in this study was determined by pseudovirus assays. Furthermore, it is possible that real-world transmissibility is not related to the efficiency of infecting cell lines tested in vitro.

In conclusion, BA.2.86 is antigenically distinct from XBB.1.5 and previous Omicron variants. Also, BA.2.86 variant is highly immune evasive and may have advantages over currently circulating variants in its ability to resist XBB-induced humoral immunity. Moreover, BA.2.86 may acquire additional mutations during its transmission. Therefore, the researchers emphasized the importance of closely monitoring and carefully evaluating the efficacy of developing XBB-based vaccines against BA.2.86.

This article was published in the Lancet Infectious Disease.

Journal Reference

Yang S et al. Antigenicity and infectivity characterisation of SARS-CoV-2 BA.2.86. Lancet Infect Dis 2023 Published Online September 19, 2023 (Open Access)

The second study

The research group from Japan conducted research on the transmissibility, infectivity, and immune resistance of the SARS-CoV-2 BA.2.86 variant. They first estimated the effective reproduction number of BA.2.86 based on the genome surveillance data until September 4, 2023, in Denmark, where multiple XBB subvariants including EG.5.1 are currently co-circulating, and twelve BA.2.86 sequences were reported. The findings indicated that BA.2.86 could have greater fitness than current circulating XBB variants including EG.5.1.

To assess the infectivity of BA.2.86, the authors prepared lentivirus-based pseudoviruses with the S proteins of BA.2.86, EG.5.1, parental BA.2, and ancestral D614G91 bearing B.1.1. The infectivity of BA.2.86 was significantly lower than that of B.1.1 and EG.5.1, which suggests that the increased fitness of BA.2.86 was not due to its increased infectivity.

The researchers then conducted neutralization assays utilizing vaccine sera to evaluate the possibility that BA.2.86 evades vaccine-induced humoral immunity. The vaccine sera were collected one month after the last vaccination. Sera from individuals vaccinated with monovalent 3rd or 4th-dose, BA.1 bivalent, and BA.5 bivalent mRNA vaccines showed minimal or no antiviral effects against BA.2.86. In addition, no antiviral effects against BA.2.86 were observed in neutralization assay with three monoclonal antibodies (bebtelovimab, sotrovimab and cilgavimab), which worked against the parental BA.2.

Finally, a neutralization assay with XBB breakthrough infection sera from fully vaccinated individuals infected with XBB.1.5, XBB.1.9, or XBB.1.16 showed that the 50% neutralization titer of XBB breakthrough infection sera against BA.2.86 was significantly lower (1.6-fold) than that against EG.5.1.

The authors concluded that these results show that BA.2.86 is one of the variants with the highest degree of immune evasion ever.

Journal Reference

The results of the study have been published on a preprint server and are currently being peer-reviewed.

Uriu1 K et al. Transmissibility, infectivity, and immune resistance of the SARS-CoV-2 BA.2.86 variant. bioRxiv preprint (Open Access)