New Omicron subvariant BA.2.86: A master of immune escape but not taking over yet

By Neha MathurReviewed by Benedette Cuffari, M.Sc.Sep 13 2023

In a recent study posted to the medRxiv preprint* server, researchers isolate BA.2.86, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant, and assess its immune-evading and replication properties.

Study: Evolution and neutralization escape of the SARS-CoV-2 BA.2.86 subvariant. Image Credit: Starshaker / Shutterstock.com

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Background

BA.2.86 is a derivative of the Omicron BA.2 subvariant. This novel SARS-CoV-2 variant shares the spike (S) protein substitution S939F and synonymous mutation C26681T with BA.2 genomes collected in South Africa in early 2022. However, the C9866T mutation, typically present in most BA.2 sequences sampled from outside South Africa, is absent in BA.2.86. 

BA.2.86 contains 30 additional mutations in its S protein relative to BA.2 and the most recently circulating SARS-CoV-2 XBB.1.5 variant. The emergence of Omicron BA.2.86 is concerning, as many of these new mutations allow for the escape of neutralizing antibodies (nAbs) induced by prior infection and vaccination.

Global genomic surveillance systems initially detected Omicron BA.2.86 in July 2023. However, it remains unclear when BA.2.86 initially emerged and began spreading, as surveillance efforts have significantly reduced since the start of the coronavirus disease 2019 (COVID-19) pandemic.

About the study

Researchers extracted viral ribonucleic acid (RNA) from the BA.2.86 swab sample to prepare whole genome sequencing (WGS) libraries, which were quantified using the Qubit double-stranded DNA (dsDNA) high-sensitivity assay. After fragment size analysis, libraries were pooled, normalized, and loaded onto the Illumina NextSeq 1000/2000 instrument to generate genome sequences for WGS analysis.

Nextclade and Pangolin versions 2.14.1 and 4.3, respectively, were used for clade and lineage assignments. Nextclade was also used to visualize the sequences and detect frameshift mutations. Oxford Nanopore sequencing was also performed.

The neutralization of BA.2.86 was compared with that of XBB.1.5 using sera from vaccinated individuals, those with a breakthrough infection from an Omicron subvariant, and those infected with only Omicron subvariants. The researchers then determined whether BA.2.86 evolved to escape neutralizing immunity relative to earlier SARS-CoV-2 strains. 

To measure the cellular spread of Omicron BA.2.86, the number of cells infected by a single cell to form an infected cell cluster was determined using a live virus focus-forming assay in Vero-TMPRSS cells. The cytopathic effect (CPE) and viral replication were also determined.

Phylogenetic analysis of the BA.2 sequences collected between November 2021 and June 2022 was also performed using data deposited in the Global Initiative on Sharing All Influenza Data (GISAID) database, aligned pairwise against Wuhan-Hu-1. The IQ-tree 2 was used to construct a phylogenetic tree.

Study findings

As compared to XBB.1.5, BA.2.86 did not exhibit significant immune evasion capabilities. However, the immune escape of BA.2.86 relative to the ancestral SARS-CoV-2 strain was five-fold greater than BA.1. Furthermore, BA.2.86 exhibited 14-fold greater escape capabilities when tested against the sera of people infected with BA.1; however, XBB.1.5 exhibited a comparable 12-fold escape.

At 20 hours post-infection, XBB.1.5 and BA.2.86 generated infection foci that were 4.5- and five-fold smaller than those of the SARS-CoV-2 ancestral strain. By 72 hours, reduced CPE was observed in BA.2.86- and XBB.1.5-infected cells as compared to ancestral SARS-CoV-2 infected cells. 

BA.2.86 appears to have descended from SARS-CoV-2 Omicron sublineages BA.1/BA.2, which were the dominant circulating strains in early 2021. Despite this extensive evolutionary trajectory, BA.2.86 did not widely spread at the population level, which may indicate that BA.2.86 originally evolved in an immunosuppressed individual.

Molecular clock analysis with TreeTime indicated that BA.2.86 likely began to spread from May 2023 onward. Since the time of this study’s publication, the researchers have deposited sequences of isolated Omicron BA.2.86 and its associated metadata in the GISAID.

Conclusions

Although Omicron BA.2.86 evolved to escape nAb-mediated immunity, convalescent plasma recognized it to a similar extent as XBB.1.5. These observations provide important insights into the comparatively slow spread of BA.2.86 relative to Omicron BA.1/BA.2.

Thus, although BA.2.86 might cause new infections at the population level now, it does not differ significantly from other SARS-CoV-2 variants currently circulating worldwide.

BA.2.86 is more closely related to sequences from Southern Africa than other regions and so may have evolved there, and that evolution led to escape from neutralizing antibodies similar in scale to recently circulating strains of SARS-CoV-2.”

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources