New study reveals BA.2.86 subvariant's surprising dance with antibodies

In a recent study posted to the bioRxiv* preprint server, a team of researchers from the United States examined the antigenicity of the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subvariant BA.2.86 using monoclonal antibodies and serum samples from individuals with previous SARS-CoV-2 infections and complete vaccinations.

Study: Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike. Image Credit: Fernando Astasio Avila / Shutterstock

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Understanding the Evolving Virus

Although the morbidity and mortality associated with the coronavirus disease 2019 (COVID-19) pandemic has been brought under control after the rapid development of various vaccines and monoclonal antibody-based treatment methods, SARS-CoV-2 continues to evolve. The emergent subvariants of the SARS-CoV-2 Omicron variant are also becoming increasingly distant in their genetic composition from their predecessors. The newly emergent BA.2.86 subvariant is as genetically divergent from the BA.2 subvariant as the Omicron BA.1 variant was from the Delta variant.

BA.2.86 carries an additional 34 mutations compared to the BA.2 variant from which it evolved, with the N-terminal domain (NTD) and the receptor binding domain (RBD) containing 13 and 14 mutations, respectively. The large number of mutations in the spike protein region is concerning because they can increase the ability of the virus to evade the neutralizing antibodies elicited by vaccinations or previous infections and the monoclonal antibodies currently in clinical use. Therefore, it is essential to evaluate the efficacy of the clinically used monoclonal antibodies and the immunity elicited by vaccinations and previous SARS-CoV-2 infections against the BA.2.86 subvariant.

Study Design and Methodology

In the present study, the researchers collected serum samples from three clinical cohorts consisting of individuals who had been vaccinated with three shots of the monovalent and two shots of the bivalent messenger ribonucleic acid (mRNA) vaccines and from individuals who had breakthrough infections from the BA.2 and XBB subvariants. Prior SARS-CoV-2 infections were confirmed using the anti-nucleoprotein enzyme-linked immunosorbent assay, while the specific strains were identified through sequencing.

Vesicular stomatitis virus was used to develop pseudotyped viruses containing the spike proteins of two versions of the BA.2.86 subvariant and the BA.2, EG.5.1, and XBB.1.5 subvariants. The pseudotyped viruses were used to evaluate the antigenicity of the BA.2.86 subvariant and compare it to that of the other subvariants through serum neutralization assays using the serum samples from the three cohorts.

A panel of 25 monoclonal antibodies that were effective against the BA.2 subvariant was used to assess the ability of BA.2.86 to evade neutralizing antibodies, with EG.5.1 and XBB.1.5 used as comparators. Of the 25 monoclonal antibodies, 20 targeted four RBD epitope classes, while the rest targeted the NTD and subdomains 1 and 2.

Additionally, the role of each of the 34 spike mutations of BA.2.86 in the antigenicity of the subvariant was assessed by synthesizing the 34 point mutations and constructing pseudotyped viruses with each of those mutations using the BA.2 subvariant as a background. The antigenicity of these pseudotyped viruses was then evaluated against the panel of 25 monoclonal antibodies.

Surface plasmon resonance was utilized to determine the binding affinity of the BA.2.86 subvariant to the viral receptor using the dimeric human angiotensin-converting enzyme-2 (ACE-2) fragment crystallizable (Fc) protein. The binding affinities of the spike proteins of two versions of BA.2.86, as well as those of the BA.2, EG.5.1, and XBB.1.5 subvariants, were tested.

Key Findings

The results reported that the BA.2.86 subvariant was not resistant to the neutralizing antibodies obtained from the serum samples of individuals with breakthrough BA.2 or XBB infections or from healthy, fully vaccinated individuals. Furthermore, the serum samples from individuals with XBB breakthrough infections showed robust neutralizing activity against BA.2.86, indicating that monovalent mRNA vaccines being developed using XBB.1.5 could protect against BA.2.86.

However, the neutralizing assays using the monoclonal antibody panel revealed that all the monoclonal antibodies that targeted subdomain 1 were not effective against the BA.2.86 subvariant. BA.2.86 was also resistant to monoclonal antibodies targeting epitopes from RBD classes 2 and 3 but was sensitive to those that targeted the epitopes from RBD classes 1 and 4/1. Moreover, while some of the novel mutations in BA.2.86 resulted in antibody resistance, other mutations resulted in antibody sensitivity, which explained why the antigenic distance between BA.2.86 and its predecessor was not significant despite the sizeable genetic distance.

Furthermore, the sensitivity to neutralization by the monoclonal antibodies targeting RBD classes 1 and 4/1 indicates that the RBD of the BA.2.86 subvariant is more exposed than that of the EG.5.1 or XBB.1.5 subvariants since the RBD class 1 and 4/1 monoclonal antibodies target the RBD’s inner face when the RBD is in the “up” configuration. However, this also indicated that BA.2.86 had a greater than two-fold binding affinity to the ACE-2 receptor since the RBD is also in the “up” configuration during receptor binding.

Overall, the findings suggested BA.2.86 was sensitive to neutralizing antibodies from human sera, especially from those with breakthrough XBB infections. However, the monoclonal antibodies that targeted epitopes in the RBD classes 2 and 3, or subdomain 1 were ineffective against BA.2.86. Furthermore, the binding affinity of BA.2.86 for the viral receptor was more than twice that of the previous subvariants.

There have been many experimental papers on BA.2.86 over last month. This one by David Ho’s group is one of most comprehensive: https://t.co/iPWlTH8MEa

I’m going to quickly summarize key points for people having hard time keeping up w all the recent BA.2.86 papers.

— Bloom Lab (@jbloom_lab) September 28, 2023

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.