Omicron variant BA.2.86 spreads faster, but current antivirals hold the line

In a recent research paper uploaded to the bioRxiv preprint* server, researchers evaluated the virological characteristics of a novel severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) Omicron lineage named BA.2.86. They conducted epidemic dynamics modeling, studies using current clinically available antivirals, and fusogenicity investigations using hamsters. Their findings revealed that relative to the globally dominant Omicron EG.5.1, the replication number of BA.2.86 is substantially higher.

Study: Virological characteristics of the SARS-CoV-2 BA.2.86 variant. Image Credit: ktsdesign / 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*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Encouragingly, four currently available antivirals could effectively treat the novel substrain, and the pathogenicity of the strain (in hamsters) was much lower than that of the parent BA.2 strain. Researchers attribute this reduced pathogenicity to low growth kinetics and decreased reproductive capacity.

Too many variants!

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the coronavirus disease 2019 (COVID-19) pandemic has claimed more than 6.9 million lives since the beginning of the outbreak in late 2019. First identified in Wuhan, China, the virus is a positive-sense single-stranded RNA virus. The ancestral virus was a host of bats, but given its intrinsic high rate of mutation, a genetic spillover event resulted in its ability to infect humans with high pathogenicity.

The progenitor of human COVID, labeled ancestral type “A” by Western researchers, retained its parent’s high mutation ability, resulting in thousands of variants of SARS-CoV-2 currently extant. Notably, the “B” type is responsible for the pandemic. Based on pathogenicity and susceptibility to vaccination and clinical intervention, the World Health Organization (WHO) has further labeled the B-type lineage into “alpha,” “beta,” “gamma,” “delta,” and most recently, “omicron.”

First detected and identified in Botswana, South Africa, on 24 November 2021, the Omicron variant, scientifically called “B.1.1.529”, and specifically its descendant XBB.1.9.2.5.1 (now called “EG.5.1) is by far the most dominant globally prevalent and devastating SARS-CoV-2 variant in the world today and the only COVID-19 virus that retains the “Variant of concern” WHO label. On 14 August 2023, however, a novel descent of XBB labeled BA.2.86 was discovered with over 30 mutations in the spike (S) protein.

Given the crucial role played by the S protein in infectivity and immune evasion, on 17 August 2023, the WHO designated BA.2.86 as a variant in need of urgent monitoring, spearheading research into its viral characteristics. By 31 October 2023, the variant was confirmed globally, though in low concentrations. The variant is hypothesized to be even faster mutating than its ancestors, with over 1,400 virus sequences discovered to date.

Research has investigated the immune evasive potential of the virus, as well as specific virological features, notably its affinity to the human receptor-binding domain (RBD). However, its mutation rate and evaluations of its infectivity, growth kinetics, and intrinsic pathogenicity in vivo remain lacking.

About the study

In the present study, researchers aimed to investigate the in vitro and in vivo virological features of the BA.2.86 lineage, especially its epidemic potential, RBD affinity, growth kinetics, immune evasive potential, and fusogenicity in hamsters. They further tested the efficacy of current clinically available antivirals in countering the disease.

The epidemic potential of BA.2.86 was evaluated by estimating its relative effective 119 reproduction number (R_e) using genome surveillance data derived from six countries with high variant prevalence. A multivariant Bayesian hierarchical multinomial logistic model was used to compute country-specific R_e as well as a global extrapolation.

The binding affinity of BA.2.56 was estimated using a yeast display technique. The binding of the S protein RBD of the novel variant to the ACE2 receptor was compared to results from XBB.1.5, which hitherto depicts the highest binding affinity of all known COVID-19 variants. They then tested the infectivity potential of the novel virus using an HIV-1-based pseudovirus. Western blotting of the derived pseudovirus was used to evaluate the cleavage efficiency of the BA.2.86S protein.

Fusogencitiy of BA.2.86 was carried out in vitro using an S 192 protein-mediated membrane fusion assay wherein surface expression levels were estimated in Calu-3/DSP_1-7 cells.

“To evaluate the sensitivity of BA.2.86 to antiviral humoral immunity 217 elicited by the breakthrough infection (BTI) with other Omicron sublineages, we 218 performed neutralization assays using BA.2 BTI sera (n = 13) and BA.5 BTI sera 219 (n = 17).”

Vero cells inoculated with BA.2.86 were used to investigate the growth kinetics of the virus in vitro. Following this, the antiviral sensitivity of the novel variant was measured against nirmatrelvir, ensitrelvir, remdesivir, and EIDD-1931. Finally, in vivo, pathogenicity of the BA.2.86 was tested in hamsters.

Study findings

The epidemic potential of BA.2.86 was found to be the highest of all known Omicron variants, with the global R_e estimated as being 1.07 times higher than EG.5.1. This is noteworthy given the increasing prevalence of BA.2.86, especially in European countries, and suggests that the novel variant will eventually replace EG.5.1 as the globally dominant COVID-19 strain. Binding affinity assays revealed that BA.2.86 had binding comparable to XBB.1.5, and significantly higher than EG.5.1 or its parental BA.2.

Psuedovirus infectivity assays revealed that, in vitro, EG.5.1 outcompetes BA.2.86, with the infectivity of the latter being comparable to its parental BA.2 strain, a viral characteristic also observed in in vitro fusogenicity. However, the cleavage efficiency of BA.2.86 was substantially higher than the ancestral BA.2 strain.

Immune evasion assays revealed that BA.2.86 has significantly more potent immune evasion potential than BA.2 and EG.5.1. However, growth kinetics assays revealed that the growth efficiency of the novel strain was much lower than the current dominant EG.5.1 strain.

“An immunofluorescence assay at 72 h postinfection (h.p.i.) further showed 238 that VeroE6/TMPRSS2 cells infected with BA.2.86 exhibited lower GFP intensity 239 than EG.5.1-infected cells. These results suggest that BA.2.86 240 showed a poorer replication capacity compared to EG.5.1 and BA.2.”

All four tested antivirals showed good efficacy against NA.2.86, with Nirmatrelvir showing the best efficacy and EIDD-193 the poorest (yet still positive). In vivo, hamster tests depicted that BA.2.86 infection resulted in body weight loss and reduced pulmonary function. However, these parameters were significantly less potent when compared to EG.5.1 infection. Viral RNA load evaluations revealed similar results (low BA.2.86 load compared to EG.5.1 and even ancestral BA.2), suggesting that BA.2.86 has low in vivo replication efficacy.

Conclusions

The present study evaluated the viral characteristics of the recently discovered BA.2.86 Omicron COVID-19 variant. The multi-analysis study revealed that despite having greater fusogenicity, binding affinity, and epidemic potential than the currently dominant EG.5.1 variant, the novel virus results in less severe infections in hamsters and reduced viral load.

“This discrepancy 290 can be explained by the replication capacity of BA.2.86. In fact, we showed that the replication kinetics of BA.2.86 is significantly lower than that of BA.2 in in vitro cell culture (at least in Vero cells) and in vivo. Therefore, our results suggest that the attenuated pathogenicity of BA.2.86 is attributed to its decreased replication capacity.”

*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.