In a recent preprint posted to the bioRxiv* server, researchers characterised two novel XBB variants, EG.5.1 and XBB.2.3, with the previous on course to turn into the dominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant.

Study: Immune Evasion and Membrane Fusion of SARS-CoV-2 XBB Subvariants EG.5.1 and XBB.2.3. Image Credit: Kateryna Kon/Shutterstock.com

*Necessary notice: bioRxiv publishes preliminary scientific reports that will not be peer-reviewed and, subsequently, mustn’t be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The unique Omicron variant arose globally in 2022 and shortly became the dominant SARS-CoV-2 variant worldwide. The XBB sublineages of Omicron evolved in early 2023. XBB.2.3 evolved directly from the Omicron XBB sublineage, while EG.5.1 is an XBB.1.5 mutant. 

The previous has two additional mutations in its spike (S), P521S within the receptor binding domain (RBD) and D253G within the N-terminal domain (NTD), while EG.5.1 has Q52H and F456L mutations within the NTD and RBD, respectively.

All XBB variants, including XBB.2.3 and EG.5.1, exhibited higher immune evasion capabilities than Omicron, specifically against neutralizing antibodies (nAbs) elicited by SARS-CoV-2 convalescence and coronavirus disease 2019 (COVID-19) vaccines based on the messenger ribonucleic acid (mRNA) technology.

Thus, the Food and Drug Administration (FDA) really useful including XBB subvariants in future iterations of COVID-19 mRNA vaccines.

Nonetheless, immune imprinting can impair vaccine efficacy against evolving variants. Thus, a three-dose vaccination series based on S of wildtype virus biases vaccine-elicited nAbs toward earlier lineages and impairs immune responses towards recently emerged Omicron sublineages.

A bivalent mRNA booster vaccine based on wildtype and BA.4/5 spikes enhances the immune response toward Omicron sublineages, albeit to a limited extent in comparison with a three-dose monovalent vaccine series.

Some methods of counteracting immune imprinting include administering extra doses of Omicron S-based mRNA vaccines or exposure to Omicron infection. Nonetheless, there may be a must reconfigure current COVID-19 mRNA vaccination approaches.

As well as, continued surveillance efforts to characterize emerging SARS-CoV-2 variants are critical.

In regards to the study

In the current study, researchers investigated S proteins of EG.5.1 and XBB.2.3 for infectivity, fusogenicity, and escape from nAbs in bivalent mRNA booster vaccinated sera, BA.4/5- and XBB.1.5-wave convalescent sera using HEK293T-ACE2 and CaLu-3 cells, and sophistication III monoclonal antibody (mAb), S309.

Moreover, they compared these parameters to spikes from the ancestral D614G and Omicron subvariants BA.4/5, XBB, XBB.1.5, and XBB.1.16.

Results

As expected, bivalent mRNA vaccination elicited relatively low nAb titers against all XBB variants, especially EG.5.1 and XBB.2.3, than D614G and Omicron BA.4/5 despite the presence of BA.4/5 S on this vaccine formulation.

The nAb response mainly targeted D614G, providing additional evidence of immune imprinting elicited by the monovalent mRNA vaccines. 

SARS-CoV-2 acquired many mutations in its evolutionary journey. Antigenic cartography evaluation has established antigenically distinct phenotypes of XBB sublineages, especially EG.5.1.

Yet, encouragingly, bivalent mRNA vaccination continues to confer higher protection against reinfection than monovalent vaccinations and natural infection. The authors noted that XBB.1.5-F456L mutation enhanced the nAb escape of EG.5.1 in comparison with XBB.1.5.

Molecular modeling demonstrated that F456L didn’t impact S-binding to S309 but likely decreased S-binding to class 1 SARS-CoV-2 mAbs, S2E12, consistent with the findings from recent studies.

Nearly all of the bivalent vaccination cohort had breakthrough infections relative to the convalescent cohorts. XBB.1.5 infections broadened nAb titers against vaccines containing XBB.1.5 and XBB.1.16 spikes.

From that logic, EG.5.1 S-containing mRNA vaccines usually tend to overcome immune imprinting and confer more immunity against XBB sublineages. 

Although infectivity of XBB.2.3 and EG.5.1 was not significantly different from XBB variants in each cell lines tested, EG.5.1 infectivity was moderately higher in 293T-ACE2 cell lines but lesser in respiratory airway epithelial cell line CaLu-3.

This alleviates concerns regarding its increased pathogenesis within the lungs. Moreover, the fusogenicity of their spikes was much like other XBB variants. 

Molecular modeling revealed the effect of XBB.1.5-F456L mutation. The substitution of phenylalanine to leucine amino acid residue in XBB.1.5 S reduced the side chain size and increased the gap between its RBD and host ACE2 receptor, which resulted in diminished RBD-ACE2 affinity.

Conclusions

To conclude, the present study found no in vitro evidence of the improved pathogenic potential of newly emerged XBB variants, EG.5.1 and XBB.2.3. Nonetheless, the necessity for in vivo and clinical evidence stays. 

The inclusion of XBB-lineage variant spikes in recent mRNA vaccine formulations could enhance their effectiveness. There stays a necessity for continued surveillance efforts for these variants to tell decisions around next-generation COVID-19 vaccination strategies. 

Some pharmaceutical firms have already proposed recent mRNA vaccine formulations containing XBB.1.5 S to the FDA, which can roll out in September 2023.

*Necessary notice: bioRxiv publishes preliminary scientific reports that will not be peer-reviewed and, subsequently, mustn’t be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.