Exploring factors favoring transmission of SARS-CoV-2 Delta sublineage AY.4.2 over the Delta variant

In a recent study posted to the bioRxiv* pre-print server, a team of researchers studied the AY.4.2 sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant to analyze the fusogenicity and neutralization sensitivity of its spike (S) protein.

Study: Fusogenicity and neutralization sensitivity of the SARS-CoV-2 Delta sublineage AY.4.2. Image Credit: Corona Borealis Studio/ShutterstockStudy: Fusogenicity and neutralization sensitivity of the SARS-CoV-2 Delta sublineage AY.4.2. Image Credit: Corona Borealis Studio/Shutterstock

The Delta lineage is heterogeneous and continues to evolve into sublineages or clades. One sublineage termed AY.4.2 has drawn considerable attention due to its continuous rise in the UK between July and December 2021. The AY.4.2 accounted for 20% of sequenced Delta cases in the UK during the third week of November 2021 and its occurrence has strongly diminished with the emergence of the Omicron variant worldwide. AY.4.2 exhibits three additional mutations - T95I, Y145H, and A222V - in the N-terminal domain (NTD) of the S protein compared to the parent Delta variant and remains poorly characterized, which hinders an understanding of the parameters that may have favored its transmission compared to the parent Delta strain.

About the study

In the present study, researchers isolated an infectious AY.4.2 strain from the nasopharyngeal swab of a symptomatic individual from the Paris region. They introduced the AY.4.2 signature mutations - T95I, Y145H, and A222V - in an expression plasmid coding the Delta protein to study the function of the AY.4.2 S protein. Further, the plasmids expressing Delta and AY.4.2 S were transfected into 293T cells to analyze antibody binding by flow cytometry.

The antibody panel comprised of 24 monoclonal antibodies (MAbs), including four RBD-targeting, four anti-RBD, and 16 anti-NTD antibodies.

The researchers also assessed the neutralizing sensitivity of anti-S antibodies (against the AY.4.2 strain) present in the sera of individuals that received either two doses of Pfizer or AstraZeneca vaccines and their samples taken after seven and five months post the second dose, respectively.

Findings

In Vero infected cells, the binding profile of neutralizing and non-neutralizing MAbs was the same for both Delta and AY.4.2 strains, as indicated by flow cytometry results. Even in S-expressing transfected 293-T cells, the antibody binding profile of both the strains remained the same, indicating that the S present at the surface of infected cells displays the same characteristics as upon expression by transfection. Overall, the AY.4.2 S exhibited similar fusogenicity and binding to ACE2 as the Delta variant.

The sensitivity of infectious AY.4.2 strain to a panel of MAbs was similar to Delta, except against Imdevimab, which showed incomplete neutralization. The maximum neutralization of MAbs reached ~100% against Delta but plateaued at 60% against the AY.4.2 strain, even at high antibody concentrations (1 µg/mL).

Sensitivity of AY.4.2 to sera from individuals who received two or three doses of Pfizer or two doses of AstraZeneca vaccines was reduced by 1.7 to 2.1 fold, compared to Delta. This decrease may be attributed to the slight reduction of the efficacy of some Imdevimab-like antibodies in the serum or targeting other RBD and NTD regions in the spike.

Overall antibody levels were similar after two doses of the Pfizer or AstraZeneca vaccines and increased by eight-fold after the boost of the Pfizer vaccine. There was no difference in the binding to the Delta and the AY.4.2 S. Performing a titration of the antibody levels in a subset of eight sera by serial dilutions gave similar results, confirming the results obtained at the 1:300 dilution. Altogether, these results indicated that the three NTD mutations were not associated with changes in S recognition by a panel of 24 monoclonal antibodies and by sera from vaccinated individuals.

Conclusions

The study has several important findings. First, the NTD mutations remotely impaired the efficacy of anti-receptor-binding domain (RBD) antibodies. Of the six MAbs targeting the NTD, only NTD-18 neutralized both strains at high concentrations. It will be worth determining whether other NTD targeting antibodies are less or more active against the AY.4.2 strain.

Further, the slightly decreased neutralizing titers did not significantly impact vaccine effectiveness against AY.4.2, at least within six to seven months post-vaccination. Lastly, the spread of AY.4.2 was not associated with functional changes in the S protein but rather with a partially reduced neutralization sensitivity.

More importantly, the researchers suggested that studying AY.4.2 strain in more relevant models in the future, such as the primary human bronchial epithelium, could help determine whether AY.4.2 is a better fit in culture systems than the parental lineage.

*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.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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