Exploring antigenic traits of SARS-CoV-2 Omicron BA.5 and BA.4 subvariants

In a recent study posted to the bioRxiv* preprint server, scientists analyzed the antigenic characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.5 and BA.4 sublineages.

Background

SARS-CoV-2 mutants have emerged constantly throughout the coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 Omicron BA.2 and BA.1 lineages appeared in late November 2021 in South Africa and harbor a substantial antigenic gap from prior SARS-CoV-2 variants and existing vaccine strains, yet a minor antigenic distance between each other.

BA.4 and BA.5, the most recent SARS-CoV-2 Omicron mutants to appear, were initially discovered in Southern Africa, where they are causing the present wave of SARS-CoV-2 infection. In addition, the Omicron BA.5 and BA.4 sublineage cases were elevating quickly in various European nations.

BA.5 and BA.4 encode similar spike (S) proteins and are more closely associated with BA.2. They share multiple mutations with BA.2, including Δ69-70, F486V, and L452R, but neither has the Q493R alteration compared to BA.2. 

About the study

In the present report, the scientists examined the antigenic features of the key Omicron BA.4/BA.5, BA.1, and BA.2 sublineages as F486V and L452R mutations were anticipated to have an antigenic impact on the SARS-CoV-2 S protein. For this, they employed sera samples from vaccinated, vaccine-breakthrough, and post-infection animal/human cohorts and currently used therapeutic monoclonal antibodies (mAbs).

The researchers characterized the antigenicity of the Omicron BA.4/BA.5 S protein in depth by comparing sera samples taken post-Omicron BA.2, or BA.1 infection, post-vaccination, and post-Omicron/Delta vaccine breakthrough infection. The team tested the susceptibility of Omicron BA.4/BA.5 sublineages to neutralization by therapeutic monoclonal antibodies (mAbs) named casirivimab/REGN10933, imbedvimab/REGN10987, and sotrovimab.

The investigators assessed three-dose vaccinated subjects (two ChAdOx1 doses plus BNT162b2 booster dose or BNT162b2 triple-vaccinated). They also analyzed the cross-reactivity between different Omicron subvariants using unvaccinated hamsters and human sera collected post-BA.2 or BA.1 infections.

Findings

The study results indicated that the three-dose vaccinated subjects exhibited a comparable decline in neutralizing titer (six to 15-fold) for all Omicron subvariants, including an eight- to 10-fold drop against the BA.5 or BA.4 sublineages. The team noticed a similar result in an older vaccinee group, with comparable reductions in all Omicron sublineages. In this same group, both the BNT162b2 triple-dose and two-dose ChAdOx1 plus BNT162b2 booster dose vaccination regimens augmented BA.4 neutralizing titers by ≥10 times comparable to BA.2 and BA.1 neutralizing levels.

Sera from non-vaccinated people who had just one known exposure to BA.1 showed a 23-fold reduction in relative neutralizing levels against BA.4 and BA.5 and a minor decline against BA. 2. Cross-neutralization of BA.4/BA.5 by BA.1-infected hamster sera dropped dramatically, whereas BA.2 dropped only a little. The decrease in cross-neutralization of BA.4/BA.5 was less pronounced in hamster sera collected after BA.2 infections, while neutralization of BA.1 was diminished by 2.3 times. A similar pattern of cross-neutralization was depicted by unvaccinated single BA.2 infection-only and non-specified Omicron infection-harboring human sera samples.

The researchers reported 3.3 times reduction in neutralization between BA.1 and BA.5/BA.4 for BA.1 breakthrough infection and 5.5 times reduction between BA.2 versus BA.4/BA.5 for BA.2 breakthrough sera. Community Omicron breakthrough infected antisera with unspecified lineage exhibited similar decreases in titer towards all Omicron subvariants. Interestingly, in hamsters, Delta breakthrough infection elicited a cross-neutralizing reaction against BA.4/BA.5 and BA.2, yet not BA.1. Furthermore, BA.1 breakthrough resulted in a substantially cross-neutralizing response, with BA.5/BA.4 being neutralized to a similar degree as BA.2 or BA.1 in hamsters.

Finally, BA.4/BA.5 displayed a broadly similar trend of mAb sensitivity to BA.2, being identified by sotrovimab less well than the SARS-CoV-2 wild-type (WT) or BA.1 S protein but slightly better by imbedvimab versus BA.1.

Conclusions

Overall, the study data illustrated that post-vaccination sera had a similar capacity to neutralize the SARS-CoV-2 Omicron BA.2, BA.1, and BA.4/BA.5 subvariants. On the other hand, previous BA.1 or BA.2 infections without COVID-19 vaccination imparted poor BA.4/BA.5 neutralizing antibody responses. COVID-19 vaccinees infected with Omicron exhibited a broader neutralizing response toward the new Omicron mutants. Besides, BA.4/BA.5 was similar to BA.2, considering the susceptibility to neutralization via therapeutic monoclonal antibodies.

To conclude, the present study depicted that the SARS-CoV-2 Omicron BA.4/BA.5 differ antigenically from BA.1 and, to a minor degree, BA.2. The increased range of neutralization upon breakthrough Omicron infections indicated that after priming with ancestral strain, booster vaccination with multivalent or heterologous antigens might be a feasible strategy for the establishment of cross-neutralizing antibody reactions.

*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.

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.