Omicron subvariants BA.2.12.1, BA.4, and BA.5 show higher neutralization resistance to antibodies

By Neha MathurJun 30 2022Reviewed by Danielle Ellis, B.Sc.

In a recent study published in The Lancet Infectious Diseases, researchers investigated the neutralization sensitivity of the emerging Omicron sub-variants, BA.2.12.1, BA.4, and BA.5.

Study: Augmented neutralisation resistance of emerging omicron subvariants BA.2.12.1, BA.4, and BA.5. Image Credit: Naeblys / Shutterstock

Background

Until recently, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) new variant of concern (VOC) Omicron’s multiple sub-variants were co-circulating globally. Now, the Omicron sub-variant BA.2.12.1, first detected in the United States, and BA.4 and BA.5 are replacing its previously predominant sub-variants BA.1 and BA.2 in several countries.

While the researchers know that at the spike (S) protein level, BA.4 and BA.5 are identical and BA.2.12.1 has unique S mutations, they do not have much information about their neutralization resistance against vaccine- or natural infection-induced neutralizing antibodies (nAbs) or therapeutic monoclonal antibodies (mAbs).

About the study

In the present study, researchers analyzed the neutralization sensitivity of BA.4, BA.5, and BA.2.12.1 against a panel of mAbs using the S-protein-bearing reporter viruses as a surrogate model. They used viruses bearing the S-protein of earlier Omicron sub-variants B.1, BA.1, or BA.2 as the reference for the study analysis.

Next, the researchers analyzed the neutralization sensitivity of BA.2.12.1 and BA.4/BA.5 against serum antibodies. They collected plasma samples from 10 unvaccinated individuals from Germany in the age group of 20 to 71 years. Five of them were male, and five were female, and they had mild coronavirus disease 2019 (COVID-19) between March and May 2022. Lastly, the team analyzed the neutralization sensitivity of the three Omicron sub-variants BA.4, BA.5, and BA.2.12.1 by the vaccination-induced antibodies.

Study findings

All Omicron sub-variants robustly evaded neutralization against a panel of 10 therapeutic mAbs, albeit with some notable differences. For instance, sotrovimab effectively neutralized BA.1 but exhibited markedly reduced neutralization of BA.2, BA.2.12.1. In addition, sotrovimab weakly neutralized BA.4 and BA.5 Omicron sub-variants in comparison to BA.1. Contrastingly, mAb cilgavimab neutralized all Omicron subvariants except BA.1. The highest efficacy against all Omicron sub-variants was exhibited by mAb bebtelovimab (LY-CoV1404).

Regarding neutralization sensitivity to prior-infection induced nAbs, those nAbs neutralized BA.1 with 2.9-times higher efficiency than B.1. Conversely, BA.2 was 27.2-times more efficiently neutralized than B.1, suggesting that most donors were BA.2-infected. Notably, BA.2.12.1 and BA.2 were similarly sensitive to neutralization by vaccine-induced nAbs, whereas BA.4/BA.5 showed reduced sensitivity compared with BA.2 and BA.2.12.1, barely 1.6-times higher than B.1.

Both BA.1 and BA.2 evaded neutralization by nAbs induced by a three-dose regimen of the BNT162b2 vaccination. However, as expected, compared to B.1, BA.1 and BA.2 showed 4.3 and 4.2 times reduced neutralization against vaccine-induced nAbs, respectively. The neutralization evasion of BA.2.12.1, BA.4, and BA.5 was much stronger against vaccine-induced nAbs than B.1. Accordingly, BA.2.12.1 showed 6.1-times reduced neutralization than B.1, and BA.4/BA.5 showed 8.1-times reduced neutralization.

Conclusions

The present study highlighted three important findings regarding Omicron sub-variants. First, human-to-human transmissions might accentuate the spread of the emerging Omicron sub-variant BA.2.12.1. Second, they observed that BA.4 and BA.5 had exceptionally high immunity evading properties and the potential to infect triple vaccinated individuals or those recovering from Omicron infection or both. Finally, they demonstrated the usefulness of therapeutic mAb, bebtelovimab (LY-CoV1404), for treating Omicron-infected individuals.