The ability of therapeutic monoclonal antibodies to neutralize SARS-CoV-2 Omicron BA.2 variant

In a recent study posted to the bioRxiv* preprint server, researchers evaluated the neutralizing capacity of the clinically approved monoclonal antibodies (mAbs) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 variant.

SARS-CoV-2 treatment using mAbs has been demonstrated to be extremely effective in reducing the disease severity. Nevertheless, the recent emergence of the highly mutated SARS-CoV-2 Omicron BA.1 variant challenged this treatment approach. 

While the Omicron BA.1 variant exhibited almost a complete evasion from the neutralization induced by the Eli Lilly and Regeneron therapeutic mAbs, Evusheld mAb cocktail (tixagevimab/cilgavimab) and Vir-7831 (sotrovimab) demonstrated substantial neutralizing capacity against this variant.

However, the SARS-CoV-2 Omicron BA.2 variant identified during late 2021 has an additional six mutations and three deletions, apart from those in the BA.1. With three of these mutations in the receptor-binding domain (RBD), BA.2 is associated with higher transmissibility than BA.1 and found to be spreading rapidly worldwide.

About the study

In the present study, the scientists evaluated the SARS-CoV-2 Omicron BA.2 neutralizing capacity of the following mAbs: casirivimab, imdevimab, casirivimab/imdevimab, bamlanivimab, etesevimab, bamlanivimab/etesevimab, tixagevimab, cilgavimab, tixagevimab/cilgavimab, and sotrovimab.

The researchers assessed the neutralizing Ab (NAb) titers of the above-mentioned mAbs against the SARS-CoV-2 BA.2, BA.1, Delta, and parental D614G variants using lentiviral pseudotype assay.

The team further evaluated the mechanism via which the Omicron BA.2 variant evades the mAb neutralization by testing viruses with individual RBD point mutations of BA.2 against each mAbs.

Study findings

The results indicate that all of the mAbs evaluated substantially neutralized the SARS-CoV-2 D614G variant. All but bamlanivimab demonstrated neutralization capacity against the SARS-CoV-2 Delta variant; the NAb titer of bamlanivimab was 39-times lower against Delta relative to the D614G variant. 

Further, a detectable NAb titer against the SARS-CoV-2 Omicron BA.1 was absent in casirivimab, imdevimab, casirivimab/imdevimab, bamlanivimab, etesevimab, bamlanivimab/etesevimab, tixagevimab, and cilgavimab. The NAb titers of the Vir-7831 and Evusheld cocktail were 108- and 14-times, respectively, lower against Omicron BA.1 relative to the D614G variant. The detectable NAb titer of none of the mAbs tested, including tixagevimab/cilgavimab and sotrovimab, did not neutralize the SARS-CoV-2 Omicron BA.2 variant. 

Structural models of SARS-CoV-2 spike (S) and Ab complexes were developed comprising mutations previously reported inducing more than a five-times decrease in neutralizing titers against the Omicron BA.1 variant combined with the BA.2 mutations detected in the study that caused a two times reduction in NAb titer.

These models indicate that while the active mutations in BA.1 were present at the viral interaction site with the Abs, the extra active mutations of the Omicron BA.2 variant are away from the interaction sites. Further, these mutations probably act via affecting the conformation of RBD S of the SARS-CoV-2 Omicron BA.2.

Conclusions

The study findings show that all therapeutic mAbs evaluated in the present study failed to neutralize the SARS-CoV-2 Omicron BA.2 variant with detectable titers in the highly sensitive lentivirus assay, thus demonstrating the difficulty in discovering a pan-neutralizing mAb against SARS-CoV-2.

While sotrovimab and tixagevimab/cilgavimab exhibited significant neutralizing titers against the Omicron BA.1 variant, they lacked neutralization ability against the BA.2 variant. Further, the present findings were in line with the previous reports indicating that the Omicron BA.1 variant was resistant to neutralization by the Eli Lilly antibody cocktails and Regeneron.

Additionally, the study suggests that the evasion of the Omicron BA.2 variant from Ab neutralization is due to the additional mutations in its RBD and N-terminal domain (NTD).

Overall, the study highlights the significance of developing treatments directed towards the Omicron BA.2 variant and potential heavily mutated future SARS-CoV-2 variants, antivirals such as nirmatrelvir and molnupiravir that target regions other than the highly conserved SARS-CoV-2 S epitopes, and devising coronavirus disease 2019 (COVID-19) vaccinations capable of inducing cross-reactive Abs and T cell responses to mitigate the SARS-CoV-2 pandemic.

*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.