The sensitivity of Omicron subvariants to therapeutic monoclonal antibodies

Monoclonal antibodies (mAbs) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been used as therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19). Though these therapeutic mAbs have benefited hospitalized COVID-19 patients, nothing is known about their therapeutic efficiency against novel SARS-CoV-2 variants.

A new study evaluates the sensitivity of the new Omicron subvariants (BA.2.11, BA.2.12.1, and BA.4/5) to eight therapeutic mAbs. A preprint version of the study is available on the bioRxiv* server while the article undergoes peer review.

Omicron subvariants

The Omicron variant of SARS-CoV-2 (BA.2) was identified in November 2021. It has been the dominant variant all over the world since May 2022. Since then, several Omicron subvariants have emerged in different countries. These subvariants have replaced the Omicron BA.2 variants in these countries. Omicron BA.2.11 subvariant is becoming dominant in France. Omicron BA.2.12.1 subvariant is becoming dominant in the U.S. Omicron BA.4/5 subvariants are becoming dominant in South Africa.

The new SARS-CoV-2 variants have to be monitored and evaluated for their transmissibility, pathogenicity, and resistance to immune responses. The emerging SARS-CoV-2 variants harbor mutations in the spike (S) protein. These mutations confer resistance to the variants against vaccines and therapeutic antibodies. BA.2.11 subvariant has the L452R mutation; BA.2.12.1 has the L452Q and S704L mutations; and BA.4/5 has L452R, HV69-70del, 45 F486V, and R493Q mutations. The L452R and L452Q mutations were also detected in Delta and Lambda variants, and these mutations affected the sensitivity of the virus to vaccine-induced neutralizing antibodies. Therefore, it is possible that the new Omicron subvariants also have reduced sensitivity towards therapeutic mAbs.

Therapeutic mAbs

The first therapeutic mAb was approved by the U. S. Food and Drug Administration (FDA) in 1986. Therapeutic mAbs are highly specific and therefore have fewer side effects. Therapeutic mAbs are used for treating several diseases, including cancers, autoimmune, metabolic, and infectious diseases. 

Anti-SARS-CoV-2 mAbs bind the virus inhibiting its entry into cells. These mAbs target the viral S protein. They have demonstrated clinical benefits in treating COVID-19. 

Currently, five anti-SARS-CoV-2 mAb products have received emergency use authorization (EUA) from FDA. These include bamlanivimab plus etesevimab, bebtelovimab, casirivimab plus imdevimab, sotrovimab, and tixagevimab plus cilgavimab.

The COVID-19 Treatment Guidelines for using anti-SARS-CoV-2 mAbs are based on current knowledge of the in vitro neutralizing activities of the mAbs against the circulating SARS-CoV-2 variants and subvariants. The mAb choice depends on the prevalent variant and its sensitivity to the mAb. These mAbs are recommended for the treatment of nonhospitalized patients with mild to moderate symptoms and who have high chances of hospitalization and progressing to severe disease.

Sensitivity of Omicron subvariants to mAbs

This study tested the possibility of reduced sensitivity of Omicron subvariants by generating pseudoviruses carrying the S proteins of Omicron subvariants BA.2.11, BA.2.12.1, and BA.4/5. The sensitivity of these pseudoviruses was tested against eight mAbs – bamlanivimab, bebtelovimab, casirivimab, cilgavimab, etesevimab, imdevimab, sotrovimab, and tixagevimab. The neutralizing potential of the mAbs against the pseudoviruses containing S proteins of the Omicron subvariants was assayed.

BA.2 was not neutralized by bamlanivimab, casirivimab, etesevimab, imdevimab, and tixagevimab. These five mAbs also failed to neutralize the new Omicron subvariants. However, pseudoviruses with BA.2 S protein with R493Q mutation were partially sensitive to casirivimab and tixagevimab. The mAb bebtelovimab was around 2 times more effective against BA.2 and all Omicron subvariants tested when compared to the wild-type strain. The mAb sotrovimab was around 20 times less effective against BA.2 compared to the wild-type strain.

The Omicron subvariants containing the L452R mutation, including BA.2.11 and BA.4/5, were more sensitive to sotrovimab than BA.2. The mAb cilgavimab was effective against BA.2. However, the pseudoviruses containing the L452R/Q mutations were around 2 to 5 times resistant to this antibody. BA.4/5 was around 30 times more resistant to cilgavimab compared to BA.2. 

Conclusion

The newly emergent SARS-CoV-2 variants show varying sensitivity to the mAbs tested compared to the wild-type strain.

The newly emerging SARS-CoV-2 variants accumulate mutations in the S proteins, the target of therapeutic mAbs. This study emphasizes the importance of rapidly evaluating the efficiency of therapeutic mAbs against novel SARS-CoV-2 variants.

*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

Dr. Shital Sarah Ahaley

Dr. Shital Sarah Ahaley is a medical writer. She completed her Bachelor's and Master's degree in Microbiology at the University of Pune. She then completed her Ph.D. at the Indian Institute of Science, Bengaluru where she studied muscle development and muscle diseases. After her Ph.D., she worked at the Indian Institute of Science, Education, and Research, Pune as a post-doctoral fellow. She then acquired and executed an independent grant from the DBT-Wellcome Trust India Alliance as an Early Career Fellow. Her work focused on RNA binding proteins and Hedgehog signaling.