Japanese Study Reveals That New SARS-CoV-2 Variants Like BA.2.11. BA.2.12.1, BA.4 And BA.5 Are Exhibiting Greater Resistance To Existing Monoclonal Drugs!
A new study by Japanese researchers from The University of Tokyo and Kobe University have found that the new SARS-CoV-2 variants like BA.2.11. BA.2.12.1, BA.4 and BA.5 are exhibiting greater resistance to existing monoclonal drugs!
To date, the Omicron BA.2 variant is the most dominant variant in the world.
However, it is fast being superseded by new emerging variants and subvariants in various geolocations around the world.
For example, the Omicron BA.2.11, BA.2.12.1 and BA.4/5 subvariants are becoming dominant in France, the USA and South Africa, respectively.
The study team evaluated the sensitivity of these new Omicron subvariants (BA.2.11, BA.2.12.1 and BA.4/5) to eight therapeutic monoclonal antibodies (bamlanivimab, bebtelovimab, casirivimab, cilgavimab, etesevimab, imdevimab, sotrovimab and tixagevimab).
Corresponding author, Professor Dr Kei Sato, Ph.D. from the University of Tokyo told Thailand Medical
News, “The study findings showed that although cilgavimab is antiviral against BA.2, the new BA.4 and BA.5 variants exhibits higher resistance to this antibody compared to BA.2 variant.”
As mutations are predominantly accumulated in the spike proteins of newly emerging SARS-CoV-2 variants, the study team suggest the importance of rapid evaluation of the efficiency of therapeutic monoclonal antibodies against novel SARS-CoV-2 variants.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.05.03.490409v1
These monoclonal antibodies (mAbs) against the SARS-CoV-2 coronavirus have been used as therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19).
Although some of these therapeutic mAbs have benefited hospitalized COVID-19 patients, nothing is known about their therapeutic efficiency against novel SARS-CoV-2 variants.
This new study is the first to evaluates the sensitivity of the new Omicron subvariants (BA.2.11, BA.2.12.1, and BA.4/5) to eight therapeutic mAbs.
The BA.2 variant 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.
It is critical that the new SARS-CoV-2 variants 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.
The 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.
It should be noted that 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.
The initial 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.
Typically, 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.
(A) Epidemics of SARS-CoV-2 lineages in in France, the USA and South Africa. The data from January 13, 2022 to April 22, 2022 (100 days) for France, the USA and South Africa were analyzed. In this figure, the SARS-CoV-2 lineages other than Delta and Omicron are shown as “others”. (B) Amino acid substitutions in S. Heatmap shows the frequency of amino acid substitutions in BA.2.11, BA.2.12.1, BA.4, and BA.5 compared to BA.2. Substitutions detected in >50% of sequences of any lineage are shown. (C) Virus neutralization assays. A neutralization assay was performed using pseudoviruses harboring the SARS-CoV-2 S proteins of Omicron subvariants [BA.2.11 (BA.2 S:L452R), BA.2.12.1 (BA.2 S:L452Q/S704L) and BA.4/5 (BA.2 S:HV69-70del/L452R/F486V/R493Q)], their derivatives (the BA.2 S bearing L452Q, S704L, HV69-70del, F486V or R493Q, respectively) or the D614G-harboring B.1.1 lineage virus (parental virus). Eight therapeutic monoclonal antibodies (bamlanivimab, bebtelovimab, casirivimab, cilgavimab, etesevimab, imdevimab, sotrovimab and tixagevimab) were tested. The assay of each antibody was performed in sextuplicate at each concentration to determine the 50% neutralization concentration. The log2 fold changes of resistance versus the parental virus (circle size) or BA.2 (color) are respectively shown.
At present, 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 existing 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 non-hospitalized patients with mild to moderate symptoms and who have high chances of hospitalization and progressing to severe disease.
The study team 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.
The research findings showed that BA.2 was not neutralized by bamlanivimab, casirivimab, etesevimab, imdevimab, and tixagevimab.
Also, these five mAbs also failed to neutralize the new Omicron subvariants.
It was found however that 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.
Importantly, the Omicron subvariants containing the L452R mutation, including BA.2.11 and BA.4/5, were more sensitive to sotrovimab than BA.2.
It was also found that the mAb cilgavimab was effective against BA.2.
But, 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.
The study findings showed that the newly emergent SARS-CoV-2 variants show varying sensitivity to the mAbs tested compared to the wild-type strain.
It was found that the newly emerging SARS-CoV-2 variants accumulate mutations in the S proteins, the target of therapeutic mAbs.
The research team emphasized the importance of rapidly evaluating the efficiency of therapeutic mAbs against emerging novel SARS-CoV-2 variants and subvariants or recombinant variants.
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