Monoclonal Antibodies More Effectively Neutralize BA.2 Than BA.1

Though many monoclonal antibodies were paused after demonstrated to be insufficient against the BA.1 Omicron subvariant, they may be more effective against BA.2.

Neutralizing monoclonal antibodies target the receptor binding domain of the SARS-CoV-2 spike protein and have demonstrated efficacy in preventing and treating early strains of COVID-19 disease. However, the BA.2 Omicron sublineage is gradually overtaking the highly infectious BA.1. Due to concerns that Omicron will not be susceptible to monoclonal antibody therapy, the US has paused distribution of several treatments.

The 2 variants are differentiated by about 21 spike protein mutations, and it is unknown whether 1 responds better to monoclonal antibodies than the other. One study, published in Nature Medicine, attempted to compare the sensitivity of BA.1 and BA.2 to see if either could be neutralized by any of 9 therapeutic monoclonal antibodies (mAbs).

Investigators from the Institut Pasteur, the CNRS, and the Vaccine Research Institute (VRI), in collaboration with Orléans Regional Hospital, the Paris Public Hospital Network (AP-HP), KU Leuven (the Catholic University of Leuven) and Université Paris Cité, examined the efficacy of monoclonal antibodies for pre-exposure prophylaxis in immunocompromised persons. They isolated a BA.2 variant from a nasopharyngeal swab, originally sequenced in Belgium.

The investigators first examining in vitro sensitivity of the BA.1, BA.2, and Delta COVID-19 strains to 9 therapeutic antibodies. Next, they tested the clinical implications of their observations by measuring the neutralizing activity in sera from 29 persons at risk of severe or fatal COVID-19, who had been treated with Ronapreve (a cocktail of two antibodies developed by Roche/Regeneron) and/or Evusheld (a cocktail of two antibodies developed by AstraZeneca).

Compared to Delta, BA.2 contains 28 mutations to the spike protein, 18 of which BA.1 shares. The investigators examined immune responses to Delta, BA.1, and BA.2 3-30 days after treatment. Participants with all antibody cocktails displayed elevated antibody levels that effectively neutralized Delta. Seven of the antibodies, Bamlanivimab, Etesevimab, Casirivimab, Sotrovimab, Adintrevimab, Regdanvimab and Tixagevima, were inactive against BA.2.

Immunocompromised persons treated with Ronapreve (Imdevimab and Casirivimab) did not neutralize BA.1 and weakly neutralized BA.2. Neutralization of BA.1 was detected in 19 out of 29 Evusheld (Tixagevimab and Cilgavimab) recipients, and all 29 of Evusheld recipients adequately neutralized BA.2.

"We show that the antibodies and corresponding sera are inactive or only weakly active against BA.1, but more active against BA.2,” said Timothée Bruel, lead author of the study and a scientist in the Virus and Immunity Unit at the Institut Pasteur. “As compared to the Delta variant, neutralizing titers were more markedly decreased against BA.1 (344-fold) than BA.2 (9-fold).”

There were 4 Omicron cases were reported among the 29 patients, including 1 severe infection. Thus, monoclonal antibodies are not a sure-fire means of protection. However, as BA.2 continues to overtake BA.1 in many countries, including the US, it is reassuring to know monoclonal antibodies are more effective in neutralizing this newly dominant Omicron subvariant.