New COVID Subvariant Resistant to All Therapeutic Antibodies

The findings indicate that new antibody therapies must be developed.

Are the currently approved antibody therapies used to treat patients who have a higher risk of developing severe COVID-19 disease also effective against the viral variants that are currently in circulation? According to a new study conducted by scientists at the German Primate Center (DPZ) – Leibniz Institute for Primate Research and Friedrich-Alexander University Erlangen-Nürnberg, the Omicron sub-lineage BQ.1.1, which is on the rise globally, is resistant to all approved antibody therapies.

An immune response is triggered as a consequence of infection with the SARS coronavirus-2 (SARS-CoV-2) or a COVID-19 vaccination, resulting in the development of neutralizing antibodies that help guard against (re)infection with SARS-CoV-2 or a severe course of the disease. By attaching to the viral spike protein, neutralizing antibodies provide protection and stop the virus from entering cells.

The Omicron subvariants BA.1, BA.4, BA.5 as well as Q.1.1 have a high number of mutations in the spike protein. Some of these mutations are escape mutations that allow the virus to escape neutralization by antibodies. In addition, resistance to biotechnologically produced antibodies, which are administered to high-risk patients as a preventive measure or as therapy for a diagnosed SARS-CoV-2 infection, is also developing. Omicron sub-lineage BQ.1.1 is the first variant resistant to all antibody therapies currently approved by the EMA (European Medicines Agency) and/or FDA (US Food and Drug Administration). Credit: Markus Hoffmann, Deutsches Primatenzentrum

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However, certain SARS-CoV-2 variants, notably the Omicron variant, avoid neutralizing antibodies and cause symptomatic infections even in vaccinated or convalescent individuals due to mutations in the spike protein. This is known as immune evasion, and it poses a hazard to high-risk populations including the elderly and people with weakened immune systems, for example, due to illness or medication.

They often fail to develop an immune response sufficient for protection from severe disease, even after full vaccination. To protect high-risk patients, biotechnologically produced antibodies are administered as a preventive measure or as an early therapy upon confirmed SARS-CoV-2 infection. Mutations in the spike protein of different SARS-CoV-2 variants confer resistance to individual antibody therapies. Therefore, it is important to regularly monitor whether therapeutic antibodies continue to be effective against currently circulating viral variants.

A team of researchers from the Infection Biology Unit at the German Primate Center – Leibniz Institute for Primate Research and the Division of Molecular Immunology at the Friedrich-Alexander-University Erlangen-Nürnberg has investigated how efficiently approved antibody therapies inhibit the currently circulating Omicron subvariants. The researchers found that the Omicron subvariant BQ.1.1, which is on the rise worldwide, is resistant to all available antibody therapies.

“For our studies, we mixed non-propagating viral particles carrying the spike protein of selected viral variants with different dilutions of the antibodies to be tested and subsequently measured the amount of antibody needed to inhibit infection of cell cultures. In total, we tested twelve individual antibodies, six of which are approved for clinical use in Europe, and four antibody cocktails” explains Prerna Arora, lead author of the study.

The researchers found that the Omicron subvariant BQ.1.1 could not be neutralized by either individual antibodies or antibody cocktails. In contrast, the currently predominant Omicron subvariant BA.5 was still neutralized by one approved antibody and two approved antibody cocktails.

“With high-risk patients in mind, we are very concerned about the Omicron subvariant BQ.1.1 being resistant to all approved antibody therapies. Particularly in regions where BQ.1.1 is widespread, physicians should not rely on antibody therapies alone when treating infected high-risk patients, but should also consider administering other drugs such as paxlovid or molnupiravir,” comments study leader Markus Hoffmann on the results of the study.

The finding that the Omicron subvariant BQ.1.1 is already resistant to a new antibody therapy that is about to be approved in the U.S. highlights the importance of developing new antibody therapies against COVID-19.

“The ever-increasing development of antibody resistance of SARS-CoV-2 variants calls for the development of new antibody therapies that are specifically targeted to currently circulating and future viral variants. Ideally, they should target regions in the spike protein that have little potential for escape mutations,” concludes Stefan Pöhlmann, head of the Infection Biology Unit at the German Primate Center – Leibniz Institute for Primate Research.

Reference: “Omicron sublineage BQ.1.1 resistance to monoclonal antibodies” by Prerna Arora, Amy Kempf, Inga Nehlmeier, Sebastian R Schulz, Hans-Martin Jäck, Stefan Pöhlmann and Markus Hoffmann, 18 November 2022, The Lancet Infectious Diseases.
DOI: 10.1016/S1473-3099(22)00733-2