The antibody resistance profile and viral receptor binding affinity of SARS-CoV-2 Omicron BQ.1, BQ.1.1, XBB, and XBB.1 subvariants

In a recent study posted to the bioRxiv* preprint server, researchers investigated the neutralizing antibody titers against the newly emergent BQ.1, BQ.1.1, XBB, and XBB.1 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants using sera from individuals with primary and booster coronavirus disease 2019 (COVID-19) vaccinations, and previous SARS-CoV-2 infections.

Study: Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Image Credit: nobeastsofierce/Shutterstock
Study: Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Image Credit: nobeastsofierce/Shutterstock

Background

Although global vaccine development efforts mitigated the large-scale morbidity and mortality associated with the COVID-19 pandemic, emergent Omicron subvariants, exhibiting immune evasion and increased transmission courtesy of numerous spike protein mutations, have become globally dominant.

However, 44%, 46%, and 32% of the recent cases in the United States, France, and the United Kingdom, respectively, have been attributed to the newly emergent BQ.1 and BQ1.1 subvariants, which first emerged in Nigeria in July 2022. In India and other regions of Asia, such as Singapore, two new subvariants, XBB and XBB.1, have emerged and become dominant.

The BQ.1 and BQ1.1 subvariants are thought to have evolved from BA.5, while recombination between the BJ.1 and BA.2.75 lineages of BA.2 resulted in the XBB and XBB.1 subvariants. While BQ.1 and BQ1.1 subvariants carry two and one additional mutations, respectively, apart from the mutations found in BA.5, the XBB and XBB.1 variants carry 14 and 15 new mutations, respectively, apart from those found in BA.2. The large number of novel spike protein mutations and the rapid spread of these four Omicron subvariants raises concerns about the efficacy of current COVID-19 vaccines in protecting against these sub-variants.

About the study

In the present study, serum samples were collected from individuals who received three doses of monovalent messenger ribonucleic acid (mRNA) vaccine (Pfizer BNT162b2 or Moderna mRNA-1273), four doses of monovalent mRNA vaccines, or three doses of monovalent vaccine and one dose of the bivalent vaccine targeting the wild-type strain and the BA.2 or BA.5 Omicron subvariant.

Sera were also obtained from vaccinated individuals (with monovalent mRNA vaccinations) who had breakthrough BA.2 or BA.4/BA.5 infections. Anti-SARS-CoV-2 nucleoprotein enzyme-linked immunosorbent assay (ELISA) was used to confirm previous SARS-CoV-2 infections.

The resistance of the four newly emergent subvariants to serum antibodies was tested by evaluating the neutralization of the BQ.1, BQ.1.1, XBB, and XBB.1 subvariants by sera from various cohorts. The results from the serum neutralization tests were used to construct an antigenic map to determine the antigenic distance between the ancestral D614G strain and the Omicron subvariants.

Pseudoviruses constructed for each subvariant, as well as those carrying individual mutations found in these subvariants, were used to evaluate the neutralizing activity of serum antibodies. A total of 23 monoclonal antibodies that targeted various SARS-CoV-2 epitopes were used to determine the susceptibility of the subvariants to neutralization. Monoclonal antibodies that were in clinical use, as well as monoclonal antibody combinations such as Evusheld, were included in this panel.

Additionally, structural modeling was performed to understand the impact of new point mutations on monoclonal antibody binding. The receptor binding affinity of the spike protein trimers of the four new subvariants, BA.2 and BA.4/BA.5 subvariants, were tested against the human angiotensin-converting enzyme-2 (ACE-2) receptor using surface plasmon resonance.

Results

The results reported that neutralization of the four new subvariants BQ.1, BQ.1.1, XBB, and XBB.1 by sera from individuals with vaccinations and previous infections was markedly reduced, irrespective of the number of vaccine doses or type of vaccine. The neutralizing antibody titers against the BQ and XBB subvariants were 13–81 fold and 66–155 fold lower, respectively, compared to those against the ancestral D614G strain.

Furthermore, the results from the antigenic mapping indicated that the antigenic distance between the newly emergent subvariants and the original Omicron variant is comparable to that between the original Omicron variant and its predecessor. However, the BQ and XBB subvariants had similar receptor binding affinities as their parental lineages, indicating that the increased transmission abilities probably stem from other factors, such as immune evasion.

The monoclonal antibodies that were effective against the original Omicron variant were ineffective against the four new subvariants. The BQ and XBB subvariants were pan-resistant to the antibodies that targeted the receptor binding domain and class 1 and 3 epitopes. The XBB subvariants were also resistant to antibodies that targeted class 2 epitopes. The additional mutations in these new subvariants seemed to have enabled them to escape the few monoclonal antibodies that were effective against the previous Omicron subvariants.

With the BQ and XBB subvariants being resistant to bebtelovimab, the only effective monoclonal antibody against the circulating SARS-CoV-2 variants, no authorized treatments remain effective against the newly emergent variants. This development is of serious concern to immunocompromised individuals who do not develop adequate immune responses to vaccines.

Conclusions

Overall, the study's results indicated that the four newly emergent SARS-CoV-2 Omicron subvariants BQ.1, BQ.1.1, XBB, and XBB.1 were partially or completely resistant to neutralization by sera from individuals with mono- and bi-valent vaccines and previous SARS-CoV-2 infections. Furthermore, the four new subvariants were resistant to all the monoclonal antibody therapies currently in clinical use.

The findings highlight concerns about the ineffectiveness of current vaccines and monoclonal antibody treatments against rapidly emerging SARS-CoV-2 variants with increased immune evasion abilities.

*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.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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