The viral fitness and antigenic relationship among Omicron sublineages

In a recent study posted to the bioRxiv* preprint server, researchers used mouse models and human airway cell cultures to investigate the relative viral replication rates and cross-neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages.

Study: Cross-neutralization and viral fitness of SARS-CoV-2 Omicron sublineages. Image Credit: FOTOGRIN/Shutterstock
Study: Cross-neutralization and viral fitness of SARS-CoV-2 Omicron sublineages. Image Credit: FOTOGRIN/Shutterstock


The SARS-CoV-2 Omicron sublineage BA.1 was first detected in November 2021. Since then, various sublineages carrying mutations that enable immune evasion and increased transmissibility have emerged, with sublineage BA.5 replacing previous variants for current global dominance.

Of all the sublineages, BA.5 exhibits the highest immune evasion ability against neutralizing antibodies elicited by vaccinations and previous SARS-CoV-2 infections. Furthermore, the Omicron sublineages carry more than 30 mutations, contributing to their increased transmissibility and immune evasion. Understanding the cross-neutralization of antibodies against and viral replication rates of the Omicron sublineages could contribute to improved vaccines against emergent SARS-CoV-2 variants.

About the study

In the present study, the researchers intranasally infected keratin 18-human angiotensin-converting enzyme-2 (K18-hACE2) mice with complementary deoxyribonucleic acid (cDNA) clones of SARS-CoV-2 Omicron BA.1, BA.2, BA.2.12.1, and BA.5 sublineages to obtain serum samples. The sera were tested for neutralizing antibody titers against the Omicron sublineages, the Delta variant, and the reference SARS-CoV-2 index USA-WA-1/2020.

Additionally, primary human airway epithelial cell cultures (HAE) were inoculated with the same Omicron sublineages to validate the mouse model results. The HAE cultures were also infected with a combination of two viruses, and competition assays were used to compare the replication kinetics of two viral sublineages. Next-generation sequencing was performed on the viral ribonucleic acid (RNA) to determine the relative viral replication rates.

The neutralization antibody titers in each serum were measured for homologous and heterologous spike proteins of the Omicron sublineages BA.1, BA.2, BA.2.12.1, BA.4.6, and BA.5, the Delta variant, and the SARS-CoV-2 index. Furthermore, each variant’s full-length spike protein was engineered onto the backbone of the attenuated USA-WA-1/2020 virus containing an mNeonGreen reporter gene instead of open-reading-frame-7. These attenuated modified viruses were then used to study the effect of amino acid changes by performing fluorescent focus reduction neutralization tests (FFRNT).

The K18-hACE2 mice infected with Omicron sublineages were challenged through intranasal inoculation with SARS-CoV-2 Omicron BA.5 sublineage since it was the most prevalent and least neutralizable sublineage in circulation worldwide. Additionally, the neutralization titer values and FFRNT results were used to create antigenic maps, which displayed the relationship between the tested Omicron sublineages and the infected mouse sera.


The results from the antigenic mapping revealed that the Omicron sublineages are antigenically clustered together and divergent from the previous SARS-CoV-2 variants, such as Alpha and Delta.

The viral fitness and relative replication rate results from the mouse model and HAE experiments suggested that the fitness of the Omicron BA.5 sublineage was greater than or equal to that of the BA.2 sublineage, followed by BA.2.12.1 and BA.1. The authors noted that BA.1 and BA.5 displayed reduced severity compared to the Delta variant, which could be attributed to lower spike protein-mediated cell-cell fusion.

The sera from infected mice exhibited significant cross-neutralization activity against the Omicron sublineages but not against USA-WA-1/2020 or the Delta variant. Furthermore, the serum sample from the BA.5 infected mouse displayed greater neutralization activity against the heterologous antigens from other sublineages than against the homologous BA.5 antigen. The viral replication and serum antibody titers also did not show consistent correlations in the infected mice.

According to the authors, given the antigenic distance between the Omicron BA.5 sublineage and the index virus, a bivalent vaccine comprising Omicron variants would elicit broader immunity and cross-reactive neutralizing antibodies against the Omicron sublineages. Preliminary clinical trials with bivalent BA.5 booster vaccines support this recommendation by exhibiting robust neutralizing action against the BA.5 sublineage.


Overall, the cross-neutralization and viral replication study using mouse models and HAE cultures suggested that the Omicron BA.5 sublineage exhibits greater or equal fitness as the BA.2 sublineage, and both sublineages exhibit increased transmissibility and immune evasion but result in less severe SARS-CoV-2 infections.

The antigenic mapping revealed that the Omicron sublineages are antigenically closer to each other than to the earlier SARS-CoV-2 variants. The authors recommend developing and clinical testing bivalent vaccines containing Omicron variants for broad neutralization of the circulating and emergent Omicron sublineages.

*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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