mRNA boosters enhance neutralization of SARS-CoV-2 BA.1, BA.2 and BA.3

A study recently published in the journal Cell Host & Microbe has described that all three sublineages of the omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit similar host cell entry efficiency and are neutralized equally by antibodies generated in response to coronavirus disease 2019 (COVID-19) booster vaccination. However, these sublineages exhibit different susceptibility to therapeutic antibody-mediated neutralization.

Study: SARS-CoV-2 Omicron sublineages show comparable cell entry but differential neutralization by therapeutic antibodies. Image Credit: Steve Heap / Shutterstock

Background

The omicron variant of SARS-CoV-2 was first detected in South Africa on November 24, 2021. Soon after its emergence, the variant became dominant in many countries across the world. The presence of more than 25 mutations in the spike protein is believed to be responsible for its high transmission and immune evasion abilities.

The omicron variant has five main sublineages, namely BA.1, BA.2, BA.3, and more recently BA.4 and BA.5. The amino acid sequences in the N-terminal domain (NTD) and receptor-binding domain (RBD) of the spike proteins differ significantly between these sublineages. Studies have shown that the BA.2 sublineage has comparatively higher transmissibility than BA.1 and BA.3 sublineages and is currently circulating predominantly in many countries, including Denmark and the UK.

In the current study, the scientists have compared the host cell entry efficiency of three omicron sublineages, BA.1, BA.2, and BA.3. In addition, they have assessed the susceptibility of these sublineages to COVID-19 vaccine- and therapeutic antibody-mediated neutralization.

Host cell entry efficiency of omicron sublineages

The analysis of spike protein sequences revealed that the BA.2 sublineage differs significantly from the other two sublineages. While the amino acid residues 24-26 are missing from the BA.2 spike NTD, these residues are present in the NTDs of BA.1 and BA.3 sublineages. In contrast, the residues 69-70 and 143-145 are absent in the BA.1 and BA.3 spikes but are present in the BA.2 spike. Besides these variations, all three sublineages contain specific and unique spike mutations.

The in vitro experiments conducted using sublineage-specific spike protein-harboring pseudovirus particles revealed that the BA.1, BA.2, and BA.3 sublineages enter human cells with higher efficiency than the ancestor SARS-CoV-2 variant (B.1). However, there was no significant difference in cell entry efficiency between the sublineages.

Regarding mode of entry, all sublineages were found to enter host cells via angiotensin-converting enzyme 2 (ACE2)-mediated pathway, similar to the ancestor virus. Specifically, the spike proteins of omicron sublineages and ancestor virus showed similar efficiency in binding ACE2. Except for the ancestor virus, all omicron sublineages showed efficient binding to mouse, bat, and human ACE2 for cell entry.

The fusion between infected and uninfected cells via spike protein leads to syncytia formation, which is believed to be responsible for COVID-19 progression. The cell-cell fusion assays conducted in the study showed that the BA.1 sublineage had a reduced ability to form syncytia compared to the SARS-CoV-2 delta variant. Moreover, no significant difference in syncytia formation was observed between omicron sublineages.

Susceptibility of omicron sublineages to antibody-mediated neutralization

A total of eight monoclonal antibodies that are used for COVID-19 therapy were tested against omicron sublineages. The findings revealed that seven out of eight tested antibodies fail to effectively neutralize the BA.2 sublineage. The only antibody that effectively neutralized BA.2 was Cilgavimab.

A high efficacy neutralization of BA.1 was carried out by Sotrovimab. Similarly, BA.3 was effectively neutralized by both Cilgavimab and Sotrovimab. However, the neutralizing efficiency of tested antibodies against omicron sublineages was lower than that against the ancestor virus.

The COVID-19 vaccine efficacy against omicron sublineages was tested using serum samples collected from vaccinated participants. Specifically, the efficacy of a three-dose regimen of homologous mRNA vaccine (Pfizer) and the heterologous mRNA and adenoviral vector vaccine (AstraZeneca) was tested.

The findings revealed that all tested vaccination regimens effectively and equivalently neutralized all three omicron variant sublineages. However, the neutralizing efficiency was 4 to 6-fold lower than that observed against the ancestor virus.

Study significance

The study highlights that omicron sublineages have comparable efficacy in entering the host cell via ACE2 receptor. The antibodies induced by a three-dose regimen of homologous or heterologous COVID-19 vaccination (two prime and one booster vaccination) can neutralize all the sublineages with equivalent efficiency. However, the majority of monoclonal therapeutic antibodies against COVID-19 fail to neutralize the most transmissible BA.2 sublineage of the omicron variant. Based on the findings, the scientists suggest that Cilgavimab might be used to treat patients with BA.2 infections.

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.