Does BA.2 breakthrough infection shift cross-neutralization activity towards the BA.4 and BA.5 Omicron sublineages?

In a recent study published in Science Immunology, researchers investigated the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) Omicron's immune escape mechanisms. Additionally, they studied the effects of Omicron BA.2 breakthrough infection in triple vaccinated individuals.

Study: Omicron BA.2 breakthrough infection enhances cross-neutralization of BA.2.12.1 and BA.4/BA.5. Image Credit: ker_vii/Shutterstock


Omicron BA.2 is the parent lineage of the highly contagious Omicron sublineages BA.4 and BA.5. The L452R and F486V mutations specific to BA.4/BA.5 confers them with the ability to escape from vaccine-induced neutralizing antibodies (nAbs) and therapeutic monoclonal antibodies (mAbs) targeting the spike (S) glycoprotein of the wild-type SARS-CoV-2 strain.

Following Omicron BA.1 breakthrough infection, individuals triply-vaccinated with messenger ribonucleic acid (mRNA) platform-based coronavirus disease 2019 (COVID-19) vaccines have adequate nAbs against Omicron BA.1, BA.2, and other SARS-CoV-2 VOCs. However, they have much-less nAbs against BA.4 and BA.5, two Omicron sublineages that now dominate globally.

About the study

Omicron BA.2 is more closely related to BA.4/BA.5, so the researchers of the present study investigated whether BA.2 breakthrough infection would shift cross-neutralization activity of vaccine-induced sera more towards BA.4/BA.5. The researchers created three cohorts of individuals, all triple-vaccinated with an mRNA-based COVID-19 vaccine. They assessed the neutralization activity of the serum samples from these cohorts against Omicron sublineages. Further, the team compared the contribution of nAbs targeting the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the wild-type S glycoprotein to Omicron neutralization.

The first cohort had individuals with no history of SARS-CoV-2 infection, termed the SARS-CoV-2 naïve cohort; all its members were triple-vaccinated with the BNT162b2 vaccine. The individuals in the remaining cohorts were triple-vaccinated with BNT162b2 or mRNA-1273, or a heterologous regimen of the mRNA COVID-19 vaccines, and yet they contracted Omicron breakthrough infections.

The researchers confirmed Omicron BA.1 breakthrough infection using a variant-specific reverse transcriptase-polymerase chain reaction (RT-PCR). However, they further validated BA.1- and BA.2-infected convalescent participants by genome sequencing. Furthermore, the researchers used a microneutralization assay based on cytopathic effect (CPE) to determine SARS-CoV-2 neutralization titers. The antibody depletion experiments depleted sera of more than 97%, and 74% of RBD-binding and NTD-binding nAbs, respectively. The researchers tested depleted sera via pseudovirus neutralization test (pVNT). 

Study findings

The authors noted that Omicron BA.2 breakthrough infection triggered nABs with broadly neutralizing activity against BA.2 and all its three descendants – BA.2.12.1, BA.4, and BA.5, in agreement with previous studies. The most likely explanation is that these Omicron sublineages have higher amino acid sequence similarity in the S glycoprotein RBD and the NTD. Perhaps this is why these Omicron BA.2 sublineages drove more efficient cross-neutralization than BA.1, which is antigenically more distant.

Specifically, BA.1 breakthrough infection could not trigger a memory recall of NTD-specific B cells due to multiple mutations within the BA.1 NTD. It is so because breakthrough infection with heterologous SARS-CoV-2 strains primarily expands a memory B cell repertoire against conserved S epitopes. Notably, serum concentrations of both NTD- or RBD-targeting nAbs were comparable across all three study cohorts, indicating that antibody potencies, not serum nAb levels varied the neutralization potential of the elicited nAbs.

Antibody-depletion and hybrid pseudovirus experiments showed that NTD-binding nAbs markedly contributed to neutralizing activity against Omicron BA.4/5 in triple-vaccinated BA.2 convalescent sera. Conversely, neutralizing activity of BA.1 convalescent sera primarily worked through RBD-binding antibodies. This finding supports the findings of previous studies showing that NTD-binding nAbs isolated from sera of BA.2-infected individuals do not neutralize BA.1.


Taken together, the study findings expanded the current knowledge on how vaccinations with the SARS-CoV-2 wild-type S-based vaccines combined with breakthrough infections with the VOCs characterize the immunity patterns within the population. This data could inform next-generation COVID-19 vaccine development against continuously emerging SARS-CoV-2 variants.

In fact, a vaccine adapted to the sequence of Omicron BA.2 sublineage could have broader neutralization potential against all emerging SARS-CoV-2 variants, including the currently predominating Omicron BA.4/BA.5 sublineages.

Journal reference:
  • Omicron Ba.2 Breakthrough Infection Enhances Cross-Neutralization Of Ba.2.12.1 And Ba.4/Ba.5. Alexander Muik, Bonny Gaby Lui, Maren Bacher, Ann-Kathrin Wallisch, Aras Toker, Andrew Finlayson, Kimberly Krüger, Orkun Ozhelvaci, Katharina Grikscheit, Sebastian Hoehl, Sandra Ciesek, Özlem Türeci, Ugur Sahin. Science Immunology. doi: 10.1126/Sciimmunol.Ade2283

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Amino Acid, Antibodies, Antibody, Assay, B Cell, Cell, Coronavirus, Coronavirus Disease COVID-19, covid-19, Genome, Glycoprotein, immunity, Omicron, Polymerase, Polymerase Chain Reaction, Pseudovirus, Receptor, Respiratory, Reverse Transcriptase, Ribonucleic Acid, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Vaccine

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Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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