What is the impact of SARS-CoV-2 Omicron BA.2 breakthrough infection on novel Omicron sublineages?

In a recent article posted to the bioRxiv* preprint server, investigators examined if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 breakthrough infection in triple vaccinated individuals boosts Omicron BA.4/BA.5 and BA.2.12.1 cross-neutralization.

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


The appearance of the SARS-CoV-2 Omicron variant of concern (VOC) during November 2021 could be regarded as a tipping point in the coronavirus disease 2019 (COVID-19) pandemic. The Omicron BA.1 variant partially evades previously developed immunity due to considerable alteration in the N-terminal domain (NTD) and the spike (S) glycoprotein receptor binding domain (RBD).

Recently, the current study's authors and several others have shown that COVID-19 BNT162b2-vaccinated people after SARS-CoV-2 Omicron BA.1 breakthrough infection possess potent serum neutralizing activity towards Omicron BA.2, BA.1, and previous VOCs, but less activity against the highly infectious Omicron BA.4 and BA.5 sublineages that have replaced previous variants.

About the study

The Omicron BA.4/BA.5 sublineages are descended from the Omicron BA.2 variant. Thus, in the present work, scientists assessed the serum neutralizing ability of the SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine three-dose recipients who had BA.2 breakthrough infection. 

The team investigated whether Omicron BA.2 breakthrough infection would change cross-neutralization reaction more towards the most recent Omicron BA.4/BA.5 sublineages, considering that Omicron BA.2 was more closely connected to BA.4/BA.5 than BA.1 variant. They compared the neutralization of various Omicron sublineages. For this, the investigators used serum samples from three distinct groups of individuals triple-vaccinated with SARS-CoV-2 mRNA vaccines like mRNA-1273 or BNT162b2. 

The study volunteers included three-dose vaccinated people with no history of COVID-19 and those who experienced breakthrough infection with either the BA.2 or BA.1 variants. Besides, convalescent sera were procured from biosample collections of the BNT162b2 vaccine studies and a non-interventional investigation that examined vaccinated individuals who had developed Omicron breakthrough infection.

An established pseudovirus neutralization test (pVNT) was used to evaluate the immune sera's neutralizing ability. Indeed, pVNT identified 50% pseudovirus neutralization (pVN50) geometric mean titers (GMTs). The researchers evaluated the GMTs of pseudoviruses containing the S glycoproteins of the SARS-CoV-2 Alpha, Delta, Beta, wild-type strain, Omicron BA.2, BA.1, and the BA.2-stemmed BA.4, BA.2.12.1 and BA.5 sublineages.

In addition, the authors described the involvement of serum antibodies against the S glycoprotein RBD versus the NTD in Omicron sublineage neutralization.


Overall, the study results illustrated that the Omicron BA.2 breakthrough infection induces broad neutralizing activity targeting BA.2 and BA.2's progenies like BA.4, BA.2.12.1, and BA.5 sublineages. These results were consistent with recent papers and recommend that, relative to breakthrough infections caused by the antigenically more remote BA.1 variant, cross-neutralization was driven more effectively by the higher sequence resemblance of BA.2 with BA.4/5 and BA.2.12.1 across the S glycoprotein RBD and the NTD.

The authors mentioned since breakthrough infection with heterologous SARS-CoV-2 strains mainly broadens a memory B cell repertoire against preserved S glycoprotein epitopes, BA.1 breakthrough infection might not evoke a robust recall of NTD-selective memory B cells due to the significant modifications within the BA.1 NTD.

According to study data from hybrid pseudovirus and antibody-depletion experiments, Omicron BA.4/5 neutralizing activity among triple-vaccinated BA.2 infection recovered sera samples was influenced significantly by NTD-binding antibodies. On the other hand, neutralizing ability of BA.1 convalescent sera was largely reliant on RBD-attaching antibodies. This result was in line with the findings that NTD-attaching antibodies recovered from BA.2 breakthrough infected people did not neutralize the BA.1 variant.


In the current study, the team showed that sera from those who received three doses of the COVID-19 mRNA vaccine and experienced BA.2 breakthrough infection were widely neutralizing toward all evaluated Omicron sublineages, including BA.2-stemmed BA.4/BA.5 and BA.2.12.1 variants, as well as prior VOCs. They found NTD antibodies from triple-vaccinated BA.2 convalescent sera considerably neutralized BA.4/BA.5 and BA.2 sublineages. Conversely, Omicron BA.1 convalescent sera samples only relied on RBD antibodies for virus neutralization.

The current findings indicate that Omicron BA.2 exposure induces strong NTD-specific recall reactions among vaccinated individuals, unlike BA.1 S glycoprotein. Hence, augment the BA.4/BA.5 sublineage neutralizations. These findings were highly relevant for establishing Omicron-adapted vaccines considering the current epidemiology, dominated by sublineages descended from BA.2 like BA.4/BA.5, and the rapid pace of ongoing evolution. The study data will advance knowledge of Omicron immune evasion processes and the impact of vaccination on variant cross-neutralization, which will help direct the development of new vaccines.

*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:
  • Alexander Muik, Bonny Gaby Lui, Maren Bacher, Ann-Kathrin Wallisch, Aras Toker, Andrew Finlayson, Kimberly Krueger, Orkun Ozhelvaci, Katharina Grikscheit, Sebastian Hoehl, Sandra Ciesek, Oezlem Tuereci, Ugur Sahin. (2022). Omicron BA.2 breakthrough infection enhances cross-neutralization of BA.2.12.1 and BA.4/BA.5. bioRxiv. doi: https://doi.org/10.1101/2022.08.02.502461 https://www.biorxiv.org/content/10.1101/2022.08.02.502461v1

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

Tags: Antibodies, Antibody, B Cell, Cell, Coronavirus, Coronavirus Disease COVID-19, covid-19, Epidemiology, Evolution, Glycoprotein, immunity, Omicron, Pandemic, Pseudovirus, Receptor, Respiratory, Ribonucleic Acid, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Vaccine, Virus

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Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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