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




In a recent article posted on Bio Rxiv*Preprint server, investigator found breakthrough infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 in a 3-dose vaccinated individual, Omicron BA.4 We investigated whether /BA.5 and BA.2.12.1 promote 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
study: Omicron BA.2 breakthrough infection promotes cross-neutralization of BA.2.12.1 and BA.4/BA.5Image Credit: Naeblys/Shutterstock


The emergence of SARS-CoV-2 Omicron variants of concern (VOCs) in November 2021 can be viewed as a turning point in the 2019 coronavirus disease (COVID-19) pandemic. Omicron BA.1 variants partially evade previously developed immunity due to significant alterations in the N-terminal domain (NTD) and spike (S) glycoprotein receptor binding domain (RBD).

Recently, the authors of the current study and several others found that people who received the COVID-19 BNT162b2 vaccine after SARS-CoV-2 Omicron BA.1 breakthrough infection were more susceptible to Omicron BA.2, BA.1, and previous demonstrated that it possesses potent serum-neutralizing activity against VOCs of However, it has low activity against the highly infectious Omicron BA.4 and BA.5 substrains that have superseded previous subspecies.

About research

The Omicron BA.4/BA.5 substrain is the descendant of the Omicron BA.2 variant. Therefore, in the current study, scientists evaluated the serum neutralization ability of her BA.2 breakthrough infected individuals who received three doses of her SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine.

Given that Omicron BA.2 is more closely associated with BA.4/BA.5 than with BA.4/BA.5, the team concluded that breakthrough infection of Omicron BA.2 was cross-neutralizing. We investigated whether it would alter the response towards the latest Omicron BA.4/BA.5 substrains. BA.1 variant. They compared neutralization of different omicron substrains. For this, the researchers used serum samples from her three different groups of individuals who had received three doses of her SARS-CoV-2 mRNA vaccine, such as mRNA-1273 or BNT162b2.

Study volunteers included people who received three doses of the vaccine with no history of COVID-19 and those who experienced breakthrough infection with either the BA.2 or BA.1 variant. , convalescent sera were sourced from the BNT162b2 vaccine study biosample collection and a non-interventional study examining vaccinated individuals who developed Omicron breakthrough infection.

It has been established pseudovirus The neutralization test (pVNT) was used to assess the neutralizing ability of the immune sera. Indeed, pVNT identified a geometric mean titer (GMT) of 50% pseudovirus neutralization (pVN50). Researchers evaluated the GMT of pseudoviruses containing S. glycoprotein SARS-CoV-2 alpha, delta, beta, wild-type strains, BA.4, BA.2.12.1, and BA.5 substrains of Omicron BA.2, BA.1, and BA.2 lineages.

Furthermore, the authors explained that serum antibodies to the S glycoprotein RBD versus NTD are involved in neutralizing the omicron sublineage.


Overall, the results of this study suggest that Omicron BA.2 breakthrough infection targets BA.2 and BA.2 progeny, such as BA.4, BA.2.12.1, and BA.5 substrains. It has been shown to induce broad neutralizing activity. These results are consistent with a recent paper showing higher sequence similarity of BA.2 with BA.4/5 and BA compared to breakthrough infections caused by antigenically more distant BA.1 variants. We suggest that sex promoted cross-neutralization more effectively. .2.12.1 crosses the S glycoprotein RBD and NTD;

The authors concluded that because breakthrough infection with heterologous SARS-CoV-2 strains primarily broadens the repertoire of memory B cells to conserved S-glycoprotein epitopes, BA.1 breakthrough infection, through profound alterations, may be associated with NTD It may not trigger strong recall of selective memory B cells. BA.1 Within the NTD.

Study data from hybrid pseudovirus and antibody depletion experiments showed that Omicron BA.4/5 neutralizing activity in serum samples recovered from BA.2 infection after three vaccinations was greatly affected by NTD-binding antibodies . On the other hand, the neutralizing ability of BA.1 convalescent sera was highly dependent on RBD-adhering antibodies. This result was consistent with the finding that her NTD-attached antibodies recovered from a BA.2 breakthrough-infected individual did not neutralize her BA.1 variant.


In the current study, the team evaluated all omicron sublineages (BA.2 stem BA.4/ BA.5 and BA.2.12.1 variants, as well as previous VOCs. They found that NTD antibodies from BA.2 convalescent sera vaccinated three times significantly neutralized BA.4/BA.5 and BA.2 substrains. Conversely, the Omicron BA.1 convalescent serum sample relied solely on her RBD antibodies for virus neutralization.

The current findings show that, unlike the BA.1 S glycoprotein, exposure to Omicron BA.2 induces strong NTD-specific recall responses among vaccinated individuals. Therefore, it potentiates BA.4/BA.5 sublineage neutralization. These findings are highly relevant to the establishment of an Omicron-adapted vaccine, given the current epidemiology, the BA.2-derived substrains such as BA.4/BA.5, and the rapid pace of ongoing evolution. was related to This study data will help advance our knowledge of the omicron immune evasion process and the impact of vaccination on mutant cross-neutralization and guide the development of new vaccines.

*Important Notices

bioRxiv publishes non-peer-reviewed, preliminary scientific reports and should not be considered conclusive, to guide clinical practice/health-related actions, or to be treated as established information .

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