SARS-CoV-2 Omicron BA.2 differs antigenically from previous variants

In a recent study published on medRxiv*server, researchers observed that the Omicron BA.2 variant of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is immunologically different from other variants, including Omicron BA.1.

Study: BA.2 omicron immunologically differs from BA.1 omicron and pre-omicron variants. Image Credit: Naeblys/Shutterstock


Mounting evidence suggests that Omicron’s BA.1 variant is immunoevasive and that vaccine-induced immunity or prior infection provides limited protection against infection with the BA.1 variant. Nevertheless, multiple exposures to SARS-CoV-2 and people with hybrid immunity (infected and then vaccinated individuals) improve neutralizing antibody (nAb) titers against BA.1.

One study revealed distinct antigenic differences of pre-Omicron, BA.1 and BA.2 variants based on susceptibility to therapeutic monoclonal antibodies. Preliminary reports have indicated that the BA.1 and BA.2 variants evade nAbs to a similar extent. Notably, many of these analyzes represented the vaccinated population, and nAb profiles in SARS-CoV-2 naïve subjects after BA.2 infection are limited.

About the study

In the present study, researchers characterized neutralization profiles against individuals infected with SARS-CoV-2 Omicron BA.2, including those with multiple antigen exposures and infection naïve subjects. A focus formation neutralization test was performed and continuous 50% neutralizing titers were calculated using non-linear regression. SARS-CoV-2 variants D614G, Alpha, Alpha with substitution E384K (Alpha+E484K), Beta, Gamma, Delta, Omicron BA.1 and BA.2 were cultured separately on Vero cells overexpressing the conversion enzyme of angiotensin 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2).

The researchers constructed antigenic maps from convalescent and doubly vaccinated groups. Antigenic variants and sera were positioned according to antibody titers in a lower dimensional space using multidimensional scaling. Antigenic distances were calculated for each serum-antigen pair from the reduction in antigen titer. One unit corresponded to a two-fold dilution of the neutralizing titers in the antigenic map. Antibody landscapes were constructed using the adjusted P.1.1 reactivity map as a reference. Neutralizing titers are plotted above the antigenic map in a third dimension in these plots.


In previously SARS-CoV-2 naïve subjects, catches were detectable after infection with Omicron BA.2 and catches against pre-Omicron, and BA.1 variants only occasionally exceeded the detection limit and were generally weak. In previously infected subjects, nAb titers were elevated against the pre-Omicron variants, although slightly lower against the Alpha variant with E484K substitution (Alpha + E484K) and the Beta variant.

Nevertheless, nAbs against Omicron BA.1 and BA.2 were observed in two and five (out of 10) individuals, respectively. In contrast, for those with hybrid immunity, a broader nAb response was observed against all variants tested, regardless of vaccine type (messenger ribonucleic acid [mRNA] or adenoviral vector vaccines).

Next, nAb titers against the SARS-CoV-2 Omicron variant were analyzed for different sample types. For example, specimens from single exposure individuals (unvaccinated and infected with an ancestral strain, Alpha, Beta, Delta or Omicron [BA.1 or BA.2]), double exposure (reinfection [pre-Omicron and BA.1] or double vaccination), or multiple exposures (two or three vaccinations and breakthrough infection). The authors found generally increased nAb titers against the Omicron BA.2 variant in those with multiple exposures, even in BA.2 naïve subjects.

Infection with either Omicron variant resulted in significantly higher nAb titers compared to wild-type or Delta participants infected with SARS-CoV-2, although they were lower in those with pre-Omicron variant infection or multiple exposures. Additionally, in most groups, especially the single/double exposure ones, nAb titers were higher against the Omicron BA.2 variant than BA.1. This indicated that the BA.2 variant may be antigenically located between the BA.1 and pre-Omicron variants although distinct from both.

In the antigenic map, the differences between BA.1 and BA.2 were substantial compared to the previous variants. The D614G, Alpha, Alpha+E484K, Beta, and Gamma variants occupied a small distance on the map, with the Delta variant roughly in the same area. The BA.1 variant was positioned apart from the other variants. Consistent with nAb data, the BA.2 variant was positioned between the pre-Omicron variant and BA.1 and equidistant from Delta and BA.1. The antibody landscapes revealed that exposures to two distinct SARS-CoV-2 variants resulted in the highest reactivity against all other variants.

Exposure to a single variant showed the most enhanced reactivity against the infected variant. In convalescent pre-variant Omicron subjects, reinfection with Omicron led to a broader antibody response. Additionally, the breakthrough with Delta or either Omicron variant elicited much higher nAb titers against all SARS-CoV-2 variants. Antibody landscapes were nearly identical for subjects with BA.1 breakthrough and those with BA.1 breakthrough after pre-Omicron infection, implying that exposure to a third variant does not substantially increase the reactivity profile as one or two exposures do.

Overall, antibody levels were higher in people with multiple exposures, and the number of exposures influenced the shape of the landscape. Antibody reactivity was generally higher in multiple exposure groups against pre-Omicron variants, but not against both Omicron sublines, except in subjects reinfected with Omicron.


Taken together, the present results revealed that the two Omicron sublines were antigenically distinct from each other and from previous variants. The authors posit three hypotheses for increased cross-neutralization after multiple exposures, even against unexposed variants. First, antibody saturation against one or more exposed variants and an increase in absolute antibody titers against unencountered variants could stimulate responses.

Second, exposure to two non-Omicron variants could stimulate responses against conserved epitopes common to Omicron sublineages. Third, after exposure to two different variants, the broad polyclonal response could explain the neutralization of Omicron. In summary, the study found that multiple exposures enhanced cross-neutralization potency, an absolute increase in antibody titers, and exposure to two distinct SARS-CoV-2 variants could potentially protect against emerging variants.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

Journal reference:

  • Annika Roessler, Antonia Netzl, Ludwig Knabl, Helena Schaefer, Samuel H Wilks, David Bante, Barbara Falkensammer, Wegene Borena, Dorothee von Laer, Derek Smith, Janine Kimpel. (2022). BA.2 omicron immunologically differs from BA.1 omicron and pre-omicron variants. medRxiv. do I:

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