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

In a recent study published on the website of the 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

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Mounting evidence suggests that the BA.1 variant of Omicron is immunoevasive and that immunity induced by a vaccine 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 (individuals infected and subsequently vaccinated) improve neutralizing antibody (nAb) titers against BA.1.

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

About the study

In the current study, researchers characterized neutralization profiles against people infected with SARS-CoV-2 Omicron BA.2, including those who had been exposed to multiple antigens and infection-naïve subjects. A focus formation neutralization test was performed and continuous 50% neutralization 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 converting enzyme angiotensin 2 (ACE2) and the 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 neutralization titers in the antigenic map. Antibody landscapes were constructed using the P.1.1 adjusted reactivity map as a reference. Neutralization titers are shown above the antigenic map in a third dimension in these graphs.

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In SARS-CoV-2-naïve subjects, NAbs were detectable after infection with Omicron BA.2 and NAbs against pre-Omicron and BA.1 variants only occasionally exceeded the detection limit and were generally low. In previously infected subjects, nAb antibody titers were high 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 variants were observed in two and five individuals (out of 10), respectively. In contrast, in individuals with hybrid immunity, a broader nAb response was observed against all variants tested, regardless of vaccine type (messenger ribonucleic acid, etc.). [mRNA] or vaccines vectored by an adenovirus).

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

Infection with either Omicron variant resulted in much higher nAb antibody titers compared to participants infected with wild-type or Delta SARS-CoV-2, although they had were lower in those who were infected before the Omicron variant or who had been exposed several times. In addition, in most groups, especially those with single or double exposure, AcN titers were higher against the Omicron BA.2 variant than against the BA.1 variant. This indicates that the BA.2 variant could be antigenically located between the BA.1 and pre-Omicron variants, although distinct from the two.

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 the nonspecific antibody data, the BA.2 variant was located between the pre-Omicron variant and the BA.1 variant and equidistant from the Delta and BA.1 variants. The antibody landscapes revealed that exposures to two distinct SARS-CoV-2 variants resulted in the strongest reactivity against all other variants.

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Exposure to a single variant showed the highest reactivity against the infected variant. In subjects recovering before the Omicron variant, reinfection with Omicron resulted in a broader antibody response. Additionally, the breakthrough of Delta or either Omicron variant elicited much higher nAb antibody titers against all SARS-CoV-2 variants. Antibody landscapes were almost identical in subjects who broke through with the BA.1 variant and those who broke through with the BA.1 variant after pre-Omicron infection, implying that a third exposure to the variant does not increase not substantially the reactivity profile as one or two exposures do.

Overall, antibody levels were higher in people who had 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.


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

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

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*bird is important

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health behavior, or be 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. doi: