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

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

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


Mounting evidence suggests that Omicron BA.1 variant is immune evasive and that vaccine- or prior infection-elicited immunity provides limited protection against infection with BA.1 variant. Nevertheless, multiple exposures to SARS-CoV-2 and those with hybrid immunity (infected and subsequently 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 the sensitivity to therapeutic monoclonal antibodies. Preliminary reports indicated that both BA.1 and BA.2 variants evade nAbs to a similar extent. Notably, several of these analyses represented the vaccinated population, and the nAb profiles in SARS-CoV-2-naïve subjects after BA.2 infection are limited.

About the study

In the present study, researchers characterized the neutralization profiles against SARS-CoV-2 Omicron BA.2-infected individuals, including those with multiple antigen exposures and infection-naïve subjects. A focus-forming neutralization assay was performed, and continuous 50% neutralizing titers were computed using non-linear regression. SARS-CoV-2 D614G, Alpha, Alpha with E384K substitution (Alpha+E484K), Beta, Gamma, Delta, Omicron BA.1 and BA.2 variants were separately grown on Vero cells overexpressing angiotensin-converting enzyme 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 based on antibody titers in a lower-dimensional space using multidimensional scaling. Antigenic distances were computed for each serum-antigen pair from titer reduction of antigen. One unit corresponded to a two-fold dilution of neutralizing titers in the antigenic map.  Antibody landscapes were built using the adjusted P.1.1 reactivity map as the reference. The neutralizing titers are plotted above the antigen map in a third dimension in these plots.


In previously SARS-CoV-2-naïve subjects, nAbs were detectable following 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 titers were high against pre-Omicron variants, albeit marginally lower against the Alpha variant with E484K substitution (Alpha+E484K) and Beta variant.

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

Next, nAb titers against the SARS-CoV-2 Omicron variant were analyzed for different types of samples. For instance, samples from individuals with a single exposure (non-vaccinated and infection with 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 generally augmented nAb titers against Omicron BA.2 variant in those with multiple exposures, even in BA.2-naïve subjects.

Infection with either Omicron variant resulted in much higher nAb titers relative to SARS-CoV-2 wildtype or Delta-infected participants, albeit lower in those with pre-Omicron variant infection or multiple exposures. Moreover, in most groups, particularly those with single/double exposure, the nAb titers were higher against Omicron BA.2 than BA.1 variant. This indicated that BA.2 variant might be antigenically situated between BA.1 and pre-Omicron variants though distinct to both.

In the antigenic map, the differences between BA.1 and BA.2 were substantial compared to previous variants. D614G, Alpha, Alpha+E484K, Beta, and Gamma variants occupied a small distance on the map, with the Delta variant roughly in the same area. BA.1 variant was positioned away from other variants. Consistent with the nAb data, BA.2 variant was positioned between pre-Omicron and BA.1 variant 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 increased reactivity against the infected variant. In pre-Omicron variant convalescent subjects, reinfection with Omicron led to a broader antibody response. Moreover, breakthrough with Delta or either Omicron variant elicited much higher nAb titers against all SARS-CoV-2 variants. Antibody landscapes were nearly identical for BA.1 breakthrough subjects and those with BA.1 breakthrough after pre-Omicron infection, implying that a third variant exposure does not substantially augment the reactivity profile as one or two exposures do.

Overall, the antibody levels were higher in those with multiple exposures, and the number of exposures influenced the landscape shape. The antibody reactivity was generally higher in multiple exposure groups against pre-Omicron variants but not against either Omicron sub-lineage, except in Omicron-reinfected subjects.


Taken together, the present findings revealed that the two Omicron sub-lineages were antigenically distinct from each other and previous variants. The authors posit three hypotheses for the augmented cross-neutralization after multiple exposures, even against non-exposed variants. First, antibody saturation against an exposed variant(s) and an increase in absolute antibody titers against unencountered variants might boost responses.

Second, exposure to two non-Omicron variants might boost responses against conserved epitopes common to Omicron sub-lineages. Third, after exposure to two different variants, the broad polyclonal response might account for Omicron neutralization. In summary, the study found that multiple exposures improved cross-neutralizing potency, an absolute increase in antibody titers, and exposure to two distinct SARS-CoV-2 variants could potentially protect against emergent variants.  

*Important notice

medRxiv 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:
Tarun Sai Lomte

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.


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