Imprinted antibody responses towards SARS-CoV-2 Omicron subvariants

A recent article posted to the bioRxiv* preprint server analyzed the imprinted antibody responses towards the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants.

Study: Imprinted antibody responses against SARS-CoV-2 Omicron sublineages. Image Credit: Corona Borealis Studio/Shutterstock
Study: Imprinted antibody responses against SARS-CoV-2 Omicron sublineages. Image Credit: Corona Borealis Studio/Shutterstock


The emergence of the SARS-CoV-2 Omicron mutant by late 2021 resulted in an increase in coronavirus disease 2019 (COVID-19) cases all across the world. Following the Omicron BA.1.1 and BA.1 sublineages, the BA.2 subvariant swept the globe. The COVID-19 pandemic has so far caused more than 516 million confirmed cases and 6.2 million deaths worldwide. Although Omicron sublineages share numerous spike (S) mutations, they have discrete S mutations, indicating antigenic shift that allows evasion of antibodies generated by prior SARS-CoV-2 vaccination or infection. 

About the study

In the present study, the researchers determined how earlier COVID-19 antigen exposure via SARS-CoV-2 vaccination or infection with one viral variant influenced immune responses to future incidences of COVID-19 linked with another viral strain. 

The team assessed humoral responses to Omicron infection in mucosa and plasma. They determined the degree of immune evasion linked with the Omicron BA.2 lineage. For this, the team measured the neutralizing activity of human plasma using a non-replicative vesicular stomatitis virus (VSV) pseudotyped with SARS-CoV S, or SARS-CoV-2 S containing Delta, Wu-G614, BA.2, or BA.1 mutations. The compared plasma encompassed six groups of individuals: 1) SARS-CoV-2-infected+two-dose vaccinated, 2) SARS-CoV-2-infected+three-dose vaccinated, 3) Delta breakthrough infection following two-dose vaccination, 4) Omicron BA.1 breakthrough after two-dose vaccination, 5) Omicron BA.1 breakthrough post-three dose vaccination, and 6) three-dose COVID-19 vaccinated.

The impact of Omicron sublineages on the neutralization activity of several clinical monoclonal antibodies (mAbs) was assessed. The authors determined the activity of S2X324 mAb against all SARS-CoV-2 variants, including the Omicron sublineages. Further, they analyzed the structural underpinnings of S2X324-induced neutralization of SARS-CoV-2 variants using cryo-electron microscopy (cryo-EM).

In addition, the investigators evaluated the potential SARS-CoV-2 mutations that imparted evasion from the S2X324-induced neutralization in vitro. Moreover, they assessed in vivo protective capacity of S2X324 therapeutically and prophylactically using Syrian hamsters challenged with SARS-CoV-2.


The study results showed that exposure to the antigenically altered SARS-CoV-2 Omicron variant causes a recall of existing memory B cells selective for epitopes common for various SARS-CoV-2 variants. Yet, the Omicron infection would not prime naive B cells to recognize Omicron-specific epitopes for a minimum of 100 days after breakthrough infection. The authors noted that immune imprinting might be favorable in activating responses to cross-reactive SARS-CoV-2 epitopes, although previous antigenic exposure significantly reduced antibody responses to several Omicron-specific epitopes. 

The team found heterogeneous polyclonal neutralizing antibodies in nasal swabs across BA.1 breakthrough cases and not in vaccinated-only subjects. In line with previous research, this inference implied that COVID-19 adenovirus-vectored or messenger ribonucleic acid (mRNA) vaccines do not induce significant mucosal antibody responses when delivered intramuscularly.

Additionally, the researchers noted that the Omicron subvariants escaped neutralization imparted by the most receptor-binding domain (RBD)-directed clinical mAbs, such as COV2-2130, COV2-2196, S2X259, Sotrovimab, and COV2-2130/COV2-2196 cocktail. Surprisingly, the neutralization potency of the S2X324 mAb was unimpacted by the S mutations of the Omicron sublineages. Moreover, they cross-reacted with all analyzed SARS-CoV-2 variants and sarbecovirus clade 1b Pangolin-Guangdong RBD. Nonetheless, more diverse sarbecovirus RBDs, including SARS-CoV, were not recognized by S2X324.

S2X324 identified an RBD epitope that partially overlaps antigenic sites IV and Ib/Ia, justifying the competition with S309 and S2H14 mAbs. S2X324 recognizes RBD residues K440, N439, L441, K444, S443, V445, G447, S446, N450, P499, R498, T500, Q506, Y501, and G502 using all six complementary-determining loops. Congruent to competition assessments, S2X324 coincided with the angiotensin-converting enzyme 2 (ACE2)-contact region on the RBD, which would sterically prevent receptor engagement. Notably, S2X324 possessed substantial neutralizing ability against SARS-CoV-2 P499S, V445T, and G446V residue substitutions and numerous mutations observed in the epitope of known viral variants, like N440K, N501Y, and N439K.

Prophylactic dosing of S2X324 or S309 immunized hamsters when challenged with SARS-CoV-2 Delta in a dose-related mode, with S2X324 displaying a three-time greater efficiency than S309, despite a 20-time difference in in vitro potency against Delta S VSV. Furthermore, prophylactic dosing of S2X324 at 5 mg/kg reduced viral RNA concentrations in the trachea and lungs of BA.2-infected hamsters to values below detection. Therapeutic S2X324 dosing at 5 and 2 mg/kg one day after the Delta challenge decreased viral RNA in the lungs by 3 and 2.5 orders of magnitude, respectively, relative to the control arm. At 2 and 5 mg/kg of S2X324, viral multiplication in the lungs was entirely abolished, whereas, at 0.1 and 0.5 mg/kg, viral replication was decreased to an order of magnitude.


The study findings illustrated that COVID-19 vaccine boosters or hybrid immunity provide significant plasma neutralizing activity against the SARS-CoV-2 Omicron BA.2 and BA.1 sublineages and associated breakthrough infections; however, vaccination alone does not elicit neutralizing effect in the nasal mucosa. While coherent with immunological imprinting, most antibodies generated from plasma cells or memory B cells of Omicron variant breakthrough infections cross-reacted with the SARS-CoV-2 Wuhan-Hu-1, BA.2, and BA.1 RBDs, Omicron primary infections evoke B cells with restricted specificity. 

In line with recent studies, the authors found that the Omicron breakthrough infections did not result in substantial titers of pan-sarbecovirus neutralizing antibodies, such as those directed against SARS-CoV. These observations were contrary to the previous reports that pre-existing immunity to SARS-CoV succeeded by SARS-CoV-2 vaccination was linked to the elicitation of pan-sarbecovirus neutralizing antibodies.  

Further, most known clinical antibodies had limited Omicron neutralizing capability. Interestingly, the scientists discovered an ultrapotent pan-SARS-CoV-2 antibody, S2X324, unaltered by any Omicron lineage S mutations, making it a promising therapeutic candidate.

*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:
Shanet Susan Alex

Written by

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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