Vaccination- and/or natural infection-induced immune responses against SARS-CoV-2 Omicron subvariants

In a recent study posted to the bioRxiv* preprint server, researchers comparatively evaluated the neutralization antibody (Ab) titers for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron VOC (variants of concern) subvariants BA.1, BA.2, BA.4/5 among individuals with ancestral B.1 (D614G) strain infections, vaccinated individuals, or with hybrid (combined) immunity from breakthrough infections (BTI) and vaccinations with Delta or Gamma VOCs.

Study: Vaccine- and BTI-elicited pre-Omicron immunity more effectively neutralizes Omicron sublineages BA.1, BA.2, BA.4 and BA.5 than pre-Omicron infection alone. Image Credit: Kateryna Kon/Shutterstock


The continual emergence of Omicron sub-VOCs has threatened vaccine efficacy and warranted the development of novel and updated anti-SARS-CoV-2 agents. It is critical to assess the cross-neutralization of immunological responses induced by either vaccination or natural infection, or both to guide policy-making and improve preparedness against COVID-19.

About the study

In the present study, researchers compared pre-Omicron BTI- and/or vaccination-induced immune responses to novel Omicron subvariants BA.1, BA.2, and BA.4/5.

The team compared the neutralization ability of sera obtained from 58 unvaccinated and D614G-infected coronavirus disease 2019 (COVID-19) patients (convalescent sera), 14 booster-vaccinated (three doses) individuals, and 16 vaccinated and Delta-infected (n=14) or Gamma-infected (n=2) BTI patients against D614G, Delta and Omicron BA.1, BA.2, BA.4/5 strains.

The unvaccinated individuals were infected between March and July 2020, and BTI patients were infected between 15 July and 20 September 2021. Triple COVID-19 vaccinees received a messenger ribonucleic acid (mRNA) booster dose between October 2021 and January 2022. COVID-19 diagnosis was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) for all patients.

Vero-E6 cells and human embryonic kidney (HEK)293T-angiotensin-converting enzyme 2 (ACE2)- transmembrane protease, serine 2 (TMPRSS2) cells were used for cell culture experiments. Multiplexed assays including SARS-CoV-2 antigens [nucleocapsid (N), spike (S), receptor-binding domain (RBD), N-terminal domain (NTD)] and S from other CoVs [SARS-CoV, Middle East respiratory syndrome CoV (MERS-CoV), OC43, HKU1] and Influenza A Hemagglutinin H3 were used to measure anti-SARS-CoV-2 immunoglobulin G (IgG) Ab titers.

Nasopharyngeal swabs (NPS) were obtained from the participants for virological assays, and next-generation sequencing (NGS) was performed. To evaluate SARS-CoV-2 VOC and sub-VOC neutralization, live virus neutralization assays and human immunodeficiency virus (HIV) pseudotype-based neutralization assays were performed. The 50% tissue culture infectious dose (TCID50), the half-maximal inhibitory concentration (IC50), and the 50% neutralizing titer (NT50) values were determined.


All Omicron sub-VOCs showed extensive immune evasion from sera of all participants compared to the D614G and Delta, although to different degrees based on sera origin. BA.1. COVID-19 convalescents could not neutralize the Omicron BA.1 sub-VOC and partially neutralized Omicron BA.2 and BA.4/5. Sera from vaccinated individuals partially neutralized the Omicron BA.2 sub-VOC but not BA.1 and BA.4/5.

BTI patient sera showed similar neutralizing titers for all Omicron sub-VOCs. BTI patient sera and convalescent sera showed the highest and lowest neutralizing potential for all Omicron sub-VOCs, respectively. The NT50:Ab ratios (Ab avidity) were significantly greater among BTI patients than among convalescents.

Moderate COVID-19 convalescents showed better neutralization responses. BA.1 and BA.2 showed the greatest resistance and sensitivity, respectively, against all sera. Omicron BA.5 escaped neutralization responses of vaccinated individuals better than natural infection-induced and hybrid immunity-induced responses.

Among COVID-19 convalescents, NT50 geometric mean titers (GMT) for B.1 (125) and Delta (153) were comparable. Even at 1:40 serum concentration, 33% and 39% of individuals could not neutralize Omicron B.1 and Delta, respectively. The NT50 GMTs for BA.2, BA.4, and BA.5 were 55, 37, and 60, respectively, significantly lesser than those against B.1 and Delta.

BA.4 was significantly more resistant than BA.2 and BA.5 and could not be neutralized by 75% of the sera. NT50:anti-S, NT50:anti-RBD, and N50:anti-NTD ratios were similar for B.1 and Delta and were lower by one log10 micron BA.1. Among boosted vaccinees, NT50 GMT titers for B.1, Delta, BA.1, BA.4 and BA.5 were 247, 345, 51, 46 and 59, respectively.

Among BTI patients, NT50 GMTs for B.1, Gamma/Delta, Omicron BA.1 sub-VOC, BA.2 sub-VOC, BA.4 sub-VOC, and Omicron BA.5 sub-VOC were 195, 330, 44, 71, 52, and 88, respectively, and NT50:Ab ratios were one log10 greater for B.1 and Delta than for Omicron sub-VOCs. Comparing NT50 values of all sera (convalescents + vaccinees + BTI patients) showed a trend of greater Delta neutralization than B.1 and much lower (1.5 log10) Omicron sub-VOC neutralization.

Overall, the study findings underscored COVID-19 vaccination importance in generating Abs with high cross-reactivity against SARS-CoV-2 VOCs and sub-VOCs and indicated that immunological imprinting by vaccines of the first-generation might limit, but not completely terminate cross-neutralization.

*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:
  • Vaccine- and BTI-elicited pre-Omicron immunity more effectively neutralizes Omicron subvariants BA.1, BA.2, BA.4 and BA.5 than pre-Omicron infection alone. Eveline Santos da Silva et al. bioRxiv. doi:

Posted in: Medical Science News | Medical Research News | Healthcare News

Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Antibody, Cell, Cell Culture, Coronavirus, Coronavirus Disease COVID-19, covid-19, Efficacy, Enzyme, HIV, immunity, Immunodeficiency, Immunoglobulin, Influenza, Kidney, MERS-CoV, Nasopharyngeal, Omicron, Polymerase, Polymerase Chain Reaction, Receptor, Respiratory, Ribonucleic Acid, SARS, SARS-CoV-2, Serine, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Tissue Culture, Transcription, Vaccine, Virus

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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