At least 3 vaccine or virus exposures are required for minimum protection against SARS-CoV-2 Omicron

In a recent pre-pressure study published on medRxiv* preprint server, researchers determine the serum neutralizing and binding activity against the severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) Omicron variant in individuals with varying levels of immunity to coronavirus disease (COVID-19).

Study: Actuation of convalescent and vaccine serum against a B.1.1.529 variant SARS-CoV-2 isolate.  Image Credit: Fit Ztudio /

Examination: Activity of convalescent and vaccine serum against a B.1.1.529 variant SARS-CoV-2 isolate. Image Credit: Fit Ztudio /

The emergence of the Omicron variant

Shortly after the first case of the SARS-CoV-2 Omicron variant (B.1.1.529) was reported in South Africa and Botswana in November 2021, the Omicron variant spread rapidly to many countries around the world.

The omicron variant is considered to be more infectious than the Delta variant due to a large number of mutations in the spike (S) protein region and about 15 amino acid changes in the receptor binding domain (RBD). Previous studies suggest that the highly antigenically distinct SARS-CoV-2 B.1.1.529 variant is associated with decreased vaccine efficacy (VE) and extensive immune evasion.

About the study

The present study determined serum neutralizing and binding activity against SARS-CoV-2 wild-type, Beta (B.1.351) and Omicron strains in convalescent COVID-19, two-dose messenger ribonucleic acid (mRNA) vaccinated, mRNA booster vaccinated, and convalescent two-dose and booster-vaccinated participants. Study participants received either Pfizer or Moderna vaccines.

Sera from vaccinated individuals mostly maintain binding to B.1.1.529 RBD. ONE shows a model of the B.1.1.529 peak protein in complex with the angiotensin-converting enzyme 2 (ACE2) receptor with B.1.1.529-specific mutations indicated. The figure is based on PDB 6M0J and 7C2L and is built in PyMol. B shows absolute titers (left) and folding reduction (right) for the combined samples, C to J shows the different groups. A one-way ANOVA with Tukey’s multiple comparison test was used to compare the neutralization titers, and significant p-values ​​(<0.05) are given in the figure. The exception is panel D was a mixed-effects model had to be used due to a lack of data point.

Convalescent and post-vaccination sera were collected from the subjects in the longitudinal observational protection associated with rapid immunity to SARS-CoV-2 (PARIS) study after receiving written informed consent. The omicron variant was antigenically characterized using the 85 serum samples collected from 54 participants.

The SARS-CoV-2 bio-samples collected from the Mount Sinai Pathogen Surveillance program were sequenced either based on spike S1 mutation profile or using an established complete virus genome sequencing approach.

Recombinant RBD proteins were produced and cloned into the mammalian expression vector pCAGGS using Expi293F cells. These proteins were then purified after transient transfections with each respective plasmid. Similarly, nucleocapsid (N) terminal domain (NTD) protein was cloned into the pVRC8400 expression vector and transiently expressed in FreeStyle ™ 293-F cells.

Serum antibody titers from convalescent COVID-19 patients and vaccine recipients were analyzed by enzyme-linked immunosorbent assay (ELISA) using recombinant RBD and NTD of SAR-CoV-2 wild-type (WA1), Beta, and Omicron strains. A multi-cycle microneutralization assay was also performed using vaccine recipients’ serum to determine the antibody neutralization ability of SARS-CoV-2 wild-type, Beta and Omicron isolates.

Survey results

In the 85 samples examined, there was a more than 14.5-fold reduction in the neutralization against the Omicron variant. In addition, 16.5% of the samples showed no neutralization against the Omicron variant. Meanwhile, there was only a quadrupling of the neutralization capacity compared to the Beta variant.

Convalescent COVID-19 patients showed low antibody neutralization against SARS-CoV-2 wild-type and beta variants and no neutralizing activity against the Omicron variant. Most of the subjects who received a two-dose Moderna or Pfizer vaccination regimen showed low but detectable antibody neutralization and had a 42-fold and 23-fold reduction in neutralization activity against the Omicron variant, respectively. In comparison, recipients of Moderna and Pfizer booster vaccines had a lower reduction in neutralization by 16.7-fold and 7.5-fold decreases, respectively.

Convalescent COVID-19 patients receiving two doses of Moderna or Pfizer vaccines, as well as those receiving three doses of the Pfizer vaccine, showed 11-fold, 14-fold, and 13-fold decreases in Omicron neutralization, respectively. Robust antibody neutralization was maintained in these three cohorts.

A 7.5-fold reduction in antibody binding to RBD in Omicron was observed in two-thirds of convalescent COVID-19 patients who showed no detectable activity after ELISA. In other groups, however, RBD binding was well maintained. Similarly, antibody binding to NTD was also well maintained with some minor reductions.


The researchers conclude that there is a significant decrease in serum neutralizing activity against the Omicron variant in convalescent COVID-19 patients and two-dose vaccinated participants. Although at reduced levels, serum neutralizing activity was maintained in two-dose or booster vaccinated convalescent COVID-19 patients. Omicron RBD and NTD binding capacity decreased in unvaccinated convalescent COVID-19 patients, whereas it was mostly maintained in vaccinated convalescent patients.

The results of the current study are consistent with previous reports on the effect of Omicron on the neutralizing activity of the serum of convalescent COVID-19 patients and vaccine recipients. This suggests that those who received booster doses in convalescent vaccinated groups have significant protection against the Omicron variant.

According to the authors, this is the first study describing RBD- and NTD-specific binding changes with respect to the Omicron variant and adding evidence pointing to the need for Omicron-specific vaccines.

*Important message

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


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