Neutralization potency against the Omicron variant of naturally expressed MBC-derived IgG antibodies from vaccinated individuals

By Dr. Tomislav Meštrović, MD, Ph.D.Reviewed by Danielle Ellis, B.Sc.Apr 8 2022

In the recent paper published in the journal Immunity, researchers have shown how the Omicron (B.1.1.529) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) successfully evaded a large fraction of antibodies derived from memory B cells (MBC), giving rise to a reduced, but incomplete immune escape.

Background

The Omicron SARS-CoV-2 variant has overcome the previously dominant Delta lineage in most countries, which points towards a robust selective advantage. The mutational profile of the Omicron variant implies both increased infectivity and improved immune escape properties.

The spike glycoprotein of the SARS-CoV-2 Omicron variant contains 32 mutations when compared to the original strain identified in Wuhan, with notable mutation hotspots in the receptor-binding domain (RBD) and N-terminal domain (NTD).

Previous studies that have analyzed MBC repertoire following mRNA vaccination in individuals recovered from coronavirus disease 2019 (COVID-19), but also those that were not infected before the vaccine have shown a substantial pool of high-affinity neutralizing antibody clones against all viral variants of concern before Omicron.

More specifically, these data implied that vaccine boosters and recalls would be an effective way forward to regenerate protective levels of antibodies in the serum to prevent the potential infection by SARS-CoV-2 variants of concern.

To appraise whether such a conclusion can still be considered true in the latest B.1.1.529 (Omicron) variant, a research group from France aimed to explore the intrinsic capacity of the MBC pool in recognizing this variant.

Appraising neutralization potential

In this paper, researchers have assessed affinity properties and neutralization potency against the SARS-CoV-2 Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies stemming from vaccinated COVID-19-recovered and previously non-infected individuals.

They have generated a recombinant Omicron RBD that harbored fifteen known and well-described mutations, such as E484K/Q/A, N501Y, K417T/N, and T478K that are found in other variants of concern, but also additional ones such as G339D, S375F, N440K, G446S, S477N, G496S, and Q493R mutations.

Furthermore, to better characterize the prevailing neutralizing potential of MBC-derived antibodies against the Omicron variant, they have tested 253 blood samples by using in vitro focus reduction neutralization assay against authentic Delta and Omicron SARS-CoV-2 variants.

Escape from ‘memory’ antibodies

Compared to other variants of concern, this study revealed how the Omicron variant can evade the recognition of a much larger proportion of MBC-derived antibodies - with only 30% retaining high affinity against the Omicron RBD. Moreover, the reduction in neutralization potency was even more striking.

If we focus on the single memory B cell level, a unique agglomeration of mutations is seen in key amino acid residues within the RBD of the SARS-CoV-2 Omicron variant. Although some of them are shared with some previous variants, there is also a panoply of unique ones, which results in a loss of affinity for up to 50% of all MBCs.

Hence it is safe to say that Omicron-specific RBD mutations expand the overall escape of memory B cell-derived antibodies; however, neutralizing MBC clones have been demonstrated in all individual samples that have been analyzed in this study.

Of course, important limitations of this research are a small number of study subjects, considering the need for in-depth MBC characterization (thus, observed differences have to be interpreted with caution), as well as a collection of samples early after the first vaccine boost in all individuals.

Implications for booster shots

Notwithstanding the robust immune escape potential of the Omicron variant, these results suggest that the MBC repertoire prompted by mRNA vaccines still provides a certain amount of protection against the Omicron variant in vaccinated individuals.

An important next step will be to characterize the long-term remodeling of the MBC repertoire after Omicron breakthrough infection in vaccinated individuals and to address whether an omicron-specific B cell response can be achieved, with the recruitment of naive B cells or the maturation of pre-existing low-affinity MBCs”, say study authors.

Answers to these questions will be crucial pieces of information on the available immune protection against Omicron variant, but also subsequent ones, to reach an informed decision whether vaccine boost aimed against variants of concern would be of interest in the future.