The identification of vaccinee-derived antibodies with broad-spectrum Omicron neutralization activity

By Dr. Liji Thomas, MDApr 12 2023Reviewed by Lily Ramsey, LLM

A recent study posted in the Cell Reports Journal reported the identification of a panel of vaccinee-derived antibodies with broad-spectrum neutralization activity. 

Study: Potent, omicron-neutralizing antibodies isolated from a patient vaccinated 6 months before omicron emergence. Image Credit: FamVeld/Shutterstock.com

Background

As the coronavirus disease 2019 (COVID-19) continues to spread, therapeutic options are running out due to the emergence of multi-resistant variants and strains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

This study reports the isolation of several broadly neutralizing antibodies directed against the currently circulating Omicron strain.

These could shed light on the road ahead for developing such broad-spectrum agents for treating coronavirus-induced disease outbreaks.

Introduction

The initial outbreak of SARS-CoV-2 was followed in a few months by the emergence of multiple variants of concern (VOCs), such as Alpha, Beta, Gamma, and Delta.

These drove new waves of infection, some of which were devastating. Each new variant typically replaced an earlier one as the dominant circulating strain, locally or globally.

Mutations in the spike protein are responsible for changes in the biological characteristics of the virus, such as increased transmissibility, evasion of host immune responses, and resistance to neutralizing antibodies. These include, in the Delta variant, for instance, T478K and L452R substitutions.

The Omicron VOC was first identified in South Africa in the latter part of 2021 and has comprised over 98% of all publicly available genomic sequences since February 2022.

The BA.1 variant of Omicron had over 30 mutations spread throughout the spike protein. Several other Omicron lineages and sublineages followed it.

The mutations associated with Omicron severely affected the ability to prevent or manage COVID-19 by inducing resistance and immune evasion, even with antibodies that targeted epitopes in highly conserved regions.

It is thus important to identify broadly neutralizing (bn) monoclonal antibodies (mAbs) that can counter such strains, whether now circulating or likely to emerge.

What did the study show?

The current study isolated several such antibodies from a Californian individual who had taken two doses of the Moderna mRNA-1273 COVID-19 vaccine.

The serum screen showed high neutralizing antibody titers active against the ancestral D614G and moderate to high titers against other VOCs such as Beta, Delta, and Omicron BA.1, BA.1.1, and BA.2.

Of these, just five neutralized both D614G and Delta, reducing infection with BA.1 pseudoviruses by over 85%.

The researchers mapped the epitopes, finding that these mAbs form pairs that simultaneously bind the SARS-CoV-2 spike protein trimer.

With three of them, which bind to the receptor binding domain, RBD-2, each fragment antigen-binding (Fab) from one antibody interacts with one spike monomer from the top of the receptor binding motif (RBM). This causes the RBDs to become upright.  

With another two mAbs, adjacent spikes are crosslinked by the interaction of each Fab with a different spike protein on the outer face. However, one of these mAbs contacts at least one RBD in the “up” position, but the other binds only to ‘down” RBDs.

Structural analysis of three mAbs showed them in complex with the spike of D614G or BA.1 spikes, using different parts of the binding surface.

It also showed the importance of examining the antibody structure before pronouncing its ability to interact with or neutralize the virus since this could differ when only the Fab fragment is examined.

The scientists also found that with some of these mAbs, the high avidity for the spike variant overcame the relatively lower affinity.

With 2A10, the bivalent binding of the antibody molecule allowed it to remain potently neutralizing even though it contacts up to eight residues that have undergone mutations in the Omicron variant.

With 2A10, there was a surprising difference in affinity for the spike proteins of the two sublineages BQ.1.1 and XBB, which have many common mutations, with both the whole antibody and the Fab of the mAb.

However, it still achieved a threefold higher neutralization potency for XBB.1.1 and XBB.1.5 than BQ.1.1 in pseudovirus assays.

Treatment with three of these mAbs, namely, 1C3, 2A10, or 1H2, caused BA.1/BA.2-infected mice to show a reduction of the viral load in the lungs to below detection levels.

This was not seen with the other antibodies. Lung pathology was also reduced in BA.2-infected mice but not BA.1.

These antibodies provide important therapeutic options to replace antibodies that were escaped.”

What are the implications?

As mutations become more frequent, antibodies have been reported to lose their potency within months of gaining approval.

Bebtelovimab received emergency use authorization on February 11, 2022 35. This authorization was revoked just nine months later with the emergence of the BQ and XBB variants, highlighting the ongoing need to develop durable therapeutics.”

These results suggest that ideal antibodies exist in the vaccine-mediated repertoire, and can be boosted from their memory response upon VOC infection or future vaccination.”

Further study is required to determine the effect on disease severity, their efficacy in humans and primates, and whether these antibodies will persist as more exposures occur.