A recent paper, currently available on bioRxiv* preprint server, reveals the potential for a common class of public antibodies to develop broad cross-neutralization against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the process known as affinity maturation – without the need for modifying viral spike glycoprotein in the vaccines.
Since the start of the coronavirus disease 2019 (COVID-19) pandemic, many SARS-CoV-2 variants of concern have emerged, with the Omicron (B.1.1.529) being the most recent one that has spread rapidly in many countries around the world.
As a result of the specific antigenic drift, the Omicron variant can successfully escape the majority of monoclonal antibodies, which includes those currently utilized in clinical practice. Furthermore, the variant displays substantially reduced sensitivity to neutralization by serum from individuals that were vaccinated or had the disease.
However, a third dose of vaccines based on the founder spike glycoprotein improved Omicron neutralization, implying either the expansion of more cross-reactive B cells in the repertoire, broader responses with affinity maturation, or both processes.
In this paper, a research group from the Karolinska Institutet in Sweden and the University of Cape Town in South Africa aimed to explore whether there is a way to induce the production of potent neutralizing antibodies capable of neutralizing all SARS-CoV-2 variants – including Omicron.
The researchers have first expressed the SARS-CoV-2 spike-specific immunoglobulin heavy chain variable 3-53 gene (IGHV3-53) with the use of monoclonal antibodies, which aremost frequently used by neutralizing SARS-CoV-2 antibodies.
More specifically, this has been isolated from memory B cells from a convalescent individual, approximately seven months after the infection with SARS-CoV-2 and prior to vaccination. Consequently, with the use of pseudovirus neutralization assay, they have investigated whether these monoclonal antibodies could cross-neutralize both the D614G mutation and Omicron.
Finally, the introduction of specific somatic hypermutations into a germline-reverted form to one such antibody was used to demonstrate the propensity of commonly elicited antibodies towards broad cross-neutralization through an affinity maturation process.
A potent bundle of antibodies
In a nutshell, the scientists have indeed described several tremendously potent neutralizing antibodies which were successful in neutralizing all SARS-CoV-2 variants of concern evaluated in this study, including Omicron.
The sequences differed sufficiently between these broad neutralizers to imply that there are distinct ways of overcoming the mutations in Omicron (but also other variants of concern) and achieving this degree of breadth and potency
Moreover, they have resolved a structure of the trimeric Omicron spike glycoprotein in complex with one of these broad monoclonal antibodies, defining in turn the structural basis for cross-neutralization events.
The importance of affinity maturation
These data highlight a true potential for a common class of antibodies to develop broad cross-neutralization of SARS-CoV-2 via affinity maturation; a process when the immune system produces antibodies of higher affinities after repeated contact with an antigen.
The broad efficacy and potency of these antibodies mean we can look at them as rather important management candidates in the wider context of an antigenically evolving pandemic. It also means that there is no urgent need to modify currently existing vaccines.
The identification of multiple broadly cross-neutralizing antibodies from this public class, capable of neutralizing Omicron without loss of potency, also suggests that these responses may be more generally achievable than previously appreciated”, say the study authors.
This means that the detection of cross-neutralizing antibodies in a convalescent individual that had the disease implies availability of specific memory B cells upon potential re-infection or vaccination, with important implications for our public health responses.
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.