A human monoclonal antibody from hybrid immunity exhibits exceptional neutralization breadth against antigenically divergent contemporary Omicron JN.1 lineage variants

Hybrid immunity offers stronger and more durable antibody-mediated protection against symptomatic SARS-CoV-2 infection. In the present study, we report the development of a durable antibody response in an individual with hybrid immunity who also received three doses of the prototype COVID-19 vaccine. Polyclonal plasma antibody obtained from this donor also showed extraordinary neutralization breadth against contemporary Omicron variants. One of the functional monoclonal antibodies (ATHS-C30) isolated from this individual, representing the IGHV4-30 lineage-specific B cell with strong binding affinity to JN.1 spike protein, showed extraordinary neutralization breadth, including variants of Omicron lineages that emerged beyond JN.1, such as KP.2, KP.3.1.1, KP.3.2, KP.3.3, LB.1 and XEC. ATHS-C30 was found to bind RBD with high affinity and showed distinct epitope specificity to the other neutralizing mAbs isolated from the same donor through the epitope binning assay. Molecular modelling of the CDHR3 sequence using existing structures indicated that ATHSC-30 belongs to the class 4 antibody, a feature that contributes to breadth, while epitope conservation analysis indicated that the majority of RBD-interacting residues of ATHSC-30 are evolutionarily conserved. Taken together, our study indicate that ATHS-C30 forms the basis of development of a robust and broadly neutralizing antibody response in this individual with hybrid immunity, which overcomes the antigenic variation by targeting highly conserved and cryptic epitopes in destabilizing the spike structure. ImportanceSARS-CoV-2 continues to pose a significant public health threat, particularly to immunocompromised individuals and older adults with underlying comorbidities. Hybrid immunity to SARS-CoV-2 in vaccinated individuals leads to the development of B cells that are qualitatively superior to those that are expected to develop in only vaccinated individuals. In the present study, we found that among individuals with hybrid immunity who developed robust, durable antigen-specific antibody responses, one developed antibody response capable of broadly cross-neutralising contemporary Omicron variants. This was correlated with development of antigen-specific B cell lineage, such as IGHV4-30, that produced antibodies with potent and extraordinary neutralisation breadth against contemporary Omicron lineages, such as KP.2, KP.3.1.1, KP.3.2, KP.3.3, LB.1 and XEC. This is believed to be due to heterologous antigen exposures driving the development of an antigen-specific B cell repertoire that, in turn, facilitates immune imprinting capable of overcoming the ineffectiveness of antibodies to effectively neutralize newly emerging Omicron variants.