Background
Observational studies have consistently reported moderate reductions in gonorrhoea incidence following immunisation with the meningococcal vaccine 4CMenB in the general population. These findings have prompted multiple randomized controlled trials in high-risk populations, whose primary endpoints exclusively rely on clinical outcomes, such as reduction of gonococcal infections at relevant mucosal sites, determined by nucleic acid amplification tests. Cross-protection of vaccine-induced responses towards the gonococcus are challenging to measure as there is uncertainty on the antigens involved and no correlates of protection are currently known.
Aim/Methods
Here, we select a gonococcal isolate panel, representative of the global population diversity and surface antigen variability, including the NHBA vaccine antigen, as sources of outer membrane vesicle (OMV) reagents, for an IgG-binding assay suitable to readout vaccine-induced humoral immune responses of 4CMenB trials.
Results
A dataset of roughly 28,000 publicly available gonococcal genomes was clustered according to the heterogeneity of 34 4CMenB OMV proteins, leading to the selection of an initial panel of 41 strains. The recently developed Life Identification Number (LIN) code and comparative whole genome sequencing analyses were used to confirm coverage across the global gonococcal population structure. Strains were phenotypically characterized for the predominant lipooligosaccharide (LOS) structures they expressed using a newly developed phenotypic typing scheme, assigning unique six-digit LOS barcodes describing glycan structures. Finally, OMVs were produced from each strain and were spotted onto an ad hoc microarray for assessing IgG binding profiles of pre- and post-4CMenB vaccinee sera from different age and at-risk groups, to stratify subject-specific and strain-specific responses induced by the vaccine.
Conclusion
By integrating genomic, phenotypic, and binding assay data, we selected a ten-strain sentinel panel representing six LIN code lineages, multiple prevalent OMV clades, heterogeneous LOS structures, and different 4CMenB-antibody binding profiles as determined using vaccinee sera. The panel represents a valuable tool to capture key subject responses that may be predictive of distinct immune profiles to the vaccine in specific cohorts and to map antigenic diversity in gonococcal strains likely to influence the breadth of 4CMenB cross-reactivity. Ultimately this panel may be used to harmonize immunogenicity assessments across 4CMenB clinical studies.
Funding: GSK