Meningococcal vaccination in adolescents and adults induces bactericidal activity against hyperinvasive complement-resistant meningococcal isolates

Background Complement-mediated killing is critical in the defense against meningococci. During a recent outbreak of invasive meningococcal serogroup W disease (IMD-W) in the Netherlands, the predominant isolates belonged to clonal complex (cc) 11, which may suggest a role for cc11-assocated traits in complement resistance. We investigated complement resistance of invasive and carriage meningococcal isolates of different serogroups and lineages. In addition, we investigated whether vaccine-induced antibodies can overcome resistance to complement-mediated killing. Methods We analyzed IMD isolates (n=56) and carriage isolates (n=19) of different serogroups and clonal lineages in the serum bactericidal antibody (SBA) assay using pooled serum from unvaccinated and vaccinated individuals. Furthermore, we determined meningococcal serogroup W geometric mean titers (GMTs) and protection levels with the routinely-used non-cc11 isolate and hyperinvasive cc11 isolates using individual serum samples from adolescents and adults 5 years postvaccination. Results The hyperinvasive IMD isolates showed high variation in their resistance to complement-mediated killing when pooled serum from unvaccinated individuals was used (median 96, range 2-1,536). When pooled sera from vaccinated individuals was used, all isolates were killed. The minimum spanning tree revealed moderate clustering of serogroup and cc, while complement resistance did not. While a significantly lower GMT was observed against cc11 meningococcal serogroup W (MenW) compared to a non-cc11 MenW isolate in vaccinated adults but not in adolescents, we found no differences in the proportion protected between these isolates. Conclusions These data show that vaccine-induced antibodies are effectively inducing complement-mediated killing of complement-resistant hyperinvasive and carriage meningococcal isolates. Short summary Meningococcal isolates of hyperinvasive lineages are resistant to complement-mediated killing but vaccine-induced antibodies effectively kill these invasive isolates. ### Competing Interest Statement K.T. received funds for an unrestricted research grant from GlaxoSmithKline (GSK) Biologicals SA, consultation fees, fees for participation in advisory boards, speaking fees and funds for unrestricted research grants from Pfizer, fees for participating in advisory boards and funds for unrestricted research grant from Merck Sharp and Dohme (MSD), all paid directly to his home institution and all outside the submitted work. N.M.v.S declares grants from GSK and MSD outside the submitted work. A.v.d.E declares a grant from Pfizer outside the submitted work. All other authors report no potential conflicts of interest. ### Clinical Trial NL4518 NL7735 ### Funding Statement This study was funded by the European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 835433, the work was supported by the Dutch Ministry of Health, Welfare and Sport. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The former ethics committee/IRB of St Antonius Ziekenhuis Nieuwegein and ethics committee/IRB 'Medical Research Ethics Committee United' (MEC-U) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors