Genomic characterization of invasive Neisseria meningitidis in Spain (2011/12-2022/23): expansion of clonal complex 213 and the potential threat to 4CMenB vaccine strain coverage

Abstract

Invasive meningococcal disease (IMD) is associated with significant global morbidity and mortality and is addressed by conjugated polysaccharide and subcapsular vaccines. In Spain, data on 4CMenB vaccine strain coverage and antimicrobial susceptibility are limited. This study aimed to describe the genomic epidemiology, predict 4CMenB vaccine strain coverage, and assess antimicrobial susceptibility of 323 Neisseria meningitidis isolates causing IMD, collected from 57 Clinical Microbiology Laboratories in Spain over 12 years (2011/12-2022/23). Whole genome sequencing was performed to identify serogroup, clonal complex (cc), and antimicrobial resistance determinants. Vaccine strain coverage for serogroup B (MenB) isolates was predicted using the genetic Meningococcal Antigen Typing System approach. The most prevalent serogroups were B (57.9%), W (21.4%), C (10.4%), and Y (8.4%). MenB predominated throughout most seasons, except during the 2019/20 season when serogroup W peaked. Post-COVID-19 pandemic, MenB remained the most frequent (70.2%). Thirteen cc were identified among MenB isolates, with cc213 being the most prevalent (40.1%). Only 28.9% of MenB isolates were predicted to be covered by 4CMenB, with cc213 showing an exceptionally low coverage rate (5.3%) due to antigenic variants poorly targeted by the vaccine. Notably, cc213 was responsible for twice the proportion of MenB cases in 4CMenB-vaccinated versus unvaccinated. All isolates were susceptible to third generation cephalosporins, and 13.5% showed penicillin resistance. This study highlights the alarming prevalence of cc213 among MenB IMD cases in Spain and the limited 4CMenB coverage against this cc. The disproportionate representation of cc213 in vaccinated individuals underscores its potential to compromise vaccine effectiveness.

Keywords: 4CMenB vaccine strain coverage; Neisseria meningitidis; antimicrobial susceptibility; cc213; gMATS; genomic epidemiology; whole genome sequencing.

Figure 1.

Distribution of 323 invasive N. meningitidis isolates collected in this study by (A) age and (B) season. Colors indicate the capsular serogroup (cnl: capsule null locus). Black arrows indicate the month and year when the 4CMenB vaccine was introduced in Spain, as well as the implementation and subsequent lifting of COVID-19 social restrictions in the country.

Figure 2.

Population description of 323 invasive Neisseria meningitidis isolates collected in this study. (A) Distribution of serogroups per clonal complex (ccND: clonal complex not defined; cnl: capsule null locus), colors indicate capsular serogroup. (B) Genomes were compared using the N. meningitidis cgMLST v3.0 scheme. The resulting distance matrices were assessed with SplitsTree4 version 4.19.0 using the NeighborNet algorithm to construct the tree. Each dot represents one genome, the color of the dot indicates the capsular serogroup of the isolate. The 10 major clonal complexes are highlighted with a black circle. The black arrows indicate the four isolates closely related to cc269 that were not assigned to that clonal complex.

Figure 3.

Prediction of 4CMenB vaccine strain coverage with the gMATS approach of serogroup B isolates per clonal complex (ccND: clonal complex not defined).

Figure 4.

Bar chart representation of (A) fHbp peptides, (B) NHBA peptides, and (C) PorA_VR2 variants identified among serogroup B isolates. Peptides are grouped based on their classification as covered, unpredictable or not covered by the gMATS approach. Colors indicate the clonal complexes of the isolates carrying each peptide (ccOthers: clonal complexes identified only once or twice in this study; ccND: clonal complex not defined). 4CMenB antigen peptides identified only once in this study are grouped under category “Others”, while category “Others*” refers specifically to variant 1 fHbp peptides.

Figure 5.

Bar chart representation of the penA alleles identified among 304 N. meningitidis isolates, along with the corresponding MIC values. The alleles are grouped based on the number of PBP2 mutations encoded, and the color represents the MIC of isolates carrying each penA allele. An asterisk indicates alleles encoding the following PBP2 mutations: F504L, A510V, I515V, and H541N.