Genetic Similarity of Gonococcal Homologs to Meningococcal Outer Membrane Proteins of Serogroup B Vaccine

Abstract

The human pathogens Neisseria gonorrhoeae and Neisseria meningitidis share high genome identity. Retrospective analysis of surveillance data from New Zealand indicates the potential cross-protective effect of outer membrane vesicle (OMV) meningococcal serogroup B vaccine (MeNZB) against N. gonorrhoeae A licensed OMV-based MenB vaccine, MenB-4C, consists of a recombinant FHbp, NhbA, NadA, and the MeNZB OMV. Previous work has identified several abundantly expressed outer membrane proteins (OMPs) as major components of the MenB-4C OMV with high sequence similarity between N. gonorrhoeae and N. meningitidis, suggesting a mechanism for cross-protection. To build off these findings, we performed comparative genomic analysis on 970 recent N. gonorrhoeae isolates collected through a U.S surveillance system against N. meningitidis serogroup B (NmB) reference sequences. We identified 1,525 proteins that were common to both Neisseria species, of which 57 proteins were predicted to be OMPs using in silico methods. Among the MenB-4C antigens, NhbA showed moderate sequence identity (73%) to the respective gonococcal homolog, was highly conserved within N. gonorrhoeae, and was predicted to be surface expressed. In contrast, the gonococcal FHbp was predicted not to be surface expressed, while NadA was absent in all N. gonorrhoeae isolates. Our work confirmed recent observations (E. A. Semchenko, A. Tan, R. Borrow, and K. L. Seib, Clin Infect Dis, 2018, https://doi.org/10.1093/cid/ciy1061) and describes homologous OMPs from a large panel of epidemiologically relevant N. gonorrhoeae strains in the United States against NmB reference strains. Based on our results, we report a set of OMPs that may contribute to the previously observed cross-protection and provide potential antigen targets to guide the next steps in gonorrhea vaccine development.IMPORTANCE Gonorrhea, a sexually transmitted disease, causes substantial global morbidity and economic burden. New prevention and control measures for this disease are urgently needed, as strains resistant to almost all classes of antibiotics available for treatment have emerged. Previous reports demonstrate that cross-protection from gonococcal infections may be conferred by meningococcal serogroup B (MenB) outer membrane vesicle (OMV)-based vaccines. Among 1,525 common proteins shared across the genomes of both N. gonorrhoeae and N. meningitidis, 57 proteins were predicted to be surface expressed (outer membrane proteins [OMPs]) and thus preferred targets for vaccine development. The majority of these OMPs showed high sequence identity between the 2 bacterial species. Our results provide valuable insight into the meningococcal antigens present in the current OMV-containing MenB-4C vaccine that may contribute to cross-protection against gonorrhea and may inform next steps in gonorrhea vaccine development.

Keywords: Bexsero; MenB-4C; Neisseria gonorrhoeae; Neisseria meningitidis; cross-protection; genetic similarity; outer membrane proteins; outer membrane vesicles; vaccine development.

FIG 1

Schematic presentation of common protein identification and assessment of proteins’ subcellular localization. Ng, N. gonorrhoeae; Nm, N. meningitidis .

FIG 2

The porA promoter region for N. gonorrhoeae and N. meningitidis. The putative meningococcal −10 and −35 locations as well as the ribosome binding site and the start codon are indicated. The porA promoter sequences for all 970 N. gonorrhoeae genomes were filtered down to 9 unique sequences. The bottom four rows consist of the porA promoter sequences for the N. meningitidis references. The gaps represent nucleotides that were missing from the respective sequence compared to the rest.

FIG 3

Amino acid sequence similarity of 57 common OMPs found in 970 N. gonorrhoeae and NmB (NZ98/254) strains. A value of 80% was set as a minimum level of sequence similarity that might confer cross-protection. The majority of the common OMPs had >90% sequence conservation in N. gonorrhoeae.

FIG 4

Phylogenetic clustering of FetA, PilQ, Omp85 (BamA), RmpM, NspA, and MtrE proteins found in 4 NmB and 970 N. gonorrhoeae strains. Each red dot represents sequences obtained from a unique N. gonorrhoeae allele. In total, 16 unique alleles were found within NmB strains, as follows: 4 for FetA, 3 for PilQ, 3 for Omp85 (BamA), 2 for RmpM, 2 for NspA and 2 for MtrE; there were 248 unique alleles within N. gonorrhoeae strains, as follows: 95 for FetA, 61 for PilQ, 44 for Omp85 (BamA), 15 for RmpM, 14 for NspA, and 19 for MtrE.