Neisseria are obligate human pathogens causing bacterial meningitis, septicaemia and gonorrhoea. Neisseria require iron for survival and can extract it directly from human transferrin for transport across the outer membrane. The transport system consists of TbpA, an integral outer membrane protein, and TbpB, a co-receptor attached to the cell surface; both proteins are potentially important vaccine and therapeutic targets. Two key questions driving Neisseria research are how human transferrin is specifically targeted, and how the bacteria liberate iron from transferrin at neutral pH. To address these questions, we solved crystal structures of the TbpA–transferrin complex and of the corresponding co-receptor TbpB. We characterized the TbpB–transferrin complex by small-angle X-ray scattering and the TbpA–TbpB–transferrin complex by electron microscopy. Our studies provide a rational basis for the specificity of TbpA for human transferrin, show how TbpA promotes iron release from transferrin, and elucidate how TbpB facilitates this process.

Serogroup B meningococcal (MenB) disease remains a serious public health problem for which a cross-protective vaccine effective against a wide range of MenB isolates has not been available. Novartis Vaccines has developed a vaccine for the prevention of MenB disease that contains four antigenic components: factor H binding protein (fHbp), neisserial adhesin A (NadA), Neisseria heparin binding antigen (NHBA) and outer membrane vesicles from a New Zealand epidemic strain (which provides PorA). This vaccine has been submitted for regulatory review in Europe so it is timely to review the design of the vaccine, results to date in clinical studies and the potential strain coverage provided by the vaccine. It is also critical to discuss the key issues for the long-term success of the vaccine which include strain coverage, potential persistence of protection, potential effects on carriage of MenB strains, potential for escape mutants and cost effectiveness.

Background. Herd protection by meningococcal vaccines is conferred by population-level reduction of meningococcal nasopharyngeal colonization. Given the inverse epidemiological association between colonization by commensal Neisseria lactamica and meningococcal disease, we investigated whether controlled infection of human volunteers with N. lactamica prevents colonization by Neisseria meningitidis. Methods. In a block-randomized human challenge study, 310 university students were inoculated with 10⁴ colony-forming units of N. lactamica or were sham-inoculated, and carriage was monitored for 26 weeks, after which all participants were reinoculated with N. lactamica and resampled 2 weeks later. Results. At baseline, natural N. meningitidis carriage in the control group was 22.4% (36/161), which increased to 33.6% (48/143) by week 26. Two weeks after inoculation of N. lactamica, 33.6% (48/143) of the challenge group became colonized with N. lactamica. In this group, meningococcal carriage reduced from 24.2% (36/149) at inoculation to 14.7% (21/143) 2 weeks after inoculation (−9.5%; P = .006). The inhibition of meningococcal carriage was only observed in carriers of N. lactamica, was due both to displacement of existing meningococci and to inhibition of new acquisition, and persisted over at least 16 weeks. Crossover inoculation of controls with N. lactamica replicated the result. Genome sequencing showed that inhibition affected multiple meningococcal sequence types. Conclusions. The inhibition of meningococcal carriage by N. lactamica is even more potent than after glycoconjugate meningococcal vaccination. Neisseria lactamica or its components could be a novel bacterial medicine to suppress meningococcal outbreaks. This observation explains the epidemiological observation of natural immunity conferred by carriage of N. lactamica. Clinical Trials Registration. NCT02249598.

The genus Bordetella consists of nine species that include important respiratory pathogens such as the ‘classical’ species B. bronchiseptica, B. pertussis and B. parapertussis and six more distantly related and less extensively studied species. Here we analyze sequence diversity and gene content of 128 genome sequences from all nine species with focus on the evolution of virulence-associated factors. Both genome-wide sequence-based and gene content-based phylogenetic trees divide the genus into three species clades. The phylogenies are congruent between species suggesting genus-wide co-evolution of sequence diversity and gene content, but less correlated within species, mainly because of strain-specific presence of many different prophages. We compared the genomes with focus on virulence-associated genes and identified multiple clade-specific, species-specific and strain-specific events of gene acquisition and gene loss, including genes encoding O-antigens, protein secretion systems and bacterial toxins. Gene loss was more frequent than gene gain throughout the evolution, and loss of hundreds of genes was associated with the origin of several species, including the recently evolved human-restricted B. pertussis and B. holmesii, B. parapertussis and the avian pathogen B. avium. Acquisition and loss of multiple genes drive the evolution and speciation in the genus Bordetella, including large scale gene loss associated with the origin of several species. Recent loss and functional inactivation of genes, including those encoding pertussis vaccine components and bacterial toxins, in individual strains emphasize ongoing evolution.

To better characterize the vaccine potential of Neisseria meningitidis transferrin binding proteins (Tbps), we have overexpressed TbpA and TbpB from Neisseria meningitidis isolate K454 in Escherichia coli . The ability to bind human transferrin was retained by both recombinant proteins, enabling purification by affinity chromotography. The recombinant Tbps were evaluated individually and in combination in a mouse intraperitoneal-infection model to determine their ability to protect against meningococcal infection and to induce cross-reactive and bactericidal antibodies. For the first time, TbpA was found to afford protection against meningococcal challenge when administered as the sole immunogen. In contrast to the protection conferred by TbpB, this protection extended to a serogroup C isolate and strain B16B6, a serogroup B isolate with a lower-molecular-weight TbpB than that from strain K454. However, serum from a TbpB-immunized rabbit was found to be significantly more bactericidal than that from a TbpA-immunized animal. Our evidence demonstrates that TbpA used as a vaccine antigen may provide protection against a wider range of meningococcal strains than does TbpB alone. This protection appears not to be due to complement-mediated lysis and indicates that serum bactericidal activity may not always be the most appropriate predictor of efficacy for protein-based meningococcal vaccines.