Comment

Outer-membrane-vesicle vaccines: old but not forgotten

Neisseria meningitidis, a gram-negative diplococcus also known as the meningococcus, causes invasive meningococcal disease (IMD) and is among the most important causes of bacterial meningitis worldwide. Rapid identification of N. meningitidis is required to facilitate appropriate antimicrobial therapy in a timely manner. The bacteria are transmitted by aerosolized or droplet secretions, transiently colonizing the nasopharyngeal mucosa. A minority of strains possess the necessary virulence factors for mucosal invasion and systemic persistence. Once in the circulation, two important traits distinguish pathogenic meningococci from other organisms – namely, their ability to proliferate rapidly in the bloodstream and their proclivity for invading the meninges. Culture and classical identification techniques remain important in the identification of N. meningitidis, while molecular diagnostics including the use of multiplex diagnostic panels for CSF evaluation are increasingly utilized. Treatment is generally initiated with a third-generation cephalosporin, with penicillin an option upon confirmation of susceptibility. Management of shock is an important consideration in treating systemic disease caused by N. meningitidis. Of increasing importance is the prevention of IMD through vaccination. In this regard, the development of progressively more effective meningococcal vaccines mirrors the more general advances in the field of vaccinology. Vaccines against five of the six major disease-causing serogroups are currently available, raising optimism that meningococcal disease can be controlled worldwide.

MenBvac® is an outer membrane vesicle (OMV)-based meningococcal vaccine. From 2006 to 2012, it was used to control a clonal B outbreak in Normandy (France). We aimed to analyse the durability of the response against the epidemic strain and coverage beyond the vaccine strain. These data should help to optimize the use of OMV-containing vaccines, such as the new 4CMenB/Bexsero® recombinant vaccine.

Serum bactericidal activity (SBA) was measured in two cohorts of children who received their first dose of MenBvac® at 1–5 years of age and accepted to provide a blood sample either one or four years after a 2 + 1 + 1 schedule. All sera were tested against the outbreak strain. Sera from responder subjects were also tested against 12 additional B or C strains which were chosen to entirely, partially, or not at all match the two variable regions (VR1 and VR2) of the PorA vaccine strain.

Only 47.9% and 31.3% of subjects showed an SBA titre consistent with protection one and four years, respectively, after the last boost. Protective SBA titres were observed in all sera against B or C strains that entirely matched P1.7,16, and was high (75–100%) for all but one strain that partially matched VR1 or VR2. Extrapolating our data to the OMV component of 4CMenB/Bexsero® suggests that 14.5% of the current B strains would be covered based on PorA matching to the OMV component of 4CMenB/Bexsero® (regardless of the coverage of the three other vaccine components).

Our data confirm that OMV-based vaccines elicit short-lasting SBA titres and may require repeated booster injections. However, strain coverage may be greater than expected.

In many ways, Neisseria meningitidis represents the prototypical pathogen for which molecular techniques have transformed in parallel the scope of basic, translational and clinical laboratory work. Fundamental biology, pathogenesis, epidemiology, diagnostics, treatment and vaccinology – meningococcal research in each of these areas has intensified in recent years with the availability of novel molecular technologies. Overall, this multidisciplined approach has revolutionized the management of meningococcal infection, making the prospect of worldwide disease control a very real possibility. At the same time, the wealth of emergent information on N. meningitidis makes it a challenging topic for clinicians and medical microbiologists to appreciate in its entirety. The goal of the current review, therefore, is to synthesize the broad molecular knowledge on this organism and present it in a manner that ties together the various sub-disciplines. It is our hope that this work can offer a detailed overview for clinical laboratorians and infectious disease physicians (the primary intended audience), integrating broad perspectives on this important pathogen.