Next-generation outer membrane vesicle vaccines against Neisseria meningitidis based on nontoxic LPS mutants

Outer membrane vesicles (OMVs) have been used extensively as experimental vaccines against Neisseria meningitidis. Classical meningococcal OMV vaccines contain wildtype lipopolysaccharide (LPS) with a hexa-acylated lipid A moiety, which is a very potent activator of the TLR4 receptor. While this may make the LPS an effective "internal" adjuvant, it also contributes to vaccine reactogenicity. Reduction of endotoxic activity has therefore been essential for the application of meningococcal OMV vaccines in humans. Classical OMV vaccines have a reduced LPS content as a result of detergent extraction, mostly with deoxycholate. An alternative method is the use of meningococcal strains with genetically detoxified LPS, in particular where mutation in the lpxL1 gene has resulted in penta-acylated lipid A with strongly attenuated endotoxic activity. This allows the use of native OMVs without any need for LPS removal by detergent extraction, making it a much easier to produce and more versatile vaccine platform. Several groups have now started the development of native OMV vaccines based on non-toxic LPS mutants, and this Commentary provides an overview of the various approaches and results thus far.