Development of vaccines against meningococcal disease

ArticleinThe Lancet 359(9316):1499-508 · May 2002with1 Reads
DOI: 10.1016/S0140-6736(02)08416-7 · Source: PubMed
Abstract
Neisseria meningitidis is a major cause of bacterial meningitis and sepsis. Polysaccharide-protein conjugate vaccines for prevention of group C disease have been licensed in Europe. Such vaccines for prevention of disease caused by groups A (which is associated with the greatest disease burden worldwide), Y, and W135 are being developed. However, conventional approaches to develop a vaccine for group B strains, which are responsible for most cases in Europe and the USA, have been largely unsuccessful. Capsular polysaccharide-based vaccines can elicit autoantibodies to host polysialic acid, whereas the ability of most non-capsular antigens to elicit broad-based immunity is limited by their antigenic diversity. Many new membrane proteins have been discovered during analyses of genomic sequencing data. These antigens are highly conserved and, in mice, elicit serum bactericidal antibodies, which are the serological hallmark of protective immunity in man. Therefore, there are many promising new vaccine candidates, and improved prospects for development of a broadly protective vaccine for group B disease, and for control of all meningococcal disease.
    • "Further, the low levels of capsule expression of some clonal complexes associated with serogroup Y during carriage [48] may render their elimination impossible with current approaches. Phase III – the elimination of serogroup B meningococci, is by far the most challenging goal both from the perspective of the tools currently available and the biology of the meningococcus [5,43]. The first, and by far the most serious problem, is that the development of a conjugate vaccine against the serogroup B polysaccharide is precluded by a combination of the poor immunogenicity of this polysaccharide and safety concerns, as it is identical to a host antigen NCAM, which decorates foetal neural tissues [49]. "
    [Show abstract] [Hide abstract] ABSTRACT: The eradication of infectious agents is an attractive means of disease control that, to date, has been achieved for only one human pathogen, the smallpox virus. The introduction of vaccines against Neisseria meningitidis into immunisation schedules, and particularly the conjugate polysaccharide vaccines which can interrupt transmission, raises the question of whether disease caused by this obligate human bacterium can be controlled, eliminated, or even eradicated. The limited number of meningococcal serogroups, lack of an animal reservoir, and importance of meningococcal disease are considerations in favour of eradication; however, the commensal nature of most infections, the high diversity of meningococcal populations, and the lack of comprehensive vaccines are all factors that suggest that this is not feasible. Indeed, any such attempt might be harmful by perturbing the human microbiome and its interaction with the immune system. On balance, the control and possible elimination of disease caused by particular disease-associated meningococcal genotypes is a more achievable and worthwhile goal.
    Full-text · Article · Jan 2016 · PLoS ONE
    • "Neisseria meningitidis (Nm) is a major cause of meningitis and septicaemia worldwide. Effective capsular polysaccharide vaccines have been developed against serogroups A, C, W135 and Y (Jodar et al., 2002; Harrison, 2006). The development of a vaccine against serogroup B has been difficult as the capsular polysaccharide, which is structurally similar to human neural glycans (Finne et al., 1983 ), is poorly immunogenic , therefore alternative antigens to the capsule have been investigated. "
    [Show abstract] [Hide abstract] ABSTRACT: Outer membrane vesicles (OMV) are released by many bacteria, and contain immunogenic antigens in addition to harmful inflammatory factors, like lipopolysaccharides. Chemically detoxified OMV have been used in vaccines against Neisseria meningitidis (Nm), however little is known about their interaction with antigen presenting cells. In this study, we investigated the interaction of Nm OMV with human dendritic cells (DC) to gain further understanding of their biological activity. We engineered a novel serogroup B Nm that is unencapsulated (siaD), expresses pentacylated lipid A (lpxL1), hence conferring reduced toxicity, and expresses an lgtB oligosaccharide structure designed to target OMV to DC via DC-SIGN. We show that the lgtB moiety is critical for internalization of NOMV by DC. Furthermore, the lgtB moiety significantly enhances DC maturation, IL-10 and IL-23 production in the presence of a pentacylated lipid A. Whilst different DC phenotypes were observed for each NOMV, this had little effect on Th1 and Th2 cell differentiation, however lgtB significantly increased Th17 cell expansion in the presence of pentacylated lipid A. We believe that lgtB/lpxL1 NOMV should be considered further as a vaccine vector, particularly considering the importance of lgtB in antigen uptake and further human studies on antigen specific responses should be considered.
    Full-text · Article · Oct 2013
    • "Its only known host is the human, and it may be carried asymptomatically by approximately 10% of the population [1]. There is currently no vaccine that is effective in all age groups and against all serogroups, despite extensive research efforts [2] [3]. Candidate antigens for inclusion in a vaccine must be expressed in the majority of strains, be antigenically conserved, and elicit a protective immune response. "
    [Show abstract] [Hide abstract] ABSTRACT: NhhA (Neisseria hia homologue) is an outer membrane protein from Neisseria meningitidis, the causative agent of meningococcal disease. The protein is surface exposed and its expression in a wide range of meningococcal strains suggests it is a promising vaccine candidate. In addition, immunization of mice with outer membrane vesicles of strains that overexpress NhhA in conjunction with one of TbpA, Omp85 or NspA results in synergistic bactericidal responses. We previously showed that the NhhA sequence is highly conserved between strains, with the majority of the differences localized to four distinct variable regions located in the amino-terminal region of the mature protein. In this study, N. meningitidis strains were constructed that over-express wild-type NhhA. Strains expressing truncated versions of NhhA, with deletions from the amino-terminal region that removed the most variable regions, were also made. These expression strains were also modified so that immunodominant, phase- and antigenically-variable outer membrane proteins were not expressed, truncated lipooligosaccharide (LOS) expression was genetically fixed (no phase variability), and capsular polysaccharide expression abolished. Outer membrane vesicles derived from these strains were used to immunize mice. As previously observed, a synergistic effect involving another antigen, TbpA, was required to demonstrate bactericidal activity. The highest bactericidal response against a heterologous strain was obtained with a truncated variant of NhhA. These results indicate that removal of (a) variable region(s) does not reduce bactericidal responses against NhhA, and that bactericidal targets exist in regions other than the variable N-teminus. This provides the basis for future examination of responses against truncated NhhA in protecting against heterologous NhhA strains, and further evaluation of truncated NhhA as a candidate for inclusion in a vaccine against all serogroups of N. meningitidis.
    Full-text · Article · Sep 2013
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