Summary Objectives Outer membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane ...proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines. Methods The OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 μg or 50 μg of MenPF-1 were delivered intra-muscularly to 52 healthy adults. Results MenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetA on PorA off compared to 51% in the strain 44/76 FetA off PorA off , demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies. Conclusion This study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.
The bacterium Neisseria meningitidis of serogroups A and W‐135 has in the recent decade caused most of the cases of meningococcal meningitis in the African meningitis belt, and there is currently no ...efficient and affordable vaccine available demonstrated to protect against both these serogroups. Previously, deoxycholate‐extracted outer membrane vesicle (OMV) vaccines against serogroup B meningococci have been shown to be safe and induce protection in humans in clonal outbreaks. The serogroup A and W‐135 strains isolated from meningitis belt epidemics demonstrate strikingly limited variation in major surface‐exposed protein structures. We have here investigated whether the OMV vaccine strategy also can be applied to prevent both serogroups A and W‐135 meningococcal disease. A novel vaccine combining OMV extracted from recent African serogroup A and W‐135 strains and adsorbed to aluminium hydroxide was developed and its antigenic characteristics and immunogenicity were studied in mice. The specificity of the antibody responses was analysed by immunoblotting and serum bactericidal activity (SBA) assays. Moreover, the bivalent A+W‐135 vaccine was compared with monovalent A and W‐135 OMV vaccines. The bivalent OMV vaccine was able to induce similar SBA titres as the monovalent A or W‐135 OMV towards both serogroups. High SBA titres were also observed against a meningococcal serogroup C strain. These results show that subcapsular antigens may be of importance when developing broadly protective and affordable vaccines for the meningitis belt.
Meningococcal meningitis is a significant global health challenge, especially for sub‐Saharan area: the African meningitis belt. Neisseria meningitidis of serogroup A (MenA) is responsible for the ...large number of epidemics that have been recorded in these countries. To determine the level of antibodies against meningococcal A polysaccharide (APS) that correlates with protection against MenA disease in the African meningitis belt, it may be important to consider antibody avidity along with quantity. In this study, two ELISA methods using the chaotropic agent ammonium thiocyanate were compared and employed to measure avidity indexes (AI) of IgG antibodies against APS in controls and in acute and convalescent sera from Ethiopian meningococcal patients. High statistical correlations between the AIs determined by the two methods were observed. The geometric mean AI (GMAI) increased with time from acute to convalescent sera indicating affinity maturation. GMAI was significantly higher in convalescent sera from the MenA patients and in sera from the controls than in acute sera from patients with meningococcal disease. A significant correlation between serum bactericidal activity titres (SBA) and concentration of IgG antibodies against APS was observed; however, our results did not indicate that determination of antibody avidities by the thiocyanate elution method gave a better correlation with SBA than anti‐APS IgG concentrations determined by the standard ELISA method.
Highlights • Vaccines for preventing serogroup AWX meningococcal disease needed in Africa. • An outer membrane vesicle (OMV) vaccine from serogroup AWX meningocci developed. • AWX-OMV vaccine shown ...to induce bactericidal and opsonic antibodies in mice. • Combination of AW-OMV with X polysaccharide also induced bactericidal antibodies. • Vaccine based on AWX-OMV or AW-OMV + X polysaccharide may prevent majority of cases.
Highlights • A meningococcal bivalent A + W dOMV vaccine was made from representative bacterial strains from the African meningitis belt. • The functional immune responses induced in mice by the A + ...W dOMV vaccine or licensed vaccines were compared. • The A + W dOMV vaccine induced higher SBA and OPA titers against serogroups A and W than the ACYW conjugate vaccine Menveo®. • The A + W dOMV vaccine induced similar serogroup A SBA and OPA titers as the monovalent A conjugate vaccine MenAfriVac®. • The A + W dOMV vaccine could be a future alternative or supplement to existing vaccines in the African meningitis belt.
Highlights • Serogroup X N. meningitidis (MenX) is emerging as a cause of meningitis in Africa. • Outbreaks were seen in Niger, Uganda, Kenya, Togo and Burkina Faso in 2006–2010. • Currently, no ...vaccine against MenX is available for the African Meningitis Belt. • The MenX polysaccharide capsule is the most likely target for vaccine development. • An affordable vaccine covering at least serogroups A, W, and X is needed.
At the two World Health Organization Collaborating Centers for Reference and Research on Meningococci in Marseilles, France, and Oslo, Norway, the multilocus sequence typing technique was used for ...the characterization of a total of 357 strains of meningococci isolated from meningitis cases in 13 African countries of the meningitis belt between 1988 and 2003. Among these strains, 278 of 357 (77.9%) belonged to the sequence type 5 (ST-5) complex; 23.2% were ST-5 and 53.5% were ST-7. ST-5 was probably introduced in Africa in 1987 and was responsible for most of the meningitis cases between 1988 and 2001. ST-7 emerged in the mid-1990s and has totally replaced ST-5 since 2002. These two STs characterized serogroup A strains and have been responsible for hundreds of thousands of cases. Fifty-two strains (14.3%) belonged to the ST-11 complex. The ST-11 complex was characterized by serogroup W135, which has been responsible for an increasing number of sporadic cases since 2000 and the first W135 epidemic ever seen in Africa (in Burkina Faso in 2002). Identification of W135 ST-11 strains in many countries is a great concern for the region. Apart from these two major clonal complexes, a few other clones, such as ST-2881, ST-181, and ST-751, were sporadically detected. Careful surveys for these clones need to be conducted, but at present they play only a minor role in the overall epidemiology of meningococcal meningitis.
Abstract
Meningococcal meningitis is a significant global health challenge, especially for sub‐Saharan area: the African meningitis belt.
N
eisseria meningitidis
of serogroup A (MenA) is responsible ...for the large number of epidemics that have been recorded in these countries. To determine the level of antibodies against meningococcal A polysaccharide (
APS
) that correlates with protection against MenA disease in the
A
frican meningitis belt, it may be important to consider antibody avidity along with quantity. In this study, two
ELISA
methods using the chaotropic agent ammonium thiocyanate were compared and employed to measure avidity indexes (
AI
) of IgG antibodies against
APS
in controls and in acute and convalescent sera from Ethiopian meningococcal patients. High statistical correlations between the
AI
s determined by the two methods were observed. The geometric mean
AI
(
GMAI
) increased with time from acute to convalescent sera indicating affinity maturation.
GMAI
was significantly higher in convalescent sera from the MenA patients and in sera from the controls than in acute sera from patients with meningococcal disease. A significant correlation between serum bactericidal activity titres (
SBA
) and concentration of IgG antibodies against
APS
was observed; however, our results did not indicate that determination of antibody avidities by the thiocyanate elution method gave a better correlation with
SBA
than anti‐
APS
IgG concentrations determined by the standard
ELISA
method.
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