Studying the potential of meningitis B secreted proteins for use in a vaccine
Dr Karl Wooldridge, University of Nottingham
The objective of this study was to discover more about a tiny protein secreted by the Meningitis B bug, which collects on its surface and can be accessed by antibodies.
Invasive meningococcal disease (meningitis and septicaemia) continues to cause severe illness with sometimes life-threatening consequences, mainly in children and young adults. Current vaccine development strategies focus on identifying individual bacterial molecules as potential vaccine components. The team around Dr Wooldridge adopted a new approach based on identifying proteins secreted by the bacteria.
They had already proven through previous studies that these proteins not only stimulate immunity against the infecting strain, but also against other strains.
Their experience of vaccine candidates using single proteins, called ‘antigens’, shows that no individual antigen is likely to protect against all strains of Meningitis B, therefore, they expect future vaccines to contain several antigens which, between them, will generate cross-protective immunity against all strains.
The main objective of this research was to assess the potential of secreted proteins as components of future multi-component vaccines against meningitis B.
This study has lead to the identification of secreted proteins, which could be part of a future vaccine against meningitis B.
This project is now complete - see the outcomes tab for more information.
Vaccine development is the optimum strategy to combat meningococcal septicaemia and meningitis. The team from the University of Nottingham, led by Dr Karl Wooldridge, had previously shown that meningococci can actively secrete several proteins during infection, but why the organism did this was unclear. The purpose of the project funded by Meningitis UK was principally to assess the potential of these meningococcal secreted proteins (MSPs) as candidates for future vaccines.
Initially, the team used genetic engineering techniques to prepare 8 different MSPs. These proteins were used to immunise mice and the resulting antibodies were tested in laboratory assays for their ability to kill meningococci. From their collection of MSPs, Dr Wooldridge’s team demonstrated that only the IgA1 protease and the FhaC protein could induce antibodies capable of killing the bacteria. In addition, the team also discovered that another of the MSPs, the AspA protein, allowed the meningococcus to avoid being ingested and killed by human white cells. Thus, the findings from this study have not only increased our understanding of the role of proteins secreted by the meningococcus during infection, but also identified two new potential vaccine candidates worthy of further study.
Vaccine potential of meningococcal secreted proteins
Dr Karl Wooldridge, University of Nottingham
The objective of this study was to discover more about a tiny protein secreted by the Meningitis B bug, which collects on its surface and can be accessed by antibodies.
Development of vaccines against serogroup B Neisseria meningitidis remains a priority, particularly in the industrialised world, including the UK. The capsular polysaccharide of serogroup B meningococci is poorly immunogenic in humans; hence, vaccine development has focused on surface-exposed subcapsular antigens. Previous attempts to develop outer membrane vesicle-based vaccines have met with limited success, thus, current approaches aim to produce preparations consisting of individually well-characterised protective antigens.
The team had recently carried out extensive studies on meningococcal secreted proteins (MSPs) and demonstrated their central roles in pathogenesis and host responses. Several key secreted proteins were also identified, some of which are associated with and exposed on the bacterial surface and, thus, are potential targets for bactericidal antibodies. MSPs may contain putative vaccine candidates capable of generating protective immunity. Preliminary proof-of-concept experiments, using a murine challenge model, have demonstrated that MSP preparations are capable of inducing cross-protective immunity against meningococcal infections. This protection was mediated, in part, by bactericidal antibodies that were cross-reactive against heterologous strains. The data confirmed that MSPs are promising vaccine candidates worthy of further investigation.
The core objective of this project was to assess the vaccine potential of a group of known and partially characterised antigenic MSPs for inclusion in future multi-component vaccine preparations.
This project is now complete - see the outcomes tab for more information.
Antisera were raised against eight each target proteins and verified for specificity. Two of these proteins, IgA protease and FhaC, were shown to elicit protective antibodies as measured by serum bactericidal activity. Thus, these proteins may be considered to be viable vaccine candidates worthy of further study. Additionally, we demonstrated that one of the purified proteins, AspA, was able to significantly inhibit phagocytosis of FITC dextran or of intact meningococci by human peripheral blood mononuclear cells. This is likely to be of importance to meningococcal infection and may have important implications for both vaccine development and our understanding of the mechanisms of pathogenesis of the meningococcus.
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