There is a recognised need to develop vaccines against the meningitis-causing bacteria Neisseria meningitidis (meningococcus). Professor Tang and his team have identified an alternative approach to vaccine design that could lead to new group B meningococcal (Meningitis B) vaccines.

Meningitis B bacteria produce a protein called factor H binding protein (fHbp). This protein helps the bacteria to survive in the human body by binding to factor H. Factor H is produced by our bodies to activate the immune system to kill bacteria. When fHbp binds to factor H, it stops factor H from working. As a result, the bacteria evade attack and are free to multiply and cause infection.

Despite the harmful nature of fHbp, scientists have discovered that this protein, when used in the right way, can be an effective part of Meningitis B vaccines. When the body is exposed to fHbp, the immune system detects the protein and produces antibodies to attack the Meningitis B bacteria. By putting fHbp into a vaccine, our immune system learns to recognise and fight Meningitis B bacteria in a safe environment. The immune system then remembers how to fight, so when exposed to Meningitis B bacteria in real life, it can quickly respond and produce antibodies to kill the bacteria. This is why fHbp is an important part of the Meningitis B vaccines currently under development.

However, using fHbp in a vaccine is not straightforward as the different strains of Meningitis B bacteria can produce the protein in three different forms. The vaccine will only work against bacteria that produce the same form of fHbp as found in the vaccine. For example, if the vaccine uses fHbp type 1, only Meningitis B bacteria that produce fHbp 1 will be targeted. The bacteria that produce fHbp types 2 or 3 will remain unharmed and free to cause infection.

Professor Tang’s group have identified an alternative fHbp protein in the sister organism, Neisseria gonorrhoeae, called gonococcal homologue fHbp (ghfp). The team are investigating whether ghfp could be used to make new vaccines to protect against a wide range of Meningitis B bacteria.

The use of ghfp in vaccine design could lead to more effective vaccines to protect against Meningitis B.

Professor Tang’s research group have made excellent progress in the first six months and have laid the foundation for analysis of ghfp as a potential vaccine candidate. Initially, the group have shown that, unlike fHbp, ghfp does not bind to the human factor H. This is good because it means that factor H is still able to kill the Meningitis B bacteria. The group have looked at the structure of ghfp and identified several parts of the protein that might be responsible for the inability to bind to factor H. These studies will show why ghfp and fHbp behave differently.

The team have also genetically modified a strain of Meningitis B bacteria to remove the single fHbp protein and have replaced it with eight different fHbp proteins. These eight fHbp proteins are the ones most commonly found in Meningitis B bacteria. They are currently testing whether the antibodies produced in response to exposure to ghfp recognise and react to the eight different types of fHbp. If they do, the antibodies may potentially be able to kill a wide range of Meningitis B bacteria. Potentially, ghfp could be a simpler, but more effective protein to use in Meningitis B vaccines.

Updated 04.01.13

Outcomes will be shown here once the project is complete.

There is a recognised need to develop universal vaccines against Neisseria meningitidis. Professor Tang and his team have identified an alternative approach to vaccine design that could lead to new meningococcal vaccines. 

Factor H binding protein (fHbp) is an important component of vaccines currently under development. Neisseria meningitidis (Nm) isolates express one of three variants of fHbp (v1, 2 or 3), defined by their predicted amino acid sequence. However, immunisation with fHbp is largely ‘variant specific’; v1 fHbp does not elicit bactericidal antibodies against Nm strains expressing either of the other variants, or vice versa. There is also evidence that high affinity binding of fH to fHbp may impair its efficacy and safety, and there are insufficient data to enable the construction of non-functional v2 and v3 fHbps.

Professor Tang and his team have identified a fHbp homologue in N. gonorrhoeae, named gonococcal homologue fHbp (ghfp); ghfp is most closely related to v3, then v2 and finally v1 fHbp (with approximately 86%, 83% and 62% amino acid identity, respectively). The overall goal of the project is to exploit ghfp as vaccine candidate and to use it to inform the design of new fHbp related vaccines. These will be evaluated in a novel, relevant model that can be used to test vaccines designed for use in humans.

Professor Tang’s research group have made excellent progress in the first six months of the project.

Determining the immunogenicity of gonococcal homologue fHbp (ghfp)

Data shows that ghfp does not bind to the human complement regulator factor H (fH). This has been shown by far western and Surface Plasmon Resonance. To determine the immunogenicity of ghfp, the team have constructed an isogenic strain of Neisseria meningitidis (Nm), MC58Δfhbp, that lacks the endogenous copy of factor H binding protein (fHbp). They have successfully introduced eight different fHbp alleles from the most common meningococcal isolates in 2007-2008 under an identical IPTG promoter to evaluate the influence of sequence variation or cross reactivity of anti-ghfp sera independent of strain background and level of protein expression. All eight of these complemented strains express functional fHbp which is recognised by polyclonal mouse sera raised against fHbp variants 1, 2 and 3. Professor Tang and team are currently in the progress of testing whether the sera raised against ghfp recognises fHbp expressed in the complemented strains.

Determining the mechanisms underlying the impaired fH binding to ghfp

Under native physiological conditions ghfp does not bind to fH even though it has a high amino acid sequence identity to fHbp (61% to v1, 83% to v2 and 86% to v3).

Looking at sequence alignments between ghfp and various fHbps, combined with recently published data about mutagenesis of V1, V2 and V3 proteins, the team have identified several amino acids that might be involved in the lack of fH binding to ghfp. They have introduced several point mutations into ghfp to change these amino acids into the corresponding residues in fHbp
V1, V2 or V3 to see if these substitutions are sufficient to confer binding to fH. Analysis of these mutants is undergoing.

Determining the immunogenicity of ghfp and modified v2/3 proteins in a biologically relevant model

After identifying key amino acids changes in ghfp, the group will test these proteins together with modified V2/V3 proteins in a biologically relevant model.

Updated 04.01.13