Dr M Christodoulides - The Adhesin Complex Protein (ACP) of Neisseria meningitidis

Neisseria meningitidis (Men) causes meningitis and septicaemia worldwide. The most important causes of disease are meningococci of groups A, B, C, W135 and Y. Fortunately, vaccines are now available for protection against A, C, W135 and Y and these are based on separating the sugar coat from these organisms and linking them to a common vaccine such as diphtheria or tetanus to form a conjugate. These vaccines have virtually eliminated disease in those countries that have introduced them, e.g. in the UK and US the reduction in group C disease has been >95%. Protection is provided by the ability of the vaccines to induce antibodies in humans that can kill the organisms. However, this sugar coat-conjugate strategy will not work for B meningococci (MenB), because the B sugar coat is poor at generating antibodies that can kill the organism and moreover it shares similarities with human proteins, so any vaccine produced using the MenB sugar coat would be problematical. What are the alternatives? For many years, the Neisseria research community has probed the membrane underneath the MenB sugar coat to try and identify those structures or proteins that can induce antibodies capable of killing MenB bacteria. Several techniques have been used, e.g. analyzing the genetic make-up of the organism (the 'reverse vaccinology approach'), analyzing the structure of the membrane (the 'proteomic', 'structural vaccinology' approach) and the human response to infection or colonization by the organism (the 'immuno-proteomic' approach). The reverse vaccinology method has now developed the first generation of defined MenB vaccines, called Bexsero/4CMenB (recently received positive opinion from the European Medicines Agency). This vaccine contains 3 proteins mixed with the membrane from a vaccine used to control disease in New Zealand and is a major step in finding a universal vaccine for MenB. But even this is not without problems: importantly, it is predicted that Bexsero will only protect against 73% of the MenB organisms present in the population. So what about the remaining 27%? Thus, there is a pressing need to identify other components of the organism that can provide broader protection against a larger number of MenB strains. Our proposed research is based on our identification of a component that may make up the difference. Using the 'proteomic' approach we identified a protein in the MenB membrane called the Adhesin Complex Protein (ACP). We show that ACP is able to induce antibodies in animals that can kill meningococci. Importantly, meningococci produce only 3 different ACP proteins in a collection of 200 different strains (unlike the proteins in Bexsero which are more variable) and antibodies to one ACP protein can kill bacteria that possess other types of ACP. This is proof of cross-protection. We also show that ACP is important for the organism to stick to human cells. Our research plans are to investigate the potential of ACP for MenB vaccine inclusion by gathering further information on the properties of this protein. We have a two-part plan to do this: In Part 1 ('the vaccine potential'), we will examine whether there are more than 3 types of ACP proteins in a larger number of MenB strains (~600), look to see if these strains produce the protein and also deduce the structure of ACP. We will also prepare new ACP-based vaccines for testing in laboratory animals to see if we can kill a larger variety of different MenB strains. In Part 2 ('the biological role'), we will deduce how ACP allows MenB to stick to human cells and identify the human molecules involved, examine whether ACP works with other MenB proteins to enable sticking and what responses by human cells are triggered by ACP sticking. In summary, our proposal is exciting, ambitious, timely and innovative; our research will build on the promising results we have already collected and provide conclusive proof that ACP should be included in new MenB vaccines.