Project overview
The purpose of this study is to determine whether deliberate infection of human volunteers with a mixture of four different strains of a genetically modified, harmless bacterium can produce antibodies that kill the bacteria responsible for causing meningococcal disease. Simultaneously, the study will show whether becoming colonised with the mixture of harmless bacteria can prevent volunteers from becoming colonised with the same mixture a second time. If the mixture of bacteria can produce antibodies that kill the meningococcal disease-causing bacteria, it is likely useful for preventing this disease. It might be used as a future 'bacterial medicine' in populations susceptible to meningococcal disease. If becoming colonised with this mixture of bacteria prevents the same bacteria from colonising a second time, then we will have shown this model of controlled human infection (CHI) is useful for identifying what elements of the immune system are responsible for this phenomenon. This knowledge is important to guide the development of new vaccines that prevent people from carrying disease-causing organisms. Without disease-causing organisms, it is impossible for disease to occur. Moreover, if disease-causing organisms are not passed between people, then everyone's risk of developing disease is also eliminated. Referred to as 'herd protection', this powerful effect could lead to vaccines that not only protect the vaccine recipient from disease, but also protect other people who have not themselves received the vaccine. The protective effect against disease using this new type of vaccine would be greater, with significant benefits to public health. In the proposed research, we will create four genetically modified strains of the harmless bacterium Neisseria lactamica (Nlac), each of which will make two foreign proteins normally made by its close cousin, the meningococcal disease-causing bacterium, Neisseria meningitidis (Nmen). Both proteins are components of existing vaccines designed to prevent meningococcal disease, which means they are known to be targeted by antibodies capable of killing Nmen. We have previously used CHI to infect volunteers with one strain of genetically modified Nlac (GM-Nlac), which makes only one of these proteins, called Neisseria Adhesin A (NadA). We showed that in the blood of half of the volunteers colonised by this strain, the ability to kill Nmen that make NadA developed over time. By adding the Nmen protein, Factor H-binding protein (FHbp) into our GM-Nlac strains, which is present on almost all strains of circulating Nmen, we predict that two things will happen: (i) more people will develop the ability to kill Nmen in their blood, (ii) the blood of these volunteers will be able to kill a wider variety of Nmen strains. Note that we need four strains because there are differences between variants of FHbp, and we want to give each volunteer's immune system examples of this variety, so they can become more broadly immunised. Importantly, whilst the current protein-based vaccines against meningococcal disease are good at protecting against illness, they have shown no ability to prevent vaccinated people from carrying the disease-causing organism. On the other hand, we have shown in previous uses of CHI that people carrying Nlac in their nose and throat are far less likely to also carry Nmen. In addition, people we know have previously carried Nmen at some point in their lives (i.e. those who have memory cells that make antibodies against the proteins of Nmen), are less hospitable to Nlac when we try to deliberately infect them. This latter point suggests there could be a role for the natural processes of infection, and our body's responses to it, in preventing bacterial colonisation and excluding these sorts of organisms from carriage. Therefore, this study could lead to the development of an entirely new way of protecting against infectious diseases, one that harnesses natural mechanisms.
