Studying the immune reaction at mucosal surfaces after vaccination with a meningitis B vaccine
Professor Robert Heyderman, University of Bristol
Professor Heyderman and his team are studying people's natural immunity to meningitis-causing bacteria. They hope that, by understanding this, they will then be able to mimic the body's natural response and make a successful vaccine against Meningitis B.
The success of existing meningitis vaccines, such as the one that protects against Meningitis C, is, in part, due to their ability to produce ‘herd immunity', where even people who have not received the vaccine are protected because carriage rates of the bacteria are reduced across the whole population.
Professor Heyderman's team believe that a successful Meningitis B vaccine not only needs to stop the harmful bacteria invading the body, but also needs to reduce the carriage rates of the bacteria that normally live harmlessly in our noses and throats.
How natural immunity happens is poorly understood, but previous research shows that naturally acquired immunity (temporary contact between the immune system and the meningococcus in the back of the throat without causing disease) may impact on this process. The researchers believe that in order to develop a MenB vaccine that is able to cause mucosal immunity and prevent MenB carriage, it is important to understand the interaction between natural immunity and vaccination.
Professor Heyderman and his team will be looking specifically at mucosal immunity as it is believed that this naturally acquired immunity can reduce carriage rates by preventing the bacteria from living in people's noses and throats. Through this research they hope to develop a vaccine that not only protects individuals from Meningitis B - but whole communities.
The researchers will administer MenB vaccine to adults and children in order to investigate the immune response in the presence of naturally occurring immunity and the influence this pre-existing immunity might have on the response to a vaccine. The findings will:
i. provide important insights into MenB immunity
ii. inform the design of novel vaccine strategies
iii. allow the testing of new vaccines as they become available
The research will provide important clues as to what happens when people become naturally immune to meningitis B, which will help us to produce a vaccine that can protect from invasive disease as well as harmless colonisation, thus leading to ‘herd immunity’.
Data has shown that following natural exposure to Meningitis B, a set of immune cells known as "regulatory T cells" develops and these are mainly found in the tonsils. These regulatory T cells can dampen down the immune response of a person. To do this they require close contact with many different types of immune cells. Professor Heyderman and his team are trying to find out whether the “dampening down” of immune cells after natural exposure, is bigger or less after vaccination. A number of new tests have been developed to allow this. Recruitment for the human trial has started and, so far, the team have analysed data from six people who have had the vaccine and two that have not. Early results suggest that having the vaccine results in a good immune response throughout the body.
Outcomes will be shown here once the project is complete.
Mechanisms of mucosal immunity to systemic immunisation with a meningococcal serogroup B outer membrane vesicle vaccine at University of Bristol
Professor Robert Heyderman, University of Bristol
Professor Heyderman and his team are studying people's natural immunity to meningitis-causing bacteria. They hope that, by understanding this, they will then be able to mimic the body's natural response and make a successful vaccine against Meningitis B.
Prevention of Neisseria meningitidis serogroup B (MenB) through vaccination is a key public health priority. Evidence from several national ‘meningitis’ vaccine programmes suggests that their success in eliminating MenC, Haemophilus influenzae type B and Streptococcus pneumoniae is, in part, due to their ability to generate herd immunity. The team have shown that naturally acquired mucosal T cell immunity to meningococcal protein antigens develops with age, is dominated by proinflammatory CD4 Th1 cells, and is modulated by the presence of CD25+ regulatory T cells (Treg). The MenB systemic immunisation studies show that systemic vaccination of young adults with MenB outer membrane vesicles does not sufficiently boost MenB specific mucosal immunity.
The researchers postulate that the mucosal response to MenB protein vaccines may be influenced by pre-existing natural immunity and propose to:
1. Determine the nature of the mucosal CD25+ Treg population that regulates MenB immunity
2. Establish whether naturally induced mucosal CD25+ Treg activity in adults and older children modulates the mucosal immune response to systemic MenB Outer Membrane Vesicle vaccination
3. Determine whether in younger children, in the absence of significant naturally acquired T cell immunity, mucosal immune responses to Neisseria meningitidis protein antigens can be induced by systemic MenB Outer Membrane Vesicle vaccination
This project will provide a unique, comprehensive picture of how systemic immunisation with an outer membrane vesicle vaccine influences, and is influenced by, naturally acquired immunity. The findings will inform the development of MenB vaccine strategies that induce herd immunity, and protect infants, older children and young adults.
Data has show that following natural exposure to MenB, a T cell population develops that dampens the protective/inflammatory immune response. These “regulatory T cells” require intimate contact with other cells to perform their role, suppress multiple cellular functions and are predominantly located in the tonsils. The team are now undertaking studies to assess whether vaccination affects these different cell types, thereby potentially enhancing or suppressing the naturally-acquired protective immune response to MenB. The following new tools have now been developed and are being implemented in the vaccine studies (below):
1) T cell assays using purified proteins/ peptides as well as OMV: the team have modified thier assays to measure responses to purified proteins (PorB and NSPA) and the proteins contained within the new MenB Novartis Vaccine. This assay will allow them to study the vaccine-induced mucosal response to these proteins.
2) T cell regulation assays: these have been further optimised for the vaccine study.
3) Measurement of antibodies in saliva: the team have developed a Multiplex system to measure salivary antibodies to vaccine antigens.
4) B cell ELISPOT Assays: the team have developed an ELISPOT assay to measure the antibodies being produced in the blood and tonsil to vaccine antigens.
Recruitment for the vaccine study has commenced and, at present, the team have complete analysed cellular data from six vaccinees and two control patients. Although both patient recruitment and laboratory experiments are ongoing, preliminary data suggests that vaccination boosts systemic T and B cell responses to the vaccine strain. Saliva and serum samples from these individuals have also been stored to allow a comparison between our cellular assays and other, established correlates of protection.
Outcomes will be shown here once the project is complete.
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