Enhancing mucosal immunity to Streptococcus pneumoniae by nasal administration of live strains attenuated in virulence

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Streptococcus pneumoniae (also called the pneumococcus) is the commonest cause of fatal bacterial infections. The pneumococcus is the commonest cause of pneumonia and a frequent cause of chest infections that are associated with deteriorations in patients with chronic lung disease, and therefore is an important cause of illness in the UK. The present vaccines used in adults and children are very effective at preventing blood borne pneumococcus infection; however they are not effective at preventing adult lung infections and there is a strong need for new methods of preventing pneumococcal pneumonia or chest infections. The pneumococcus is frequently found at the back of the throat causing a low level infection without any associated illness. We and others have shown that colonisation of the throat with the pneumococcus stimulates the host's immune response that can prevent future infection. This suggests a potential strategy to prevent pneumococcal lung infections could be to deliberately spray the nose with live pneumococcal bacteria on an annual basis shortly before the peak period for pneumococcal infections (the winter). To do so the bacteria would have to be genetically altered so they are unable to prevent serious infections such as pneumonia or septicaemia. In this proposal we will use a human model of pneumococcal colonisation to test whether administering genetically altered pneumococci unable to cause severe infection to the nose prevents pneumococcal infection in humans. If so then we could use this as a strategy to prevent pneumococcal lung infections in those people who are particularly susceptible eg the elderly and those with chronic lung disease. The model of pneumococcal carriage has been used in Liverpool for the past 5 years safely with no serious adverse effects, and is a proven method of assessing the immune response to colonisation with the pneumococcus.Our plan would be to:1. Make mutants in the pneumococcal strain used for the human colonisation model that prevent it from causing severe infection but do allow it to colonise the throat. These mutants will be tested in mouse models to confirm they are safe to use yet retain the ability to stimulate a significant immune response after colonising the throat.2. We will then select two of these mutant pneumococci strains to be used in the human colonisation model; young healthy volunteers will have the bacteria inoculated into their noses and then nasal wash fluid and blood samples collected over the next few days and weeks. 35 volunteers will be given for each strain of bacteria, with an additional 35 volunteers given unmutated bacteria and 35 mock infected. These volunteers will then be challenged by intranasal inoculation of wild type pneumococci to see whether the immune response to previous colonisation with pneumococcal mutants reduced in virulence prevents subsequent colonisation with 'normal' pneumococci.3. The immune response to pneumococcal colonisation in the volunteers will be assessed using conventional tests of antibody and white cell responses and the nasal wash fluid and blood samples. Results will be compared for before and after colonisation. In addition, whether any increases in antibodies after colonisation protects against pneumococcal infection will be tested by injecting the serum from the blood samples into mice before infecting them with pneumococci. These experiments will provide proof of whether artificial infection of the throat with a safe avirulent pneumococci can cause a strong immune response and therefore could be a strategy for preventing pneumococcal lung infection. If so, the next step would be safety testing and a clinical trial of this approach in older individuals or those at high risk of pneumococcal lung infection.