Identifying groups of meningitis C bacteria which may become resistant to antibodies produced by the current vaccine
Professor Christoph Tang, Centre for Molecular Microbiology and Infection, London
Professor Tang looked at new strains of meningitis C causing bacteria which may, in time, become resistant to the current vaccine.
The meningitis C vaccine introduced across the UK in 1999 for everyone under the age of 20 has been hugely successful, resulting in a 90 per cent reduction in cases. But, as with all bacteria, the bacteria responsible for causing meningitis C may change and develop new strains. Such changes may mean that the vaccine is no longer effective.
It is known that bacteria are able to change quickly (for example they can rapidly become resistant to antibiotics), so the team around Professor Tang searched through a collection of strains and found that there are already bacteria around that can withstand immune responses raised by the MenC vaccine.
It was important to determine how these strains manage to survive in order to counteract these modes of resistance early on.
The aim of this study was to pinpoint exactly how some MenC bacteria avoid killing. This should allow for quick detection and help inform what approaches should be taken to combat these strains before they spread and become common.
By determining what causes strains to become resistant to vaccine induced immunity, we can limit their spread and therefore preserve the effectiveness of the current MenC vaccine.
This project is now complete - see the outcomes tab for more information.
The researchers were able to pinpoint what causes some bacteria to become resistant to immune responses stimulated by the MenC vaccine. They identified three resistant strains* that all carried a genetic alteration that changed the bacterial capsule, thus making it resistant to immune responses aimed at normal MenC capsules.
This information enables researchers to identify resistant MenC strains currently present in the community and to understand, monitor and hopefully contain the spread of these strains.
*The resistant strains were all from Spanish isolates. No resistant strains were found in the UK.
Characterisation of serogroup CN meningitidis strains resistant to killing by anti-capsular antibodies
Professor Christoph Tang, Centre for Molecular Microbiology and Infection, London
Professor Tang looked at new strains of meningitis C causing bacteria which may, in time, become resistant to the current vaccine.
A major concern that could undermine the success of the conjugate vaccine against serogroup CN meningitidis (MenC) is the emergence of strains that resist killing by immune sera. In anticipation of this, 109 MenC isolates were screened and four resistant strains (R strains) were identified, with one surviving even in high titres of immune serum. This demonstrates that mechanisms already exist in Neisseria Meningitidis from which resistance against Meningococcal type C conjugate vaccines can evolve and spread, posing a real threat to the long-term success of the vaccine. This project characterised the basis of resistance in the R strains.
This study aimed to determine whether changes in capsule biosynthesis were responsible for the resistance by analysing the composition of the capsule and by establishing whether the resistant strains remain resistant compared with other strains even when they are unable to express a capsule. The entire capsule biosynthesis loci in resistant strains was sequenced and compared to sensitive strains to define the genetic basis for resistance. The project aimed also to determine whether the resistant stains harbour distinct genes that contribute to their resistance using DNA microarray analysis. It also investigated whether they possess other mechanisms of resistance, such as the ability to recruit negative regulators of the complement system. If these approaches were not informative, genetic linkage analysis would be carried out in order to define the genomic regions of resistant strains that confer resistance to fully sensitive strains.
Understanding how the resistant strains avoid killing in immune serum is crucial for developing methods to rapidly detect their emergence, and for designing preventive measures to protect against their spread.
This project is now complete - see the outcomes tab for more information.
The aim of identifying the molecular basis for the resistance of some MenC strains has been achieved. All three resistant strains* harboured an identical polymorphism in the capsule biosynthesis locus (an insertion sequence in the intergenic region between the sia and ctr operons). It was demonstrated that this change is responsible for the change in resistance, through up-regulation of gene expression and an increase in the amount of capsule on the bacterial surface.
Subsequent work has shown that this change is over-represented in samples from individuals with disease compared to samples from carriers. Therefore, researchers can determine which meningococcal strains are circulating in the community that have this genetic change, and know the basis for this. Such information is vital in understanding the epidemiology of outbreaks and the spread of novel strains in the population.
*The resistant strains were all from Spanish isolates. No resistant strains were found in the UK.
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