Discovering new methods of inhibiting carriage of Neisseria meningitidis
Professor Rob Read, University of Sheffield & Professor Andrew Gorringe, HPA Porton Down
Following the success of their previous Meningitis UK funded study, Professor Read and Professor Gorringe will determine the effect of Neisseria lactamica on the carriage of Neisseria meningitidis.
In the future it is likely that we will replace the current schedule of injected vaccines with interventions that interrupt transmission of infections in more subtle ways. The agent that causes meningococcal disease (Neisseria meningitidis) colonises the nasopharynx of individuals. In most people, the bacterium is harmless and survives for months in the nasopharynx before moving on by droplet spread to others. In a minority of people, colonisation of the nasopharynx leads to penetration of the bloodstream and disease.
Studies with powerful vaccines have shown that they can reduce disease rates even amongst people who haven't been vaccinated, suggesting that they may interfere with colonisation rates amongst those vaccinated, which reduces overall transmission in the population. Simply reducing colonisation amongst target groups may protect them, and the rest of the population as well.
In a previous Meningitis UK funded study in which the team investigated cross protective antibodies, they found incidentally that inoculating adult volunteers with Neisseria lactamica, a harmless 'cousin' of Neisseria meningitidis, possibly prevents N. meningitidis carriage.
Therefore, the team propose a large experimental challenge study to establish whether N. lactamica does or does not inhibit colonisation by N. meningitidis. They will also determine whether N. lactamica displaces existing N. meningitidis carriage, and whether there are individuals who are innately resistant to any Neisseria carriage (because such people would not require any vaccination at all). If the findings are positive, the team will perform future mechanistic investigations.
The study is currently recruiting for volunteers to take part in the trial. This is taking place at the Royal Hallamshire Hospital in Sheffield and will start in mid October 2011 and run for six months. See more information about volunteering for the study.
If is established that Neisseria lactamica does prevent carriage of Neisseria meningitidis, this could lead to novel mechanisms of reducing colonisation in targeted groups, possibly in the form of a nasal medication.
Project Aims
The primary aim of the study was to assess whether nasal administration of N.lactamica was able to:
a) prevent
acquisition and
b) displace
carriage of N.meningitidis from the
nose and throat of volunteers.
In order to assess the effect of N.lactamica on acquisition and displacement of N.meningitidis, students at Sheffield Hallam University and Sheffield University were recruited into one of two groups:
1.
The ‘intervention’ group, who were inoculated with N.lactamica
2.
The ‘control’ group, who were not inoculated with N.lactamica
Methodology
Throat swabs will be performed on the students in the intervention group prior to inoculation. These students will then return for follow-up throat swabs at weeks 2, 4, 8, 12, 16 and 24. At week 24 all students will be inoculated with N. lactamica and will return at week 26 for a final throat swab.
Ethics Committee Amendments
Two minor changes have been made to the project in order to ensure that the results are robust and meaningful.
1. Recruitment
The study began recruiting on the 19th September 2011 with the release of email advertisements and attendance at University fresher’s week events. 167 people were recruited to the study in the first two weeks. The study initially aimed to recruit from two university cohorts, but by the end of October recruitment from the second cohort had slowed down. The researchers were concerned that this might lead to a delay in giving the first inoculation with N.lactamica, which could lead to bias in the results and to problems with timing the study visits over the university holiday period. Consequently, an amendment was submitted to the ethics committee proposing that students from the University of Sheffield could be recruited into the Sheffield Hallam cohort. This amendment was passed on 22nd November 2011. To date, the retention of participants in the study has been good, with a less than 10% drop out rate. This has largely been achieved by an active approach to following up participants who fail to attend appointments.
2. Baseline demographics
Baseline demographics of the control and intervention group showed that N.meningitidis rates were not significantly different at baseline between the two groups. The groups were similar for most characteristics ensuring no bias in future comparisons, but there were statistically significant differences in gender, and year of undergraduate study. Tobacco smoke exposure also seemed to be different between the two groups but there was some question about the reliability of the data due to the ambiguous nature of the question asked. An ethics amendment was submitted and later approved allowing the administration of a questionnaire to all participants to collect further, more robust data on tobacco smoke exposure in the study population.
Initial Results
Initial results are very promising. There has been a reduction in the number of individuals carrying the meningitis-causing bacteria, N.meningitidis, in their nose and throat in the group who had been inoculated with N.lactamica (the intervention group). N.lactamica was administered to this group at weeks 2, 4, 8 and 16. The difference in carriage between the two groups reaches a statistically significant level at weeks 8 and 16. Further work needs to be done to look at whether the above effect is due to the prevention of individuals acquiring N.meningitidis or displacement of N.meningitidis carriage in those who were carrying the bacteria before inoculation.
Final phase
The study is now entering its final phase of re-inoculation of all volunteers with N.lactamica. The primary aim of this part of the study is to determine whether there are individuals who are relatively resistant to N.meningitidis carriage. This will be achieved by attempting to induce N.lactamica carriage in those individuals in the intervention group in whom initial inoculation was unsuccessful and who have not carried N.meningitidis at any point during the study. The study hypothesis suggests there are a group of people who will continue to fail to carry N.lactamica despite a repeated inoculation attempt.
In addition to the completion of the research study visits to collect samples from the students, the next six months will see a continuation of the analysis of the study data. This will include exploration of whether the observed effect of N.lactamica challenge on N.meningitidis carriage is due to displacement or prevention of acquisition.
Updated: 08.05.12
The outcomes of this project will appear here after completion.
Competitive carriage of Neisseria spp.; discovering new methods of inhibiting carriage of Neisseria meningitidis
Professor Rob Read, University of Sheffield & Professor Andrew Gorringe, HPA Porton Down
Following the success of their previous Meningitis UK funded study, Professor Read and Professor Gorringe will determine the effect of Neisseria lactamica on the carriage of Neisseria meningitidis.
Recent epidemiology suggests that a proportion of the efficacy of meningococcal vaccines is due to their effects on asymptomatic colonisation by Neisseria meningitidis. Future strategies for protection may focus away from generating systemic antibody towards colonisation-prevention.
Professor Read and Professor Gorringe recently completed a Meningitis UK-funded study to investigate induction of cross-protective meningococcal antibody during experimental human nasopharyngeal challenge by Nesseria lactamica. They found incidentally that meningococcal colonisation by Nesseria meningitidis may be restricted by the physical presence of N. lactamica, and that some people may be relatively resistant to carriage of Neisseria spp. Both of these discoveries would have important implications for our understanding of nasopharyngeal colonisation and inform future prevention strategies, however the study was not originally powered to show this.
The team propose a prospective operator-blind human challenge study in which 300 young adult volunteers will receive intranasal N. lactamica or PBS-control. Nasopharyngeal colonisation by Neisseria spp. will be monitored over 6 months. The research will determine (a) whether N. lactamica carriage inhibits subsequent acquisition of meningococcal carriage, (b) whether there are individuals who are intrinsically relatively resistant to Neisseria carriage using crossover-re-challenge and (c) whether inoculation of N. lactamica can displace existing N. meningitidis carriage.
Samples of nasal washes and brush biopsies of nasopharyngeal mucosa will be taken and stored for future studies which will only be undertaken if the results of this study are positive.
Recruitment
Lactamica 2 study began recruiting on the 19th September 2011 with the release of email advertisements and attendance at University fresher’s week events. The screening visits began on 23rd September and recruitment was initially successful enrolling 167 people to the study in the first two weeks. These participants were predominantly from one cohort and recruitment from the second cohort in the study lagged behind. By the end of October recruitment from the second cohort had almost halted, despite additional attempts to raise awareness about the study. At this point there was concern that if recruitment continued at such as slow rate there would be a significant lag in when individuals were inoculated with Neisseria lactamica which was may have led to bias in the results. In addition a prolonged recruitment phase would have led to problems with timing of study visits over the university holiday period. Consequently in late November an amendment was submitted to the ethics committee proposing to alter the allocation of participants to allow students from the University of Sheffield to be recruited into the Sheffield Hallam cohort. This amendment was passed on 22nd November 2011. To date the retention of participants in the study, has been good. 280 volunteers attended visit 6, which corresponds to a 90.3% retention rate. This has largely been achieved by an active approach to following up participants who fail to attend appointments.
Baseline Demographics
Baseline demographics of the control and N.lactamica challenge group showed that N.meningitidis rates were not significantly different at baseline between the two groups. The groups were similar for most demographic variables, but there were significant differences in gender (p= 0.019) and year of undergraduate study (p=0.05). Tobacco smoke exposure also seemed to be different between the two groups (p=0.034) but there was some question about the reliability of the data due to the ambiguous nature of the question asked. An ethics amendment was later submitted and approved allowing the administration of a questionnaire to all participants at visit 7 to collect further, more robust data on tobacco smoke exposure in the study population.
Initial Results
The primary aim of the study was to assess whether inoculation with N.lactamica was able to a) prevent acquisition and b) displace carriage of N.meningitidis. Initial results have shown a reduction in N.meningitidis carriage in the N.lactamica challenge group at weeks 2, 4, 8 and 16. This difference reaches statistical significance at weeks 8 and 16. Further work needs to be done looking at whether this effect is due to a prevention of acquisition or displacement of N.meningitidis carriage.
The Final Phase
The study is now entering its final phase of re-inoculation of all volunteers with N.lactamica. The primary aim of this part of the study is to determine whether there are individuals who are relatively resistant to Neisseria spp. carriage. This will be achieved by attempting to induce Neisseria lactamica carriage in those individuals in the N.lactamica challenge group in whom initial inoculation was unsuccessful and who have not carried N.meningitidis at any point during the study. The research hypothesis suggests there are a group of people who will continue to fail to carry N.lactamica despite a repeated inoculation attempt.
In addition to the completion of the research study visits, the next six months will see a continuation of the analysis of the study data. This will include exploration of whether the observed effect of N.lactamica challenge on N.meningitidis carriage is due to displacement or prevention of acquisition. Whole genome sequencing of the N.meningitidis strains will help to answer this question. Multivariate analysis will be used to adjust for baseline N.meningitidis carriage and those covariates which were found to be statistically significantly different at baseline.
Updated: 08.05.12
The outcomes of this project will appear here after completion.
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