Measuring the impact of the Chlamydia trachomatis epidemic: new serological assays to assess disease burden (Bristol)

Lead Research Organisation: University of Bristol
Department Name: Community-Based Medicine

Abstract

We intend to develop a blood test capable of detecting how many people have ever been sexually infected by chlamydia. In addition, we hope to develop a test to identify women, who’s fertility has been damaged by chlamydia. Chlamydia is the commonest treatable sexually transmitted disease in Britain. Up to one in 10 young people are infected, the majority not knowing they have it. Untreated chlamydia can cause pelvic inflammatory disease (inflammation in a woman’s womb), which can result in infertility and life-threatening (ectopic) pregnancies. It is estimated to cost the NHS over £100million a year. The government has, therefore, introduced a National Chlamydia Screening Programme (NCSP) in England. It is important that the NCSP can demonstrate that it is effective.

Post- infection antibodies are produced, which can be detected in a blood sample and examination of women with high antibody levels has shown that most have womb damage. Developing antibody tests for serial use, will allow us to: 1)assess the effectiveness of the chlamydial screening programme in reducing the number of people infected, and also in preventing chlamydial pelvic inflammatory disease(PID). 2) identify women who have had chlamydial PID at an early stage and who may need subsequent assistance to conceive. 3) identify some women who may have ongoing chlamydial infection with ‘silent’ PID and who might benefit from treatment. No tests currently exist which are capable of doing this.

Technical Summary

Chlamydia trachomatis is the most common curable sexually transmitted infection in Britain. In opportunistic screening programmes 5-10% of sexually active women under 25 are ?currently? infected. These programmes recruit a selected fraction of the population and largely exclude men. C. trachomatis is frequently asymptomatic and if untreated is a major cause of pelvic inflammatory disease (PID) and tubal infertility, conditions which are difficult to diagnose non-invasively. While screening gives some indication of current infection, little is known about the proportion of the population ever infected with C. trachomatis (cumulative incidence) and of these who have ever developed pelvic disease.

Antibody assays, if sufficiently accurate, could be used in epidemiological studies as a measure of population disease burden, and thus as a measure of the population impact of screening programmes over time (e.g. antibody prevalence by age 25); as a measure of previous undiagnosed infection; and, through the use of quantitative antibody assays, as a potential clinical tool for screening of PID and tubal adhesions and therefore subfertility. However no practical assays, which have been sufficiently rigorously assessed, exist for these purposes.

We propose to develop and characterise sensitive, specific, and high throughput chlamydia antibody tests for use as sero-epidemiological tools to assess disease burden and clinical outcome associated with C. trachomatis genital tract infection:

The two tests will be:
1) An enzyme linked immunosorbent assay, using a C. trachomatis-specific recombinant protein.
2) A modification of the whole immunofluoresence test (WIF) based on flow cytometry (WIF-FC).

There is some evidence that WIF antibody titres correlates with tubal damage, but interpretation of the assay is problematic as it also detects cross reactive C. pneumoniae antibodies. To address this, we shall preadsorb test sera with C. pneumoniae lipopolysaccharide, derived from an Escherichia coli expression system.

Specificity and sensitivity of these novel antibody assays as markers of prior infection will be assessed using sera from patients with C. trachomatis diagnosed by standard clinical methods (e.g. PCR), at differing time periods following infection, and anonymised sera of C. trachomatis unexposed controls aged 10-14yrs from a serum bank. These will be compared to one of the best performing commercially available assays. We will then extend the evaluation to establish whether quantitative modified WIF antibody ?titres? can be utilised as a serological test predicting pelvic disease by testing sera from patients with serological evidence of prior C. trachomatis infection with and without laparoscopic evidence of pelvic disease.
 
Description NIHR Biomedical Research Centre at Imperial College London
Amount £240,575 (GBP)
Organisation National Institute for Health Research 
Department NIHR Imperial Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start  
 
Title Serum bank of individuals patients ever exposed to C. trachomatis and never exposed. 
Description Stored at Imperial College London we have serum bank of 356 patients previously infected with C trachomatis and 747 individuals who have nver been exposed 
Type Of Material Database/Collection of Data/Biological Samples 
Provided To Others? No  
Impact This was used to characterise the pgp3 assay which we developed 
 
Title pgp3 ELISA 
Description A recombinant pgp3 protein used as an antigen to develop a sensitive and specific enzyme linked immunosorbent assay 
Type Of Material Technology assay or reagent 
Year Produced 2011 
Provided To Others? Yes  
Impact The HPA has included pgp3 serology as a potential tool to greatly improve ease, scope and efficiency of monitoring chlamydia prevalence. "HPA's monitoring and evaluation of the National Chlamydia Screening Programme." http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1317131166558 
URL http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1317131166558
 
Description Imperial collaboration 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I have provided the expertise necessary to exploit this assay
Collaborator Contribution I work closely with Prof McClure who has the technical expertise to develop serology assays
Impact See publications and Grant report:G050004. This grant was a joint submission with G0500152
 
Description Public Health england 
Organisation Public Health England
Department Centre of Infectious Disease Surveillance and Control
Country United Kingdom 
Sector Public 
PI Contribution Having developed and validated and demonstrated its superiority over commercial ELISAs we have conducted two pilot studies on chlamydia seroprevalence in the community. We have undertaken an extensive population study to determine with some accuracy seroprevalence figures in the UK. This was done in close collaboration with PHE who have provided the samples and carried out the statistical analysis . This was accepted for publication in 2013 by PLOS One. Since then our collaboration has developed through the recent award to University of Bristol of NIHR Health Protection Research Units: Evaluation of Interventions program grant in 2014, in which the development of the methodologies to use chlamydia serology (Pgp3 antibody) to monitor and evaluate the effectiveness of the National Chlamydia Screening Programme is a workstream
Collaborator Contribution Specimen provision and statisitcal support
Impact We have had two papers published: one on how antibody detection changes with time since detection and 2) changes in population based seroprevalence over time.
Start Year 2009
 
Title pgp3 ELISA 
Description This is a sensitive and specific antobdy test for Chlamydia trachomatis which performs significantly better than commercially available assays. 
Type Support Tool - For Medical Intervention
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2010
Development Status Actively seeking support
Impact We are in the process of applying for funding to utilise this assay in order to better understand the natural history of chlamydia infection. At this point we are investigating its potential to determine the efficacy of the National Chlamydia Screening Programme.