Get real: developing diagnostic tests for infectious diseases

How test kits developed by Diagnostics for the Real World, a spin-out from the University of Cambridge supported by Technology Transfer, have the potential to transform the diagnosis of chlamydia and other common infections across the world.

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"If all we do is to develop a technology, and all we have are patents, publications or prototypes, then we would have failed," says Dr Helen Lee, Associate Professor and Reader in Medical Biotechnology at the University of Cambridge. "We want to produce high-quality diagnostic tests and deliver them into the hands of those who need them the most."

The tests she mentions include the Chlamydia Rapid Test, developed by her team to detect the world's most common bacterial sexually transmitted infection (STI). Untreated, chlamydia can lead to infertility in women and blindness in babies born to infected mothers.

The rapid test developed by Dr Lee and her team can detect the bacteria responsible for the infection in under 30 minutes using non-invasive samples. The test is simple to use and stable in high heat and humidity - conditions often found in developing countries. Distributors for the test are in place for the UK, France and the Philippines, and distributors for other countries such as Peru, China and India are under discussion.

Firm foundations

While working in a leading diagnostic company in the USA, Dr Lee became increasingly interested in finding a way to tackle the dearth of affordable and appropriate diagnostic tests for the developing world.

Such tests tend not to be economically attractive to large pharmaceutical companies, so Dr Lee and a few of her colleagues left industry and came to the University of Cambridge in 1996 to establish the Diagnostic Development Unit.

Most chlamydia screening programmes currently in place use the 'nucleic acid amplification test' (NAAT), which detects the DNA or RNA of the chlamydia bacteria in samples taken from patients.

These tests require the bacterial nucleic acid to be extracted and amplified in complex chemical reactions that require specialised equipment and reagents, as well as highly trained laboratory personnel. In many settings these tests cannot be performed, and samples must be sent away for testing, causing a delay in diagnosis that can allow the infection to spread further among communities.

Almost 10 per cent of sexually active young people have chlamydia, yet some 70 per cent of women and 50 per cent of men infected have no symptoms, and do know that they carry the infection.

"Chlamydia is one case where the tests need to go to the people, and not the people to the testing site," says Dr Lee. So she and her colleagues set about creating a kit that was simple to use, cheap to produce and that could provide almost immediate results.

"While the NAAT is more sensitive than our rapid test, chlamydia control is not just about the sensitivity of one particular test over another - it's about how many people you can screen and treat. Access to testing followed by immediate treatment is far more critical."

She explains that treating chlamydia is simple: "It's one pill, one time". The control of chlamydia is really in the effective screening of infected individuals, efficient contact tracing - to allow you to treat the patient's sexual partners - and then to re-screen the at-risk groups.

The researchers developed the base technology called SAS (Signal Amplification System) to improve the sensitivity of a rapid test. SAS underpins the Chlamydia Rapid Test and led to the team winning the prestigious Tech Museum Award for innovation from The Tech Museum of Innovation in San Jose, California.

To commercialise the test, which recently received regulatory approval in Europe and in Canada, the group created a spin-out company called Diagnostics for the Real World in 2002.

Technology Transfer at the Wellcome Trust played a key role in the development of the technology and the formation of the company. "The Trust was there every step of the way," says Dr Lee, "from funding the basic research to the development of the prototype, scale-up, validation of the production process and clinical trials."

The success of the company, she adds, is based on the balance of doing well and doing good. The company operates a two-tiered pricing system so that it sells its rapid test kits in developing countries almost at cost, but at a premium in developed countries.

The Chlamydia Rapid Test has been evaluated both in the UK and in developing countries, with some impressive results (see video and 'In the field' below). The chlamydia test has been modified for trachoma, an eye disease caused by the same bacteria, and has been tested on children in Tanzania.

Facing the future

"Now that we have completed the development of the base technology, we are busy applying it to other targets. We have already completed the clinical trial of our second product - a rapid and sensitive test for hepatitis B infection," says Dr Lee. The researchers are also using the technology to develop the diagnosis of another sexually transmitted infection, gonorrhoea.

The group has also developed a technology called SAMBA (Simple AMplification-Based Assay) to detect nucleic acid targets at point of care. This is being used in two tests for HIV: one to detect HIV in babies born to infected mothers, and another to monitor whether HIV-positive patients are becoming resistant to particular HIV drug regimens.

"People often think of innovation as just being clever. To me, it has to do with the ability to deal with failure," says Dr Lee. "When you start, you only have an idea of what you want to do but no clue as to how to get there.

"Fundamentally, you fail every day until you find the way and you need pretty broad shoulders - it is the perseverance and ability to deal with failures day in and day out that has got us to where we are."

In the field

Australian gynaecologist Richard Skinner is one of the first people to put the Chlamydia Rapid Test into use in the developing world. Around three years ago, he launched a cervical pap test (cervical smear) programme in Tonga. "It became very obvious that there are other health issues related to this area - specifically STIs, which are a huge problem in many Pacific countries," he says.

"Because there have been no screening programmes in these countries, chlamydia has become an endemic infection, constantly present in some parts of the population." According to the World Health Organization, over 40 per cent of women under 25 attending antenatal clinics in Samoa are positive for chlamydia.

"I had been trying to set up a chlamydia screening programme there, and I was considering setting up a lab and then sending the samples to Melbourne for testing, but this is not very cost effective or quick," says Dr Skinner. He then heard about the Chlamydia Rapid Test and got in touch with Dr Lee, who sent him 300 kits for use in Samoa.

Chlamydia frequently occurs without causing any symptoms, which means it can be hard to find a suitable volume of patients necessary for testing. Instead, he focused his research on pregnant women, an accessible, young population of people who attend antenatal clinics.

During the clinic, patients were tested by nurses, and any women with positive results were given antibiotics - not just for them but also for their sexual partners.

Treating partners of those infected is vital to defeat the infection, yet so-called 'contact tracing' is extremely hard in some countries, including Samoa, where the population is dispersed among remote villages and there's no postal service. "It's a huge advantage to be able to treat these patients before they leave for the village," says Dr Skinner.

His experience of using the rapid test was positive: "What's particularly good is that you don't need extensive training or lab facilities," he says. "It's easy to train the nurses to use the test, which is also very acceptable to the patients."

"Previously, I'd walk into the clinic knowing that nearly half of the women there had chlamydia, but that I had no means to diagnose it. They'd give birth infected with chlamydia, putting themselves at risk of pelvic infection and their babies at risk of chest or eye infections," says Dr Skinner. "Now with the Chlamydia Rapid Test we can start to tackle this - a helpless, hopeless situation has changed."

Updates

Chlamydia Rapid Test Distribution

A distribution agreement has been completed with Oxoid Italy, Portugal and Spain, with sales and marketing in each country working to launch the test in early March 2010.
Instructions for use and all advertising documents have been translated into five languages (English, French, Spanish, Portuguese and Italian).
The Chlamydia Rapid Test has been registered in Spain and Portugal, with Italian registration expected by the end of February 2010.
Sales continue to be strong in France, with Oxoid France ordering emergency shipments twice after running out of kits. At the end of February, all remaining stock in Sunnyvale was shipped to Oxoid France. Production for a further 10 000 test lots has begun.
Female kits received product regulatory approval in Canada.
Orders have been received from India, Seychelles, Vanuatu, St Helena and the Falklands, with requests for quotes from Cuba, Colombia, Mexico and Kenya.
A distribution agreement has also been reached with Immunochem, Peru. The company recently sponsored a special session on the Chlamydia Rapid Test at an international infectious disease meeting in Lima. The product is under evaluation by the Department of Health in Peru.

Chlamydia Rapid Test Feedback

India: "At a technical level, the test is being very well received by the labs and they truly love it" - Avi Chauduri.
France: No field problems have been reported since the launch.
Vanuatu: This is the first instance of the test being used in resource-poor settings and this has raised unexpected problems. A simplified instruction sheet with pictorials is being developed, addressing basic issues such as vortexing.