Clinical studies bring GIFT of sexual health closer for women

A South African innovation designed to screen for inflammation associated with HIV infections and improve women’s sexual and reproductive health has been manufactured and entered its first in-field clinical studies. Close to 700 women will be involved in the validation of the Genital Inflammation Test (GIFT) developed at the University of Cape Town (UCT).

Almost 700 women will be involved in the validation of the Genital Inflammation Test (GIFT) developed at the University of Cape Town (UCT).

GIFT is the focus of an international collaboration of almost exclusively female scientists led by Prof Jo-Ann Passmore of UCT and Dr Lindi Masson, originally of UCT but now of the Burnet Institute in Australia. The trial development includes a partnership with Cape Town biotechnology company Medical Diagnostech under the leadership of Ashley Uys and Lyndon Mungar.

GIFT intends to be a low-cost rapid test to detect vaginal inflammation, one of the biggest drivers of HIV risk in young women. It is often caused by sexually transmitted infections (STIs) and bacterial vaginosis.

These conditions are typically treatable with antibiotics, but because most women don’t have symptoms, they are often undiagnosed and untreated. And that’s where GIFT’s developers believe the test could fundamentally transform the landscape.

The clinical studies in South Africa, Zimbabwe and Madagascar are a key step in confirming the performance of the lateral flow test, which uses very sensitive antibodies to identify inflammation biomarkers, even when they are present in amounts weighing a few trillionths of a gram (picograms).

Once the results of the studies have been analysed, the GIFT device will be finalised and registered with funding from the Technology Innovation Agency and the South African Medical Research Council (SAMRC). Then the focus will switch to commercialisation.

“Developing effective ways to reduce HIV risk in women in South Africa is critical. Since a significant proportion of [HIV] risk comes from undiagnosed but treatable STIs, improved STI management using innovations like GIFT is something that is urgently needed,” said Passmore.

Inflammatory enemy

GIFT’s roots lie in the discovery that South African women with asymptomatic STIs and bacterial vaginosis — a disturbance of healthy bacterial communities — had levels of vaginal inflammation similar to women with symptoms.

This is worrying, because inflammation makes it easier for HIV infection to occur. If left untreated it can also lead to pelvic inflammatory disease, pre-term labour, fallopian tube injury, scarring of the upper reproductive tract and infertility.

“Treatable STIs and bacterial vaginosis are highly prevalent in South Africa and other resource-limited settings, and we found that even though most women don’t have symptoms, only women with symptoms are treated,” said Masson. “This is because etiological testing is too costly for implementation in these settings.”

Aiming to develop a low-cost diagnostic, the GIFT team began by identifying and evaluating biomarkers of inflammation. Then it turned its attention to the development of a device to measure the biomarkers.

Dr Monalisa Manhanzva, who is project managing GIFT, and Dr Fezile Khumalo, who is building the Translational Research Hub at UCT, helped work on the development of the device.

“Development of the GIFT device has been quite challenging because the inflammation biomarkers are present in the vagina in very low (picogram) concentrations,” said Manhanzva.

“We were tasked with identifying antibodies capable of detecting these extremely low concentrations and yielding a visible result to the naked eye. This led to us meticulously screening thousands of different antibody combinations.”

Khumalo added: “The beauty of the innovation lies in its simplicity to both test for inflammation and interpret the results. We used a simple method with standard components to keep costs low and ensure user-friendliness. This informed our product profile, which made it easier to develop and manufacture for the clinical study.

“It’s really just a standard lateral flow test but able to detect very low amounts of inflammation. Once we found the right antibodies that were sensitive enough, getting the rest right and manufacturing was relatively straightforward.”

Passmore said: “Measuring these biomarkers in vaginal samples was another challenge altogether. Vaginal samples are messy – mucous is not our friend. We had to find innovative ways to make sure we reliably detected the biomarkers, irrespective of the sample matrix.”

Covid to the rescue

The team’s next challenge in developing a test suitable for low-resource settings was to find a way to process vaginal swab samples in the simplest way possible.

“Usually we use a vortex to mix up samples in the lab and get all of the samples out of the vaginal swab,” said Masson.

“For this, we learnt from the Covid-19 pandemic that used some great approaches for processing nasal swabs by hand. Micaela Lurie, whose PhD I am co-supervising with Jo-Ann, showed if we used soft tubes, we could squeeze the swab inside the tube between our fingers and effectively wring out the swab, and this worked even better than our standard lab processing methods.”

When it came to manufacturing the test, the GIFT team forged what Masson called a “unique partnership” with Medical Diagnostech, a developer and manufacturer of lateral flow test kits.

“The work done at UCT to identify the biomarkers for the GIFT project enabled us to optimally develop a product for clinical trials within a short period of time. These collaborations are critical to maximise commercialisation of quality first-to-world products” said Uys from Medical Diagnostech.

This private-public partnership is unusual due to intellectual property and confidentiality issues, said Masson. But the company “allowed our UCT students and post-docs to work in their labs, side by side with their staff, during most of the device development process”.

Khumalo said: “This joining of teams and minds meant we were able to expedite the development process and share experience. The academic and industry perspectives were invaluable to our ability to progress to this stage.”

Validation studies begin

The test kits have been shipped to clinical study sites at the Desmond Tutu Health Foundation Youth Centre in Masiphumelele, Cape Town, Spilhaus Clinical Research Site in Harare, and Befelatanana University Hospital Centre for Gynaecology and Obstetrics in Antananarivo.

Masson said 225 women will join the study from each site, with two tests for each patient: one administered by a nurse, the other by a laboratory technician.

“Alongside this, we’re evaluating the stability of the devices under varying conditions.”

Data from the clinical studies will measure the accuracy of the GIFT device; its performance compared with the current standard of care — syndromic management that misses most cases of the conditions that cause inflammation (STIs and bacterial vaginosis); and the tests’ acceptability, feasibility and cost-effectiveness. A sensitivity analysis will look at subgroups of patients with varying disease severity.

This work is being done through key partnerships with GIFT team members at:

• Institut Pasteur de Madagascar;
• Organisation for Public Health Interventions and Development (Zimbabwe);
• London School of Hygiene & Tropical Medicine (UK);
• University Medical Centre Utrecht (Netherlands);
• Institut Pasteur (France); and
• Hitotsubashi University (Japan).

“It is important to us that we communicate the results of the GIFT performance with the women who helped us test the device [by participating in the clinical studies], and the broader communities where the studies happened,” said Passmore.

“The willingness of women from South Africa, Madagascar and Zimbabwe to partner with us by giving vaginal samples to allow us to develop the device makes this study a true collaboration. We are co-developing the device with the women who are participating.”

The next steps

The GIFT team has secured funding from the Technology Innovation Agency to finalise and register the device, and conduct pre-market testing. Funding from the SAMRC will allow for a streamlined clinical trial for registration of the device.

Masson said the UCT Health Economics Unit is working on a GIFT cost-effectiveness analysis. “Our aim is for the cost of the device to be as low as possible and we have a number of strategies to achieve this.”

Passmore said: “The antibodies are the major expense of the device itself, so we’re making our own antibodies.”

Masson said previous cost-effectiveness work by the Health Economics Unit showed healthcare workers’ salaries were by far the biggest cost associated with implementation.

“Self-testing may overcome this barrier, so we are exploring this approach too.”

The final step will be to commercialise GIFT, and Masson and Passmore are hoping the device will be continue to be manufactured in South Africa.

“It is important to develop capacity and invest in human capital in Africa, to make tests in Africa for Africa. This has always been a key aim of the work we do,” said Passmore.

The clinical studies are a key milestone in GIFT’s journey, but Masson said women remain at the heart of the mission.

“We know from previous studies that STIs and bacterial vaginosis rates are high in South Africa if you test for them — sometimes as high as 70% — but that most women do not get diagnosed. The social and economic burden is massive, but until there are low-cost options to address this, prevalence will remain high.”

“The journey of developing a new test is demanding. It requires determination, flexibility and dedication to tackling the ever-changing challenges in healthcare,” said Manhanzva.

“Success comes through teamwork and partnerships with experts from different fields, all working together to overcome obstacles and drive the innovation forward.”