Tackling trypanosomiasis in cattle in sub-Saharan Africa

Animal African trypanosomiasis (AAT) is a devastating disease affecting livestock in Sub-Saharan Africa and, more recently, South America. It is caused by several species of Trypanosoma parasites, which are transmitted by tsetse flies (in Africa), causing animals to suffer from fever, weakness, lethargy and anaemia. The resulting weight loss, low fertility and reduced milk yields have a huge economic impact on the people who depend on these animals. The disease has been said to lie at the heart of poverty in Africa.

The project, initiated by Dr Gavin Wright, former group leader at the Wellcome Sanger Institute and now Professor at Hull York Medical School and the University of York and Dr Delphine Autheman, former Sanger Postdoctoral Fellow and now Research Associate at The Hull York Medical School, aims to tackle animal trypanosomiasis by advancing the research and protocols to find an effective vaccine against the disease. Both vaccines discovered by their team were protected and patented by the Sanger Institute. Protecting the invention gives the Institute control and the upper hand in ensuring that a final vaccine can be distributed fairly to the countries that need it most in line with the Institute’s charitable objectives.

During their time at the Sanger Institute, Gavin and Delphine found a way to combat animal trypanosomiasis, or nagana as it is known in endemic countries. To expand the scope and impact of the research, they involved the Genomics Innovation team at the Sanger Institute, which used its industrial network and funding from a Translation Award  to bring critical complementary expertise and capability into the project. Together, they recruited a veterinary clinical trial specialist to map the clinical development path for a possible vaccine in cattle and advise on the clinical trial design. Two studies were developed to understand how the discoveries could lead to immunity against the disease in cattle in the UK and to begin to develop a vaccine trial protocol.

There are different species of Trypanosoma parasites. Trypanosoma cruzi, for example, is responsible for Chagas disease in South America. At the Sanger Institute, Gavin and Delphine’s work focused on two species that infect cattle and other animals humans depend on: Trypanosoma vivax and Trypanosoma congolense.

“In terms of economic impact, Trypanosoma vivax and Trypanosoma congolense are devastating diseases. They are a huge problem in sub-Saharan Africa, where they kill the cattle millions of people rely on to live. There is, at the moment, no good cure or solution to this.”

Dr Gary Dillon,
Senior Business Development Manager at the Wellcome Sanger Institute who worked with Gavin to bring the project forward

At the Sanger Institute, a selection of pathogens of interest to the research community have been sequenced to understand their genomic information and find ways to combat the diseases they cause. These pathogens include Mycobacterium leprae - the bacterium causing leprosy - or Plasmodium falciparum, the deadliest of the malaria-causing parasites that causes over 600,000 deaths each year, predominantly of young children in Africa. Trypanosoma vivax and Trypanosoma congolense are also on the list, allowing researchers to look for vulnerabilities that could be targeted, in this case, with a vaccine.

“The project we worked on back in 2019 used reverse vaccinology,” said Gavin. “This process involves going through the parasite’s genome sequence, and then, from certain architectural features of the proteins that are encoded by the genes, identify those that are likely to be on the surface of the organism.”

As these proteins are expressed at the surface of the parasites, they are likely to be more accessible by antibodies, making them potential vaccine targets - exactly what Gavin and Delphine were after. “We created a catalogue of the proteins which we thought could be expressed on the surface of the Animal African Trypanosomes parasites we were targeting,” Delphine explains.

The type of vaccine they were looking to develop is called a subunit vaccine. A subunit vaccine is one in which certain features of a pathogen are replicated - in this case the shape of the protein found on the surface of the pathogen - so that when the vaccine is given to an animal or person, their immune system detects that protein, which is foreign to the body, and produces antibodies to fight it. The same kind of approach was taken towards the COVID-19 vaccine with the now famous ‘spike’ protein, for example.

The main challenge, however, was that contrary to the SARS-COV-2, which is a virus, Trypanosoma vivax and Trypanosoma congolense are protozoa - single-celled microscopic animals - and far more complicated.

“The main challenge when trying to develop a vaccine against parasites is that they can have over 5,000 protein-coding genes in their genomes. That means over 5,000 possible targets. How to identify which of those thousands of proteins could be the one you need to create an effective vaccine?”

Professor Gavin Wright,
Hull York Medical School and the University of York, and former Group Leader at the Wellcome Sanger Institute

Trypanosomes live in the blood of their infected animals causing chronic infections that wear down the animal, eventually dying from the disease. The fact that they live in the blood tells scientists that trypanosomes have evolved sophisticated ways of combating the immune system. For many years, vaccinating against these parasites was deemed impossible. The culprit - a protein called the Variable Surface Glycoprotein (VSG), which is the trypanosome’s main defence.

VSG is a highly variable protein covered in long chains of sugars that the parasite uses to escape the immune system. Trypanosomes characteristically switch their surface coat (varying the VSG) every time the immune system starts to recognise the invader. This ability to cloak itself, and switch cloaks when threatened is why the parasite has long been considered near impossible to vaccinate against; it was deemed too much of a moving target.

“Mammals can make good antibody responses against these particular proteins. Once they do, this antibody-based immune response can kill the parasites. However, because the parasites have so many different versions of VSG, they switch to a different version - as if it switched to a different coat.

“In this way, the immune system takes some time to fight back, the new coat not being recognised by that first wave of antibodies. So again, the parasite will escape the immune system, until there is a second wave of immune cells that target the second coat.

“However, once the second wave of antibodies is out to defend, the parasite switches to yet another version of the protein, a third coat, that is no longer recognised by the antibodies that have been so far elicited. The immune system will then respond again, and the pattern is repeated until the animal is worn down and the disease becomes lethal.”

Professor Gavin Wright

Using genomic information Gavin, Delphine and their collaborators looked for surface proteins large enough to reach beyond the VSG’s protective coat and produced a library  of about 40 to 50 proteins present on the parasite’s surface that could be targeted by the immune system. Proteins that wouldn’t switch, unlike the VSG protein.

It just so happened that these particular parasites that infect cattle can infect mice too. They systematically vaccinated mice with each one of the proteins they had identified. They were looking out for a strong immune response.

“Out of the 40 or so proteins, we found two that gave strong protection levels. The most interesting of which was one that we called V23,” says Delphine. This protein, which they localised at the boundary between the parasite’s flagellum - a hairlike tail that enables the parasite to move - and its body seemed to elicit sterile protection. Mice that had been vaccinated against this particular protein were protected from infection.

The work didn’t stop there. Gavin, Delphine and their collaborators continued studying the vaccine response and were able to work out some of the immunological mechanisms of protection so that they could show that there were multiple reasons why antibodies were able to kill this parasite. The most effective of which was via an immune mechanism called complement - a mechanism by which the immune system punches holes in the membranes of the parasite’s body, ultimately leading to its death.

Even though the discovery was exciting, there was still a major roadblock in the pathway towards a viable veterinary vaccine for cattle. In fact, the rationale behind understanding the immunological mechanisms of protection was to help translate their mice findings into cattle. “Mice are quite well understood animals in research. We know how to create a vaccine protocol in mice. However, we need to make this work in cattle,” said Gavin. Most of the work in this space is undertaken by commercial companies that produce vaccines for livestock for commercial profit. There's very little understanding in the research community as to how to make good antibody responses in livestock and, historically, trypanosomiasis work has focused on drugs, not vaccines.

That’s when the Sanger’s Genomics Innovation office’s expertise came in - with funding and support, Gavin and collaborators were able to generate immunogenicity data using cattle in the UK and engage a consultant to develop a draft clinical protocol. This preliminary work was successful - it demonstrated that a vaccine was feasible and managed to convince larger funders, the Gates Foundation in this case, to continue funding the work. Today, veterinary clinical trials are being progressed with a contract research organisation in Morocco, funded through the Gates Foundation. The first trials are now being planned and if successful, the Genomics Innovation office at Sanger hopes a vaccine could be available in five years.

“Before we took this project on, it was generally considered impossible to vaccinate against trypanosomiasis due to the coat-changing mechanism of the parasite. We felt we were a bit crazy when we decided to take this on.

“Now looking back, I’m glad we had the support, core funding and expertise at the Sanger Institute to move forward. I’m thrilled to see how it develops and hope we can get a full vaccine trial that is successful for cattle in the upcoming years.”

Professor Gavin Wright