Tackling leishmaniasis: Research offers hope against neglected disease

Leishmaniasis: A stealthy parasitic menace

Leishmaniasis, a parasitic disease transmitted by sand fly bites, has plagued human populations for centuries.

Leishmaniasis can cause severe disablement and can even be fatal. More than one billion people live in areas endemic for leishmaniasis and are at risk of infection, and there are over one million estimated cases every year.

Regardless of this stark reality, leishmaniasis often exists under the radar. It is classed as a neglected tropical disease by the World Health Organization (WHO), a term used to describe diseases that largely affect impoverished populations and receive inadequate attention and resources due to their association with poverty.

However, Professor Paul Kaye, Professor of Immunology at Hull York Medical School, is leading ground-breaking research to unravel the complexities of leishmaniasis and is at the forefront of trialling a new vaccine in a bid to halt this persistent disease.

He has dedicated his career to exploring ways to develop new interventions that target the host's immune response, and also gain a better understanding of how certain immune cells work.

What is leishmaniaSis?

Leishmaniasis is caused by single-celled parasites of the infected female phlebotomine sand fly; a tiny insect only 2-3mm long, making it incredibly difficult to see to the human eye.

Cutaneous leishmaniasis, the most common form of leishmaniasis, manifests as skin lesions that may self-heal or become chronic, leading to disfiguration. The disease's impact extends beyond its physical symptoms, affecting mental health and societal well-being.

Professor Kaye said of cutaneous leishmaniasis, “In some cases it will spread across the skin, so almost the entire surface of the skin will be parasitized.

“Quality of life chances go down, particularly for children, and for females; marriage prospects, life at school, all these sorts of things become severely impacted. The impact of leishmaniasis extends well beyond the clinical disease.”

Another form of the disease, called visceral leishmaniasis is the most severe form of infection; it affects internal organs, including the spleen, liver, and bone marrow, and can be fatal if left untreated.

Professor Kaye explained, “Visceral leishmaniasis leads to a loss of immune function. This disease is also found in Mediterranean countries, where many people don’t realise this is a public health problem; it can affect people who are immunosuppressed, such as people who have HIV, are taking drugs for arthritis, or having cancer treatment.”

Treatment options for leishmaniasis are limited and expensive and are similar to cancer chemotherapy – quite literally administering poison to kill the disease, which comes with risks and side-effects.

The lack of investment from major pharmaceutical companies, coupled with limited purchasing power in affected regions, perpetuates a cycle of poverty and insufficient research.

The research

In Professor Paul Kaye's lab, the primary focus remains on understanding how leishmaniasis affects the immune system. They're exploring ways to develop new interventions that target the host's immune response and also gaining a better understanding of how certain immune cells work.

Professor Kaye's team adopts a holistic approach to combat leishmaniasis. Their research spans various disciplines, from immunology and molecular biology to clinical studies and mental health. His research team have active collaborations in Brazil, India, Sri Lanka and across East Africa – areas of the world which are disproportionality affected by leishmaniasis.

It is this approach which is paving the way for a better future in areas severely affected by leishmaniasis.

Human infection model

Professor Kaye's team have developed a vaccine aimed at harnessing the power of the immune system against leishmaniasis.

To fully evaluate the potential benefits of a vaccine, the team has developed a controlled human infection model, where volunteers are exposed to the leishmaniasis parasite. This offers a unique opportunity to observe and analyse the body's initial responses to infection, and to assess the effectiveness of vaccines in a rapid and controlled manner.

The research paper for this work is published in Nature Communications. The research is a collaboration between the Hull York Medical School, the University of York, the Department of Parasitology at Charles University in Prague, the Department of Microbiology and Immunology at McGill University in Montreal, the Center for Geographic Medicine and Tropical Diseases at Tel Aviv University, Vibalogics GmbH, Cuxhaven and the Hebrew University-Hadassah Medical School in Jerusalem.

The research was funded by a Developmental Pathways Funding Scheme award from the UK Medical Research Council and the Department for International Development.

Highlighting the collaborative nature of this work, Professor Kaye partners with Hull York Medical School colleagues Professor Charles Lacey, a Professor of Medicine, and Professor Alison Layton, a clinical dermatologist and Clinical Lead in the Skin Research Centre.

Professor Layton's expertise in dermatology has proven synergistic with the study's objectives. Professor Kaye said, “While seemingly distinct from leishmaniasis, many skin diseases share commonality with the parasitic infection. These crossovers have enriched the team's insights, especially concerning the social implications of these conditions.”

In an exciting development, the National Institute of Health (NIH) in the United States has expressed enthusiastic interest in adopting this human infection model, a resounding testament to its potential impact.

Professor Kaye explained, “The NIH is an institution with an impressive track record in leishmaniasis research and a translational clinical facility of remarkable proportions, which signifies the magnitude of their commitment to this area of research. So for the model to potentially be taken up there is very exciting.”

At its core, the human infection model is a transformative tool for comprehending infection biology. It offers an accelerated and controlled approach to testing and evaluating vaccines and emerging treatments. This methodology outpaces previous capabilities, providing a rapid and efficient means of analysis.

Vaccine trials

Clinical trials, funded by The Wellcome Trust, demonstrated the safety and effectiveness of the new vaccine, offering hope for treating and preventing the disease.

Professor Kaye said, “The results from the clinical trial are very encouraging. They show that the vaccine we have developed is safe and immunogenic in patients. It is now important to test this vaccine further to see if it can prevent the disease.”

The new vaccine, called ChAd63-KH, uses a non-replicating virus to introduce genes that code for Leishmania proteins into the human body. The design of the vaccine is very similar to the Oxford / Astra Zeneca vaccine being used to prevent COVID-19.

In the first clinical trials, ChAd63-KH was tested to see if it can be used to treat rather than prevent disease. The vaccine was given to patients with a chronic skin form of leishmaniasis and was shown to be safe and to stimulate immune responses associated with a cure. The research paper is published in the journal Molecular Therapy. The research is a collaboration between Hull York Medical School, the Institute of Endemic Diseases, Khartoum, the Department of Biotechnologies, University of Siena, Queen Mary University of London, the University of Edinburgh and the Robert Koch Institute, Berlin.  

Future goal: A lasting legacy

While progress in the development and trials of the new vaccine is encouraging, pollical challenges persist.

The disease's prevalence in conflict zones complicates research efforts and limits accessibility to affected populations.

Professor Kaye said, “Conflict is winning; leishmaniasis has always been a disease that’s associated with areas of political and social unrest.

“Syria, for example, had the best the best health surveillance system for leishmaniasis in the Middle East, but since the conflict in Syria started, many thousands of cases have emerged; surveillance systems and the ability to provide drugs falter and conditions become more conducive for disease transmission.”

Nevertheless, Professor Kaye is committed to tackling leishmaniasis and improving global health for all.

Professor Kaye's research at Hull York Medical School exemplifies the potential of multidisciplinary collaboration and international partnerships to combat neglected tropical diseases, across multiple continents.

Their collaborations with researchers across the globe are vital, enabling them to set up immunology labs in countries heavily affected by the disease. The goal is to empower local researchers, fostering self-sufficiency in conducting research that addresses the unique challenges of endemic regions.

Professor Kaye explained, “The model now is as much as possible for the research to be done in countries where disease is endemic. This involves us supporting capacity building and training and developing local infrastructure. We have helped to setup laboratories in affected countries, so they are self-sufficient to do this work.”

Through his innovative approaches, Professor Kaye continues to drive change in a disease often overshadowed by more prominent health concerns.

His work has been featured in a recent Nature article, ‘In search of a vaccine for leishmaniasis’, a feature focusing on how immunisation will provide much needed protection against the neglected parasitic disease in conflict zones.

As Professor Kaye and his team continues his research against leishmaniasis, his work carries the promise of improved prevention, and brighter prospects for affected communities worldwide.

For more information about this work, please contact Professor Paul Kaye, Professor of Immunology in the Experimental Medicine and Biomedicine group.