Towards a vaccine against the most neglected of neglected tropical diseases?

Discovery of vaccine target for devastating livestock disease could change lives of millions in sub-Saharan Africa.

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The first time I became aware of African trypanosomiasis was in Saint Camille General Reference Hospital of Kabinda, a city in the Kasai-oriental province of the Democratic Republic of Congo. During the few weeks I spent in the medical biology lab of the hospital for the French NGO ‘Biologie Sans Frontières’, at least one person was diagnosed with the Human African trypanosomiasis (HAT) or Sleeping sickness. I clearly remember seeing the elongated trypanosome parasites wriggling in a biopsy of a patient on a microscope slide prepared by a medical technician because he knew of my interest in parasites. That moment was in 2010, and since then, HAT cases have gradually dropped from an estimated 10,000 clinical cases to below 1000 cases in 2019. This progress towards controlling this disease is mainly due to improved diagnostics and treatment accessibility, as well as implementation of control measures for the tsetse fly – the blood feeding insect vector that transmits these parasites. Lessons from other insect-borne diseases such as malaria, however, suggest that these successes may be only temporary due to increasing drug resistance and the existence of animal reservoirs. The development and deployment of an effective vaccine against HAT would be the ideal solution to safeguard the 65 million people who live at risk of this disease.

While I was in Kabinda, I didn’t realise that Neglected Tropical diseases also affect animals, which included trypanosome parasites. In animals, the disease is called Animal African trypanosomiasis or Nagana which comes from the Zulu word that means ‘depressed spirit’. Different species of Trypanosome infect a wide spectrum of animals including the native fauna and domestic livestock. The infections cause severe clinical symptoms that include severe anaemia and lethargy and are responsible for the deaths of over 3 million cattle every year. As a consequence, this disease means that people living in the tsetse belt of Africa struggle to keep alive the cows, goats and pigs which they depend on for milk, food and draught power. Such is the impact of this disease on human livelihoods that the Food and Agriculture Organisation of the United Nations described this disease to “lie at the heart of Africa’s struggles against poverty”.

Despite the considerable impact of this livestock disease on human livelihoods, there has been comparatively little attention on the two main trypanosome species responsible for Nagana, Trypanosoma vivax and Trypanosoma congolense.

For our vaccine study, we decided to focus on T. vivax because its cell surface-associated proteins have been well characterised, and an experimentally-tractable mouse infection model was available. T. vivax shares many features with the other African trypanosomes but one major and important difference is its ability to be transmitted by blood-feeding insects other than tsetse flies which explains why the parasite has been exported and can be transmitted in counties outside of Africa. T. vivax is now becoming an increasing threat in at least 13 countries within South America.

T. vivax bloodstream parasite isolated from blood and visualised using electron microscopy. Image credit: David Goulding Sanger Institute

African trypanosomes are fascinating organisms because they are able to thrive directly within host blood despite being constantly exposed to the immune system.

Like chameleons, which change the colour of their skin to stay invisible in their environment, trypanosomes continuously change the molecular shape of their surface using variants of a variable surface glycoprotein (VSG) that covers their surface. This well-described process, called “antigenic variation”, render the host immune system ineffective and allow the parasites to establish chronic infections that are characterised by recurrent waves of parasites.

The trypanosome cell surface has evolved in such a way that it is almost impenetrable to host antibodies. This is due to the VSGs that form a densely-packed shield that is constantly changing by a dynamic recycling process where the proteins expressed on their surface are internalised into a specialised organelle localised at the base of their flagellum called the flagella pocket which clears surface-bound antibodies in a matter of seconds.  

These different lines of defence allow trypanosomes to prevent the host from acquiring high titres of antibodies directed against invariant surface proteins that might be essential for their survival.

Because trypanosomes have developed sophisticated mechanisms to escape the host immune system, vaccination against these organisms was thought to be unachievable. The most realistic option for developing a vaccine against trypanosomes appeared to be an anti-disease vaccine targeting the symptoms of the infection rather than the parasites themselves.

Using a genome-led vaccinology approach, we identified one invariant surface protein localised at the boundary between the flagellum and the cell body of the parasite that, when used as a vaccine, induces protective immunity against T. vivax infection. We named this protein IFX for Invariant Flagellum vivaX antigen.

Immunofluorescence staining of T. vivax with rabbit anti-IFX antiserum (red) counterstained with DAPI (blue) demonstrates localization of IFX to the flagellum

 Animals vaccinated with IFX elicited long-lasting immunity to T. vivax infection because they were still protected 150 days after the last vaccination. An important question to address is to understand what makes IFX a good vaccine target: it is due to its specific localisation, a difference in the kinetics of its cell surface recycling, or both? This would help us to identify other potential vaccine targets for T. vivax or, crucially, other trypanosome species that cause disease.

Our results showed that antibodies elicited by IFX vaccination are important for protection against trypanosomes. We found that the antibody isotype able to recruit immune effectors such as complement and bind activating Fc receptors, substantially increase the potency of trypanosome clearance. To practically show the usefulness of this result, we demonstrated that a vaccine formulation using an adjuvant that biases the elicited antibody isotype towards these immune-effector recruiting antibody isotypes was more effective. These findings suggest an important role for antibody-mediated immune effector recruitment in the control of trypanosome infections which has also been demonstrated for other parasitic diseases such as malaria.

The next important step will be to replicate these results in cattle, the main target animal for Nagana. This will involve developing a cattle model of T. vivax infection suitable for vaccine studies, and filling in some gaps in cattle immunology such as defining which antibody isotypes are able to recruit immune effectors in cattle.

Our results raise the possibility that vaccination against trypanosomes is achievable and could pave the way for finding vaccine candidates against life-threatening diseases amongst the Neglected tropical diseases, including Sleeping sickness and Chagas disease.

Delphine Autheman

Post-doctoral researcher, Wellcome Sanger Institute