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29 Jun 2020

Forming a front-line defence against malaria

Malaria research has been bolstered by a new vaccine strategy that builds an army of parasite-killing immune cells in the liver, squashing the infection before it enters the blood stream.

By Dr Lauren Holz and Yu Cheng Chua at the Doherty Institute

The malaria parasite is as complex as it is lethal. With thousands of different variations wreaking havoc across the globe, it’s extremely dangerous for our planet’s most vulnerable populations, such as those in resource-poor nations. It’s estimated that there are more than 200 million cases of malaria each year and, devastatingly, almost half a million deaths[1]. To put this in perspective, it’s roughly the equivalent of the current death toll that’s attributed to COVID-19 at the time of writing - every single year.

The need for an effective global malaria vaccine is urgent, but it’s a challenge that has been baffling scientists for more than 30 years. Building upon the latest research, however, our team has developed a powerful vaccine strategy that develops immunity in the liver through generating immune-fighting tissue resident memory cells (Trm). The result, published in Science Immunology, could be the most promising vaccine candidate to date.

The window of opportunity

The research centres around a crucial stage in the life cycle of malaria, which takes place in the liver. The malaria lifecycle begins with a mosquito that transmits immature Plasmodium parasites through a small bite on the skin, setting a dangerous chain of events into motion. The parasites infect the liver, where they quietly develop and mature for several days, before they are released in to the blood stream and run rampant. The parasites multiply by millions, infecting red blood cells and causing symptoms that can include fever, multi-organ failure and - for some - death.  

For decades, malaria vaccine research has targeted the blood stage of the infection. However, there’s a distinct window of opportunity prior to this where you can eliminate the parasites in the liver to prevent the blood stage of the infection. Through using a vaccine to generate Trm cells in the liver, you can produce an army of cells that will patrol the liver looking for infection, and rapidly eliminate an infection as soon as its identified.

Our research investigated the effectiveness of using a vaccine - the glycolipid-peptide conjugate vaccine – to generate Trm cells in the liver and offer protection from malaria. We tested our approach in mice, finding that the vaccine was powerfully effective, generating an abundance of Trm cells and offering the mice complete protection from the parasite. We compared the efficacy of our vaccine side-by-side to the current gold standard malaria vaccine, radiation-attenuated sporozoites (RAS), and found that the new vaccine was much more effective at generating liver Trm cells and protecting mice from malaria.

There were several additional strengths to the new vaccine to note. Firstly, the malaria-specific Trm cells it generates are long-lived and have a half-life of more than 400 days. Trm cells generated by other vaccination strategies, such as RAS, can also eliminate parasites in the liver but require multiple doses to generate protection and the Trm cells have a much shorter half-life (under two months), so our novel vaccine protects for much longer. Secondly, the vaccine has a straightforward delivery; a single vaccine generates a large number of malaria specific Trm cells and can be utilised again and again to offer protection from the malaria parasite.

Essentially, our team has produced an incredibly promising vaccine.

A collaborative effort

The journey to producing a vaccine candidate can be a long one, and the research behind the glycolipid-peptide conjugate vaccine is no different.

Around five years ago, the Heath laboratory, based at the Doherty Institute, began collaborating with our New Zealand colleagues at Avalia Immunotherapies on this research. This includes Professor Gavin Painter, also based at the Ferrier Research Institute, and Professor Ian Hermans, from the Malaghan Institute of Medical Research, who were essential in supporting the creation of this vaccine.

As the chemist, Professor Painter and his team were responsible for generating our vaccine, while research by Professor Hermans on natural killer T (NKT) cells, which are also activated by our vaccine, underpinned the development of this novel vaccine platform.

At the Doherty Institute, many of our scientists with wide-ranging expertise were brought together to contribute to this research. This includes researchers in the Godfrey laboratory and Turner laboratory (now based at Monash University), with expertise in innate immunology and adaptive immunology, and others specialising in malaria and Trm cells.  

It’s through our collaborative and collegial research community that innovative approaches to vaccines can be produced. It’s also the strength of this community that will support the continued development of the glycolipid-peptide conjugate vaccine in carrying this research forward.

Our vaccine is only a small step away from testing in humans. To get to this next level, we need to identify human malaria targets to combine with our vaccine. This goal is being hotly pursued with our New Zealand collaborators and Avalia Immunotherapies and is within sight of achievement.

This research offers a successful vaccine strategy for providing protection against malaria that’s simple, powerful and effective. It opens the door for further research into Trm cells and brings us closer towards developing an effective malaria vaccine for global use.