Very slow developing malaria pathogens could be suitable as a vaccine

A mosquito taking a blood meal. Malaria pathogens enter the host's skin with its saliva. Image: Antonio Lenzen, Heidelberg University Hospital

Scientists from the Heidelberg Medical Faculty at Heidelberg University, the Centre for Infectious Diseases at Heidelberg University Hospital and the German Center for Infection Research have successfully tested a new approach for a malaria vaccine in animal experiments: As a vaccine, they used genetically modified malaria parasites that developed normally in the mosquito but at a significantly slower rate in the mouse. When later infected with unmodified pathogens, the rodents were protected from severe illnesses and typical malaria symptoms did not occur. The results have been published online in the journal EMBO Molecular Medicine.

Vaccines against the tropical infectious disease malaria are the subject of intensive research worldwide. However, there is currently no vaccine that is sufficiently reliable and affordable. Scientists from the Faculty of Medicine at Heidelberg University, the Centre for Infectious Diseases at Heidelberg University Hospital (UKHD) and the German Center for Infection Research (DZIF) have developed a new approach that has already been successfully tested on animals. They used genetically modified malaria parasites that proliferated so slowly in mice after being transmitted by mosquitoes that the animals' immune system was able to fight them successfully. An immune memory was formed that protected the immunised animals to varying degrees from severe symptoms during subsequent malaria infections. The findings could support the development of reliable vaccines in the future. 

Dr Julia Sattler, DZIF scientist and first author of the recently published paper, was looking for a way to prepare the immune system for an infection with plasmodia in the best possible way. "The pathogen develops from the so-called sporozoites, which are transmitted through the mosquito bite, via stages in the liver to those in the blood, which cause the severe symptoms. Therefore, a complete 'harmless' infection should work best—better than, for example, individual protein fragments of the pathogens," she says. 

Slow development activates immune system in the long run

Research in a gene database helped in the search for a "harmless" Plasmodium parasite: half of the parasite's approximately 5,000 genes have already been decoded and described to a certain extent. It is known, which of these genes could influence the speed of development of the parasite in the blood. The team succeeded in cultivating 17 lines of the rodent parasite Plasmodium berghei, in each of which one of these developmental genes was switched off. Some of these lines actually developed at a significantly slower rate, but largely normally in the mosquito and the liver of infected mice. Two lines were successfully combated by the mice's immune system. 

"These two main candidates for a vaccine were also the slowest lines. They took around three to four times as long to develop and multiply as unmodified plasmodia," says Dr Sattler. The slowest line achieved the safest vaccination effect: in subsequent infections with unmodified pathogens after three, six and twelve months, none of the vaccinated animals died; they were either completely protected against malaria or developed only mild symptoms that healed on their own. 

Transfer of the method to humans challenging

The team led by Prof. Friedrich Frischknecht, research group leader at the Centre for Infectious Diseases at the UKHD and scientist in the DZIF research area Malaria and Neglected Tropical Diseases, is currently working on transferring the method to humans. The researchers have already produced two lines of the human malaria pathogen, Plasmodium falciparum, with a slower growth rate. However, Plasmodium falciparum does not reproduce in mice. 

"Although we can produce the genetically modified human-infecting parasites, they do not go through their complete development cycle in the laboratory. This makes it difficult to filter out the most suitable variants. So far, we have been using blood and cell cultures, but this is hardly comparable with the situation in living organisms," says Prof. Frischknecht. "We think that our approach is promising, but there is still a long way to go before we can test it on humans. Nevertheless, it is already providing us with valuable information for the development of reliable vaccines."

Reliable vaccine urgently needed

Around 250 million people contract malaria every year, some 95 per cent of them in Africa. More than 600,000 die from the disease every year, mainly children under the age of five. The pathogens are transmitted by mosquitoes and initially infect liver cells in the body. There they develop into an aggressive form that invades red blood cells, multiplies there en masse and destroys the blood cells in the process. This causes the often life-threatening symptoms of malaria: recurrent bouts of fever, anaemia, vascular occlusion and even organ failure and coma. Sooner or later, the pathogens develop resistance to medication. A vaccination would be a better solution. However, current vaccination approaches using fragments of certain pathogen proteins or degenerated complete parasites offer either only unsatisfactory protection against severe cases or are too expensive.

Sattler JM, Keiber L, Abdelrahim A, Zheng X, Jäcklin M, Zechel L, Moreau CA, Steinbrück S, Fischer M, Janse CJ, Hoffmann A, Hentzschel F, Frischknecht F; Experimental vaccination by single dose sporozoite injection of blood-stage attenuated malaria parasites; EMBO Mol Med Aug 5 2024, Epub, doi10.1038/s44321-024-00101-6

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