Identification of gene in malarial parasite brings researchers one step closer to an effective live vaccine microbiologystudy

The malaria parasite is still killing almost half a million people every year. A project has now identified a gene that holds out the prospect of a safe, effective live vaccine. The study is published in PLOS One.

“There is probably no other disease in human history that has cost more human lives than malaria,” says biologist Volker Heussler. Although deaths from this mosquito-borne disease have declined in recent decades, it still kills more than 400,000 people annually, with more than 200 million new infections each year.

Measures such as insecticide-treated walls and mosquito nets do contain the disease. “But to permanently eradicate malaria, we also need effective, long-lasting vaccine protection,” says Heussler, Director of the Institute of Cell Biology at the University of Bern. It is precisely this that current vaccines do not offer, but Heussler’s team has taken a new approach and identified a gene in the malaria parasite that brings research one step closer to effective immunization.

The liver must be the final stop

One reason behind the difficulty is the complex life cycle of the Plasmodium falciparum parasite. This protozoan, a single-celled organism, enters human blood via a mosquito bite and quickly travels to the liver cells, where it multiplies over several days. Tens of thousands of parasites are then released into the blood, where they infect red blood cells and trigger severe bouts of fever.

Current approved vaccines target only a single parasite protein, activating a limited range of immune cells. The vaccine provides protection to a maximum of 70% of those vaccinated, lasting about a year without a booster before antibody levels decline. “While it’s, of course, better than nothing, it’s anything but ideal,” says Heussler.

Consequently, Heussler and his team, alongside other research groups, have adopted a new approach—a vaccine comprising a complete but weakened parasite. This offers the immune system many more targets, and similar types of vaccines have already been used successfully against viral infectious diseases such as measles. They are considered safe and have few side effects.

Previously, scientists attempted to weaken the malaria parasite using radiation, but this method lacked precision. However, researchers are now employing targeted genetic modifications to ensure the parasite reaches only the liver and is not released into the bloodstream, i.e., preventing it from causing malaria.

A further benefit of this approach is that the parasite remains in the liver for several days. These are ideal conditions for stimulating the immune system and forming memory cells, as previous research has shown. “The infection of the liver cells is a bottleneck, where we can arrest and eliminate the parasites,” explains Heussler.

Using large-scale screening, the researchers searched for genes whose loss does not kill the pathogen but halts its development in the liver phase. They tested 1,500 different parasite variants, each with a different gene knocked out. For these studies, they used the protozoan Plasmodium berghei, a close relative of Plasmodium falciparum that infects mice rather than humans.

The danger of breakthrough infections

As hoped, they found a genetically modified parasite with the required characteristics. It traveled to and multiplied in the liver but was not then released into the blood. This weakened pathogen could be a strong candidate for effective immunization. However, Heussler urges caution. “With a vaccine that will be administered millions of times, we have to be sure that the weakened parasite doesn’t break through in isolated cases and cause malaria.” This risk could arise if the protozoa have an alternative, albeit rarely used or less effective, metabolic pathway to bypass the intended blockage.

To avoid these types of devastating breakthroughs, it would ideally be necessary to have a parasite that is weakened in several ways, i.e., in which at least two genes are knocked out, impairing different metabolic pathways. Heussler has now been able to generate and test such a double knockout: In addition to the gene found by his group, he also switched off another gene in the pathogen. This gene, identified by a U.S. research group, similarly arrested the parasite in the liver phase.

The first trials with the double-attenuated parasite produced extremely promising results. The mice vaccinated with it were fully protected against malaria and did not fall ill as a result of vaccination, even at a very high dose. Heussler now hopes that these results can be transferred to the human parasite Plasmodium falciparum. However, a truly safe vaccine is still a long way off. It may even require a triple knockout. “If breakthroughs still occurred, the new vaccine could be discarded immediately.”