A new method for creating an antimalarial vaccine
Malaria vaccine: really yes?
Maxim Rousseau, Polit.roo
Scientists have announced the creation of a powerful and safe vaccine against malaria. To do this, they changed only three genes in the genome of the causative agent of this disease. The first experimental tests of the new vaccine have demonstrated its high effectiveness, so perhaps the long-standing dream of doctors about an antimalarial vaccine is finally close to fulfillment.
Malaria affects more than 200 million people annually, mainly in tropical and subtropical countries. More than 400 thousand sick people die. People in Africa and Southeast Asia are most affected by malaria. A vaccine against this disease could save many lives, but it is extremely difficult to create it because of the biological characteristics of its causative agent - a single–celled creature, malarial plasmodium.
Recall that human disease is caused by four representatives of the genus Plasmodium: Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale and Plasmodium malariae. Up to 90% of cases of the disease are accounted for by one of them – Plasmodium falciparum.After the bite of a malarial mosquito, plasmodia that have penetrated into the human body with blood flow enter the liver and are introduced into its cells. It takes them only about half an hour. Plasmodia divide repeatedly inside liver cells. After some time, a new generation of plasmodium penetrates not into liver cells, but into red blood cells. Inside the red blood cells, they continue to divide until the blood cells burst and the red blood cells that overflowed them come out into the blood plasma. This happens synchronously and with a clear periodicity, depending on the type of plasmodium, once every 48 or 72 hours. It is at these moments that the patient has an attack: the temperature rises, chills appear, and so on. Plasmodium cells re-penetrate into red blood cells and the process is repeated many times. Finally, plasmodia interrupt the cycle of asexual reproduction and form cells of the sexual stage – gametocytes. They remain inside the red blood cells until they are lucky enough to get into the intestines of a malarial mosquito that has bitten a sick person. In the mosquito's body, gametocytes merge, the formed cells divide repeatedly again and rush into the salivary glands of the insect in order to get into the human body from there.
Immunity to malaria, whether natural or artificial, occurs with difficulty. In people who have been ill, resistance to the pathogen usually occurs only after several infections. Moreover, their immunity acts not only on one of the four types of plasmodium, but only on a certain strain of it. The thing is that plasmodium has a high frequency of mutations. As a result, the structure of proteins on the surface of its cells often changes, so the antibodies that provide immunity cease to recognize these cells.
Therefore, the most commonly used means of combating malaria are not aimed at preventing the disease, but at combating the pathogen that has already entered the body (quinine, chloroquine, artemisinin). There are also methods aimed at malaria vectors – mosquitoes from the genus Anopheles. For example, with the help of genome editing, mosquitoes are made unable to tolerate malaria, or drugs are offered from which mosquitoes that have drunk blood die. Preventive agents such as repellents and mosquito nets also play an important role in the fight against malaria.
But scientists do not stop trying to create a vaccine that would make many people immune to malaria at once. The most successful example until recently was the RTS vaccine, S/AS01, known by the commercial name Mosquirix. The European Medicines Agency approved its use in the summer of 2015. At the moment, this is the only licensed malaria vaccine. The vaccine was conceived and created in the late 1980s by Belgian scientists from SmithKline Beecham Biologicals (now it is called GlaxoSmithKline Vaccines). Later, scientists from the Walter Reed Military Institute of the US Department of Defense participated in its development, and the Bill and Belinda Gates Foundation and PATH were engaged in financing.
The RTS,S/AS01 vaccine uses the gene of one of the Plasmodium falciparum proteins, as well as the protein envelope of the hepatitis B virus. After receiving the vaccine, antibodies begin to be produced in the body that prevent the penetration of plasmodium into liver cells. But the effectiveness of the RTS,S/AS01 vaccine is low – it ranges from 27% to 39% when vaccinating infants. At the same time, patients need to be vaccinated four times. But this is the best that scientists could offer, so in 2018 a large-scale campaign for antimalarial vaccination in three countries of tropical Africa is already planned.
Other strategies were also proposed, implying the use of "live vaccines", that is, the malaria plasmodia themselves, weakened by radiation, so that they could no longer infect the body's cells, but served to train the immune system to recognize similar full-fledged pathogens. A very extreme method involved intentionally infecting people with malaria, followed by the use of antimalarial drugs to cure them quickly, giving the body immunity. These methods turned out to be ineffective for the same reason that makes it difficult for people who have been ill to develop natural immunity. Plasmodium is too volatile.
The new method is based on the results of reading the genome of malaria plasmodium. The Plasmodium falciparum genome was decoded in 2002 (the genome of the main malaria vector of the Anopheles gambiae mosquito was decoded at the same time), and in 2008 the Plasmodium vivax genome was also sequenced. At the same time, more than 5,300 genes were identified, including those responsible for important functions for plasmodium, for example, penetration into red blood cells or the formation of hypnozoite, a "sleeping cell" that is at rest inside liver cells and can cause the disease to return years later.
A group of scientists led by parasitologist Stefan Kappe from the Center for the Study of Infectious Diseases in Seattle has created a "genetically attenuated parasite" (GAP). This is a form of Plasmodium falciparum, in which three genes that allow plasmodium to move in the blood stream are disabled.
In the experiment, GAP was injected into experimental mice, which then received full-fledged plasmodium. The mice were completely protected from the disease. The scientists then infected GAP with malaria mosquitoes. Ten volunteer people gave themselves to be bitten by these mosquitoes (each got 150-200 bites). None of the participants in the experiment showed signs of malaria, and a large number of antibodies were found in their blood. The results of the work are published in the journal Science Translational Medicine (Kublin et al., Complete attention of genetically engineered Plasmodium falciparum sporozoites in human subjects).
Of course, the new method does not solve the problem of variability of the causative agent of malaria. It is still tied to a specific strain and its closest varieties. But in the first test, it showed significantly higher efficiency than its main competitor. The new method has a significant advantage in comparison with the use of plasmodium weakened by radiation. Radioactive radiation damages plasmodium DNA in random places, whereas now scientists can control that the right genes are turned off.
But we must not forget that from the first experiment to the full proof of the effectiveness and safety of the new vaccine, there is still a long way to go, in which large-scale clinical trials with a large number of participants will be required. So far, only the safety of the vaccine has been established on the first ten volunteers. The next stage of the test should be the infection of volunteers who received the vaccine with a viable strain of plasmodium (in case of the first symptoms of the disease, participants in such experiments, of course, are immediately given antimalarial drugs). The creators of the vaccine have planned this test for 2017.
The method of vaccination through mosquito bites, which was used in the first experiment, will be difficult to implement if the vaccine is used for large populations. Therefore, it is necessary to invent a method of cultivating genetically weakened plasmodia in the laboratory to make a vaccine out of them. Also, Stefan Kappe does not rule out that some more genes will be turned off in plasmodium if it turns out that in this case the vaccine will be more effective.
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10.01.2017