Malaria vaccine gets a parasite boost in the liver

Malaria continues to be one of the worst infectious disease threats to human health. According to the World Health Organization, there were 229 million clinical cases of malaria in 2019, with more than 400,000 deaths reported from the disease.¹..More than 140 years have passed since then Plasmodium malaria The parasite has been identified as the causative agent of malaria. Malaria is a vaccine that provides a high level of protection against. Plasmodium malaria The infection is not yet on the market.The production of such vaccines has been hampered by genomic complexity Plasmodium malaria, Has about 5,300 genes², And by the elaborate life cycle of the parasite.

writing Nature, Mwakingwe-Omari et al..³ Report vaccination strategies live, using the whole Plasmodium falciparum A parasite that provides an unparalleled level of protection against infection. This work represents a major advance in the quest for an effective malaria vaccine.

Human infection by Plasmodium falciparum It begins when a mosquito-borne parasite (in the form known as sporozoite) moves from the bloodstream to the liver and infects major cells in organs called hepatocytes (Figure 1). There, the parasite grows and replicates. This stage of the liver in its life cycle is not associated with the symptoms of any disease. Within a week, tens of thousands of parasites are produced in a form that can infect red blood cells. They enter the blood and multiply in red blood cells, which can cause illness and death.

Sporozoite and liver stage parasites, collectively referred to as pre-erythrocyte (PE) parasites, have been targets for vaccine development since observations over 50 years ago have raised interest as promising targets.These observations show that immunization with high doses of sporozoite attenuated by radiotherapy resulted in subsequent parasite infections in humans infected with malaria parasites in animal models and controlled human malaria infection (CHMI) test environments. Showed that it can give protection^Four,Five.. However, subsequent vaccine efforts have instead focused on developing malaria vaccines that target a single parasitic protein (called CSP) expressed at the PE stage.These efforts culminated in a licensed vaccine that provides moderate short-term protection against malaria.⁶.. Updated versions of CSP-based vaccines have achieved improved levels of protection in Phase II clinical trials⁷..

Given the limitations of the vaccine approach using a single parasite protein, vaccines using whole raw PE parasites that infect the liver but do not cause malaria have revived as a promising alternative strategy.⁸..Immunization due to replication deficiency Plasmodium falciparum Radiation attenuation sporozoite (PfLicense plate—RAS), which infects the liver but is unable to grow into a parasite at the liver stage, remains the most studied all-parasite vaccine to date. At high doses, this type of vaccine induces a strong defense against CHMI. When tested in Africa, it was less effective than that observed at CHMI, but provided protection against natural malaria infections.⁹..

In an all-parasite vaccine approach called chemical prophylaxis, sporozoite, which is completely infectious, is given with drugs such as chloroquin, which kills the form of the parasite’s blood stage. The chloroquine-supported form of this vaccine has been shown to provide sterile immunity in CHMI studies, even with one-eighteenth of the amount of parasites used by scientists in the study. PfLicense plate—RAS vaccine. However, evidence that the introduced parasites can transition to a lethal blood-stage infection, and that the blood-stage infection itself can impair defensive immunity at the liver stage, raises concerns about this approach. I will.^Ten..

To address these issues, Mwakingwe-Omari et al. Have reported a total parasite vaccine that administers the drug pyrimethamine a few days after immunization with infectious sporozoite. This timing of drug administration kills parasites at the liver stage during development in the liver (Figure 1). Low-dose vaccination using this approach had minimal protection against CHMI when tested with the same (homologous) parasite strain used for vaccination (NF54 of African origin). However, when the parasite dose was increased fourfold, nearly 90% of vaccinated individuals gained sterile immunity. This level of protection is comparable to that achieved against allogeneic parasite strains using the chloroquine vaccination approach.^Ten,11.. High levels of protection from homologous strains as a result of vaccination with chloroquine have also been confirmed by Mwakingwe-Omari et al.

Significant obstacles to the development of successful malaria vaccines Plasmodium falciparum stock.This partially explains the lower protection provided by high doses PfLicense plate—Comparison with the results of the CHMI trial, which tested protection against African RAS and homologous strains^12,13.. To test how pyrimethamine-treated all-parasite vaccination works outside the laboratory setting, Mwakingwe-Omari et al. Worked on a strain different from the NF54 strain used for vaccination (found in Brazil). CHMI was performed using 7G8 strain. Impressively, the author’s vaccination strategy maintained nearly 80% sterile immunity with 7G8 CHMI, even though the 7G8 strain was very different from hundreds of Africans. Plasmodium falciparum Strains characterized so far¹⁴, NF54 included.

The immune response underlying human all-parasite-borne vaccination protection is not well understood.Animal models show that immune cells called CD8T cells, which eliminate parasite-infected hepatocytes, play an important role.¹⁵.. Immunoprotection in Mwakingwe-Omari and colleagues’ studies has been correlated with a higher frequency of circulating subsets of γδ T cells, a type of immune cell that has been shown to promote superior response by CD8 T cells in animal models. It was.¹⁶..

Malaria rodent model¹⁷ It has been shown that the encounter between components of parasites (protein fragments called antigens) that are developing at the liver stage and components of the immune system is important for initiating an effective defense response against parasites. It has been. Well, Mwakingwe-Omari et al. For the first time in humans, we establish that antigens from parasites at the liver stage are important for the induction of immunity across resistant strains. Plasmodium falciparum infection. In addition, the author’s observation that pyrimethamine was not as protective as chloroquine was that the parasite developed an immune response by using a type of vaccination that achieved full liver stage development but was unable to proceed to the blood stage of infection. It suggests the possibility of further enhancement.

However, some problems remain that limit this type of vaccine approach to half of humans at risk of malaria. Of most concern is that three doses of these live parasite vaccines require strict compliance when taking the accompanying medications to prevent malaria caused by the vaccination. While this is feasible in controlled clinical trials, it is difficult to do when immunizing billions of people. Therefore, although there is strong evidence of immunity directed at the human liver stage as a result of vaccination and drug treatment of live parasites, a method of essentially weakening the parasites of the vaccine is desirable. This eliminates the need for associated parasite control agents and avoids associated safety issues. A genetically attenuated parasite vaccine. Parasites are weakened by engineered deletions of genes essential for liver stage development.¹⁸, May represent future strategies.

Another issue to consider is that the total parasite vaccine strategy now requires the production of sporozoite in live mosquitoes, which poses a daunting challenge in expanding production. This could be overcome by investing in technology that enables large-scale production of all sporozoite vaccines.

Finally, this study by Mwakingwe-Omari et al.. Enhanced the importance of PE antigens in inducing protective immunity after total parasite vaccination. Future efforts to identify which PE antigens are recognized by CD8 T cells should also reactivate the individual antigen vaccine approach. Investigating both of these immunization measures and the immune response to vaccination is a priority in the malaria-vaccine field and should certainly receive new impetus from the work of Mwakingwe-Omari and his colleagues.

Competing profits

SHIK is pursuing a genetically attenuated all-parasite approach to malaria vaccines.