September 24, 2021

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Nature: How to use live vaccines to eradicate malaria?

Nature: How to use live vaccines to eradicate malaria? 

Nature: How to use live vaccines to eradicate malaria?

Nature: How to use live vaccines to eradicate malaria?  For a long time, malaria is one of the most serious diseases threatening human health. According to the World Health Organization, there were 229 million clinical cases of malaria worldwide in 2019, and more than 400,000 people died from this disease.

Vaccines are an important means to eliminate infectious diseases. Since Plasmodium Parasites was identified as a pathogen of malaria more than a hundred years ago, the academic community has been working hard to develop a highly effective vaccine against malaria infection. However, no anti-malarial vaccine has been put on the market so far. The challenge of research and development comes from the complex pathogen genome (more than 5300 genes) and the complex life cycle (blood-liver-blood).

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In order to overcome these challenges, Agnes Mwakingwe-Omari of the GlaxoSmithKline Vaccine Research Center in Rockville, Maryland, USA, reported the use of complete live Plasmodium falciparum (Plasmodium falciparum) as a vaccine, supplemented with chemical drugs (pyrimethamine). And chloroquine) to control the new vaccination strategy. Related research results were published in the top journal Nature[1].


https://www.nature.com/articles/s41586-021-03684-z

Their live vaccination strategy is based on the life history of the malaria pathogen-Plasmodium in the human body. The malaria parasite enters the blood through the bite of Anopheles mosquitoes and transfers to the liver in the form of sporozoites to proliferate in the liver cell vacuoles (vacuolar). No symptoms sometimes appear, and then the malaria parasite returns to the bloodstream, invading red blood cells and causing disease symptoms (Figure 2). The sporozoite and liver stage parasites, also known as pre-erythrocyte stage (PE) parasites, are important targets for vaccine development.

Nature: How to use live vaccines to eradicate malaria? 
Figure 2. Life history of malaria parasites in humans and vaccine development strategies

Image source: Nature[2]

Previous studies have used radiation-attenuated live vaccination (Pf SPZ-RAS) strategy. After vaccination, the vaccine cannot proliferate in the liver, and the protection against malaria is weak. Mwakingwe-Omari and others chose complete live parasites as vaccines, supplemented by drug treatment to kill parasites in a specific period of their life history to achieve the immune effect, for which they carried out a series of clinical experiments.

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In low-dose experiments, they compared the safety and effectiveness of live vaccines (dose 5.12 × 10E4) supplemented with chloroquine (CQ) and pyrimethamine (PYR). The results show that pyrimethamine can kill parasites that reside in the middle stage of liver development. This vaccination method can minimize human malaria infections (CHMI) caused by homologous pathogens (the African pathogen homologous to the vaccination, NF54) ( image 3).

Nature: How to use live vaccines to eradicate malaria? 
Figure 3. Quantitative PCR detection of resident parasites in the human liver after inoculation with live vaccines supplemented with drugs. Image source: Nature[1]

However, in the high-dose vaccination (dose 2×105) experiment, 87.5% and 77.8% of the vaccinators in the live vaccination supplemented with pyrimethamine treatment group [PfSPZ-CVac(PYR)] effectively controlled the homologous pathogen (N54 ) And human malaria infections with heterologous pathogens (South American pathogen 7G8 which is different from the vaccination). The live vaccination supplemented with chloroquine treatment group [PfSPZ-CVac(CQ)] showed that 100% of the vaccinators effectively controlled human malaria infections with heterologous pathogens (7-8) (Figure 4).

Nature: How to use live vaccines to eradicate malaria? 
Figure 4. Effective control rate of PfSPZ-CVac (PYR) and PfSPZ-CVac (CQ) against homologous and heterologous pathogen infections Picture source: Nature[1]

At present, the internal mechanism of the intact live vaccine inducing immune response in the human body is still unclear. However, previous studies in animal models have shown that immune cells CD8T play a key role in eliminating the infection of parasites on liver cells. The study by Mwakin-gwe-Omari et al. found that the immune protection is related to the high-frequency circulation of γδ T cell subsets, which promoted the superior responses of CD8 T cells in animal models (Figure 5).


Figure 5. Vδ2 γδ T cells are related to immune protection

Image source: Nature[1]

They also studied the antibody response of live vaccination supplemented with drug therapy (PfSPZ-CVac) strategy. Enzyme-linked immunosorbent analysis (ELISA) showed that the median expression level of the antibody IgG PfCSP in the vaccine-protected group was higher than that in the unvaccinated infection group.

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In short, Mwakingwe Omari et al. demonstrated for the first time in human experiments that antibodies from liver-resident parasites are essential for inducing long-lasting anti-malarial immunity that transcends strain boundaries. In addition, they observed that the protective effect of pyrimethamine is not as good as that of chloroquine. This implies that the intact hepatic development of the parasite can be maintained during vaccine development without entering the blood infection phase, so as to further enhance the immune response.

Of course, there are still many problems that need to be solved for the method of live vaccination supplemented by drugs to move towards clinical application:

1. The vaccinated person has to vaccinate three times and take antimalarial drugs in strict accordance with the regulations in the later stage. Such strict control conditions are difficult to implement among billions of people. Future research also needs to detoxify live vaccines in essence, not drug control.

2. There are technical challenges in the large-scale production of live vaccines.

3. Future research needs to determine which antigens of pre-erythrocytic vaccines are recognized by CD8 T cells in order to develop personalized antigen vaccines.

(source:internet, reference only)


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