The malaria pathogen develops in its human host in several stages. Initially, sporozoites, which are transmitted by mosquitoes during blood feeding, quickly penetrate the liver cells. Here they reproduce asexually before they enter the bloodstream and penetrate the erythrocytes (red blood cells).

Clinical malaria is caused by the red blood cell stages, while sporozoites and parasites in the liver stage do not cause symptoms of the disease.

Great strides have been made in malaria elimination this century, including the recent announcement that the WHO declared China malaria-free. This success was mainly achieved through control measures aimed at the transmission of the parasite by mosquitoes, as well as through rapid diagnosis and treatment. However, progress in eliminating malaria in many other countries has been limited over the past decade, confirming the need for a high-potency vaccine as the ultimate solution to eradicating this mosquito-borne disease. Of the five types of malaria that infect humans, Plasmodium falciparum is the deadliest, and this is the focus of attempts to make an effective vaccine.

A promising concept that is currently being developed is to attack the pre-erythrocytic stages of the parasite, thus providing protection before symptoms appear.

Pre-erythrocyte stage vaccines

One approach has been to use a vaccine that targets an abundant molecule on the surface of sporozoites – the circumsporozoite protein. This vaccine, named RTS, S and also known as Mosquirix, has been shown to provide short-term protection for very young children in a Phase II study involving over 12,000 children in African countries.

Malaria sporozoites. Source: fiickr.com. Credit Electric Manna, NIAID.

Another approach has been to inoculate whole sporozoites that have been irradiated or genetically attenuated so that they enter the liver, but then their development stops. This would elicit an immunological response but not cause clinical systems. This is the concept behind a vaccine developed by Sanaria Inc. of Rockville, Maryland, called the Sanaria PfSPZ vaccine. It has been shown to protect against the same strain of parasites used in the vaccine (homologous) and in the field, against different (heterologous) strains, but with reduced efficacy in laboratory-based controlled human malaria infections (CHMI).

Use of live undefeated parasites

Sanaria’s latest vaccine developments have gone a step further and their new vaccines contain live ones P. falciparum Sporozoites that are still infectious. To prevent the development of clinical malaria, the vaccination regimen involves the administration of anti-malarial prophylaxis. This is known as chemoprophylaxis vaccination (CVac). Using chloroquine, which kills parasites once they enter the bloodstream, they reported that the PfSPZ-CVac (CQ) vaccine provides good, long-lasting protection against the same strain of parasites as the homologous strain used in the vaccine, even at low levels Cans.

It appeared that exposure of the immune system to blood stage parasites might be a requirement for this vaccine to work, but is there any chance that parasites could escape chloroquine treatment and lead to vaccination-induced infection?

Another concern was that the PfSPZ-CVac (CQ) vaccine did not appear to protect against heterologous strains. Because there is a wide variety of varieties P. falciparum a marketable vaccine would have to protect against many strains worldwide.

A multi-author article by Mwakingwe-Omari and colleagues recently published in Nature describes a further development that addresses these concerns.

Last development

Their new experimental regime included:

i) CHMI using their original vaccine PfSPZ-CVac (CQ) or PfSPZ-CVac with a different prophylaxis, pyrimethamine, PfSPZ-CVac (PYR). Pyrimethamine kills parasites earlier than chloroquine while they are still multiplying in the liver cells and before they enter the bloodstream.

ii) Low and high doses of vaccine were tested.

iii) The strain of malaria used to make these vaccines comes from West Africa. In the CHMI studies, they challenged this homologous staining, but also a strain from Brazil (heterologous strain) that has a highly divergent genome, proteome and CD8 T-cell immunome.

The previously shown high degree of protection of PfSPZ-CVac (CQ) against homologous provocation was confirmed and fortunately a four-fold increase in dose achieved 100% protection against the heterologous strain.

Malaria parasites in the liver stage. Attribution: Janse ~ enwiki, CC BY-SA 3.0, via Wikimedia Commons

Increasing the vaccine dose also improved the effectiveness of PfSPZ-CVac (PYR), which reached 88% for homologous and 78% for heterologous CHMI provocation 3 months after vaccination. This level of protection was better than irradiated sporozoites and showed that exposure to parasites at the blood stage is not required.

An immune response that includes a subset of T-cell expansion was generated by both vaccines and increased from the low to the high dose of PfSPZ-CVac (PYR). This showed that antigens from parasites at the liver stage are important initiators of immunity. Further studies comparing these two vaccines could provide more information about the development of an immune response from malaria parasites.

As expected, subpatented parasitemia was detected by quantitative PCR (but not by microscopic analysis) in all participants vaccinated with PfSPZ-CVac (CQ) and occurred before chloroquine was able to clear the parasites. The potential for breakthrough parasitemia could be a problem in the area where immunization compliance is not 100% for many.

No parasitemia was found in the participants vaccinated with PfSPZ-CVac (PYR), as no parasites entered the blood.

What now?

The protection the PfSPZ-CVac (PYR) offers in these clinical trials is impressive and a field trial in Mali is currently ongoing. Although the vaccination regimen can be difficult to use in the field due to compliance issues, the authors note that pyrimethamine is widely used for prophylaxis in parts of Africa and has an excellent safety profile. It would be challenging to increase sporozoite production (currently extracted from infected mosquitoes) to the number required to deliver millions of doses. However, the authors suggest that this approach might prove suitable for travelers visiting Africa for a short period of time. You will most likely stick to the three-dose vaccination schedule and accompanying drug treatment, and would require far fewer doses than would be required to cover populations exposed to malaria.

In the future, a vaccine based on genetically modified parasites that live longer in the liver but cannot get into the bloodstream may be preferable as it would expose the immune system more than currently available GM parasites and eliminate the need for pyrimethamine treatment .

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