An early-stage clinical trial of an unusual experimental malaria vaccine shows it is safe, generates an immune response, and may provide 100% protection against malaria infection in healthy adults, the best result for a malaria vaccine so far.

The trial tested the PfSPZ vaccine, developed by Sanaria Inc of Rockville, Maryland, in the US.

The trial investigators included researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health in the US, and other collaborators, who write about their findings in this week's online issue of Science.

No current vaccine for malaria

According to the World Health Organization (WHO), over 200 million people worldwide became infected with malaria in 2010, and over 600,000 died of it, most of them young children in Africa where a child dies of malaria every minute.

There is currently no vaccine for malaria, which is caused by five different strains of Plasmodium, a parasite that lives in the gut of the female Anopheles mosquito and passes to humans through her bite.

This video at YouTube shows a mosquito hunting for a blood vessel:

The infectious parasites delivered to the body via the mosquito are in the immature phase (called sporozoite). They travel to and multiply in liver cells that eventually burst and release mature parasites into the bloodstream, at which time symptoms develop.

New vaccine uses live weakened parasite

The PfSPZ vaccine is unusual in that it does not use a handful of parasite proteins to provoke a immune response but live weakened forms of the whole, immature, "sporozoite" phase of the parasite.

Stephen Hoffman, CEO of Sanaria, has been on a quest to find a malaria vaccine for decades. His unusual approach of using the whole weakened form of the parasite dates back to experiments he carried out in the 1970s.

Stephen Hoffman hit the headlines in 2008 when he experimented on himself by allowing irradiated malaria-infected mosquitoes to bite his arm.

Now many experiments later, the same idea is behind the PfSPZ vaccine tested in this latest trial.

The challenge to produce the vaccine was huge. Mosquitoes had to be bred in sterile conditions on a massive scale, fed on parasite infected blood, and then irradiated to weaken the parasite - but not kill it - so it can infect people but not cause disease.

Then billions of weakened parasites (in their immature sporozoite phase) had to be harvested from the salivary glands of the irradiated mosquitoes, purified, and frozen.

The promise of the PfSPZ vaccine

The PfSPZ vaccine has been tested in a phase I clinical trial, which took place at the NIAID Vaccine Research Center, in Bethesda, Maryland, and recruited 40 adult volunteers aged 20 to 44. The participants were given a range of intravenous vaccine doses, and some (the controls) were not vaccinated at all.

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Mosquitos transfer malaria by passing a parasite from its gut into the bloodstream of humans when it bites.

They were then monitored closely for 7 days after vaccination, during which the researchers observed no serious adverse effects, and no malaria infections, related to the vaccinations.

Blood tests showed that the participants who received the highest total dosage of vaccine made more antibodies against malaria and more immune system T-cells specific to the vaccine.

The effectiveness of the vaccine was then tested in the standard way for malaria vaccine testing. Three weeks after the final vaccination, both the vaccinated and non-vaccinated participants were exposed to bites by five mosquitoes carrying the P. falciparum strain, the same one the vaccine was made from.

Effective at high dosage

The results showed that higher dosages of the intravenous vaccine were linked to protection against malaria.

All six participants who received five doses remained free of malaria, while five of the six unvaccinated participants were infected, as were three of the nine who received only four doses of the vaccine.

Principal trial investigator Robert A. Seder, chief of the Cellular Immunology Section of the NIAID Vaccine Research Center, told the press:

"In this trial, we showed in principle that sporozoites can be developed into a malaria vaccine that confers high levels of protection and is made using the good manufacturing practices that are required for vaccine licensure."

Future challenges and plans

An important challenge for the future of the PfSPZ Vaccine is the fact its success relies on it having to be given intravenously, which is unusual for a vaccine.

Previous studies of the same vaccine have shown that the more common ways of giving vaccines, such as into the skin (intradermal) or under the skin (subcutaneous), were not as effective and did not produce as strong an immune response as the intraveous route.

It was the results of an intradermal and subcutaneous trial of PfSPZ that caused this team to push ahead with an intravenous trial.

Seder says:

"Despite this challenge, these trial results are a promising first step in generating high-level protection against malaria, and they allow for future studies to optimize the dose, schedule and delivery route of the candidate vaccine."

The researchers are now planning further studies of the vaccine, including ones that will evaluate different doses, whether it works against other strains of Plasmodium, and how long the protection lasts.

They may also revisit the possibility that subcutaneous or intradermal delivery will give the same level of protection as seen in this study.

A statement from Sanaria says the vaccine developer expects future clinical trials in Africa, the US and Europe will lead to licensing of "an affordable vaccine" for use in mass campaigns in countries most affected by malaria, predominantly in Africa, where most victims are children.

The company says the vaccine is also intended for use by tourists, business people, diplomats, aid workers, and the military.

Written by Catharine Paddock PhD