PfSPZ Vaccine

In the first half of the 20th century there were first attempts to protect people from malaria. At the beginning Pasteur´s approach of developing bacterial vaccines was used as a big hope in eradication of this fatal disease. But inactivated malaria sporozoites (by formalin) were ineffective in inducing the protection.

In 1948 inactivated merozoites with an adjuvant were used for preventing lethal malaria to kill a group of monkeys. But the strong toxicity of the adjuvant and inability to obtain sufficient count of parasites from human blood stopped further efforts in this way.[1]

In 1967 irradiated malaria sporozoites (extracted from salivary glands of infected mosquitos) induced immune response in mice without the need of the adjuvant and similar evidence obtained in human volunteer trials. The mice were exposed to irradiated mosquitos infected by malaria parasites. Mice and volunteers did not acquire malaria because mosquitos and the sporozoites were irradiated and their immune cells triggered response that could protect them from following infection.[2][3] Yet this approach was not further developed during problems with obtaining sufficient number of sporozoites and with the harvesting of parasites.

Later, modern adjuvants and the possibility of preparing of single parasite proteins started another way to obtain malaria vaccine. Today, a vaccine called RTS,S based on coat protein of sporozoites of the Plasmodium falciparum is the most advanced subunit vaccine and is in the phase III clinical trials. It protects about 50% of subjects infected by controlled human malaria infection (CHMI) after 2 – 3 weeks and about 23% at 5 months after last immunization.[4] In large III phase trial in Africa RTS,S/AS01 reduced acquired malaria over a 12 months period by 31,3% and 36,6%.[5]

In 2003 Sanaria ran trials in which falciparum sporozoites were manually dissected from salivary glands of mosquitos, irradiated and preserved before inoculation with one goal: to develop and commercialize a non-replicating, metabolically active PfSPZ vaccine.[6]

In human volunteer trials PfSPZ was applied subcutaneously (SC) or intradermally (ID) and such as it showed only modest immune response. When PfSPZ Vaccine was injected intravenously (IV) to nonhuman primates or mice it finally triggers CD8+ T-cells producing IFNγ. These T cells are believed to be the main immunologic mechanism to fight malaria in liver.

The PfSPZ Vaccine candidate has granted fast track designation by the U.S. Food and Drug Administration in September 2016.[7]

CD8+ T cells play a key role in killing Plasmodium developing in liver. Mice or monkeys which received monoclonal antibody to the CD8 lost protection by this type of vaccine. Once the antibody application was stopped, the protection was returned.[8][9] Plasmodium is injected by infected mosquito into the bloodstream of the host in the form of sporozoites, which travel to the liver and invade liver cells, where sporozoites divide and produce tens of thousands merozoites per one cell. RTS,S is prepared to stop malaria in phase after the injection. PfSPZ Vaccine is made of attenuated sporozites, which are active and travel to liver cells, where CD8+ T cells producing IFNγ are activated. Frequencies of PfSPZ-specific CD3+CD4+, CD3+CD8+, CD3+γδ T cells are dose-dependent. PfSPZ-specific CD3+CD8+ T cells were found in 7 of 12 protected subjects in the human volunteer trial.[10] These cells are required for protection in most individuals and are primarily situated in the liver because of the persistence of parasite antigens and retained as tissue memory cells.[11]

Two first clinical trials of IV administration of PfSPZ were conducted. Previous ID or IC clinical trials didn´t trigger adequate immune response. Series of clinical trials of the PfSPZ Vaccine administered with IV injection are planned in 2014 in Africa, Europe, and the United States to expand critical data on the vaccine for clinical development as a method to prevent malaria.[12] The trial involved 57 people and demonstrated complete protection against malaria in all six patients that received the highest dose. As of 2014, Sanaria planned to test the vaccine in larger trials in Mali, Tanzania, Equatorial Guinea, the U.S. and Germany. Optimally, it could be filed with regulators by 2017.

Sanaria is preparing development of a robot that can dissect salivary glands of mosquitos. This step should make preparation and further development of vaccine much faster and easier.[13]

In 2016, another article with further results from the trials was published.[14]

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