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.

In 2014 Sanaria promoted an Indiegogo campaign to develop a robot that could dissect salivary glands of mosquitos, to make preparation and further development of vaccine much faster and easier.[7] The crowdfunding campaign ended, after being backed by $45,024 of the $250,000 goal.[8]

The PfSPZ Vaccine candidate was granted fast track designation by the U.S. Food and Drug Administration in September 2016.[9]

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.[10][11] 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.[12] 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.[13]

PfSPZ vaccines are cryopreserved and stored in LNVP freezers[14] below -150 °C and distributed using dry vapor cryoshippers that also maintain temperature below -150 °C. Cryoshippers[15] are self-contained mobile storage units that have hold times of ~14 to 28 days or more depending on model and packaging and are highly suited for last-mile transportation, particularly in Africa. Cryoshippers are used extensively in the livestock breeding, CAR-T and cellular therapies industries. LNVP distribution uses a simple hub-and-spoke model [16]and cryoshippers stay at the immunization sites as temporary storage units that may be recharged with LN2. Advantages of the LNVP cold chain are a) independence from electricity, b) no requirement for fridges, freezers or refrigerated transport, c) no narrow temperature requirements, d) reduced chances for temperature deviations, e) no moving parts, and f) energy efficiency. LN2 is widely available, including in African countries, making LNVP distribution easier than the 2-8 °C and the dry ice and ultralow freezer-based cold chains of Ervebo (vs ebola)[17][18] and certain SARS-CoV-2[19] vaccines. Modeling LNVP distribution[20] also indicated costs would be no different per 3-dose regimen than the 2-8 °C cold chain for lyophilized vaccines.

Two first clinical trials of IV administration of PfSPZ were conducted in 2013. Previous ID or IC clinical trials didn't trigger adequate immune response. A 2014 phase 1 trial with the PfSPZ Vaccine found that more than half of the participants were protected from malaria infection for over a year after the trial.[21][22] A study published in 2017 reported complete protection after 10 weeks with three doses of PfSPZ-CVac.[23] In April 2019, a phase 3 trial in Bioko was announced, scheduled to start in early 2020.[24]

• https://sanaria.com