PfSPZ Vaccine

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PfSPZ vaccine is an trial anti-malaric vaccine which is made of non-replicating irradiated whole sporozoites with metabolic activity. It is still in I phase of clinical trials. PfSPZ is the acronym of words: Plasmodium falciparum (Pf) sporozoites (SPZ).

History

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) was uneffective 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 need of the adjuvant and similar evidence was obtained in human volunteer trials. They was 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 wasn´t 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 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.

Mechanism

[[cytotoxic t cell|CD8+ T cells] play a key role in killing Plasmodium developing in liver. Mice ore 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[7][8]. 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 thousends 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[9]. 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[10].

Clinical trials

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 now planned in Africa, Europe, and the United States to expand critical data on the vaccine for clinical development as a method to prevent malaria[11].



References

  1. ^ Freund, J. & Thomson, K. J. Immunization of monkeys against malaria by means of killed parasites with adjuvants. Am. J. Trop. Med. Hyg. 28, 1–22 (1948), PMID 18898694
  2. ^ Nussenzweig, R. S., Vanderberg, J., Most, H. & Orton, C. Protective Immunity produced by the Injection of X-irradiated Sporozoites of Plasmodium berghei. Nature 216, 160–162 (1967), PMID 6057225
  3. ^ Rieckmann, K. H., Carson, P. E., Beaudoin, R. L., Cassells, J. S. & Sell, K. W. Sporozoite induced immunity in man against an ethiopian strain of Plasmodium falciparum. Trans. R. Soc. Trop. Med. Hyg. 68, 258–259 (1974), PMID 4608063
  4. ^ Kester, K. E. et al. Randomized, Double‐Blind, Phase 2a Trial of Falciparum Malaria Vaccines RTS,S/AS01B and RTS,S/AS02A in Malaria‐Naive Adults: Safety, Efficacy, and Immunologic Associates of Protection. J. Infect. Dis. 200, 337–346 (2009), PMID 19569965
  5. ^ The RTS,S Clinical Trials Partnership. A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants. N. Engl. J. Med. 367, 2284–2295 (2012), PMID 23136909
  6. ^ Luke, T. C. Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine. J. Exp. Biol. 206, 3803–3808 (2003), PMID 14506215
  7. ^ Epstein, J. E. et al. Live Attenuated Malaria Vaccine Designed to Protect Through Hepatic CD8+ T Cell Immunity. Science 334, 475–480 (2011), PMID 21903775
  8. ^ Weiss, W. R. & Jiang, C. G. Protective CD8+ T lymphocytes in Primates Immunized with Malaria Sporozoites. PLoS ONE 7, e31247 (2012), PMID 23136909
  9. ^ Seder, R. A. et al. Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine. Science 341, 1359–1365 (2013), PMID 23929949
  10. ^ Cockburn, I. A. et al. Prolonged Antigen Presentation Is Required for Optimal CD8+ T Cell Responses against Malaria Liver Stage Parasites. PLoS Pathog. 6, e1000877 (2010), PMID 20463809
  11. ^ Seder, R. A. et al. Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine. Science 341, 1359–1365 (2013), PMID 23929949
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