PfSPZ Vaccine

PfSPZ Vaccine is a candidate malaria vaccine made of non-replicating irradiated whole sporozoites and developed by Sanaria. PfSPZ is the acronym of words: Plasmodium falciparum (Pf) and sporozoites (SPZ). Clinical trials have been promising, but it has been subject to some criticism regarding its ultimate feasibility with regard to large-scale production and delivery in Africa, since it must be stored in liquid nitrogen (at −195.79 °C (77 K; −320 °F) or colder).

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) 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]

Mechanism

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]

Clinical trials

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.[14][15] A study published in 2017 reported complete protection after 10 weeks with three doses of PfSPZ-CVac.[16] In April 2019, a phase 3 trial in Bioko was announced, scheduled to start in early 2020.[17]

References

  1. ↑ Freund, J; Thomson, K. J. (1948). "Immunization of monkeys against malaria by means of killed parasites with adjuvants". The American Journal of Tropical Medicine and Hygiene. 28 (1): 1–22. doi:10.4269/ajtmh.1948.s1-28.1. PMID 18898694.
  2. ↑ Nussenzweig, R. S.; Vanderberg, J; Most, H; Orton, C (1967). "Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei". Nature. 216 (5111): 160–2. Bibcode:1967Natur.216..160N. doi:10.1038/216160a0. PMID 6057225. S2CID 4283134.
  3. ↑ Rieckmann, K. H.; Carson, P. E.; Beaudoin, R. L.; Cassells, J. S.; Sell, K. W. (1974). "Letter: Sporozoite induced immunity in man against an Ethiopian strain of Plasmodium falciparum". Transactions of the Royal Society of Tropical Medicine and Hygiene. 68 (3): 258–9. doi:10.1016/0035-9203(74)90129-1. PMID 4608063.
  4. ↑ Kester, K. E.; Cummings, J. F.; Ofori-Anyinam, O; Ockenhouse, C. F.; Krzych, U; Moris, P; Schwenk, R; Nielsen, R. A.; Debebe, Z; Pinelis, E; Juompan, L; Williams, J; Dowler, M; Stewart, V. A.; Wirtz, R. A.; Dubois, M. C.; Lievens, M; Cohen, J; Ballou, W. R.; Heppner Jr, D. G.; Rts, S Vaccine Evaluation (2009). "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". The Journal of Infectious Diseases. 200 (3): 337–46. doi:10.1086/600120. PMID 19569965.
  5. ↑ Rts, S Clinical Trials; Agnandji, S. T.; Lell, B; Fernandes, J. F.; Abossolo, B. P.; Methogo, B. G.; Kabwende, A. L.; Adegnika, A. A.; Mordmüller, B; Issifou, S; Kremsner, P. G.; Sacarlal, J; Aide, P; Lanaspa, M; Aponte, J. J.; Machevo, S; Acacio, S; Bulo, H; Sigauque, B; MacEte, E; Alonso, P; Abdulla, S; Salim, N; Minja, R; Mpina, M; Ahmed, S; Ali, A. M.; Mtoro, A. T.; Hamad, A. S.; et al. (2012). "A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants" (PDF). New England Journal of Medicine. 367 (24): 2284–95. doi:10.1056/NEJMoa1208394. PMID 23136909.
  6. ↑ Luke, T. C.; Hoffman, S. L. (2003). "Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine". The Journal of Experimental Biology. 206 (Pt 21): 3803–8. doi:10.1242/jeb.00644. PMID 14506215.
  7. ↑ "Sanaria Inc. To Launch Crowdfunding Campaign For Sporobottm, A Mosquito-Dissecting Robot For Accelerating Manufacture Of Sanaria's Malaria Vaccine". Sanaria. 30 April 2014. Retrieved 25 August 2020.
  8. ↑ "Malaria Vaccine Robot - Robot vs. Mosquito Sanaria - SporoBot". Indiegogo. Retrieved 25 August 2020.
  9. ↑ "SANARIA PfSPZ VACCINE AGAINST MALARIA RECEIVES FDA FAST TRACK DESIGNATION" (PDF). Sanaria Inc. 22 September 2016. Archived from the original (PDF) on 23 October 2016. Retrieved 23 January 2017.
  10. ↑ Epstein, J. E.; Tewari, K; Lyke, K. E.; Sim, B. K.; Billingsley, P. F.; Laurens, M. B.; Gunasekera, A; Chakravarty, S; James, E. R.; Sedegah, M; Richman, A; Velmurugan, S; Reyes, S; Li, M; Tucker, K; Ahumada, A; Ruben, A. J.; Li, T; Stafford, R; Eappen, A. G.; Tamminga, C; Bennett, J. W.; Ockenhouse, C. F.; Murphy, J. R.; Komisar, J; Thomas, N; Loyevsky, M; Birkett, A; Plowe, C. V.; et al. (2011). "Live attenuated malaria vaccine designed to protect through hepatic CD8⁺ T cell immunity". Science. 334 (6055): 475–80. Bibcode:2011Sci...334..475E. doi:10.1126/science.1211548. PMID 21903775. S2CID 206536528.
  11. ↑ Rts, S Clinical Trials; Agnandji, S. T.; Lell, B; Fernandes, J. F.; Abossolo, B. P.; Methogo, B. G.; Kabwende, A. L.; Adegnika, A. A.; Mordmüller, B; Issifou, S; Kremsner, P. G.; Sacarlal, J; Aide, P; Lanaspa, M; Aponte, J. J.; Machevo, S; Acacio, S; Bulo, H; Sigauque, B; MacEte, E; Alonso, P; Abdulla, S; Salim, N; Minja, R; Mpina, M; Ahmed, S; Ali, A. M.; Mtoro, A. T.; Hamad, A. S.; et al. (2012). "A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants" (PDF). New England Journal of Medicine. 367 (24): 2284–95. doi:10.1056/NEJMoa1208394. PMID 23136909.
  12. ↑ Seder, R. A.; Chang, L. J.; Enama, M. E.; Zephir, K. L.; Sarwar, U. N.; Gordon, I. J.; Holman, L. A.; James, E. R.; Billingsley, P. F.; Gunasekera, A; Richman, A; Chakravarty, S; Manoj, A; Velmurugan, S; Li, M; Ruben, A. J.; Li, T; Eappen, A. G.; Stafford, R. E.; Plummer, S. H.; Hendel, C. S.; Novik, L; Costner, P. J.; Mendoza, F. H.; Saunders, J. G.; Nason, M. C.; Richardson, J. H.; Murphy, J; Davidson, S. A.; et al. (2013). "Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine". Science. 341 (6152): 1359–65. Bibcode:2013Sci...341.1359S. doi:10.1126/science.1241800. PMID 23929949. S2CID 22462258.
  13. ↑ Cockburn, I. A.; Chen, Y. C.; Overstreet, M. G.; Lees, J. R.; Van Rooijen, N; Farber, D. L.; Zavala, F (2010). "Prolonged antigen presentation is required for optimal CD8+ T cell responses against malaria liver stage parasites". PLOS Pathogens. 6 (5): e1000877. doi:10.1371/journal.ppat.1000877. PMC 2865532. PMID 20463809.
  14. ↑ Ishizuka, et al. (2016). "Protection against malaria at 1 year and immune correlates following PfSPZ vaccination". Nature Medicine. 22 (6): 614–623. doi:10.1038/nm.4110. PMID 27158907. S2CID 205396815.
  15. ↑ Feller, Stephen (10 May 2016). "Malaria vaccine shown to be safe, effective in phase 1 trial - More than half of volunteers in the small study did not contract malaria when exposed to mosquitoes more than a year after their last dose of the vaccine". UPI. Retrieved 25 August 2020.
  16. ↑ "Nature report describes complete protection after 10 weeks with three doses of PfSPZ- CVac" (Press release). 15 February 2017.
  17. ↑ Butler, Declan (16 April 2019). "Promising malaria vaccine to be tested in first large field trial - The vaccine can confer up to 100% protection and will be tested in 2,100 people on the west African island of Bioko". Nature. doi:10.1038/d41586-019-01232-4. PMID 32291409. Retrieved 25 August 2020.
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