First-in-human evaluation of genetically attenuated Plasmodium falciparum sporozoites administered by bite of Anopheles mosquitoes to adult volunteers

Live attenuated pre-erythrocytic malaria vaccines

“…69 In volunteers immunized with GAP, it was shown that exposure to 200 bites induced antibody responses against CSP but not LSA-1 or blood stage antigens. 60 In addition, we showed that volunteer sera collected 3 months after exposure to GAP inhibited sporozoite invasion of hepatocytes at levels comparable to those observed in sera collected 2 weeks after a series of high doses of PfSPZ, and these levels were strongly correlated with antibody titers against CSP. 70 Further studies will be needed to establish whether these functional antibodies correlate with protection against malaria.…”

“…58,59 These promising results led to a dose escalation human clinical safety trial of the p36/p52 double knockout. 60 This parasite was determined to be safe and well tolerated, and no breakthroughs were observed after the bite of 5 infected mosquitoes. However, 1 out of 6 volunteers experienced blood stage parasitemia after a second dose of 200 infective bites, suggesting that this mutant was not completely attenuated.…”

“…80 Although the lack of protection data for GAP-vaccinated volunteers limits the interpretation of the results, initial analyses suggest that CD4 C T cells generated IFNg, IL2 and TNF in response to sporozoite stimulation, whereas CD8 C T cells mainly produced IFNg. 60 Stimulation with individual antigens also showed that CD8 C T cells were mostly responsible for production of IFNg, while TNF was mostly produced by CD4 C T cells. The human experimental vaccination studies described above have provided many clues regarding factors that contribute to anti-malarial immunity, but they…”

“…However, 1 out of 6 volunteers experienced blood stage parasitemia after a second dose of 200 infective bites, suggesting that this mutant was not completely attenuated. 60 In consequence, a triple knockout parasite in which sap1 is deleted in addition to p36 and p52 was constructed, and recently shown to be completely attenuated in a humanized mouse model with human hepatocytes and red blood cells. 61 It will be interesting to compare the protection elicited by this strategy in human volunteers to those that use irradiated and chemically attenuated parasites.…”

IFN-γ protects hepatocytes againstPlasmodium vivaxinfection via LAP-like degradation of sporozoites

“…The mechanisms by which ∼50% of parasites are able to avoid IFN-γ-mediated clearance, and the autophagyindependent mechanisms of IFN-γ-mediated clearance of parasites, remain to be determined and should be the subject of future study. Finally, it would be of particular interest to examine the role of autophagy during hepatocyte infection by irradiated or genetically attenuated sporozoites, as this would provide clues to how this vaccination strategy has been so successful in inducing CD8 T-cell responses and preventing malaria infection in mice and man (11)(12)(13).…”