are results from our publications: T cells are required for the induction of sterile immunity by irradiated Plasmodium sporozoite vaccination. Whole-sporozoite vaccines confer sterilizing immunity to malaria-naive individuals by unknown mechanisms. In the first PfSPZ Vaccine trial ever in a malaria-endemic population, we observed that V2 T cells were significantly elevated and V9/V2 transcripts ranked as the most upregulated in vaccinees who were protected from Plasmodium falciparum infection. In a mouse model, absence of T cells during vaccination impaired protective CD8 T cell responses and ablated sterile protection. T cells were not required for circumsporozoite protein-specific Ab responses, and T cell depletion before infectious challenge did not ablate protection. T cells alone were insufficient to induce protection and required the presence of CD8+ dendritic cells. In the absence of T cells, CD8+ dendritic cells did not accumulate in the livers of vaccinated mice. Altogether, our results show that T cells were essential for the induction of sterile immunity during whole-organism vaccination, but are not required as mediators of sterile immunity at the time of sporozoite challenge. In addition to these published results, we have seen progress in our other trials of whole organism vaccines. PfSPZ CVac-PYR2 (NIAID Protocol 17-I-0067) This is a phase 1 dose escalation study to investigate the safety and tolerability of Sanaria PfSPZ Challenge (NF54) administered by DVI , combined with CQ or PYR treatment. The study is also designed to explore the immunogenicity and protective efficacy of this regimen, given as 3-dose series, against homologous (NF54) and heterologous (7G8) CHMI. In a previous trial completed by LMIV (NIAID Protocol 15-I-0169), we had shown that PfSPZ CVac-PYR and CVac-CQ were well tolerated, and for all subjects receiving PfSPZ CVac-PYR, sensitive qPCR for malaria parasite detection was negative at all timepoints during the PfSPZ CVac Phase. Further, 2/11 individuals who received the CVac-PYR regimen had sterile protection against homologous CHMI while 4/5 CVac-CQ were protected. The protective efficacy seen with PfSPZ CVac-CQ was similar to previously reported with this regimen, and the protection seen with CVac-PYR justified further assessment of this regimen at higher dosages. The PfSPZ CVac-PYR2 study was therefore launched to assess higher dosages. The pilot phase of the PfSPZ CVac-PYR arms (Arm 1) began in June 2017. As reported last year, the Arm 1a pilot (50,000 PfSPZ + 50 mg of PYR on d2, 3), Arm 1b pilot (100,000 PfSPZ + 50 mg of PYR on d2, 3), and Arm 1d pilot (200,000 PfSPZ + 50 mg of PYR on d2, 3) all successfully prevented patent and subpatent parasitemia from 6 days through 14 days post PfSPZ Challenge. In addition, the PfSPZ CVac-PYR regimen has been safe and well tolerated by subjects. The Arm 5a pilot (100,000 PfSPZ + CQ x 2) were also safe and well tolerated by subjects. Both subjects were qPCR positive as expected on days 7 and 8 post PfSPZ Challenge exposure. However, with the next pilot groups (Arm 1dR; n=2; and Arm 5b; n=2) using 200,000 PfSPZ and CQ, several Grade 2 and 3 AE associated temporally with parasitemia were observed. Consequently, with the start the main phase of the study in early 2018 with Arm 2 (200,000 PfSPZ + 50 mg of PYR on d2, 3) and Arm 3 (200,000 PfSPZ + weekly CQ ), those receiving PfSPZ and chloroquine were pre-emptively treated with NSAIDs on expected days of high parasitemia which averted the Grade 2 and 3 AE. Although the trial is ongoing with scheduled completion in 2019, emerging data has provided exciting evidence that sterile immunity is seen in both arms against heterologous CHMI with 7G8 parasites. This is the first evidence that CVac does not require blood stage parasite exposure to induce high levels of sterile immunity.

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Zaidi, Irfan; Duffy, Patrick E (2018) Response to Comment on ""?? T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations"". J Immunol 200:1533-1534
Pichugin, Alexander; Zarling, Stasya; Perazzo, Leah et al. (2018) Identification of a Novel CD8 T Cell Epitope Derived from Plasmodium berghei Protective Liver-Stage Antigen. Front Immunol 9:91
Conteh, Solomon; Anderson, Charles; Lambert, Lynn et al. (2017) Grammomys surdaster, the Natural Host for Plasmodium berghei Parasites, as a Model to Study Whole-Organism Vaccines Against Malaria. Am J Trop Med Hyg 96:835-841
Hobbs, Charlotte V; Anderson, Charles; Neal, Jillian et al. (2017) Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge. J Infect Dis 215:122-130
Sissoko, Mahamadou S; Healy, Sara A; Katile, Abdoulaye et al. (2017) Safety and efficacy of PfSPZ Vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial. Lancet Infect Dis 17:498-509
Sahu, Tejram; Lambert, Lynn; Herrod, Jessica et al. (2015) Chloroquine neither eliminates liver stage parasites nor delays their development in a murine Chemoprophylaxis Vaccination model. Front Microbiol 6:283
Hoffman, Stephen L; Vekemans, Johan; Richie, Thomas L et al. (2015) The march toward malaria vaccines. Vaccine 33 Suppl 4:D13-23
Richie, Thomas L; Billingsley, Peter F; Sim, B Kim Lee et al. (2015) Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines. Vaccine 33:7452-61
Hoffman, Stephen L; Vekemans, Johan; Richie, Thomas L et al. (2015) The March Toward Malaria Vaccines. Am J Prev Med 49:S319-33