A Randomized, Double-Blind, Placebo-Controlled Phase 1 Trial to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of Sanaria(R) PfSPZ-LARC2 Vaccine, a Late-Arresting, Replication-Competent, Genetically Attenuated Plasmodium Falciparum Vaccine by Controlled Human Malaria Infection in Malaria-Naïve Healthy Adults

简要总结

详细描述

This randomized, double-blind, placebo-controlled, Phase 1 trial will enroll up to 22 malaria-naïve, adult participants to test safety, tolerability, immunogenicity, and efficacy of the genetically attenuated Plasmodium falciparum sporozoite vaccine (PfSPZ-LARC2) Vaccine. PfSPZ-LARC2 Vaccine is a late-arresting, replication-competent whole Plasmodium falciparum sporozoite product. We hypothesize that the PfSPZ-LARC2 Vaccine will be safe from breakthrough infection by virtue of deletion of two key parasite genes Mei2 and LINUP and may be more immunogenic and protective than previously tested early arresting sporozoite vaccines. The vaccine will be produced by Sanaria, Inc. and will be administered by direct venous inoculation (DVI). Placebo control participants will be included in all stages of the study. The study will start with a small set of double-blind, placebo-controlled sentinel participants who will be enrolled first to initially confirm adequate vaccine attenuation before enrolling the remainder of the participants in the study. Vaccine or placebo will be administered three times to participants of the study and then all eligible participants will undergo Controlled Human Malaria Infection (CHMI) to measure protective efficacy compared to placebo. All participants who meet the treatment criteria will be treated with a standard dose of Malarone(R) or Coartem(R). Participants will be observed for adverse events after each PfSPZ-LARC2 Vaccine or placebo administration as follows. Solicited local and systemic Adverse Events (AEs) related to the vaccine will be recorded beginning of the day of first vaccine administration and continuing through six days after each administration. During the vaccination phase, clinical laboratory evaluations for safety will be performed on venous blood with laboratory toxicities will be monitored from the time of first PfSPZ-LARC2 administration through 14 days after the last PfSPZ-LARC2 administration. Unsolicited AEs related to vaccination will be recorded from the time of first PfSPZ-LARC2 administration through 28 days after the last PfSPZ-LARC2 administration. Serious adverse events (SAEs) will be recorded from the time of first PfSPZ-LARC2 administration through the end of study follow up. Participants will also be monitored for possible breakthrough peripheral parasitemia with Plasmodium 18S rRNA qRT-PCR testing and, if any breakthrough infections are detected, solicited systemic AEs related to such breakthrough infections would be recorded from seven days after each PfSPZ-LARC2 administration until 28 days after each administration. Twelve to 16 weeks after the last vaccine administration, all participants who completed any of the vaccinations will undergo CHMI using P. falciparum strain 7G8 using the Sanaria product PfSPZ Challenge (7G8) at a DVI-administered dose of 3.2x103. Participants will be followed for AEs and evidence of blood-stage infection by Plasmodium 18S rRNA RT-PCR for up to 28 days post-CHMI. Participants showing evidence of infection based on the criteria defined in the protocol will be treated using FDA-approved anti-malarial medication. In addition to safety, tolerability, and efficacy analyses, humoral and cellular immunity of the vaccine will also be evaluated. The primary objective is to assess the tolerability and safety of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation. The secondary objectives are 1) To assess the efficacy of different PfSPZ-LARC2 Vaccine regimens against CHMI using standard CHMI procedures 2) To assess humoral and cell-mediated immune responses to Pf antigens induced by PfSPZ-LARC2 Vaccine administration.

主要结局

次要结局

• Median Net Optical Density (OD) 1.0 IgG antibodies to Plasmodium falciparum Circumsporozoite Protein (PfCSP)(Up to 16 weeks post-vaccination)
• Percentage of malaria specific CD4+, CD8+, and gamma delta T cells expressing IFN-gamma and/or IL-2(Up to 16 weeks post-vaccination)
• Proportion of participants with Malaria infection following Controlled Human Malaria Infection (CHMI)(Through 28 days following Controlled Human Malaria Infection (CHMI))