Safety and Protective Efficacy of Genetically Attenuated PfSPZ-GA1 Vaccine in Healthy Dutch Volunteers
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a first-in-human, randomized clinical trial of PfSPZ-GA1 Vaccine (genetically
      attenuated PfSPZ) in healthy malaria-naïve adult volunteers. This Phase 1 trial is divided
      into two stages, Stage A and B. Stage A is an open label, single center, dose escalation
      study in 19 volunteers. Stage B is a multi-center, double blind, randomized,
      placebo-controlled trial in 48 volunteers. The primary objective of this study is to
      determine the safety and tolerability of direct venous inoculation (DVI) of PfSPZ-GA1 Vaccine
      in healthy adults.
    

Detailed description: 
      Stage A, a Phase 1 dose-escalation study, will take place at Leiden University Medical Centre
      (LUMC). Stage B, a randomized, double-blind, placebo-controlled trial, will be conducted at
      LUMC and Radboudumc University Medical Centers (RUMC).

      In Stage A, 19 healthy, adult volunteers will be allocated into three groups to receive
      increasing doses of PfSPZ-GA1 Vaccine by DVI. Group 1 (n=3) will receive one dose of 1.35 x
      10^5 PfSPZ of PfSPZ-GA1 Vaccine. If this dose is safe for 28 days after inoculation, then
      Group 2 (n=3) will receive one dose of 4.5 x 10^5 PfSPZ of PfSPZ-GA1 Vaccine. If this dose is
      safe for 28 days after inoculation, Group 3 (n=13) will receive one dose of 9.0 x 10^5 PfSPZ
      of PfSPZ-GA1 Vaccine. Volunteers will be followed closely for monitoring of adverse events
      and possible breakthrough blood infections by testing for the presence of parasitemia by
      qPCR. All volunteers will be treated with a curative regimen of atovaquone/proguanil (A/P)
      should break-through parasites be detected in the peripheral blood, or at the end of the
      follow-up period (28 days) if they are not qPCR positive. Six months after the inoculation, a
      final visit will take place to assess adverse events.

      If inoculation is deemed safe after 28 days for Group 3 and criteria for proceeding to Stage
      B are met, the trial will continue to Stage B. In Stage B, 48 healthy, adult volunteers will
      be randomized into four groups at 2 centers, LUMC and RUMC (24 volunteers at each site). Each
      group will receive 3 repeat doses, 8 weeks apart, of PfSPZ-GA1 Vaccine (low and high doses),
      PfSPZ Vaccine (radiation attenuated sporozoites), or normal saline (NS) placebo (as control)
      via DVI. Group 4 (n=13) will receive 9.0 x 10^5 PfSPZ of PfSPZ-GA1 Vaccine/dose. Group 5
      (n=13) will receive 4.5 x 10^5 PfSPZ of PfSPZ-GA1 Vaccine/dose. Groups 6 (n=13) and 7 (n=9)
      will receive 4.5 x 10^5 PfSPZ Vaccine and NS placebo per dose, respectively. Three weeks
      after the last inoculation, all immunized volunteers and placebo controls (Group 7) will
      undergo a CHMI with five NF54-infected mosquitoes (wild-type) to determine degree of
      protection. After the CHMI, volunteers will be followed closely for monitoring of adverse
      events and blood stage infections, and will be seen once daily from day 6 until day 21 after
      infection and on day 28. All volunteers will be treated with a curative regimen of
      antimalarials, which may be A/P or alternatively artemether/lumefantrine dosed according to
      Dutch clinical practice, at the time of detection of blood stage parasitemia by qPCR or 28
      days after CHMI. Adverse events will be assessed up to 6 months after the CHMI.
    

Intervention name(s): PfSPZ-GA1 Vaccine; PfSPZ Vaccine; Normal Saline; Mosquito-bite CHMI
Intervention type(s): Biological; Biological; Other; Biological
Intervention description(s): Aseptic, purified, cryopreserved, genetically attenuated P. falciparum sporozoites (Pf∆b9∆slarp), strain NF54; Aseptic, purified, cryopreserved, radiation attenuated P. falciparum sporozoites (PfSPZ Vaccine), strain NF54; 0.9% sodium chloride; Bites of 5 infected mosquitoes of NF54 strain
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Plasmodium falciparum; PfSPZ Vaccine; PfSPZ-GA1 Vaccine; Controlled human malaria infection (CHMI); Genetically attenuated sporozoites; Plasmodium falciparum sporozoites (PfSPZ)