Sanaria PfSPZ Challenge With Pyrimethamine or Chloroquine Chemoprophylaxis Vaccination (PfSPZ-CVac Approach): A Randomized Double Blind Placebo Controlled Phase I/II Trial to Determine Safety and Protective Efficacy Against Natural Plasmodium Falcipa...
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      Malaria remains a major global health problem. Malaria is spread by the bite of mosquitos.
      Africa is the region of the world where most people get malaria. Sanaria PfSPZ Challenge is a
      malaria vaccine. Researchers want to see if the vaccine combined with partner drugs can help
      protect against malaria.

      Objective:

      To test if injections with 3 monthly doses of Sanaria PfSPZ Challenge, combined with either
      pyrimethamine (PYR) or chloroquine as a partner drug, is safe, tolerable, and effective.

      Eligibility:

      Healthy people ages 18-50 years who live in Bancoumana, Mali, or nearby

      Design:

      Participants will be screened with the Malaria Comprehension Exam to check their
      understanding of the study. They will have a medical history. They will have a physical exam.
      They will have blood tests, urine tests, and heart tests.

      Participants will join either the pilot study or the main study.

      Participants will be assigned to groups. Depending on their group, they will get at least one
      injection of either a placebo or the vaccine. They may have up to 3 vaccines, 4 weeks apart.
      The injection will be into a vein with a needle.

      Participants will also take pyrimethamine or chloroquine by mouth. They will also take
      standard doses of antimalarial drugs by mouth.

      Participants will have blood tests throughout the study.

      Participants may develop a rash or injection site reaction. If this happens, photos of the
      site may be taken.

      Participants will be observed for infection for many days after the injections.
    

Detailed description: 
      Human studies have shown that immunization by the bite of Plasmodium falciparum (Pf)
      sporozoite (SPZ)-infected mosquitoes (chemoprophylaxis with sporozoites [CPS]) or by
      injecting aseptic, purified, cryopreserved sporozoites (SPZ) with needle and syringe (PfSPZ
      chemoprophylaxis vaccination, Sanaria PfSPZ-CVac) under drug coverage with chloroquine can
      provide >80% protection against homologous controlled human malaria infection (CHMI)
      (Roestenberg, McCall et al. 2009, Roestenberg, Teirlinck et al. 2011, Mordmuller, Surat et
      al. 2017). The protective immunity induced by CPS/PfSPZ-CVac is thought to target sporozoite
      and liver stage antigens, but the transient parasitemia observed under chloroquine
      prophylaxis may additionally induce immune responses targeting blood stage parasites that
      contribute to protection. It is important to understand the contribution of each stage in
      this model as transient parasitemia in the immunization process adds a safety concern and may
      impair the development of immunity.

      We have conducted two phase 1 studies to explore whether significant protective efficacy can
      be achieved with exclusively pre-erythrocytic (sporozoite/liver stage) exposure in this model
      using PYR chemoprophylaxis. This drug, unlike chloroquine, kills the parasites in the liver,
      so there is no period of transient parasitemia following immunization. These studies in
      malaria na(SqrRoot) ve adults demonstrated that PfSPZ-CVac (with PYR administered 2 & 3 days
      after injection) is safe, well-tolerated, and can prevent subpatent and patent parasitemia
      after PfSPZ injection. The NCT02511054 study used the same dose (5.12x104 PfSPZ) that has
      resulted in >80% protection in previous trials of PfSPZ-CVac (chloroquine), showed only 2/9
      vaccinees were protected against a homologous (same strain of Pf as the vaccine) CHMI. In
      trials using irradiated SPZ, increasing the dose of PfSPZ used for immunization has resulted
      in higher protective efficacy. Therefore, in an ongoing trial, NCT03083847, we have increased
      the PfSPZ dose about 4-fold up to 2.0x105 PfSPZ, with preliminary results show markedly
      improved protection against both homologous and heterologous CHMI in healthy US adults (7/8
      and 4/4 study subjects uninfected, respectively). This is the first demonstration that the
      PfSPZ-CVac approach can confer sterile protection without blood stage exposure.

      Building on these promising results from PfSPZ-CVac (pyrimethamine) in the US, this proposed
      study in a malaria-endemic, adult population in Bancoumana, Mali will initially assess, in a
      pilot phase, the safety and tolerability of still higher doses of PfSPZ Challenge (4.0x105
      PfSPZ) in combination with PYR (day 0;) or chloroquine (days -2, +5). The higher PfSPZ dose
      is hypothesized to be necessary to achieve significant efficacy against naturally transmitted
      malaria in malaria-experienced populations. Once this higher dose of PfSPZ is determined to
      be safe and tolerable and that earlier PYR dosing prevents patent parasitemia, the main phase
      will explore the effect of both earlier PYR dosing and a higher dosage of PfSPZ used for
      immunization in the development of protective immunity against natural malaria infection. The
      results of this study will contribute to understanding the targets and mechanisms of immunity
      against Pf malaria infection, and how the degree of prior exposure to the parasite
      (pre-erythrocytic and/or erythrocytic stages) impacts these responses and subsequent
      protective efficacy in field settings.

      After completion of follow up in the main phase, all participants that are still enrolled in
      the study will be offered a booster dose of the vaccine (4th dose) with a single dose of
      4x10^5 PfSPZ Challenge or normal saline (aligned with what they received in the main phase of
      the study) at approximately 11 months post 3rd vaccination. The booster dose is timed to
      allow administration well before the beginning of the ensuing malaria transmission season.
      Participants will then be followed for approximately 6 months to assess safety and vaccine
      efficacy through this second transmission season.
    

Intervention name(s): Chloroquine Phosphate; PfSPZ Challenge; Pyrimethamine; Coartem; ibuprofen
Intervention type(s): Drug; Biological; Drug; Drug; Drug
Intervention description(s): Chloroquine phosphate is approved for suppressive treatment (prophylaxis) and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of Pf. Chloroquine is a blood-stage schizonticide, highly active against replicating forms of blood-stage drug- sensitive parasites. As such, it is routinely employed as first-line prophylaxis against development of patent parasitemia and clinical malaria in non-immune travelers to areas with chloroquine sensitive Pf. In the pilot, chloroquine administration will begin with a loading dose 2 days prior to PfSPZ Challenge and finishing with a maintenance dose 5 days after PfSPZ Challenge. In the main phase, chloroquine will be first administered as a loading dose 2 days prior to PfSPZ Challenge and continuing weekly using a maintenance dose for a total of 10 doses, finishing with a last dose 5 days after the third injection with PfSPZ Challenge.; PfSPZ Challenge (NF54) acts as the immunogen in the PfSPZ-CVac approach to vaccinating against malaria. Participants will receive either one (in the pilot phase) or 3 (in the main phase) 400,000 or 300,000 aseptic, purified, cryopreserved, fully infectious PfSPZ injections by DVI (with concurrent administration of antimalarial drugs). Following immunization, participants in the main phase will be followed through the transmission season in order to assess vaccine efficacy.; Pyrimethamine has been FDA approved for acute treatment and chemoprophylaxis of malaria due to susceptible strains of plasmodia.
Pyrimethamine has been shown to possess both liver and blood stage activity. In this study, we plan to use a higher dose of pyrimethamine, 75 mg orally for either one or two days each month. The pilot arms will receive either a total of 1 daily dose or 2 daily doses. The main arms will receive a total of 3 daily doses or a total of 6 doses.; Antimalarial (Coartem ) will be administered to all participants twice during the study, approximately 2 weeks prior to the first vaccination in order to clear pre-existing parasitemia that may interfere with immunity development. The second dose will be given approximately 2 weeks prior to the 3rd vaccination in order to clear any parasitemia infection that may have happened naturally during the vaccination period and prior to the follow up period.; Ibuprofen likewise is not a part of the investigational product/regimen, but will be provided to participants in the chloroquine arm (Arm 4) if required to mitigate typical symptoms of malaria infection such as headache, myalgia, fever and chills.
Intervention MeSH terms: Chloroquine; Chloroquine diphosphate; Pyrimethamine; Artemether, Lumefantrine Drug Combination; Ibuprofen
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Other
Keywords: Field; Immunity; Chemoprophylaxis with Sporozoites; Vaccine; Malaria-Experienced