Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Phase 1 Trial to Determine Safety and Protective Efficacy of Sanaria PfSPZ Challenge With Concurrent Pyrimethamine Treatment That Inhibits Development of Asexual B...
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Malaria is a severe infection caused by a parasite. People can get malaria if a mosquito
      that carries the parasite bites them. Although malaria does not occur in the United States,
      many people in Africa, Asia, and South America do get malaria. In some cases, malaria can
      cause death. In 2013 alone, 584,000 people died due to malaria. Researchers want to find ways
      to prevent and treat malaria.

      Objective:

      - To find out if combining live, infectious malaria parasites (known as Sanaria PfSPZ
      Challenge) and two FDA approved drugs that kill malaria parasites (pyrimethamine [PYR] and
      chloroquine [CQ]) is safe and can provide people protection against malaria. The Sanaria
      PfSPZ Challenge has been used in other studies without significant side effects.

      Eligibility:

        -  Healthy people ages 18-50 who weigh less than 170 pounds and are not pregnant or
           breastfeeding

        -  No history of hepatitis B, hepatitis C, or HIV infection

        -  Not currently enrolled in a clinical trial that involves a research drug or vaccine

        -  Have not traveled to an area with high malaria transmission within the last 5 years

        -  Never diagnosed with malaria in the past

      Design:

        -  Participants will be in 1 of 4 groups.

        -  Participants will receive a combination of injections and drugs. What combination they
           will receive will depend on what group they are in. This combination of injections and
           drugs may include:

             -  Injections of Sanaria PfSPZ Challenge (live, infectious malaria parasites) into a
                vein

             -  FDA approved antimalarial drug called chloroquine (CQ)

             -  FDA approved antimalarial drug called pyrimethamine (PYR)

             -  FDA approved antimalarial drug called Malarone

             -  The study will last approximately 3-7 months (depending on which group participants
                are in).

        -  There will be up to 68 study visits for three groups. One group will have up to 27 study
           visits. During the study visits, participants may have:

             -  Medical history review

             -  Physical exams

             -  Electrocardiogram (ECG): soft electrodes will be placed on the skin. A machine will
                record the heart s electrical signals to evaluate heart function.

             -  Blood and urine tests

             -  Medication given in the clinic under direct observation

             -  Injection of Sanaria PfSPZ Challenge into a vein

             -  Participants will receive a diary, thermometer, and ruler to record their body
                temperature and any symptoms.
    

Detailed description: 
      Human studies have shown that immunization by the bite PfSPZ-infected mosquitoes under drug
      coverage with chloroquine, an approach called chemoprophylaxis with sporozoites (CPS),
      infection treatment vaccination (ITV), or chemoprophylaxis vaccination (CVac) can provide
      high level, long term protection against homologous controlled human malaria infection
      (CHMI). The Sanaria PfSPZ-CVac approach duplicates this with an injectable sporozoite (SPZ)
      regimen (aseptic, purified, cryopreserved SPZ). In both approaches, whether mosquitoes or a
      syringe are used for SPZ administration, when chloroquine is used as the chemoprophylactic
      agent, transient, limited, asexual erythrocytic stage (AES) parasitemia develops. However,
      exposure to liver stage parasites only, without having any parasites completing liver stage
      development and entering the blood, thereby reducing the potential to induce blood stage
      immunity, likewise has been shown in animal studies to induce protective immunity upon
      subsequent challenge with homologous parasites, indicating that the transient parasitemia is
      not integral to inducing protection. To achieve this requires a different partner drug
      regimen that includes activity against liver stage parasites.

      Our approach, using PfSPZ-CVac with pyrimethamine (PYR), will assess this in humans. This
      phase 1 study will investigate the safety, tolerability, immunogenicity, and protective
      efficacy following liver stage only parasite exposure of direct venous inoculation (DVI) with
      aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (Sanaria PfSPZ
      Challenge), under chloroquine and pyrimethamine chemoprophylaxis, to induce stage specific
      sterile protection. By adding pyrimethamine chemoprophylaxis to chloroquine, liver stages
      will develop but should be killed before merozoites are released into the blood stream. The
      subjects will thus be exposed only to liver stage parasites (qPCR and blood smear negative).
      With this strategy, we will determine if protective immunity can develop without exposure to
      AES parasites and additionally whether it will minimize clinical symptoms associated with
      blood stage exposure. The timing of the pyrimethamine dose is critical to ensure the efficacy
      of pyrimethamine as causal prophylaxis, yet still allow for maximal antigenic exposure of
      liver-stage parasites to the host. An additional potential benefit of preventing AES
      parasitemia is the elimination of the immunosuppression associated with AES parasitemia.

      This trial will be the first step in establishing a new regimen for the PfSPZ-CVac approach,
      exposure to liver stage parasites without subsequent blood stage parasites, assessing
      protection against homologous CHMI. In future trials, the two-drug regimen can be assessed
      for protection against heterologous Pf infection and longevity of protection. The results of
      the study will contribute to understanding the targets and mechanisms of immunity against Pf
      malaria infection.
    

Intervention name(s): Chloroquine (CQ); Pyrimethamine (PYR); Sanaria PfSPZ Challenge (NF54)
Intervention type(s): Drug; Drug; Biological
Intervention description(s): Chloroquine Phosphate is a 4-aminoquinoline compound that is commercially available for oral administration. It is a white, odorless, bitter tasting, crystalline substance freely soluble in water; and widely used for the treatment andprophylaxis of malaria. It is supplied and manufactured in tablets of 500 mg (equivalent to 300 mg chloroquine phosphaste base); PYR is a folic acid antagonist that is commercially available; and has been commonly used as antimalarial drug for both treatment and prevention of malaria, usually in combination with sulfadoxine in adults, pregnant women, and children worldwide. It is manufactured in tablets of 25 mg.; Sanaria PfSPZ Challenge are aseptic, cryopreserved P.falciparum sporozoites used for CHMI trials, produced by the biotechnology company; Sanaria Inc. In brief, manufacture includes the production, under traditional environmental conditions, of eggs from a colony of A. stephensi mosquitoes housed in a controlled environmental chamber. The sporozoites are purified, counted, and, at a specified concentration, cryopreserved. Cryopreservation commences with the addition of cryoprotective additives to the purified sporozoites to produce the Sanaria PfSPZ Challenge product. Sanaria PfSPZ Challenge is dispensed into screw-cap vials containing 15,000, 50,000, or 100,000 PfSPZ in a 20 L aliquot. Sanaria PfSPZ Challenge is stored in liquid nitrogen vapour phase at 140 (Infinite)C to -196 (Infinite)C.
Intervention MeSH terms: Chloroquine; Pyrimethamine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Immunogenicity; Liver Stage; Parasites; Blood; Infection