Dose Escalation PfSPZ-CVac
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      People get malaria from bites from infected mosquitos. Researchers are studying a vaccine
      strategy. They will give people malaria parasites by injecting them with live infectious
      malaria parasites with antimalarial medications and then see if this strategy prevents
      malaria infection while off antimalarial medications.

      Objective:

      To see if combining a high dose of live, infectious malaria parasites (known as Sanaria PfSPZ
      Challenge) and two FDA approved drugs that kill malaria parasites (pyrimethamine [PYR] OR
      chloroquine [CQ]) is safe and can provide people protection against malaria.

      Eligibility:

      Healthy adults ages 18-50 who:

        -  are not pregnant or breastfeeding or planning on becoming pregnant while in the study

        -  are not infected with HIV, Hepatitis B or Hepatitis C

        -  have reliable early morning access to the NIH Clinical Center

        -  are able to come to the outpatient clinic frequently, sometimes daily

        -  have not been diagnosed with malaria within the past 10 years

      Design:

        -  Participants will be screened with medical history and physical exam. They will have
           heart, blood, and urine tests.

        -  Participants will have blood drawn for tests at most visits.

        -  Participants will keep track of their temperature and symptoms during some sections of
           the study.

        -  Participants will join one part of the study.

      Part 1 is one month:

        -  Participants will get the parasites by an injection into a vein on day 1 and receive
           antimalarial medications.

        -  They will have daily visits on days 7-14

        -  They will take another antimalarial at visits on days 15-17.

        -  The final visit will be on day 29.

      Part 2 is seven months:

        -  For the first 3 months, participants will get the parasite injection into a vein for 3
           injections in total. Each injection will occur once per month while taking an
           antimalarial drug.

        -  They will have daily visits on days 7-14 after the first injection, and on days 7-11
           after the second and third injection.

        -  They will have a final (fourth) injection around month 6 without any antimalarial
           medication.

        -  After this fourth injection, participants may have up to 21 daily visits from day 7
           after injection until end of study.

      Part 3 is one month:

        -  Participants will get the parasites by injection into a vein on day 1 without
           antimalarial medications.

        -  They will have visits almost every day starting day 7 from injection.

        -  They will take an antimalarial medication when they are diagnosed with malaria

        -  They will return for final end of study visit on days 27-29.
    

Detailed description: 
      Human studies have shown that immunization by the bite Plasmodium falciparum (Pf)
      sporozoite(SPZ)-infected mosquitoes under drug coverage with chloroquine, an approach called
      chemoprophylaxis with sporozoites (CPS) or infection treatment vaccination (ITV), can provide
      high level, long term protection against homologous controlled human malaria infection
      (CHMI). The Sanaria PfSPZ chemoprophylaxis vaccination (PfSPZ CVac) approach duplicates this
      with an injectable SPZ regimen. In both approaches, whether mosquitoes or syringes are used
      for SPZ administration, when chloroquine is used as the chemoprophylactic agent, transient,
      limited, asexual erythrocytic stage is seen in the majority of participants. Thus the
      question remains whether the significant protective efficacy seen can be achieved with
      pre-erythrocytic (sporozoite/liver stage) exposure only.

      Previously, we performed a phase 1 study to investigate the safety, tolerability,
      immunogenicity, and protective efficacy of Sanaria PfSPZ CVac with chloroquine (sporozoites,
      liver, and blood stage) or pyrimethamine with chloroquine (sporozoites and liver stage only)
      to further describe stage specific sterile protection (NIAID protocol #15-I-0169). In this
      study, we demonstrated that pyrimethamine is safe to administer, well tolerated, and can
      prevent subpatent and patent parasitemia (qPCR and blood smear negative) 100% of the time
      during Sanaria PfSPZ CVac. The study also duplicated the results previously reported with
      Sanaria PfSPZ CVac with chloroquine in terms of safety profile and protective efficacy
      against homologous CHMI. Although a combination of Sanaria PfSPZ- CVac with pyrimethamine and
      PfSPZ Challenge at 51,200 PfSPZ did not provide a significant protection level against
      homologous CHMI, we demonstrated that some subjects did develop protective immunity without
      any evidence of blood stage exposure during PfSPZ-CVac.

      Building on these results and taking the lessons learned from other pre-erythrocytic vaccine
      studies and models that have shown the importance of reaching a minimal antigen threshold
      required for the development of sterile immunity, this proposed study will assess the safety,
      tolerability, immunogenicity, and protective efficacy of increasing the dose of Sanaria PfSPZ
      Challenge sporozoites while receiving the same, or, if needed to successfully prevent
      parasitemia, a higher dose of pyrimethamine. Unlike the first study, however, pyrimethamine
      will be administered by itself as the partner drug, and will not be co-administered with
      chloroquine. The efficacy of PfSPZ-CVac with pyrimethamine will be assessed against CHMI with
      homologous parasites (Arm 2a) and CHMI with heterologous parasites (Arm 2b). Additionally, we
      will explore the impact of increasing the dose of Sanaria PfSPZ Challenge sporozoites while
      receiving chloroquine alone prophylaxis. The efficacy of PfSPZ-CVac with chloroquine will be
      assessed only against CHMI with heterologous parasites (Arm 3), as protection against
      homologous parasites has now been shown in two separate trials. It will thus be possible to
      compare the efficacy of the two partner drugs against heterologous CHMI. The results of this
      study will contribute to understanding the targets and mechanisms of immunity against Pf
      malaria infection and how the degree of exposure to the parasite (pre-erythrocytic or
      erythrocytic stage only or both) impacts these responses and subsequent protective efficacy.
    

Intervention name(s): Chloroquine Phosphate; Pyrimethamine; Sanaria PfSPZ Challenge
Intervention type(s): Drug; Drug; Biological
Intervention description(s): Chloroquine has been widely used for treatment and prophylaxis of malaria since 1946 (Most, London et al. 1984). It was the treatment of choice for uncomplicated malaria for decades because it was safe, well tolerated, affordable and highly effective for the treatment of malaria. However, increasing spread of chloroquine- resistant Pf over the last two decades has severely limited its use (Wellems 2002). Chloroquine phosphate is U.S Food and Drug Administration (FDA) approved for suppressive treatment (prophylaxis) and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of Pf.; Pyrimethamine is a folic acid antagonist that 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 (Organization April 2013 (rev. January2014); Sanaria Inc has manufactured two strains of Sanaria PfSPZ Challenge: NF54 and 7G8. The Sanaria PfSPZ Challenge contains fully infectious PfSPZ purified from the salivary glands of Anopheles stephensi mosquitoes raised under aseptic conditions. The infectious PfSPZ are formulated in cryoprotectant to maintain potency for an extended period. Sanaria PfSPZ Challenge (NF54) is known to be susceptible to chloroquine, pyrimethamine, atovaquone, artesunate, but not mefloquine. Sanaria PfSPZ Challenge (7G8) is known to be susceptible to mefloquine, atovaquone, artemether and artesunate but not to chloroquine or pyrimethamine.
Intervention MeSH terms: Chloroquine; Chloroquine diphosphate; Pyrimethamine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Malaria; Parasitemia; Immune; Responses; Sporozoites