Dose Escalation PfSPZ-CVac
Condition: Malaria
MeSH terms: Malaria
Intervention: Chloroquine Phosphate; Pyrimethamine; Sanaria PfSPZ Challenge
Intervention description: 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
Phase: Phase 1
Study type: Interventional
Primary purpose: Prevention
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Malaria; Parasitemia; Immune; Responses; Sporozoites

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Age greater than or equal to 18 and less than or equal to 50 years.

          -  In good general health and without clinically significant medical history

          -  Malaria comprehension exam completed, passed (a score of greater than or equal to 80%
             or per investigator s discretion) and reviewed prior to enrollment

          -  Reliable access to the clinical trial center and availability to participate for
             duration of study

          -  Females of childbearing potential must be willing to use reliable contraception (as
             defined below) from 21 days prior to study day -2 to 28 days following last Sanaria
             PfSPZ Challenge exposure

          -  Subject to the judgment and discretion of the PI, female participants who meet ANY ONE
             of the criteria listed immediately below, may not be required to take any additional
             measures to avoid pregnancy. Such participants will be counseled on risks at the time
             of consent and at appropriate points (e.g. when pregnancy testing occurs) during the
             study:

               -  Females who have had their uterus, and/or BOTH ovaries removed

               -  Females who have had BOTH fallopian tubes surgically 'tied' or removed

               -  Females who are above the age of 45 and have spontaneously had no menses at any
                  point during the past 12 or more consecutive months (i.e. have reached menopause)

               -  Females who, in the conservative and reasonable judgment of the PI (e.g. due to
                  sexual orientation or serious life choice (such as being celibate clergy or
                  transgender), during the entire trial will NOT participate in any potentially
                  reproductive sexual contact

               -  Females who, in the conservative and reasonable judgment of the PI, are in a
                  monogamous stable relationship with a male who has undergone vasectomy at least 4
                  months prior or another procedure/medical condition that deems the male sterile

          -  Subject to the judgment and discretion of the PI, female participants who DO NOT meet
             ANY of the criteria listed above, will be appropriately counseled on reproductive
             risks and pregnancy avoidance, and will be required to adhere to the following
             measures and agree to 2 methods of pregnancy prevention as noted below:

               -  CATEGORY 1: a highly effective hormonal method to prevent pregnancy [e.g.
                  CONSISTENT, CONTINUOUS use of contraceptive pill, patch, ring, implant or
                  injection], and/or IUD or equivalent

               -  IN ADDITION TO CATEGORY 2: a barrier method to be used at the time of potentially
                  reproductive sexual activity (e.g. [male/female condom, 'cap,' or diaphragm] +
                  spermicide).

        EXCLUSION CRITERIA:

          -  Currently is breast-feeding (if female).

          -  Pregnancy as determined by a positive urine or serum human choriogonadotropin (beta-
             hCG) test at any point during the study (if female).

          -  Recent travel to a malaria endemic area within 5 years of enrollment (Endemic areas
             are defined per the CDC website. Factors such as but not limited to use of antimalaria
             prophylaxis during travel, length of stay, activities during the travel, history of
             illnesses within 30 days of travel will be considered to determine the likelihood that
             the subject was exposed to malaria)

          -  Planned travel to a malaria endemic area (as defined by the Center for Disease
             Control) during the study period

          -  Reported history of confirmed malaria diagnosis on peripheral blood smear or by
             clinical history in the past 10 years.

          -  Hemoglobin, WBC, platelets, ALT, and creatinine outside of local lab normal range
             (subjects may be included at the investigator s discretion for not clinically
             significant values outside of normal range)

          -  Abnormal urinalysis as defined by positive urine glucose, protein, and red blood
             cells. Subject can be included if investigator determine the abnormality is not
             clinically significant .

          -  BMI < 17 or BMI > 35

          -  Anticipated use during the study period, or use within the following periods prior to
             enrollment:

               -  Investigational malaria vaccine within the last five years

               -  Malaria chemoprophylaxis within 6 months

               -  Chronic systemic immunosuppressive medications (>14 days) within 6 months
                  (e.g.cytotoxic medications, oral/parental corticosteroids >0.5 mg/kg/day
                  prednisone or equivalent). Corticosteroid nasal spray for allergic rhinitis and
                  topical corticosteroids for mild, uncomplicated dermatitis are allowed.

               -  Blood products or immunoglobulins within 6 months

               -  Systemic antibiotics with antimalarial effects within 30 days (such as
                  clindamycin, doxycycline)

               -  Investigational or non-registered product or vaccine within 30 days

               -  Receipt of a live vaccine within 28 days or a killed vaccine within the 14 days
                  prior to Sanaria PfSPZ Challenge

               -  Medications known to interact with pyrimethamine and/or chloroquine (for the main
                  and pilot study participants ONLY), atovaquone, proguanil (ALL participants)

          -  Reported history of:

               -  Sickle cell disease, sickle cell trait, or other hemoglobinopathies

               -  Splenectomy or functional asplenia

               -  Systemic anaphylaxis

               -  Any allergic reactions to study drugs (pyrimethamine, chloroquine) or NSAIDs,
                  atovaquone, proguanil

               -  Documented history of chronic or active neurologic disease (including seizures,
                  uncontrolled migraine headaches)

               -  Psoriasis or porphyria

               -  Ocular diseases including retinopathy or visual field defects

          -  Clinically significant medical condition, physical examination findings, other
             clinically significant abnormal laboratory results, or past medical history that may
             have clinically significant implications for current health status and participation
             in the study in the opinion of the Investigator. A clinically significant condition or
             process includes but is not limited to:

               -  A process that would affect the immune response, or requires medication that
                  affects the immune response

               -  Any contraindication to repeated phlebotomy

               -  A condition or process in which signs or symptoms could be confused with
                  reactions to malaria challenge and/or infection, including dermatologic
                  abnormalities at the site of sporozoite inoculation

               -  A chronic or subclinical condition which could be exacerbated by administration
                  of any of the PfSPZ-CVac components or malaria infection

          -  History of, or known active cardiac disease including: (1) prior myocardial infarction
             (heart attack); (2) angina pectoris; (3) congestive heart failure; (4) valvular heart
             disease; (5) cardiomyopathy; (6) pericarditis; (7) stroke or transient ischemic
             attack; (8) exertional chest pain or shortness of breath; or ( 9) other heart
             conditions under the care of a doctor

          -  Clinically significant ECG findings, as determined by the expert study cardiologist

          -  Moderate or high risk for coronary heart disease (CHD) based on NHANES I
             cardiovascular risk assessment

          -  Acute illness at the time of enrollment

          -  Infection with HIV, Hepatitis B, Hepatitis C

          -  Psychiatric condition that precludes compliance with the protocol including but not
             limited to:

               -  Psychosis within the past 3 years

               -  Ongoing risk for suicide, or history of suicide attempt or gesture within the
                  past 3 years

          -  Suspected or known current alcohol or drug abuse as defined by the American
             Psychiatric Association in the DSM V at the discretion of the PI

          -  Clinical trial staff and/or Sanaria Inc. employees with direct involvement in the
             conduct of the trial are excluded from participation.

          -  Participating in other clinical trials involving investigational interventions or off
             label medication use during the study period (excluding participation in the optional
             long term follow up visits). Participation in other trials such as observational or
             imaging studies will be discussed with the investigators.

          -  Any other finding that, in the judgment of the Investigator, would interfere with, or
             serve as a contraindication to, protocol adherence, assessment of safety or
             reactogenicity, or a subject s ability to give informed consent, or increase the risk
             of having an adverse outcome from participating in the study.