PfSPZ Challenge in Non-immune Adults in Baltimore, USA

The proposed study is a single center, randomized and controlled human study to optimize
controlled human malaria infection (CHMI) administered by direct venous inoculation (DVI). 30
to 36 participants will be randomized to one of five groups and will be inoculated with PfSPZ
Challenge DVI. All participants recruited will be healthy adults aged between 18 and 45
years. The study duration is 4 months, participation duration is estimated to be 2 months.
Safety and infectivity data will be collected for each study product and dose-level. Sera
will be collected at baseline and at study day 29 for antibody assays. Participants, and
clinical and laboratory investigators will be blinded to group allocation. The study primary
endpoint will be reached at study day 29, at which time an interim study report will be
generated. The investigators, the sponsor, the data and statistical analysis team, and
Sanaria staff will meet in person or by teleconference on day 43 to review infection,
pre-patent period, and adverse event results. These results will be made available to members
of the International PfSPZ Consortium (I-PfSPZ-C) and if required, to regulatory authorities,
including the FDA, to facilitate other PfSPZ Challenge CHMI studies with the appropriate
disclaimers. Participants will be followed as outpatients for malaria diagnosis, treatment
and follow-up to study day 57. Malaria positivity will be determined by qPCR diagnostics with
microscopy as a backup. Participants who test positive for malaria and those who remain
negative at study day 29 will be treated with oral atovaquone-proguanil. The primary
objective of this study is to assess the safety and reactogenicity of PfSPZ Challenge
administered by DVI using 7G8 and NF54 P. falciparum strains. Secondary objectives are to 1)
assess the infectivity of four escalating doses of direct venous inoculation (DVI) of the 7G8
clone in comparison with an established dose (100% infective) DVI of the NF54 strain and 2)
assess the time to malaria patency for escalating doses of the 7G8 clone compared to a single
dose of the NF54 strain.

Inclusion Criteria:

1. Healthy adults between the ages of 18 and 45 years, inclusive 2. Able and willing to
participate for the duration of the study 3. Able and willing to provide written (not
proxy) informed consent 4. Provides informed consent and correctly answers greater than or
equal to 70% on the post consent quiz before any study procedures, and is available for all
study visits -Note: Two attempts permitted 5. Females of childbearing potential must agree
to practice highly effective contraception -Note: Contraception must be practiced from 30
days before the time of enrollment until at least 30 days following inoculation (such as
double barrier methods (condoms plus foam or spermicide, diaphragm plus foam or
spermicide), licensed intrauterine devices (IUDs), intravaginal or intra/transdermal or
oral hormonal methods initiated at least 30 days before inoculation or challenge,
documented surgical sterilization via tubal ligation the essure procedure or hysterectomy,
abstinence or a vasectomized partner). The contraceptive method should remain unchanged
throughout the required period 6. Is in good health, as determined by vital signs (heart
rate, blood pressure, oral temperature); medical history; normal laboratory ranges listed
in Appendix C; and a physical examination -Note: hemoglobin, white blood cell count,
platelet count, glucose (random), serum alanine aminotransferase (ALT), serum creatinine,
urine protein and urine blood 7. Agree not to travel to a malaria endemic region during
study days 1-29 8. Willing to avoid non-study related blood donation from screening until 3
years (45) following P. falciparum challenge 9. Able to understand and comply with planned
study procedures including daily outpatient follow-up visits beginning 5 days after
inoculation

Exclusion Criteria:

1. Any history of malaria infection, or travel to a malaria endemic region within 3 months
before planned date of CHMI 2. History of long-term residence (>5 years) in an area known
to have significant transmission of P. falciparum 3. Positive serology for human
immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B surface antigen
(HBsAg) 4. Positive sickle cell screening test or known hemoglobinopathy 5. Current or
recent (within the last four weeks) treatment with parenteral or oral corticosteroids
(intranasal or inhaled steroids are acceptable), or other immunosuppressive agents, or
chemotherapy 6. Screening laboratory values outside protocol-specified acceptable normal
ranges as noted in Appendix C, except hematuria>1+ detected during menses for females.
Note: For females who are menstruating, urinalysis frequently tests positive for blood and
is not an indicator of poor health status or increased risk; other exceptions include ALT
and creatinine below the lower limit of the reference range 7. Known hypersensitivity to
components of PfSPZ Challenge, atovaquone-proguanil or artemether-lumefantrine 8. History
of acute or chronic medical conditions including, but not limited to, disorders of the
liver, kidney, lung, heart, nervous system, or other metabolic or autoimmune/inflammatory
conditions 9. History of anaphylaxis or severe hypersensitivity reaction 10. Receipt of an
investigational product on study days -31 to -1 or planned receipt of an investigational
product on study days 1-57. 11. Any condition that, in the opinion of the investigator,
would affect a participant's ability to understand or comply with the study protocol or
would jeopardize a participant's safety or rights 12. Use or planned use of any drug with
anti-malarial activity 30 days before or after CHMI Note: Medications with antimalarial
activity include trimethoprim-sulfamethoxazole, azithromycin, erythromycin, tetracycline,
doxycycline, minocycline, clindamycin, ciprofloxacin, levofloxacin, norfloxacin and
rifampin 13. Planned surgery 30 days before or after CHMI 14. History of drug or alcohol
abuse within the last five years 15. Receipt of blood or blood products in the previous six
months or donation of a unit of blood within two months before screening 16. History of
schizophrenia, bipolar disorder or other psychiatric condition that makes study compliance
difficult Note: Subjects with psychoses or history of suicide attempt or gesture in the 3
years before study entry, ongoing risk for suicide. 17. History of diabetes mellitus with
the exception of pregnancy-induced diabetes that has resolved 18. Has evidence of increased
cardiovascular disease risk (defined as > 10%, 5 year risk) as determined by the method of
Gaziano (46) Note: Risk factors include sex, age (years), systolic blood pressure (mm Hg),
smoking status, body mass index (BMI, kg/mm2), reported diabetes status, and blood
pressure. 19. Abnormal screening ECG Note: Pathologic Q wave and significant ST-T wave
changes, left ventricular hypertrophy, non-sinus rhythm except isolated premature atrial or
ventricular contractions, right of left bundle branch block, advanced A-V heart block
(secondary or tertiary), QT/QTc interval >450 ms 20. Body mass index (BMI) >40 21. Known
hypersensitivity to atovaquone-proguanil or artemether-lumefantrine 22. Anticipated
medication use during the 28-day post-challenge period known to interact with
atovaquone-proguanil or artemether-lumefantrine Note: Such as rifampin, carbamazepine,
phenytoin, St. John's wort, cimetidine, metoclopramide, antacids, and kaolin 23. Personal
beliefs that prevent receipt of human serum albumin 24. Immunization with more than three
other vaccines within the past month and through study day 57 after CHMI 25. Previous
vaccination with a candidate malaria vaccine or participation in a CHMI study 26. History
of splenectomy 27. Pregnant or lactating females