rCSP/AP10-602 [GLA-LSQ] Vaccine Trial

This is a phase I, single-site, dose escalation study to evaluate the safety, immunogenicity,
and efficacy of the recombinant circumsporozoite protein (rCSP) antigen malaria vaccine
administered with and without AP 10-602 [Glucopyranosyl Lipid A (GLA) in liposome Quillaja
saponaria 21 formulation (LSQ)]. The study population will consist of 56 healthy male and
female adults aged 18 to 45 years old and be conducted at the Center for Vaccine Development
(CVD) in Baltimore, Maryland. Forty healthy, malaria-naïve volunteers will receive rCSP
vaccination with AP 10-602 [GLA-LSQ] adjuvant. Ten volunteers will receive rCSP alone. Each
dose-escalating group will receive 3 intramuscular (IM) total doses of vaccine on days 1, 29,
and 85. Group 1 will receive a dose of 10 mcg rCSP + AP 10-602 [GLA-LSQ] (5 mcg GLA - 2 mcg
LSQ) at each injection; Group 2 will receive 30 mcg rCSP + AP 10-602 [GLA-LSQ] (5 mcg GLA - 2
mcg LSQ); Group 3 will receive 30 mcg rCSP without adjuvant; and Group 4 will receive 60 mcg
rCSP + AP 10-602 [GLA-LSQ] (5 mcg GLA - 2 mcg LSQ). Group 5 will receive a dose of 30 mcg
rCSP + AP 10-602 [GLA-LSQ] (5 mcg GLA - 2 mcg LSQ) if immunogenicity analysis conducted 28
days post-2nd dose in Groups 2 and 3 show promise (at least fourfold increase in geometric
mean anti-CSP antibody or geometric mean anti-CSP titer of 20). Otherwise, group 5 will
receive or 60 mcg rCSP + AP 10-602 [GLA-LSQ] (5 mcg GLA - 2 mcg LSQ). Groups will be
vaccinated in a stepwise manner following a "telescoped" design. A sixth group of 6
volunteers (Group 6) will receive no vaccinations and will be used as an infectivity control
for a Controlled Human Malaria Infection (CHMI) challenge. Groups 4 and 5 will also undergo
the CHMI challenge together, 28 days after the last vaccination. The patient participation
duration is expected to be up to 510 days for Groups 1, 2, 3, 4, and 5; and up to 117 days
for Group 6. The entire study duration is approximately 675 days. This study will test two
hypotheses: (1) the rCSP/AP 10-602 [GLA-LSQ] candidate malaria vaccine will induce an immune
response in a dose-dependent manner as measured by anti-CSP antibody titer via ELISA and (2)
the rCSP/AP 10-602 [GLA-LSQ] candidate malaria vaccine will provide a minimum of 50% efficacy
in vaccines compared to unvaccinated infectivity controls. The primary objective is to assess
the safety and reactogenicity of candidate rCSP/AP 10-602 [GLA-LSQ] malaria vaccine when
administered intramuscularly on a 1, 29, and 85 day schedule to healthy malaria-naive adults
aged 18-45 years. The secondary objectives are to (1) assess immunogenicity of rCSP/AP 10-602
[GLA-LSQ] malaria vaccine when administered intramuscularly on a 1, 29, and 85 day schedule
and (2) to assess the preliminary efficacy of candidate rCSP/AP 10-602 [GLA-LSQ] malaria
vaccine against infection with Plasmodium falciparum malaria (defined as P. falciparum
asexual parasitemia or a delay in patency of infection > 2 days versus unimmunized
infectivity controls) under Controlled Human Malaria Infection (CHMI).

Inclusion Criteria:

1. Healthy adults (males and non-pregnant, non-lactating females) 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 > / = 70% on the post consent quiz
before any study procedures and is available for all study visits.

5. Females of childbearing potential and males must agree to practice highly effective
contraception.

- Contraception must be practiced from 30 days before the time of enrollment until
at least 30 days following the third vaccine dose for groups 1, 2 and 3, and the
malaria challenge event for groups 4, 5 and 6 (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 study participation.

6. Is in good health, as determined by vital signs (heart rate, blood pressure, oral
temperature); medical history; normal laboratory ranges; and a physical examination.

- Laboratory ranges include: 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 the entire course of the trial.

8. Willing to avoid non-study related blood donation for the duration of participation in
the study or until at least 1 year after receiving the last investigational vaccine,
whichever is longer.

9. Able to understand and comply with planned study procedures including daily outpatient
follow-up visits beginning 5 days after malaria challenge (groups 4, 5, and 6 only).

10. Willing to avoid non-study related blood donation for 3 years following P. falciparum
challenge (groups 4, 5, and 6 only).

Exclusion Criteria:

1. Any history of malaria infection, or travel to a malaria endemic region within 6
months before first vaccination.

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 (groups 4, 5 and 6 only)

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. History of splenectomy.

7. Screening laboratory values outside protocol-specified acceptable normal ranges,
except hematuria > 1 + detected during menses for females (for females who are
menstruating, urinalysis frequently tests positive for blood and is not an indicator
of poor health status or increased risk).

8. Vaccination with a live vaccine within the past 30 days or with a nonreplicating,
inactivated, or subunit vaccine within the last 14 days.

9. Known hypersensitivity to components of the vaccine for groups 1, 2, 3, 4 and 5; or to
the adjuvant for groups 1, 2, 4 and 5.

10. 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.

11. History of anaphylaxis or severe hypersensitivity reaction.

12. History of Guillain-Barre syndrome or severe adverse reaction to any vaccination.

13. Severe asthma, as defined by an emergency room visit or hospitalization within the
last 12 months.

14. Pregnant or breastfeeding women or women who plan to become pregnant before day 115 in
groups 1, 2 and 3; or before 30 days post-malaria challenge in groups 4, 5 and 6.

15. Concurrent participation in other investigational protocols or receipt of an
investigational product within the previous 30 days.

16. Planned receipt of an investigational product within 28 days following the last
vaccination dose or malaria challenge.

17. 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.

18. History of previous receipt of a candidate malaria vaccine or a vaccine containing the
GLA-LSQ adjuvant.

19. Use or planned use of any drug with anti-malarial activity 30 days before, or after
malaria challenge (groups 4, 5 and 6 only).

- Medications with antimalarial activity include trimethoprim-sulfamethoxazole,
azithromycin, erythromycin, tetracycline, doxycycline, minocycline, clindamycin,
ciprofloxacin, levofloxacin, norfloxacin and rifampin

20. Planned surgery 30 days before or after vaccination or malaria challenge.

21. History of drug or alcohol abuse within the last five years.

22. Receipt of blood or blood products in the previous six months or donation of a unit of
blood within two months before screening.

23. History of schizophrenia, bipolar disorder or other psychiatric condition that makes
study compliance difficult.

- Subjects with psychoses or history of suicide attempt or gesture in the 3 years
before study entry, ongoing risk for suicide.

24. History of diabetes mellitus with the exception of pregnancy-induced diabetes that has
resolved

25. Has evidence of increased cardiovascular disease risk (defined as > 10%, 5 year risk)
as determined by the method of Gaziano (groups 4, 5 and 6 only).

- Risk factors include sex, age (years), systolic blood pressure (mm Hg), smoking
status, body mass index (BMI, kg / mm^2), reported diabetes status, and blood
pressure.

26. Abnormal screening ECG (groups 4, 5, and 6 only).

- 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

27. Known hypersensitivity to mosquito bites, artemether-lumefantrine or
atovaquone-proguanil (groups 4, 5 and 6 only).

28. Anticipated medication use during the 28-day post-challenge period that are known to
interact with artemether/lumefantrine or atovaquone/proguanil, such as cimetidine,
metoclopramide, antacids, and kaolin (groups 4, 5 and 6 only).

29. Previous participation in a CHMI study.