Safety, Immunogenicity, and Protective Efficacy of Radiation Attenuated Plasmodium Falciparum NF54 Sporozoites in Healthy African Adults in Mali

It is known that humans can be protected against malaria by repeated immunization with radiation attenuated sporozoites. Traditionally, those sporozoites are administered by exposing the vaccinee to at least 1000 bites of sporozoite infected irradiated mosquitoes, an approach that is unsuitable for mass vaccination campaigns. Recently, Sanaria, Inc. developed a process for manufacturing, in compliance with current Good Manufacturing Practices (cGMPs) aseptic, purified, radiation attenuated cryopreserved sporozoites from a well characterized isolate of P. falciparum (Hoffman et al., 2010). This product, which is called PfSPZ Vaccine, can be administered by needle and syringe. Previous studies conducted by the Vaccine Research Center and the Navy have established that IV administration of PfSPZ Vaccine can induce sterile protection against controlled human malaria infection (CHMI) with a homologous strain of P. falciparum in up to 100% of malaria na(SqrRoot) ve individuals (Seder et al., 2013). A recent study conducted as collaboration among the Malaria Research and Training Center (MRTC, Mali), the Laboratory of Malaria Immunology and Vaccinology (LMIV) National Institute of Allergy and Infectious Diseases (NIAID), and Sanaria, Inc. (Sissoko et al., unpublished) has shown that sterile protection against naturally occurring malaria infection can be achieved, but not at the level seen in the US nor at the level desired.

The next logical step in an attempt to improve protective efficacy in the targeted endemic population is to increase the PfSPZ Vaccine dose, increasing the interval between the first and second doses to 8 weeks (as was done in WRAIR 2080 in the group receiving 3 doses of 4.5x105 PfSPZ), and reducing the numbers of doses to three. Additionally, in this study design, we also can begin to understand how the standard controlled human malaria infection (CHMI) model may be used in the field and start to explore the impact of such factors as malaria co infection and drug treatment have on vaccine responses.

The initial dose escalation pilot study will focus on safety and tolerability of the PfSPZ Vaccine. A defined number of subjects enrolled during the pilot study will also undergo further evaluation, including randomization to receive or not receive drug treatment immediately prior to each vaccination and examination of protective efficacy against homologous CHMI via PfSPZ Challenge. The targeted dose (18x105 PfSPZ Vaccine), if safe and tolerable, will be administered to a larger cohort in a double blind, randomized, placebo controlled trial to examine the protective efficacy of the vaccine against naturally occurring infection. PfSPZ Vaccinees (Arm 2) from the main study will be re enrolled the following malaria transmission along with age, sex, and village matched controls (re enrolled Arm 3, additional controls) to explore the duration of protection through another malaria transmission season.

Subjects will be recruited from rural villages in Mali. The study will be conducted as collaboration among MRTC, LMIV/NIAID, and Sanaria, Inc.

• INCLUSION CRITERIA PILOT and MAIN STUDY:

Subjects must fulfill all the following criteria to be eligible for the pilot and main study:

• Age greater than or equal to 18 and less than or equal to 50 years
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process
• In good general health and without clinically significant medical history
• Willing to have blood samples stored for future research
• Available for the duration of the study
• Females of childbearing potential must be willing to use reliable contraception (as defined below) from 21 days prior to Study Day 1 to 3 months after the last vaccination.

• Reliable methods of birth control include one of the following: confirmed pharmacologic contraceptives (parenteral) delivery; intrauterine or implantable device.
• Reliable methods of birth control include concurrent use of a pharmacologic and a barrier method, i.e., two of the following: confirmed pharmacological contraceptives (oral, transdermal) delivery or vaginal ring AND condoms with spermicide or diaphragm with spermicide.

Non-childbearing women will also be required to report date of last menstrual period, history of surgical sterility (i.e., tubal ligation, hysterectomy) or premature ovarian insufficiency (POI), and will have urine or serum pregnancy test performed per protocol.

Inclusion criteria

DURATION STUDY:

Subjects must fulfill all the following criteria to be eligible for the duration study:

• Age greater than or equal to 18 and less than or equal to 52 years
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process
• In good general health and without clinically significant medical history
• Willing to have blood samples stored for future research
• Available for the duration of the study
• Participated in the main phase of this protocol (Arms 2,3) AND received all three vaccinations OR suitable to serve as a matched control for such an individual.

Exclusion criteria

PILOT and MAIN STUDY:

A subject will be excluded from participating in the pilot or main trial if any one of the following criteria is fulfilled:

• Pregnancy, as determined by a positive urine or serum human choriogonadotropin (beta-hCG) test (if female)
• Currently breast-feeding (if female)
• Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the participant to understand and comply with the study protocol
• Hemoglobin, WBC, absolute neutrophils, and platelets outside the local laboratory defined limits of normal (subjects may be included at the investigator's discretion for not clinically significant values)
• Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal (subjects may be included at the investigator's discretion for not clinically significant values)
• Infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B (HBV)
• Known or documented sickle cell disease by history (Note: known sickle cell trait is NOT exclusionary)
• Clinically significant abnormal ECG
• Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies including urinalysis
• History of receiving any investigational product within the past 30 days
• Participation or planned participation in a clinical trial with an investigational product prior to completion of the follow-up visit 28 days following last vaccination OR planned participation in an investigational vaccine study until the last required protocol visit
• Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months.
• History of a severe allergic reaction or anaphylaxis
• Severe asthma (defined as asthma that is unstable or required emergent care, urgent care, hospitalization, or intubation during the past 2 years, or that has rquired the use of oral or parenteral corticosteroids at any time during the past 2 years.
• Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sj(SqrRoot)(Delta)gren s syndrome, or autoimmune thrombocytopenia
• Known immunodeficiency syndrome
• Known asplenia or functional asplenia
• Use of:

• Chronic (greater than or equal to 14 days) oral or intravenous corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs within 30 days of vaccination
• Use of antimalarials or systemic antibiotics with known antimalarial activity within 30 days prior to the first vaccine
• Receipt of a live vaccine within the past 4 weeks or a killed vaccine within the past 2 weeks prior to Vaccination #1 and every subsequent vaccination day
• Receipt of immunoglobulins and/or blood products within the past 6 months
• Previous receipt of an investigational malaria vaccine in the last 5 years
• Known allergies or contraindication against: ASAQ or Coartem
• Other condition(s) that, in the opinion of the investigator, would jeopardize the safety or rights of a participant participating in the trial, interfere with the evaluation of the study objectives, or would render the subject unable to comply with the protocol.

Exclusion criteria

DURATION STUDY:

Subjects must

• Known to be pregnant by history or as determined by a positive urine or serum human choriogonadotropin (Beta-hCG) test (if female)
• Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the participant to understand and comply with the study protocol
• Hemoglobin, WBC, absolute neutrophils, and platelets outside the local laboratory defined limits of normal (subjects may be included at the investigator's discretion for not clinically significant values)
• Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal (subjects may be included at the investigator's discretion for not clinically significant values)
• Infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B (HBV)
• Known or documented sickle cell disease by history (Note: known sickle cell trait is NOT exclusionary)
• Receipt of artemether/lumefantrine within less than 14 days from enrollment.
• Knwn allergies or contraindications (such as significant cardiac disease; prolonged QTc greater than 450 ms; currently taking medications that may prolong your QTc; serious side effects from artemether/lumefantrine in the past) to study treatment (artemether/lumefantrine)
• Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies including urinalysis
• Enrollment in another investigational trial during the study period (participating in screening for other investigational trials is permitted).
• Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months.
• Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sj(SqrRoot)(Delta)gren s syndrome, or autoimmune thrombocytopenia
• Known immunodeficiency syndrome
• Known asplenia or functional asplenia
• Use of Chronic (greater than or equal to 14 days) oral or intravenous corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs within 30 days of Study Day 0
• Other condition(s) that, in the opinion of the investigator, would jeopardize the safety or rights of a participant participating in the trial, interfere with the evaluation of the study objectives, or would render the subject unable to comply with the protocol.