Field Trial of PfSPZ-LARC2 Vaccine in Burkinabe Adults

This is a randomized, double-blind, placebo-controlled, single-center phase 2 clinical trial in healthy adults.

The trial will compare a single dose regimen (6x10^5 PfSPZ administered once) to a two dose regimen (4x10^5 PfSPZ administered twice). There are three groups:

Group 1: two doses of PfSPZ-LARC2 Vaccine (4x10^5 PfSPZ) four weeks apart.

Group 2: one dose of normal saline placebo and one dose of PfSPZ-LARC2 Vaccine (6x10^5 PfSPZ) four weeks apart.

Group 3: two doses of normal saline placebo four weeks apart.

All participants will be cleared of any existing parasitemia by (minimally) a three day treatment course of artemether /lumefantrine. This will be done 5-6 weeks prior to the first dose of investigational product, to prevent the known immunosuppressive effects of parasitemia on the induction of protective immunity and to prevent such infections from recrudescing later in the trial. If, at a pre-immunization visit 2 weeks before the first dose, any participant is positive by TBS, they will be retreated with the same regimen of artemether/lumefantrine. Clearance will be repeated 2 weeks before the second dose in all participants.

For the first immunization (V1), group 1 will receive one dose of vaccine (4x10^5 PfSPZ) and groups 2 and 3 will receive one dose of normal saline (NS placebo). Four weeks later, group 1 will receive a second dose of vaccine (4x10^5 PfSPZ), group 2 will receive a first dose of vaccine (6x10^5 PfSPZ) and group 3 will receive a second dose of normal saline. A syringe of vaccine and a syringe of normal saline are indistinguishable, facilitating the double-blind design. All administrations will be by direct venous inoculation (DVI).

Monitoring for adverse events (AEs) will take place during the 28-day interval between immunizations and for 28 days after the second immunization (56 days in total). Local (site of injection) AEs will be solicited for two days, systemic AEs will be solicited for 14 days and unsolicited AEs will be collected for 28 days after each immunization. In addition, participants will be instructed to notify the clinical team day or night should symptoms suggestive of malaria develop. Any symptoms consistent with malaria will be immediately investigated by TBS, which will be repeated if symptoms are ongoing - daily if the initial TBS is negative and symptoms are grade 1 or 2 in severity, or every 8 to 12 hours if initial TBS is negative and symptoms are grade 3 in severity. Malaria signs and symptoms include fever (axillary temperature in > 37.5°C [>99.5°F]), subjective fever, headache, dizziness, malaise, fatigue, chills, rigors, sweats, myalgia, arthralgia, nausea, vomiting, diarrhea, abdominal pain, cough and chest pain. Finally, medically-attended adverse events (MAAEs) and serious adverse events (SAEs) will be monitored throughout the trial. Laboratory tests (white blood count, neutrophil count, lymphocyte count, hemoglobin, platelets, creatinine, alanine aminotransferase) will be done on the day of each immunization and 7 days after each immunization.

Two weeks following immunization, active and passive surveillance for clinical malaria and malaria infection will begin. Passive detection will be achieved by encouraging all participants to immediately report any signs or symptoms consistent with malaria to the clinical team, which will be available 24/7. A TBS will be obtained as quickly as possible and read.

Active surveillance will consist of obtaining a TBS every two weeks from the entire study cohort starting two weeks after the second immunization, regardless of symptoms. These will be read in real-time only if there are malaria signs and symptoms. At each two week visit, participants will be reminded of the importance of contacting the clinical team if they develop malaria symptoms. The primary efficacy endpoint will be after 24 weeks of surveillance (26 weeks after immunization). Efficacy will also be calculated after the full 40 weeks of follow-up.

Surveillance will continue past the 24 week primary endpoint until at least 40 weeks, with an option to continue for a second season of surveillance if merited by efficacy demonstrated during the first rainy season and identification of funding for additional follow-up. If there is no continuation, the last study visit will be at 40 weeks of surveillance (42 weeks after second immunization).

At each two week visit when blood is sampled for TBS and at any time that TBS is made for the purpose of diagnosing clinical malaria, dried blood spots will be collected for possible later analysis by qPCR as an exploratory objective.

Prior to treating any malaria infection, blood samples will be obtained to allow for conducting genetic analyses of parasites. After treatment for malaria, 28 days of person-time at risk will be discounted (because of protection afforded by piperaquine), and then surveillance will continue to collect data on any additional parasitemias or clinical cases.

Inclusion criteria

• Healthy males and females, based on clinical and laboratory findings
• From the age 18 to 50 years
• Adults with a Body Mass Index (BMI) 18 to 30 Kg/m2.
• Residence in the study area for the duration of the study.
• Agreement to release medical information and to inform the study doctor concerning contraindications for participation in the study.
• Willingness to be attended to by a study clinician and take all necessary medications prescribed during study period.
• Agreement to provide contact information of a third party household member or close friend to study team.
• Agreement not to participate in another clinical trial during the study period.
• Agreement not to donate blood during the study period (until final clearance is completed)
• Able and willing to complete the study visit schedule over the study follow up period.
• Willingness to undergo HIV, hepatitis B (HBV), hepatitis C (HCV), and sickle cell anemia tests.
• Volunteer participant can demonstrate their understanding of the study by responding correctly to 18 out of 20 true/false statements (in a maximum of two repeat attempts for those who failed to pass in the first attempt).
• Signed written informed consent, in accordance with local practice.
• Has not been treated with any antimalarial medication for at least two weeks prior to the initial clearance treatment.
• Female volunteers aged 18 years and above must be non-pregnant (as demonstrated by a negative urine pregnancy test), and provide consent / assent of their willingness to take protocol-defined measures not to become pregnant during pre-treatment and immunization period and until 28 days after the second immunization. Acceptable measures to not become pregnant include oral or implanted contraceptives, IUD, abstinence, sterilization or sterile sexual partner. Women with a history of surgical or chemical sterilization (e.g., tubal ligation, hysterectomy, other) must provide written documentation of the procedure from a health care provider.
• Demonstration of the ability to complete pre-vaccination drug clearance without significant untoward effects.

Exclusion criteria

• Unable to provide informed consent including inability to pass the test of understanding.
• Receipt of a malaria vaccine in a prior clinical trial.
• History of a splenectomy or sickle cell disease.
• History of a neurologic disorder (including non-febrile seizures or complex febrile seizures) or formal history of migraine headache.
• Current use of systemic immunosuppressant pharmacotherapy.
• Receipt of a live vaccine within 4 weeks of first immunization or of 3 or more non-live vaccines within 2 weeks of first immunization.
• Women who are breast-feeding, pregnant or planning to become pregnant during the study period.
• Known allergy to artemether-lumefantrine (AL), dihydroartemisinin-piperaquine (DHA-P), or any component of the investigational products.
• History of anaphylaxis or other life-threatening reaction to a vaccine.
• Participation in any study involving investigational vaccine or drug within 4 weeks prior to enrollment that in the estimation of the site PI might adversely affect the individual's safety or the quality of data to be collected.
• Evidence of increased cardiovascular disease risk; defined as >10% five-year risk by non-laboratory method (Gaziano, 2008).
• Plan to participate in another investigational vaccine/drug research during the study.
• Plan for major surgery between enrollment until last study visit.
• Use or planned use of any drug with anti-malarial activity that is not specified by the protocol.
• Anticipated use of medications known to cause drug interactions with DHA-P (antiarrhythmics, neuroleptics, macrolide antibiotics, fluoroquinolones, imidazole and triazole antifungal agents, quinine, halofantrine, pentamidine and saquinavir, certain non-sedating antihistamines, all of which can affect QT intervals ) or AL (the same list of drugs affecting QT intervals plus rifampin, carbamazepine, phenytoin, St. John's wort and antiretroviral drugs).
• Positive HIV, HBsAg or HCV serology.
• History of or evidence for other chronic disease conditions including cancer, diabetes, renal failure, hypertension, tuberculosis, etc.
• History of arrythmias or cardiac disease, or an abnormal electrocardiogram, defined as one showing prolonged QT interval, pathologic Q waves and significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm including isolated premature ventricular contractions, but excluding isolated premature atrial contractions; right or left bundle branch block; or advanced (secondary or tertiary) A-V heart block; or other clinically significant abnormalities on the electrocardiogram.
• Any clinically significant deviation from the normal range in biochemistry or hematology tests measured at screening and not resolving (grade 1 abnormalities are allowed).
• Any medical, psychiatric, social, behavioral or occupational condition or situation (including active alcohol or drug abuse affecting social function) that, in the judgment of the site PI, impairs the participant's ability to give informed consent, increases the risk to the participant of participation in the study, affects the ability of the participant to participate fully in the study, or might negatively impact the quality, consistency, integrity or interpretation of data derived from their participation in the study.
• Inability to complete a course of malaria treatment prior to receipt of investigational product.