Age De-escalation Clinical Trial to Evaluate the Safety, Tolerability and Immunogenicity of a Late Liver Stage-arresting, Replication-competent Plasmodium Falciparum Sporozoite Vaccine (Sanaria® PfSPZ-LARC2 Vaccine) Administered by Direct Venous Inoculation to Malaria-exposed Adults and Children in Burkina Faso
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Sanaria Inc.
- 入组人数
- 75
- 试验地点
- 1
- 主要终点
- Assess safety, namely adequacy of attenuation, of PfSPZ-LARC2 Vaccine by measuring number of trial participants with presence of breakthrough blood stage infection
研究概览
简要总结
This is a first-in-humans randomized, double-blind, placebo-controlled, age de-escalation Phase 1 trial of Plasmodium falciparum (Pf) late liver stage-arresting replication-competent (LARC) sporozoite (SPZ) malaria vaccine (Sanaria® PfSPZ-LARC2 Vaccine) administered to healthy, malaria-exposed adults and children by direct venous inoculation (DVI) to determine safety, tolerability, and immunogenicity. The PfSPZ comprising PfSPZ-LARC2 Vaccine contain a double gene deletion, of the Mei2 and LINUP genes. As a result, they undergo developmental arrest in the late liver stages without releasing merozoites into the blood stream (no blood stage parasites are produced, either asexual or sexual). Because Pf parasites with the LARC phenotype replicate in the liver before disintegrating, they amplify and diversify parasite protein expression and are expected to be a potent immunogen to induce anti-malarial immunity, equaling or exceeding the potency and efficacy of the replication-competent chemo-attenuated Sanaria® PfSPZ-CVac (chloroquine). Because the parasites are intrinsically attenuated, they are also expected to be safe and well tolerated, similar to radiation-attenuated Sanaria® PfSPZ Vaccine and to the single-gene(Mei2)-deleted GA2 parasites (also LARC phenotype) tested at the Leiden University Medical Center (LUMC), which, like PfSPZ-LARC2 Vaccine, disintegrate after replicating in the liver. PfSPZ-LARC2 Vaccine thus avoids the safety concerns associated with PfSPZ-CVac, which uses fully infectious, non-attenuated parasites to achieve replication and depends on co-administered chloroquine for attenuation. In summary, the genetically attenuated PfSPZ-LARC2 Vaccine should combine the best-in-class immunogenic potency and protective efficacy of PfSPZ-CVac (chloroquine) with the excellent safety and tolerability of intrinsically attenuated PfSPZ Vaccine and GA2 vaccine.
This trial is designed to test the hypotheses that:
- The vaccine is safe and well tolerated in each age group.
- The true rate of breakthrough blood stage infection (or other concerning adverse events) is less than about 5%, with an 95% confidence level (this will be the level of confidence that there are no breakthroughs if no breakthroughs occur in the 50 participants receiving PfSPZ-LARC2 Vaccine).
详细描述
This is a randomized, double-blind, placebo-controlled, single-center Phase 1 clinical trial. The dose of PfSPZ to be tested in all age groups is 2.0x10e5, the same as the dose used in an NIH study of PfSPZ-CVac (chloroquine) which resulted in 100% vaccine efficacy against a heterologous controlled human malaria infection (CHMI) conducted 12 weeks after immunization]. 100% heterologous protection at 12 weeks represents the best protection ever recorded for a malaria vaccine. The selected dose, 2.0x10e5 PfSPZ, is roughly similar to the dose used in the GA2 study at LUMC. In one of the two adult groups, however, the 10 participants receiving vaccine will be administered a two-fold higher dose - 4.0x10e5 PfSPZ - to assess the risk of breakthrough more stringently in a malaria-experienced adult population at low risk for serious complications of malaria infection. If this high dose of PfSPZ does not lead to breakthrough in adults, it is unlikely that a 2-fold lower dose will lead to breakthrough in children.
There will be three cohorts of participants initiated in staggered fashion. These consist of 2 groups of adults in cohort 1 (receiving, respectively, 2.0x10e5 PfSPZ and 4.0x10e5 PfSPZ), followed by 2 groups of adolescents/older children in cohort 2 (each receiving 2.0x10e5 PfSPZ), followed by 1 group of younger children in cohort 3 (receiving 2.0x10e5 PfSPZ). Each group will be composed of 15 participants, 10 to receive PfSPZ-LARC2 Vaccine, and 5 to receive normal saline (NS) placebo, with randomized, blinded, 2:1 allocation to vaccine and placebo in each group. Each group will begin with a pilot group of 2 vaccinees and 1 placebo recipient three or more days before the rest of the cohort initiates, as a safety precaution. In the two cohorts with two groups, the pilot group for the second group will be initiated at least 3 days after the pilot group for the first group. A Safety Monitoring Committee (SMC) will review safety and tolerability data before proceeding to the next cohort.
Each group except group 1 (2.0x10e5 PfSPZ adult group) will receive only a single dose. This is because the risk of breakthrough is thought to be greatest after a first exposure; thereafter, the vaccine-induced immunity from the first dose reduces the risk of breakthrough after subsequent doses . Administering a single "highest-risk-of-breakthrough" first dose in all four age groups allows follow-up without the complexity of intervening second and third immunizations. However, it is theoretically possible (without any supporting evidence) that the biology associated with repeated dosing of LARC2 parasites could be different from this expectation. For this reason, group 1 will be administered second and third doses of 2.0x10e5 PfSPZ, each dose with 28 days of follow-up. It is noted that in the first GA2 trial in Leiden, 9 participants were immunized by mosquito bite three times at monthly intervals and there was no breakthrough after any of the doses. Including 3 doses in group 1 will additionally allow measurement of the immunogenicity of a standard 3-dose regimen for this vaccine (doses on Days 1, 29 and 57) in a malaria-exposed population, allowing comparison with a planned trial in Seattle, where malaria-naive adults will receive the same 3-dose regimen.
Cohort 1:
Group 1 (20-50-year-olds): 15 participants receive 3 injections of 2.0x10e5 PfSPZ or NS (days 1, 29 and 57).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
parasitology teams laboratory teams clinical teams
入排标准
- 年龄范围
- 1 Year 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy males and females, based on clinical and laboratory findings
- •From the age 1 to 50 years
- •Adults with a Body Mass Index (BMI) 18 to 30 Kg/m2; or adolescents, and children with Z-score of the selected indicator ([weight-for-height], [(height and BMI) for age]) category within ±2SD.
- •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 (subjects 21 years of age and older) or the parent / guardian signing the informed consent (for subjects <21 years of age) is able to demonstrate their understanding of the study by responding correctly to 9 out of 10 true/false statements (in a maximum of two attempts for those who failed to respond correctly to all true/false statements in the first attempt)
- •Signed written informed consent, in accordance with local practice, provided by adult volunteers, parents or legal representatives and relevant assent for children participants as applicable
- •Has not been treated with any antimalarial medication for at least two weeks prior to the initial clearance treatment.
- •Female volunteers aged 12 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 the study and safety follow-up period. Acceptable measures to not become pregnant include oral or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, abstinence, use of a condom by the sexual partner or sterile sexual partner during the entire study. 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.
- •One additional inclusion criterion is demonstration of the ability to complete pre-vaccination drug clearance without significant untoward effects.
排除标准
- •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 atovaquone-proguanil (AP), dihydroartemisinin-piperaquine (DHA-P), artemether-lumefantrine (AL), 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 would precede or coincide with vaccination through to 28 days after the last dose of vaccine.
- •Anticipated use of medications known to cause drug interactions with DHAP (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 - see Section2.2.1.3) 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.
- •One additional exclusion criterion is inability to take a course of malaria treatment prior to receipt of investigational product.
研究组 & 干预措施
Cohort 1: Group 1a Adult 2x10e5 PfSPZ-LARC2 Vaccine
20-50-year-olds: 10 participants receive 3 injections of 2.0x10e5 PfSPZ-LARC2 Vaccine
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Cohort 1: Group 1b Adult Normal Saline
20-50-year-olds: 5 participants receive 3 injections of normal saline
干预措施: Normal Saline (Placebo) (Biological)
Cohort 1: Group 2a Adult 4x10e5 PfSPZ-LARC2 Vaccine
20-50-year-olds: 10 participants receive single injection of 4.0x10e5 PfSPZ-LARC2 Vaccine
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Cohort 2: Group 3a 11-17year old 2x10e5 PfSPZ-LARC2 Vaccine
11-17-year-olds: 10 participants receive single injection of 2.0x10e5 PfSPZ-LARC2 Vaccine
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Cohort 2: Group 3b 11-17 year-olds Normal Saline
11-17-year-olds: 5 participants receive single injection of Normal Saline
干预措施: Normal Saline (Placebo) (Biological)
Cohort 2: Group 4a 6-10-year old 2x10e5 PfSPZ-LARC2 Vaccine
6-10-year-olds: 10 participants receive single injection of 2.0x10e5 PfSPZ-LARC2 Vaccine
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Cohort 2: Group 4b 6-10-year old Normal Saline
6-10-year-olds: 5 participants receive single injection of Normal Saline
干预措施: Normal Saline (Placebo) (Biological)
Cohort 3: Group 5a 1-5-year old 2x10e5 PfSPZ-LARC2 Vaccine
1-5-year-olds: 10 participants receive one injection of 2.0x10e5 PfSPZ-LARC2 Vaccine
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Cohort 3: Group 5b 1-5-year old Normal Saline
1-5-year-olds: 5 participants receive one injection of Normal Saline
干预措施: Normal Saline (Placebo) (Biological)
Cohort 1: Group 2b: Adults Normal Saline
20-50 year olds: 5 participants receive single injection of Normal Saline
干预措施: Normal Saline (Placebo) (Biological)
结局指标
主要结局
Assess safety, namely adequacy of attenuation, of PfSPZ-LARC2 Vaccine by measuring number of trial participants with presence of breakthrough blood stage infection
时间窗: First 28 days after immunization with PfSPZ-LARC2 Vaccine
Number of trial participants with presence of breakthrough blood stage infection during the first 28 days after immunization shown to be the vaccine strain. Participants will be followed for parasitemia by thick blood smear (TBS) after immunization. TBS to monitor for Pf blood stage infections will be performed every two days from Day 7 (day +6) to Day 19 (day +18) and then on Days 21, 24 and 29 (days +20, +23 and +28) .
Assess the safety of PfSPZ-LARC2 administration by measuring incidence of related grade 3 solicited and unsolicited adverse events (AEs) in the 28 days after PfSPZ-LARC2 Vaccine administration
时间窗: First 28 days after immunization with PfSPZ-LARC2 Vaccine
Participants will be followed for solicited and unsolicited adverse events 28 days after immunization. Incidence of possibly related, probably related or definitely related (a) grade 3 solicited adverse events (AEs) in the 28 days after PfSPZ-LARC2 Vaccine administration; and (b) grade 3 unsolicited AEs in the 28 days after PfSPZ-LARC2 Vaccine administration will be measured.
Assess the safety of PfSPZ-LARC2 administration by measuring incidence of related grade 3 abnormal laboratory values one week after PfSPZ-LARC2 Vaccine administration
时间窗: 7 days after immunization with PfSPZ-LARC2 Vaccine
Incidence of possibly related, probably related or definitely related grade 3 abnormal laboratory values one week after PfSPZ-LARC2 Vaccine administration;
Assess the safety of PfSPZ-LARC2 administration by measuring incidence of related serious adverse events (SAEs) throughout the study period
时间窗: Entire study period (approximately 6 months)
Incidence of possibly related, probably related or definitely related serious adverse events (SAEs) throughout the study period.
次要结局
- To further assess safety following vaccination by measuring incidence of mild to moderate solicited and unsolicited AEs in the 28 days after injection of PfSPZ-LARC2 Vaccine(First 28 days following immunization with PfSPZ-LARC2 Vaccine)
- To further assess safety following vaccination by measuring incidence of mild to moderate abnormal laboratory values one week after injection of PfSPZ-LARC2 Vaccine(7 days after immunization with PfSPZ-LARC2 Vaccine)
- To identify immune responses following vaccination and their association with age and sex by measuring Anti-P. falciparum circumsporozoite protein antibody levels two weeks after PfSPZ-LARC2 Vaccine administration.(14 days after immunization with PfSPZ-LARC2 Vaccine)