Randomized, Double-Blind, Placebo-Controlled Trial to Assess Safety, Immunogenicity, and Protective Efficacy Against Naturally Transmitted Plasmodium Falciparum Malaria of One and Two Dose Regimens of a Late Liver Stage-arresting, Replication-competent Plasmodium Falciparum Sporozoite Vaccine (Sanaria® PfSPZ-LARC2 Vaccine) in Healthy Malaria-Exposed Adults in Burkina Faso
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Sanaria Inc.
- 入组人数
- 180
- 试验地点
- 1
- 主要终点
- Vaccine efficacy of PfSPZ-LARC2 Vaccine as compared to normal saline, placebo against first Pf infection as detected by thick blood smear (TBS).
研究概览
简要总结
This is a phase 2 clinical trial of a Plasmodium falciparum (Pf) late liver stage-arresting replication-competent (LARC) sporozoite (SPZ) vaccine (Sanaria® PfSPZ-LARC2 Vaccine) that will assess field efficacy in Africa.
The PfSPZ comprising PfSPZ-LARC2 Vaccine contain a double deletion of the genes encoding the Mei2 and LINUP proteins, both of which are required for transition from liver to blood stage malaria. As a result, mei2-/linup- parasites 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, and the parasite life cycle does not progress. 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) vaccine approach. Because the parasites are intrinsically attenuated, they are expected to be safe and well tolerated, similar to radiation-attenuated Sanaria® PfSPZ Vaccine, to the replication deficient, early arresting PfSPZ-GA1 Vaccine, and to the single-gene(mei2)-deleted GA2 (LARC1) parasites tested at the Leiden University Medical Center that provided 90% protection against CHMI after a single dose.
The active treatments to be assessed for efficacy are one immunization of 6.0x10^5 PfSPZ or two immunizations with 4.0x10^5 PfSPZ of PfSPZ-LARC2 Vaccine four weeks apart, timed so that the immunization of the one dose regimen coincides with the second immunization of the two dose regimen.
The alternative treatment is immunization with normal saline (placebo group), which is indistinguishable from the test article.
The primary variable of interest is whether and when trial participants develop Pf malaria parasitemia during surveillance. Malaria parasitemia will be detected by thick blood smear (TBS), which will be performed every two weeks starting two weeks after the second vaccination (to allow time for the vaccine to work) and extending to week 26 after the second vaccination (24-week surveillance period). Surveillance will continue for 40 weeks but the primary outcome will be determined at 24 weeks of surveillance so the data are comparable to other studies of PfSPZ vaccines.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Sponsor's clinical and regulatory teams
入排标准
- 年龄范围
- 18 Years 至 50 Years（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 18 to 50 years
- •Adults with a Body Mass Index (BMI) 18 to 30 Kg/m
- •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.
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 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.
研究组 & 干预措施
Group 2 SIngle Dose Vaccine Group
Group 2: one dose of normal saline placebo and one dose of PfSPZ-LARC2 Vaccine (6x10^5 PfSPZ) four weeks apart.
干预措施: Genetically attenuated PfSPZ Vaccine (Biological)
Group 2 SIngle Dose Vaccine Group
Group 2: one dose of normal saline placebo and one dose of PfSPZ-LARC2 Vaccine (6x10^5 PfSPZ) four weeks apart.
干预措施: Normal Saline (0.9% Sodium Chloride) (Other)
Group 1 Double Dose Vaccine Group
Group 1: two doses of PfSPZ-LARC2 Vaccine (4x10^5 PfSPZ) four weeks apart.
干预措施: Genetically attenuated PfSPZ Vaccine (Biological)
Group 3 Placebo
Group 3: two doses of normal saline placebo four weeks apart.
干预措施: Normal Saline (0.9% Sodium Chloride) (Other)
结局指标
主要结局
Vaccine efficacy of PfSPZ-LARC2 Vaccine as compared to normal saline, placebo against first Pf infection as detected by thick blood smear (TBS).
时间窗: 2-24 weeks after last dose of vaccine or placebo
TBS positive for asexual Pf at any parasite density collected every 2 weeks and at any time participants present with symptoms of malaria, starting 2 weeks after last dose of vaccine or placebo and extending 24 additional weeks.
次要结局
- Safety and tolerability of PfSPZ-LARC2 Vaccine - solicited AEs(14 days post each administration of vaccine or placebo)
- Safety and tolerability of PfSPZ-LARC2 Vaccine- laboratory abnormalities(1 week post each administration of vaccine or placebo)
- Safety and tolerability of PfSPZ-LARC2 Vaccine- unsolicited AEs(28 days post each administration of vaccine or placebo)
- Safety and tolerability of PfSPZ-LARC2 Vaccine- SAEs(After the first administration of vaccine or placebo until the end of the study)
- Safety and tolerability of PfSPZ-LARC2 Vaccine- break-through vaccine strain blood stage infections(After the first administration of vaccine or placebo until the end of the study)
- Vaccine efficacy against naturally transmitted first Pf clinical malaria(2 weeks after last dose of vaccine or placebo and extending 24 additional weeks.)
- Antibody responses following vaccination and their association with vaccine efficacy(Two weeks to 24 weeks after the last immunization)