A Phase 1 Controlled Human Malaria Infection (CHMI) Study to Evaluate the Safety, Immunogenicity, and Efficacy of a Late Liver Stage-arresting, Replication-competent Plasmodium Falciparum Sporozoite Vaccine (Sanaria® PfSPZ-LARC2 Vaccine) Administered as a Single Dose to Malaria-exposed Adults in Burkina Faso
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- Sanaria Inc.
- 入组人数
- 45
- 试验地点
- 1
- 主要终点
- Efficacy of PfSPZ-LARC2 Vaccine against infection with Plasmodium falciparum malaria (defined as asexual parasitemia) after Controlled Human Malaria Infection (CHMI)
研究概览
简要总结
This is a randomized, double-blind, placebo-controlled, 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 by direct venous inoculation (DVI) to determine safety, immunogenicity, and efficacy against controlled human malaria infection (CHMI).
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.
CHMI will be performed using PfSPZ Challenge (NF54), composed of PfSPZ that are genetically intact and fully infectious. Because PfSPZ-LARC2 vaccine is also based on the Pf strain NF54, CHMI using PfSPZ Challenge (NF54) is considered homologous to the vaccine. It will be performed 6 weeks after the single administration of PfSPZ-LARC2 Vaccine or normal saline placebo (with an option to shorten the interval to 4 weeks if logistical issues arise, such as a risk that CHMI follow-up will overlap with the rainy season).
详细描述
This is a randomized, double-blind, placebo-controlled, single-center Phase 1 clinical trial of PfSPZ-LARC2 Vaccine to be conducted in healthy non-pregnant, non-lactating adults in Burkina Faso. PfSPZ-LARC2 Vaccine is composed of aseptic, purified, vialed, cryopreserved, genetically altered PfNF54 sporozoites (SPZ) that are stored in liquid nitrogen vapor phase (LNVP). After thawing, the vaccine is diluted and administered by direct venous inoculation (DVI).
The trial will compare a low dose of 2x10^5 PfSPZ to a high dose of 6x10^5 PfSPZ. There are three groups:
Group 1: one dose of PfSPZ-LARC2 Vaccine (2x10^5 PfSPZ) Group 2: one dose of PfSPZ-LARC2 Vaccine (6x10^5 PfSPZ) Group 3: one dose of normal saline placebo
The goal is to have one highly protective group (the high dose group) and one modestly protective group (2x10^5 PfSPZ) so that there are adequate numbers of protected and non-protected participants to support the secondary and exploratory objectives of identifying immunological correlates of protection. Before study start, if evidence emerges that 4x10^5 PfSPZ would address the aim of the high dose group (providing high level protection) as effectively as 6x10^5 PfSPZ, the protocol permits using 4x10^5 PfSPZ as the higher dose instead of 6x10^5 PfSPZ.
All participants will be cleared of any existing parasitemia by a three-day treatment course of artemether/lumefantrine (AL). Before treatment, samples will be collected for thick blood smear (TBS) for real-time reading and dried blood spots (DBS) on filter paper for retrospective PCR. Assessment by rapid diagnostic test (RDT) may be included as an option for information purposes. Drug clearance will be done 5-6 weeks before the first dose of investigational product. AL will be administered by study staff using directly observed therapy (DOT).
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
Study participants, clinical investigators (including the PI) and all other staff involved in measuring study outcomes will remain blinded to treatment allocation until the data are cleaned and locked. Similarly, Sanaria clinical and regulatory teams will be blinded. The site PI will be responsible for strict maintenance of the blind. Only the Pharmaceutical Operations team responsible for syringe preparation and the unblinded statistician from the data management vendor will be unblinded from the onset of the trial.
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 (note: an effort will be made to recruit roughly equal numbers of males and females, although a balanced sex ratio is not required)
- •From 18 to 50 years of age
- •Adults with a Body Mass Index (BMI) 18 to 30 Kg/m^2
- •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 testing
- •Able to 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 before the initial clearance treatment.
- •Female volunteers 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.
- •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 before 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
- •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 56 days after controlled human malaria infection (CHMI)
- •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
- •Positive sickle cell trait or disease testing
- •History of or evidence for other chronic disease conditions including cancer, diabetes, renal failure, hypertension, and tuberculosis
- •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 before receipt of investigational product
研究组 & 干预措施
Group 2 High Dose Vaccine group
one dose of PfSPZ-LARC2 Vaccine (6x10^5 PfSPZ)
干预措施: PfSPZ Challenge (Biological)
Group 1 Low dose Vaccine group
one dose of PfSPZ-LARC2 Vaccine (2x10^5 PfSPZ)
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Group 1 Low dose Vaccine group
one dose of PfSPZ-LARC2 Vaccine (2x10^5 PfSPZ)
干预措施: PfSPZ Challenge (Biological)
Group 2 High Dose Vaccine group
one dose of PfSPZ-LARC2 Vaccine (6x10^5 PfSPZ)
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Group 3 control
one dose of normal saline placebo
干预措施: PfSPZ Challenge (Biological)
Group 3 control
one dose of normal saline placebo
干预措施: Normal Saline (Other)
结局指标
主要结局
Efficacy of PfSPZ-LARC2 Vaccine against infection with Plasmodium falciparum malaria (defined as asexual parasitemia) after Controlled Human Malaria Infection (CHMI)
时间窗: Study day 43 (day of CHMI) to Study day 71 (28 days after CHMI)
Frequency of P. falciparum asexual parasitemia in each vaccine group relative to controls after controlled human malaria infection (CHMI). Participants will be followed as outpatients for malaria diagnosis, treatment, and follow-up for four weeks after CHMI until day CHMI+28. Malaria positivity will be determined in real time by TBS microscopy read immediately and with qPCR diagnostics based on concurrent DBS completed retrospectively.
Safety and tolerability of PfSPZ-LARC2 Vaccine administration in malaria-exposed Burkinabe adults- grade 3 solicited AEs
时间窗: Study day 1 (day of immunization) to study day 15
Incidence of grade 3 solicited adverse events (AEs) in the 14 days after PfSPZ-LARC2 Vaccine administration
Safety and tolerability of PfSPZ-LARC2 Vaccine administration in malaria-exposed Burkinabe adults- grade 3 unsolicited AEs
时间窗: study day 1 (day of immunization) to study day 29
Incidence of grade 3 unsolicited AEs in the 28 days after PfSPZ-LARC2 Vaccine administration
Safety and tolerability of PfSPZ-LARC2 Vaccine administration in malaria-exposed Burkinabe adults- grade 3 laboratory AEs
时间窗: study day 1 (day of immunization) to study day 8
Incidence of grade 3 abnormal laboratory values one week after PfSPZ-LARC2 Vaccine administration
Safety and tolerability of PfSPZ-LARC2 Vaccine administration in malaria-exposed Burkinabe adults- related SAEs
时间窗: Study day 1 to Study day 183 (end of study visit)
Incidence of possibly related, probably related or definitely related serious adverse events (SAEs) throughout the study period
次要结局
- Humoral immune responses to PfCSP (circumsporozoite protein) after vaccination(study day 1 to study day 71)
- Correlation of humoral immune responses to PfCSP (anti-PfCSP antibody levels 2 weeks after immunization) with protection (frequency of Pf asexual parasitemia in vaccinees relative to controls after CHMI)(Study day 1 to Study day 71)