Safety and Immunogenicity of the Placental Malaria Vaccine Candidate PAMVAC Adjuvanted With Alhydrogel, GLA-SE or GLA-LSQ in Healthy Malaria-Naïve Adults and Healthy, Lifelong Malaria-Exposed, Nulligravid Adult Women
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 66
- 试验地点
- 1
- 主要终点
- Number and grade of adverse events (Grade 1-3 and serious adverse events) possibly, likely and definitely related to vaccination
研究概览
简要总结
Despite having developed robust acquired immunity against complications of malaria, women can return to a susceptible state during their first pregnancies and contribute significantly to the burden of severe malaria in highly endemic areas. Naturally acquired protection against placental malaria correlates with the presence of high concentration of immunoglobulin G molecules (IgGs) against VAR2CSA, a parasite protein of the var gene family that is essential for the binding of infected erythrocytes to CSA in the placenta.
To induce high concentrations of specific IgGs, subjects will receive escalating doses of PAMVAC vaccine antigen adjuvanted with Alhydrogel, Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) or Glucopyranosyl Lipid Adjuvant-Liposome-QS-21 Formulation (GLA-LSQ). Three injections with the same dosage and adjuvant will be done, each 28 days apart (Day 0, 28 and 56). Control subjects will receive physiological saline instead of the vaccine and dose escalation will be staggered to ensure safety during the trial.
详细描述
Phase 1, staggered, two-center, dose-escalation trial. The trial will be conducted in two stages. The first in Germany (first in man and dose escalation) and the second in a malaria-endemic area in the target group (randomized, controlled, dose-finding).
First in man administration and dose escalation from 20 to 50 μg per injection of PAMVAC adjuvanted with Alhydrogel, GLA-SE and GLA-LSQ will be done in healthy, malaria-naïve adults in Germany (Stage 1).
Subsequently, PAMVAC will be administered to healthy, lifelong malaria-exposed nulligravid women in Benin at doses of 50 and 100 μg, adjuvanted with Alhydrogel and GLA-SE (Stage 2).
The PAMVAC vaccine is a VAR2CSA protein-based vaccine, aiming to protect fetus and mother against the adverse effects of placental malaria during pregnancy. As the interaction between the parasite protein VAR2CSA and CSA in the human placenta is a key element in the pathogenesis of placental malaria, a vaccine should elicit the type of immunoglobulins that block the binding of VAR2CSA to CSA. A small sub-unit of the VAR2CSA protein (ID1-ID2a) has been selected as the PAMVAC vaccine antigen. In animal models IgGs induced by immunization with the recombinant PAMVAC antigen are able to inhibit homologous parasite-infected erythrocyte adhesion to CSA in vitro.
The three adjuvants are Alhydrogel, an aluminum hydroxide gel widely used as adjuvant in this trial; GLA-SE and GLA-LSQ, synthetic TLR-4 agonists with a strong immune stimulatory effect formulated either in a stable oil-in-water emulsion (SE) or together with QS-21 (Saponin derived from the Quillaja saponaria tree) as liposome (LSQ).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy male and female volunteers aged 18-45 years.
- •Able and willing (in the investigator's opinion) to comply with all trial requirements.
- •General good health based on history and clinical examination
- •Written informed consent
- •Women only: Must agree to practice continuous effective contraception for the duration of the trial (a method which results in a low failure rate; i.e. less than 1% per year). Women will be counseled about effective contraception methods and, if required, can be provided with adequate contraceptives by the investigator team.
- •Available to participate in follow up for the duration of trial (36 weeks following first injection)
- •Reachable by phone during the whole trial period
排除标准
- •Pregnancy, lactation or intention to become pregnant during the trial
- •Previous participation in a malaria vaccine trial
- •HIV infection
- •Any confirmed or suspected immunosuppressive or immunodeficient state, asplenia, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed)
- •Presence of autoimmune diseases requiring systemic treatment (e.g. rheumatic diseases)
- •Use of immunoglobulins or blood products within 3 months prior to enrolment
- •Receipt of an investigational product in the 30 days preceding enrolment, or planned receipt during the trial period
- •History of malaria or travel in malaria-endemic areas within the past 6 months
- •Intention to travel to malaria endemic countries during the trial period
- •History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ)
- •History of serious psychiatric condition that may affect participation in the trial
- •Any other serious chronic illness requiring hospital specialist supervision
- •Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 60 g (men) or 40 g (women) per day or a carbohydrate deficient transferrin (CDT) level ≥2.5%
- •Suspected or known injecting drug abuse in the 5 years preceding enrolment
- •Positive for hepatitis B surface antigen (HBs-antigen)
- •Seropositive for hepatitis C virus (antibodies to HCV)
- •Volunteers unable to be closely followed for social, geographic or psychological reasons
- •Known hypersensitivity to any of the vaccine components (adjuvant or peptide)
- •Any clinically significant abnormal finding on biochemistry or hematology blood tests, urine analysis or clinical examination
- •History of seizure, except for sporadic febrile convulsions in childhood
- •Any other significant disease, disorder or finding which, in the opinion of the investigator, may significantly increase the risk to the volunteer because of participation in the trial; affect the ability of the volunteer to participate in the trial or impair interpretation of the trial data.
结局指标
主要结局
Number and grade of adverse events (Grade 1-3 and serious adverse events) possibly, likely and definitely related to vaccination
时间窗: From the first administration of the interventions through study completion, an average of 1 and a half years
次要结局
- Area under the curve of anti-PAMVAC IgG concentration(Before first administration, 1, 4, 5, 8, 9, 12, 24 and 36 weeks after first administration)