Evaluation of Reproducibility of a Sporozoite Challenge Model for Plasmodium Vivax in Human Volunteers
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 2
- 主要终点
- Infection for P. Vivax
研究概览
简要总结
The study is a randomized open label clinical trial to verify the reproducibility of a sporozoite challenge model for Plasmodium vivax in humans. The verification of the reproducibility of such a model will make it possible to evaluate the efficacy of candidate P. vivax vaccines in Phase 2a trials. The study is divided into two successive steps:
Step A Parasite Blood Donation: Volunteers will be recruited passively from a group of patients who present with active P. vivax infection and accept to donate infected blood. Samples of P. vivax infected blood will be collected and will be screened for infectious diseases, according to standard blood bank procedures. Colonized Anopheles albimanus mosquitoes will be fed with this blood using a Membrane Feeding Assay (MFA). Sixteen (16) days after, selected positive mosquito batches will be used for step B.
Step B Challenge: After informed consent signature, a total of 18 healthy volunteers will be randomly allocated to Groups 1, 2 and 3, of 6 volunteers each and will be challenged with the bite of 3±1, P. vivax infected mosquitoes. Each group will be exposed to a different isolated parasite. Volunteers will be closely monitored post infection, and will be treated as soon as blood infection becomes patent as ascertained by microscopic examination of thick blood smears (TBS). Comparison of data obtained in the three different groups will be used to determine reproducibility of challenge model.
Primary objective: To demonstrate that naïve human volunteers can be safely and reproducibly infected by the bite of An. albimanus mosquitoes carrying P. vivax sporozoites in their salivary glands.
Secondary objective: To determine the influence of the type of parasite isolated on reproducibility and safety of the challenge model with P. vivax in human volunteers
Hypothesis:It is possible to safely develop a reproducible P. vivax infection in human volunteers using P. vivax experimentally infected An. albimanus mosquitoes.
详细描述
Study design
A randomized, open-label clinical trial was designed to standardize a P. vivax sporozoite challenge model in malaria-naïve volunteers, specifically, the relationship between the number of infectious mosquito bites and the likelihood of developing patent parasitemia detectable by Giemsa-stained thick blood smear (TBS). The study was divided into two steps. Step A was designed to produce mature P. vivax sporozoites suitable for inoculation into humans; and Step B was designed to assess the safety and reproducibility of the sporozoite challenge. For Step A, patients with infective P. vivax gametocytes detected by TBS were recruited from the outpatient clinics at the Immunology Institute (IDIV) in Cali and Buenaventura, Colombia. Patients donated 35 mL of whole blood, which was screened for co-infections that could potentially represent a threat to the health of volunteers. The blood was then artificially fed to Anopheles mosquitoes.14 For Step B, malaria-naive subjects were exposed to the bites of 3 ± 1, 6 ± 1, or 9 ± 1 infected mosquitoes to determine the prepatent period of the infection and its reproducibility.
Blood donation and blood quality assurance
The EDTA vacutainer tubes (Becton Dickinson, Franklin Lakes, NJ) were used to collect 35 mL of whole blood from each infected patient, which were divided into two aliquots: a 15 mL sample for mosquito feeding and a 20 mL sample that was transported to the blood bank of the Valle del Lili Clinic for routine screening for a panel of common infectious agents (viral, bacterial, parasitic), including confirmation of Plasmodium species ( P. vivax, P. falciparum, P. malariae) by polymerase chain reaction (PCR) (Table 2).15 The rationale behind the blood screening and direct mosquito feeding on human volunteers was based on two premises: 1) standard blood bank screening is universally accepted as a safety procedure that ensures that no pathogens are transmitted from human-to-human during a blood transfusion. Therefore, blood samples determined to be negative for pathogens other than P. vivax by standard blood bank screening should be safe enough to be transferred from human-to-human through a mosquito bite. 2) Anopheles mosquitoes have not been reported to trans mit any pathogen other than Plasmodium. Before the study, we carried out an extensive bibliographic search and consulted with U.S. and Colombian experts on virology, parasitology, and entomology about potential pathogens that might be transmitted by Anopheles and could represent a threat for the volunteers exposed to challenge. There was a consensus that as yet no other pathogen had been reported to be transmitted by Anopheles mosquitoes, including those comprised in the blood bank screening. However, mosquitoes were discarded using a biosafety procedure if after feeding blood was confirmed to have any co-infection.
Mosquito infection
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
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, adult male or non-pregnant females (18-45 years of age).
- •Capacity to sign a free informed consent form of participation along with two witnesses.
- •Use of adequate contraceptive method from the initiation of the study until three months after sporozoite challenge.
- •No plans to travel to malaria endemic areas during the course of the study (a year).
- •No plans to travel outside the study area from the 7th day until 31st day after the challenge.
- •Reachable by phone during the whole study period.
- •Able to participate during the whole study period.
排除标准
- •Are less than 18 and over 45 years of age.
- •Are female who is pregnant at serum positive B-HCG screening, planning to become pregnant or who is nursing.
- •Have a Duffy negative phenotype.
- •Have a G-6-PD deficiency or any other hemoglobinopathy.
- •Current or past infection with any species of malaria as demonstrated by a positive TBS on screening or history of a documented positive blood smear. P. vivax IFAT of 1
- •Have a known history of allergy to antimalarial drugs or immediate type hypersensitivity reactions to mosquito bites.
- •Clinical or laboratory evidence of significant systemic disease, including hepatic, renal, cardiac, immunologic or hematological disease, HIV positive or have any other known immunodeficiency (including receiving immunosuppressive therapy or a history of splenectomy); infected with hepatitis B or C virus; have a history of autoimmune disease (including inflammatory bowel disease, hemolytic anemia, autoimmune hepatitis, rheumatoid arthritis, lupus, etc.) or connective tissue disease or have any other serious underlying medical condition.
- •Clinically significant laboratory abnormalities as determined by the Investigator(s).
- •Plan to have surgery between enrollment and the end of the challenge follow-up.
- •Previous history of alcoholism or drugs use which interfere with social activities of the volunteer
- •Have any other conditions that are determined by at least two concurring investigators that may interfere with the capacity to provide free and willing informed consent.
结局指标
主要结局
Infection for P. Vivax
时间窗: Twenty eight days
Thick blood smear was performed to patients daily on days 7 to 23, and every other day until day 29. Any prove of P. vivax infection was considered positive and confirmed later by real time polymerase chain reaction (rPCR).
次要结局
未报告次要终点