Development of a P. vivax immunization and sporozoite challenge model for human

描述（由申请人提供）：疟疾辐照孢子子（ir -spz）疫苗接种是最有希望预防人类疟原虫红细胞前阶段发展的方法之一，因此可以预防疟疾疾病。在人类和动物模型中进行的研究可重复地证明，这种疫苗接种策略始终诱导固体无菌保护。本研究的目的是在人类志愿者中标准化间日疟原虫iir -spz疫苗模型。这一总体目标将通过解决以下具体目标来实现：1)对人类志愿者接种间日疟原虫irr spz疫苗的保护功效进行原理证明研究；2)评估所有研究参与者的免疫反应，寻找免疫保护的相关因素。研究将涉及间日疟原虫感染个体作为寄生虫供体和达菲+ (Fy+)和Fy-健康志愿者，这些志愿者将使用辐照或未辐照的间日疟原虫感染蚊子进行连续免疫（10-15次）。共有24名疟疾新手志愿者将被分配到四组（A- d），每组6名志愿者。A组（Fy+）和B组（Fy-）志愿者将接种irr- spz疫苗。C组（Fy-志愿者）将接种活疫苗。疫苗接种方案完成后，包括对照组D组（未接种疫苗）在内的所有志愿者将受到受感染蚊子叮咬的挑战。将密切跟踪志愿者，并通过厚血涂片评估专利感染的发展情况，以评估疫苗接种的保护效果。受感染的志愿者将立即接受标准抗疟疾治疗。对间日疟原虫红细胞前抗原（包括整个寄生虫）的特异性免疫反应将通过测量B细胞、CD4+和CD8+ T细胞反应以及Th1/Th2细胞因子的产生来研究。本研究收集的试剂（血清/细胞）将用于筛选具有开发疫苗潜力的新基因/抗原。免疫学分析有望确定免疫保护的相关因素。拟议的实验将在哥伦比亚的疟疾疫苗和药物开发中心（MVDC）进行，并得到美国和欧洲合作者的支持。参与小组将独特的能力和物理设施结合起来，进行拟议的临床试验和免疫学研究，并为开发间日疟原虫疟疾疫苗作出贡献。

DESCRIPTION (provided by applicant): Vaccination with malaria irradiated sporozoites (irr-spz) represents one of the most promising means to prevent the development of pre-erythrocytic stages of human Plasmodia and therefore of preventing malaria disease. Studies conducted in human and animal models have reproducibly demonstrated that this vaccination strategy consistently induces solid sterile protection. The purpose of this research is to standardize a Plasmodium vivax irr-spz vaccine model in human volunteers. This general objective will be approached by addressing the following specific aims: 1) To conduct proof- of-principle studies on the protective efficacy of P. vivax irr spz vaccination in human volunteers; and 2) To evaluate the immune responses in all study participants and search for immune correlates of protection. Studies will involve P. vivax-infected individuals serving as parasite donors and both Duffy+ (Fy+) and Fy- healthy volunteers that will be serially immunized (10-15 times) with irradiated or non- irradiated P. vivax infected mosquitoes. A total of 24 malaria naive volunteers will be allocated to four groups (A-D) of six volunteers each. Group A (Fy+) and group B (Fy-) volunteers will be vaccinated with irr- spz. Group C (Fy- volunteers) will be vaccinated with live spz. After the vaccination protocol is completed, all volunteers, including a control group D (not vaccinated) will be challenged by the bite of infected mosquitoes. Volunteers will be closely followed and development of patent infection will be assessed by thick blood smear to assess the protective efficacy of the vaccination. Infected volunteers will be immediately treated with standard antimalarial therapy. Specific immune response to P. vivax pre-erythrocytic antigens including whole parasites will be studied by measuring B cell, CD4+ and CD8+ T cell responses as well as Th1/Th2 cytokine production. Reagents (sera/cells) collected during this study will be used to screen for novel genes/antigens with potential for vaccine development. Immunological analyses are expected to allow the identification of immune correlates of protection. The proposed experiments will be performed at the Malaria Vaccine and Drug Development Center (MVDC) in Colombia, with support from US and European collaborators. The participating teams combine unique capabilities and physical facilities for the conduct of the proposed clinical trial and immunological studies as well as to contribute to the development of a P. vivax malaria vaccine. PUBLIC HEALTH RELEVANCE: Vaccines represent the most cost-effective measure to control transmissible diseases. Therefore, a malaria vaccine that prevents parasite transmission from mosquito to human or its development in human beings would become a valuable tool to avoid malaria in travelers and in individuals living in endemic regions, estimated to be 2.5 billion exposed humans.