Universal Attenuated Sporozoite Vaccine and Challenge System

通用减毒子孢子疫苗和攻击系统

• 批准号: 9295935
• 负责人: STEPHEN Lev HOFFMAN
• 金额: $ 97.04万
• 依托单位: SANARIA, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295935
• 关键词: Adult; Africa; African; Asia; Attenuated; Brazil; C10; Cattle; Chemoprophylaxis; Chloroquine; Clinical; Clinical Trials; Combined Vaccines; Country; Data; Development; Dose; East Coast Fever; Epitopes; Equatorial Guinea; Erythrocytes; Foundations; Funding; Genome; Genomics; Germany; Ghana; Human; Immune response; Immunity; Immunization; Infant; Kenya; Licensure; Liver; Mali; Methods; Military Personnel; National Institute of Allergy and Infectious Disease; Nature; Parasitemia; Parasites; Pathway interactions; Phase; Phase III Clinical Trials; Plasmodium falciparum; Plasmodium falciparum vaccine; Pneumococcal conjugate vaccine; Program Development; Proteome; Radiation; Regimen; Safety; Ships; Site; Small Business Innovation Research Grant; Sporozoite vaccine; Sporozoites; Sterility; Syringes; System; T-Lymphocyte Epitopes; Tanzania; Theileria; Theileria parva; Time; United States National Institutes of Health; Vaccination; Vaccines; Venous; base; clinical toxicology; cost; efficacy study; immunogenicity; improved; irradiation; malaria infection; meetings; pre-clinical; protective efficacy; success; transmission process; vaccine efficacy

ABSTRACT Sanaria’s Plasmodium falciparum (Pf) sporozoite (SPZ) vaccines development program is receiving global support. Trials of PfSPZ Vaccine (radiation attenuated PfSPZ) or PfSPZ-CVac (PfSPZ Chemoprophylaxis Vaccine) administered by direct venous inoculation (DVI), including ~1,500 adults to infants were initiated in December 2015 (Tanzania, U.S.) or will be initiated in early 2016 in Mali, Kenya (~500 infants), Ghana, Equatorial Guinea, Germany and 3 additional U.S. sites. These trials will assess 3-, 2- or 1-dose regimens, as 100% protective efficacy at 9 weeks after last dose has been established with a 3-dose regimen. Protective efficacy has been shown to be durable against controlled malaria infection (CHMI) for at least a year, and against intense natural transmission in Mali of heterogeneous strains of Pf for at least 6 months. PfSPZ Vaccine and PfSPZ-CVac are comprised of PfSPZ of the NF54 strain of Pf. Short-term protection (3 weeks) by PfSPZ Vaccine against a heterologous (different from the vaccine strain) CHMI with Pf7G8 parasites was 80%, but despite a significant delay in onset of parasitemia, 6 month sterile protective efficacy was only 10%. Sanaria is taking two approaches to improving protective efficacy against heterologous/heterogeneous strains. The 1st is to increase the dose of PfSPZ (NF54) per immunization based on the hypothesis that this will broaden and strengthen the protective immune responses against shared dominant and sub-dominant epitopes. All of the trials described above utilize this approach. The 2nd and potentially more efficient approach will be to combine PfSPZ from different strains of Pf in the same vaccine. Our analysis of genomic sequence data, predicted proteomes, and predicted T cell epitopes indicates that using two strains of Pf should be sufficient. This project fills an important gap. We have funding from VRC, NIAID, NIH to conduct a clinical trial of a multivalent PfSPZ vaccine, but require the funds to manufacture, characterize, and release the multi-valent vaccine, and to navigate the regulatory/clinical affairs pathways required to initiate the trial. In this Phase IIB SBIR project, we propose to, 1) Manufacture and QC release chloroquine sensitive PfSPZ Challenge of a W African Pf clone (NF166) that can be used for CHMI studies and as a component of a multi-strain PfSPZ-CVac; 2) Manufacture and release PfSPZ Vaccine based on the Brazilian Pf clone (7G8) and PfSPZ Vaccine (NF54) for a two-strain/clone PfSPZ Vaccine combination; 3) Manufacture and release PfSPZ Challenge (7G8) and PfSPZ Challenge (NF54) for a two-strain combination PfSPZ-CVac; and 4) Conduct an end of phase 2 meeting with FDA to propose and finalize a plan for using phase 3 CHMI trials with PfSPZ Challenge (NF54, 7G8, NF135.C10, and NF166) to replace phase 3 field trials to establish protective efficacy of the vaccines. Success will reduce the time to licensure of a PfSPZ vaccine for travelers/military by at least a year and save > $50M. It will also facilitate more rapid development of all pre-erythrocytic stage vaccines intended to provide the high level (>80%) protection required for a vaccine for travelers, military, and elimination campaigns.

摘要 Sanaria的恶性疟原虫（Pf）子孢子（SPZ）疫苗开发计划正在接受全球 支持. PfSPZ疫苗（放射减毒PfSPZ）或PfSPZ-CVac（PfSPZ化学预防）的试验 通过直接静脉接种（DVI）接种疫苗，包括约1，500名成人至婴儿， 2015年12月（坦桑尼亚，美国）或将于2016年初在马里、肯尼亚（约500名婴儿）、加纳、 赤道几内亚、德国和另外3个美国研究中心。这些试验将评估3次、2次或1次给药方案， 采用3次给药方案，已确立末次给药后9周的100%保护效力。保护 已证明对控制性疟疾感染（CHMI）的效力可持续至少一年， 至少6个月内可以对抗Pf异质菌株在马里的强烈自然传播。PfSPZ 疫苗和PfSPZ-CVac由PfNF 54菌株的PfSPZ组成。 PfSPZ疫苗针对具有Pf 7 G8寄生虫的异源（不同于疫苗株）CHMI的比例为80%， 但尽管寄生虫血症的发作显著延迟，6个月的无菌保护效力仅为10%。 Sanaria正在采取两种方法来提高对异源/异质菌株的保护效力。 第一种方法是增加每次免疫的PfSPZ（NF 54）剂量，其假设是： 扩大和加强保护性免疫反应， 表位上述所有试验都采用了这种方法。第二种可能更有效的方法 将来自不同Pf菌株的联合收割机PfSPZ组合在同一疫苗中。我们对基因组序列的分析 数据、预测的蛋白质组和预测的T细胞表位表明，使用两种Pf菌株应该是可行的。 足够了。这个项目填补了一个重要的空白。我们有VRC，NIAID，NIH的资金来进行临床试验 多价PfSPZ疫苗，但需要资金来制造，表征和释放多价PfSPZ疫苗。 疫苗，并导航启动试验所需的监管/临床事务途径。在本阶段IIB SBIR项目，我们建议，1）生产和QC释放氯喹敏感PfSPZ挑战W 非洲Pf克隆（NF 166），其可用于CHMI研究并作为多菌株PfSPZ-CVac的组分; 2)基于巴西Pf克隆（7 G8）和PfSPZ疫苗（NF 54）生产和放行PfSPZ疫苗 2株/克隆PfSPZ疫苗组合; 3）生产和放行PfSPZ攻毒（7 G8）， PfSPZ-CVac双菌株组合的PfSPZ攻毒（NF 54）;以及4）召开第2阶段结束会议 与FDA一起提出并最终确定使用PfSPZ挑战的3期CHMI试验（NF 54，7 G8， NF135.C10和NF 166）取代3期田间试验，以确定疫苗的保护效力。成功 将为旅行者/军人减少PfSPZ疫苗的许可时间至少一年，并节省> 5000万美元。它 还将促进旨在提供高免疫应答的所有红细胞前阶段疫苗的更快速开发。 水平（>80%）的保护需要疫苗的旅行者，军事和消除运动。