A Chemical Vaccine for Malaria

疟疾化学疫苗

• 批准号: 10221510
• 负责人: Theresa A Shapiro
• 金额: $ 47.37万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221510
• 关键词: Affect; Animals; Antimalarials; Area; Atovaquone resistance; Attention; Behavioral; Blood; Chemical Vaccines; Chemicals; Chloroguanide; Chloroquine; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Coin; Culicidae; Data; Development; Dose; Doxycycline; Drug Kinetics; Drug Targeting; Drug resistance; Erythrocytes; Evaluation; Falciparum Malaria; Formulation; Foundations; Future; Histopathology; Human; Immunocompromised Host; In Vitro; Infection; Injectable; Injections; International; Intramuscular; Intramuscular Injections; Liver; Malaria; Malaria Vaccines; Mefloquine; Mus; Muscle; Oral; Parasites; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma; Plasmodium berghei; Pneumocystis carinii Pneumonia; Populations at Risk; Primaquine; Prophylactic treatment; Protocols documentation; Records; Reporting; Resistance; Role; Safety; Site; Sporozoites; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Toxoplasmosis; Vaccines; Visit; Work; atovaquone; cost; design; drug-sensitive; experimental study; fitness; high throughput screening; histopathological examination; improved; nanoparticulate; novel strategies; pill; preclinical evaluation; prevent; prophylactic; response; scaffold; sound; tool; transmission process; vaccine candidate

Chemical vaccines for malaria, long-acting causal prophylactic drugs given by injection, are recognized as a promising new approach for longterm protection against infection. Such therapy would benefit populations at risk, not just those living in endemic areas but also the tens of millions of nonimmune travellers who visit these areas every year. International malaria control efforts, though highly successful appear to have slowed, and the availability of a chemical vaccine would provide a new tool to reduce seasonal transmission and sustain already-accomplished malaria control. Broad-spectrum antiprotozoal atovaquone is used at high dose to prophylax and treat immunocompromised patients for Pneumocystis jirovecii pneumonia or toxoplasmosis; atovaquone, at substantially lower dose and in fixed combination with proguanil is also used for causal prophylaxis and treatment of malaria. In some 20 years of use, atovaquone alone and atovaquone+proguanil have track records of safety and efficacy in humans. We previously established that nanoparticulate atovaquone given intramuscularly could protect mice for up to 4 weeks against a lethal sporozoite challenge. In more recent preliminary studies an alternative formulation of atovaquone protects for at least 8 weeks, the longest interval tested, with no behavioral evidence of muscle toxicity. The proposed work is designed to extend these preliminary findings, by establishing the longest interval of protection, obtaining atovaquone levels at the time of challenge so as to complete pharmacokinetic-pharmacodynamic analyses, and conducting a preliminary histopathological examination of muscle at the injection site. Alone among the malaria prophylaxis drugs, atovaquone is administered in combination with a second drug, proguanil. Unequivocally required for treatment of established erythrocytic infection, the necessity of proguanil for causal prophylaxis of malaria has not been well- examined. Proposed experiments in mice will evaluate the contribution of proguanil to causal protection against challenge by atovaquone-sensitive and atovaquone-resistant sporozoites. This information will provide a sound basis for deciding whether an atovaquone chemical vaccine must also include proguanil. Experiments in this project will lay the foundation for a Phase 1/2a clinical trial of atovaquone with or without proguanil, and they furnish a template for preclinical evaluation of chemical vaccine candidates in the future.

疟疾化学疫苗是注射用的长效致病性预防药物，被认为是 一种有前途的长期预防感染的新方法。这样的治疗将受益 面临风险的人群，不仅是那些生活在流行地区的人，还包括数千万未免疫的人 每年访问这些地区的游客。国际疟疾控制努力虽然非常成功 似乎已经放缓，化学疫苗的出现将提供一种新的工具来减少 季节性传播并维持已经完成的疟疾控制。广谱抗原虫药 高剂量阿托伐醌用于预防和治疗免疫功能低下患者的肺孢子菌 耶氏肺炎或弓形虫病；阿托伐醌，剂量显着降低且固定组合 与氯胍一起还用于疟疾的因果预防和治疗。在大约20年的使用过程中， 单独使用阿托伐醌和阿托伐醌+氯胍对人类有安全性和有效性的跟踪记录。我们 此前已证实，肌肉注射纳米颗粒阿托伐醌可以保护小鼠长达 4 周对抗致命子孢子挑战。在最近的初步研究中，一种替代配方 阿托伐醌的保护时间至少为 8 周，这是测试的最长间隔，没有行为证据表明 肌肉毒性。拟议的工作旨在通过建立 最长的保护间隔，在挑战时获得阿托伐醌水平，以完成 药代动力学-药效学分析，并进行初步的组织病理学检查 注射部位的肌肉。在疟疾预防药物中，阿托伐醌是唯一一种用于预防疟疾的药物。 与第二种药物氯胍联合使用。明确需要治疗已确定的 红细胞感染，氯胍用于因果性预防疟疾的必要性尚未得到充分认识。 检查了。拟议的小鼠实验将评估氯胍对因果保护的贡献 对抗阿托伐醌敏感和阿托伐醌抗性子孢子的攻击。该信息将 为决定阿托伐醌化学疫苗是否还必须包含氯胍提供了合理的基础。 该项目的实验将为阿托伐醌的 1/2a 期临床试验奠定基础 不含氯胍，他们为化学疫苗候选物的临床前评估提供了模板 未来。