A Chemical Vaccine for Malaria

疟疾化学疫苗

基本信息

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
项目类别：
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

项目摘要

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.

疟疾的化学疫苗，注射注射的长效因果预防药物被认为是长期保护感染的一种有希望的新方法。这种疗法将受益人口处于危险之中，不仅是居住在地方性地区的人群，而且还处于危险之中每年访问这些地区的旅行者。国际疟疾控制工作，尽管非常成功似乎放缓了，化学疫苗的可用性将提供一种新工具来减少季节性传播并维持已经有了疟疾的疟疾控制。广谱抗植物 Atovaquone在高剂量上用于预防和治疗免疫功能低下的患者肺炎 Jirovecii肺炎或弓形虫病； atovaquone，以较低的剂量和固定组合带有前卫的可因果预防和治疗疟疾。在大约20年的使用中，单独使用Atovaquone和Atovaquone+Proguanil具有人类安全性和功效的记录。我们以前确定纳米颗粒的atovaquone给定肌内可以保护小鼠以达到 4周针对致命的孢子虫挑战。在最近的初步研究中 Atovaquone的保护至少8周，最长的间隔测试，没有行为证据表明肌肉毒性。拟议的工作旨在通过建立这些初步发现来扩展这些初步发现最长的保护间隔，在挑战时获得atovaquone水平以完成药代动力学 - 药效分析，并进行初步组织病理学检查注射部位的肌肉。仅在预防疟疾药物中，atovaquone被施用结合第二种药物Proguanil。毫无疑问地治疗已建立的红细胞感染，前卫预防疟疾的必要性尚未得到很好的检查。在小鼠中提出的实验将评估前卫对因果保护的贡献反对阿托伐夸夸酮敏感和抗抗反抗的孢子虫的挑战。这些信息将为决定是否还必须包括poguanil，为确定是否还必须包括Atovaquone化学疫苗。该项目的实验将为Atovaquone的1/2A临床试验奠定基础没有前卫，它们提供了一个模板，用于临床前评估化学疫苗的候选物未来。