A Chemical Vaccine for Malaria

疟疾化学疫苗是通过注射方式提供的长效因果预防药物，被认为是 一种有希望的长期预防感染的新方法。这样的治疗将会受益 处于危险中的人群，不仅是那些生活在流行区的人，而且还有数千万非免疫的人 每年到这些地区旅游的游客。国际疟疾控制努力，尽管非常成功 似乎已经放缓，化学疫苗的可获得性将提供一个新的工具来减少 季节性传播和维持已经完成的疟疾控制。广谱抗原虫药物 大剂量阿托瓦酮用于预防和治疗免疫功能低下的肺孢子虫病 地塞米松肺炎或弓形虫病；阿托瓦酮，剂量显著较低，并以固定组合 普罗瓜尼也用于疟疾的因果预防和治疗。在大约20年的使用中， 阿托瓦酮单独和阿托瓦酮+普罗瓜尼在人类身上都有安全性和有效性的记录。我们 先前已经证实，肌肉注射纳米阿托瓦酮可以保护小鼠 4周来对抗致命的子孢子挑战。在最近的初步研究中，一种替代配方 阿托瓦酮的保护作用至少持续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 最长保护间隔，在挑战时达到阿托瓦酮水平以完成 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，阿托瓦酮是唯一一种在 与另一种药物普罗瓜尼联合使用。明确要求治疗已确诊的 对于红细胞感染，普罗瓜尼用于疟疾因果预防的必要性一直不是很好。 检查过了。拟在小鼠身上进行的实验将评估普罗瓜尼对因果保护的贡献 抵抗阿托瓦酮敏感和抗阿托瓦酮的子孢子的攻击。此信息将 为决定阿托瓦酮化学疫苗是否也必须包括普罗瓜尼提供可靠的基础。 该项目的实验将为阿托瓦酮1/2a期临床试验奠定基础。 他们为化学疫苗候选的临床前评估提供了一个模板 未来。

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.