SALMONELLA VECTORS FOR MEROZOITE SURFACE PROTEIN 1 (MSP 1)

疟疾是一个极其重要的公共卫生问题 发展中世界。这项建议的长期目标是 开发一种疫苗，以降低疟疾的发病率和死亡率 恶性疟原虫疟疾。为了实现这一目标，我们建议 提高疟疾寄生虫抗原的免疫原性 融合多肽的多用途表达载体 这已被证明可以增强其他病毒的免疫原性 沙门氏菌携带者体内的非免疫原性异源抗原。 以前的研究表明，这种结构可以口头和 可能同样有效地活着或被杀，因此潜在地避免了 给艾滋病毒携带者接种活细菌疫苗的问题 感染。我们选择研究的抗原是裂殖子表面 蛋白质-1(MSP-1)，已被证明可预防感染 体外和体内通过抗体依赖的恶性疟原虫 机制。这项提议的具体目的是发展小说 MSP-1 42 kDa C末端片段表达载体的构建 (MSP-142)使用这种方法，2]测试这些化合物的免疫原性 在小鼠中构建，并确定它们是否能引发抗体 体外抑制恶性疟原虫生长，3]检测 这些构建物在猴子体内的免疫原性，4]挑战免疫 猴子来确定免疫是否能预防感染 与恶性疟原虫同源的FVO寄生虫，以及挑战 为猴子接种疫苗以确定免疫是否能预防 感染异源(FUP)恶性疟原虫。这 战略，如果成功，提供了一个经济的潜力 基于口服灭活的疟疾疫苗(和 因此无毒)沙门氏菌。

Malaria is a public health problem of overwhelming importance for the developing world. The long-term objective of this proposal is to develop a vaccine that reduces the morbidity and mortality of Plasmodium falciparum malaria. Toward that objective we propose to enhance the immunogenicity of malaria parasite antigens by using a multipurpose plasmid vector for the expression of fusion polypeptides that has been shown to enhance the immunogenicty of otherwise non-immunogenic heterologous antigens in a Salmonella carrier. Previous studies indicate that such constructs may be given orally and may be equally effective live or killed, thus potentially obviating the problem of giving a live bacterial vaccine to persons with HIV infection. The antigen we have chosen to study is Merozoite Surface Protein-1 (MSP-1), which has been shown to protect against infection with P. falciparum in vitro and in vivo by an antibody-dependent mechanism. The specific aims of this proposal are to 1] develop novel plasmid constructs expressing the 42 kDa C-terminal fragment of MSP-1 (MSP-142) using this approach, 2] Test the immunogenicity of these constructs in mice, and determine whether they elicit antibodies that inhibit the growth of P. falciparum in vitro, 3] Test the immunogenicity of these constructs in monkeys, 4] Challenge immunized monkeys to determine whether immunization protects against infection with the homologous FVO P. falciparum parasite, and 5] Challenge immunized monkeys to determine whether immunization protects against infection with a heterologous (FUP) P. falciparum parasite. This strategy, if successful, offers the potential for an economical malaria vaccine based on the oral administration of killed (and therefore nontoxic) Salmonella.