Immunizing Against Malaria by Inducing Both Protective Antibodies and CD8 T Cells

通过诱导保护性抗体和 CD8 T 细胞进行疟疾免疫

• 批准号: 8495921
• 负责人: B. KIM LEE SIM
• 金额: $ 30万
• 依托单位: PROTEIN POTENTIAL, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495921
• 关键词: Adenoviruses; Adjuvant; Africa; Animals; Antibodies; Antibody Formation; Antigens; Attenuated; Biological; Businesses; CD4 Positive T Lymphocytes; CD8B1 gene; Cessation of life; Child; Clinical; Clinical Trials; Colony-forming units; Cyclic GMP; Data; Development; Dose; Drug Formulations; Enzyme-Linked Immunosorbent Assay; Exposure to; Falciparum Malaria; Foundations; Goals; Human; Immune response; Immune system; Immunity; Immunization; Licensing; Liposomes; Listeria monocytogenes; Longevity; Malaria; Malaria Vaccines; Marketing; Mediating; Memory; Methods; Military Personnel; Mus; Oils; Outcome; Parasitemia; Phase; Phase III Clinical Trials; Plant Extracts; Plasmodium falciparum; Plasmodium falciparum vaccine; Population; Proteins; QS21; Recombinants; Regimen; Rodent; Series; Sporozoite vaccine; Sporozoites; T cell response; T-Lymphocyte; Testing; Time; Vaccines; Water; base; circumsporozoite protein; cost; immunogenicity; innovation; monophosphoryl lipid A; nonhuman primate; pathogen; prevent; protective efficacy; research study; response; success; volunteer

DESCRIPTION (provided by applicant): Malaria causes at least 250 million cases and nearly 1 million deaths per year. GSK's malaria vaccine, RTS, S/AS01 is being tested in a Phase 3 clinical trial, and is likely to be licensed for use in children in the developing world, if safe ad effective. This vaccine is based entirely on the repeat region and carboxy terminus of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP). It is administered with an adjuvant AS01, which includes liposomes, monophosphoryl lipid A, and a purified plant extract, QS21, but was initially developed with an oil in water-based adjuvant. Downselection of adjuvants for clinical trials was done through a series of iterative studies in mice and non-human primates (NHPs). In its final formulation this vacccine protects 50% of volunteers against experimental challenge with Pf for 2 weeks after last dose, and 22% of volunteers for 6 months. Protection is thought to be primarily mediated by antibodies against the repeat region of PfCSP and possibly CD4+ T cell responses against the C' terminus of the PfCSP. The vaccine does not induce meaningful CD8+ T cell responses. However, many malariologists believe that long- term protection will be dependent on induction of Pf-specific CD8+ T cell immunity, as has been obseved in mice and NHPs immunized with irradiated sporozoites. RTS, S/AS01 is not being considered for non-immune travelers and military personnel, because its protective efficacy is too low. A vaccine for this population needs to provide >80% protective immunity for at least 6 months to have a substantial market. We hypothesize that by adding highly functional, protective CD8+ T cell responses to antibody responses against the PfCSP, such protective immunity can be achieved. Recombinant adenovirus (Ad) expressing proteins like the PfCSP is currently a popular method for inducing CD8+ T cell responses in humans. However, despite the induction of antigen-specific CD8+ T cell responses of very high magnitude such Ad-based vaccines have not been highly protective in humans, especially against malaria. Recently, it was shown in mice that recombinant attenuated Listeria monocytogenes (Lm) induced much higher quality (functional) CD8+ T cell responses than did recombinant Ad5. We will use a heterologous prime-boost regimen combining an adjuvanted recombinant PfCSP protein (rPfCSP) and Lm expressing PfCSP (Lm-PfCSP). The goal of this strategy is to induce PfCSP- specific protective antibodies and protective CD8+ and CD4+ T cell responses that provide >80% protection that is sustained for at least 6 months. In Phase I we will identify combinations of rPfCSP, adjuvant and Lm- PfCSP that induce high level antibodies, and CD8+ and CD4+ T cell responses in mice. In Phase II we will take the approach used by GSK, and use immunogenicity in NHPs to downselect combinations for clinical trials of a vaccine that is intended to have efficacy adequate to prevent >80% of vaccinees from developing Pf parasitemia; a vaccine suitable for the potential multi-billion dollar non-immune traveler, business, and military markets, and for eliminating Pf in geographically focused campaigns in the developing world.

描述（由申请人提供）：疟疾每年至少造成2.5亿例病例和近100万例死亡。 GSK的疟疾疫苗，RTS，S/AS01正在3阶段临床试验中进行测试，如果有效的话，可能会在发展中国家的儿童中使用许可。该疫苗完全基于恶性疟原虫（PF）外孢子菌蛋白（CSP）的重复区域和羧基末端。它由辅助AS01施用，其中包括脂质体，单磷酸脂质A和纯化的植物提取物QS21，但最初是在水性佐剂中用油开发的。通过在小鼠和非人类灵长类动物（NHP）的一系列迭代研究中，对辅助试验的佐剂进行下选择。在最终配方中，该发电机在上次剂量后2周保护50％的志愿者免受PF的实验挑战，而22％的志愿者持续了6个月。保护被认为主要是由针对PFCSP重复区域的抗体介导的，可能是针对PFCSP的C末端的CD4+ T细胞反应。该疫苗不会诱导有意义的CD8+ T细胞反应。然而，许多疟疾学家认为，长期保护将取决于PF特异性CD8+ T细胞免疫的诱导，正如在小鼠中所理解的，并用辐照的孢子虫免疫的NHP。对于非免疫旅行者和军事人员而言，RTS，S/AS01不被考虑，因为其保护效果太低。该人群的疫苗至少需要在6个月内提供> 80％的保护性免疫，才能拥有大量市场。我们假设，通过对针对PFCSP的抗体反应添加高功能，保护性CD8+ T细胞反应，可以实现这种保护性免疫。像PFCSP这样表达蛋白质的重组腺病毒（AD）当前是诱导人类CD8+ T细胞反应的流行方法。然而，尽管诱导了非常高的抗原特异性CD8+ T细胞反应，但这种基于AD的疫苗的疫苗在人类中并没有高度保护性，尤其是针对疟疾。最近，在小鼠中表明，重组单核细胞增生李斯特菌（LM）引起的质量（功能性）CD8+ T细胞反应比重组AD5高得多。我们将使用结合辅助重组PFCSP蛋白（RPFCSP）和LM表达PFCSP（LM-PFCSP）的异源原始促进方案。该策略的目的是诱导PFCSP-特异性保护抗体以及保护性CD8+和CD4+ T细胞反应，可提供至少6个月的保护> 80％的保护。在第一阶段，我们将确定诱导高水平抗体的RPFCSP，辅助和LM-PFCSP的组合，以及小鼠中CD8+和CD4+ T细胞反应的组合。在第二阶段，我们将采用GSK使用的方法，并在NHP中使用免疫原性来降低组合，以进行疫苗的临床试验，该疫苗旨在具有足够的功效，以防止> 80％的疫苗发育中的PF寄生虫病；一种疫苗，适用于潜在的数十亿美元的非免疫旅行者，商业和军事市场，并在发展中国家中消除了PF的PF。