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: 8251057
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251057
• 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. PUBLIC HEALTH RELEVANCE: Malaria causes 400-500 million clinical cases and >1 million deaths annually, is responsible for >1% loss of GDP in Africa annually and is a serious concern for travelers and military personnel. Protein Potential's goal is to develop and commercialize a >90% protective malaria vaccine for primary markets with a potential for >$1 billion annual revenues; 1) travelers from the developed world, and 2) all populations in the developing world. Success in this project will significantly decrease the cost of development and time to market for this malaria vaccine.

描述（由申请人提供）：疟疾每年造成至少2.5亿例病例，近100万人死亡。GSK的疟疾疫苗RTS，S/AS 01正在进行3期临床试验，如果安全有效，很可能被批准用于发展中国家的儿童。该疫苗完全基于恶性疟原虫（Pf）环子孢子蛋白（CSP）的重复区和羧基末端。它与佐剂AS 01一起给药，佐剂AS 01包括脂质体、单磷酰脂质A和纯化的植物提取物QS 21，但最初是用水基佐剂中的油开发的。通过在小鼠和非人灵长类动物（NHP）中的一系列迭代研究来进行用于临床试验的佐剂的向下选择。在其最终制剂中，该疫苗保护50%的志愿者在末次给药后2周内免受Pf的实验性攻击，22%的志愿者保护6个月。保护被认为主要由针对PfCSP的重复区的抗体介导，并且可能由针对PfCSP的C'末端的CD 4 + T细胞应答介导。疫苗不会诱导有意义的CD 8 + T细胞应答。然而，许多疟疾学家认为，长期保护将依赖于Pf-specific CD 8 + T细胞免疫的诱导，如在用辐射的子孢子免疫的小鼠和NHP中观察到的。RTS，S/AS 01不被考虑用于非免疫旅行者和军事人员，因为其保护效力太低。针对这一人群的疫苗需要提供至少6个月的>80%的保护性免疫，才能有可观的市场。我们假设，通过将高功能的保护性CD 8 + T细胞应答添加到针对PfCSP的抗体应答中，可以实现这种保护性免疫。表达蛋白质如PfCSP的重组腺病毒（Ad）目前是用于在人中诱导CD 8 + T细胞应答的流行方法。然而，尽管诱导了非常高量级的抗原特异性CD 8 + T细胞应答，但这种基于Ad的疫苗在人类中没有高度保护性，特别是针对疟疾。最近，在小鼠中显示重组减毒单核细胞增生李斯特菌（Lm）诱导比重组Ad 5高得多的质量（功能性）的CD 8 + T细胞应答。我们将使用异源初免-加强方案，其组合佐剂化重组PfCSP蛋白（rPfCSP）和表达Lm的PfCSP（Lm-PfCSP）。该策略的目标是诱导PfCSP特异性保护性抗体和保护性CD 8+和CD 4 + T细胞应答，其提供>80%的保护，持续至少6个月。在I期，我们将鉴定rPfCSP、佐剂和Lm-PfCSP的组合，其在小鼠中诱导高水平抗体以及CD 8+和CD 4 + T细胞应答。在第二阶段，我们将采用GSK使用的方法，并使用NHP的免疫原性来选择用于临床试验的疫苗组合，该疫苗旨在具有足以预防>80%的疫苗接种者发生Pf寄生虫血症的效力;该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，并在发展中国家的地理集中运动中消除Pf。 公共卫生关系：疟疾每年造成4 - 5亿临床病例和> 100万人死亡，每年造成非洲GDP损失>1%，并且是旅行者和军事人员的严重关切。Protein Potential的目标是为主要市场开发和商业化一种保护性>90%的疟疾疫苗，年收入可能超过10亿美元; 1）来自发达国家的旅行者，2）发展中国家的所有人口。这一项目的成功将大大降低这种疟疾疫苗的开发成本和上市时间。