Contribution of Pfs48/45 to Malaria Transmission-Blocking Immunity

Pfs48/45 对疟疾传播阻断免疫的贡献

• 批准号: 8427982
• 负责人: Kim C Williamson
• 金额: $ 7.27万
• 依托单位: LOYOLA UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-11 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427982
• 关键词: Affect; African; Amino Acid Sequence; Antibodies; Antibody Formation; Antigens; Back; Biological Assay; Blood; Blood Circulation; Blood specimen; Cessation of life; Child; Chimera organism; Cleaved cell; Clinical; Clinical Trials; Country; Culicidae; Cysteine; DNA; Data; Development; Disease; Enzyme-Linked Immunosorbent Assay; Epidemiology; Epitopes; Exposure to; Fertilization; Genetic; Genetic Polymorphism; Genetic Variation; Germ Cells; Ghana; Giemsa stain; Glutamates; Goals; Human; Immune response; Immune system; Immunity; Immunoassay; In Vitro; Incidence; Individual; Infection; Insecticides; Lead; Local Government; Malaria; Measures; Membrane; Membrane Proteins; Midgut; Monitor; Monoclonal Antibodies; Natural Immunity; Parasites; Phase; Plasma; Plasmodium; Plasmodium falciparum; Population; Pregnant Women; Prevalence; Production; Proteins; Rattus; Recombinant Proteins; Recombinants; Reporting; Residual state; Reverse Transcriptase Polymerase Chain Reaction; Role; ST13 gene; Sampling; Serum; Staging; Structure; Surface; Testing; Time; Vaccine Antigen; Vaccines; base; disulfide bond; feeding; high risk; immunogenicity; improved; insight; optimism; public health relevance; response; safety study; screening; tool; transmission process; vaccine candidate; vaccine efficacy; vector control; volunteer

DESCRIPTION (provided by applicant): To successfully eliminate malaria, which continues to be responsible for 8% of all the deaths of children under five, new malaria control strategies are needed, including transmission blocking (TxB) vaccines. Toward this goal, we have recently produced correctly-folded P. falciparum gametocyte surface protein P48/45 (Pfs48/45) in a form that is ready for GMP production (GMZ3) and induces antibodies that disrupt parasite infectivity to mosquitoes in a standard membrane feed using in vitro culture-adapted parasites. We hypothesize that anti-GMZ3 antibodies will also block the ability of natural parasite isolates to infect mosquitoes and that naturally acquired TxB immunity will correlate with the presence of antibodies that recognize GMZ3 indicating that it is a good vaccine candidate. To test this we propose to AIM 1) evaluate the ability of anti-GMZ3 antibodies produced in rats to block the infectivity of natural isolates to mosquitoes. We will also evaluate AIMS 2 & 3) whether natural parasite exposure induces Pfs48/45/GMZ3 antibodies that contribute to transmission-blocking immunity. Pfs48/45 is one of four Plasmodium proteins (Pfs48/45 and P230, P25 and P28) that are the targets of monoclonal antibodies that effectively block malaria Tx and have been targeted as vaccine candidates. All these proteins are relatively cysteine-rich with multiple disulfide bonds resulting in antibody epitopes that are dependent on tertiary structure rather than linear amino acid sequence. Only P25 has advanced to a Phase Ia clinical trial, but further development has been slow due to limited immunogenicity and the lack of boosting during a natural malaria infection. Both Pfs48/45 and Pfs230 are expressed as the parasite undergoes sexual differentiation into gametocytes in the human host and naturally occurring anti-Pfs48/45 antibodies have been found after exposure to malaria. This suggests that the immune response against a Pfs48/45 or Pfs230-based TxB vaccine could be boosted during a natural infection enhancing the efficacy of the vaccine. The project proposed here will directly evaluate the potential of GMZ3 as a vaccine candidate against natural isolates. It augments ongoing epidemiologic and clinical safety studies by directly comparing transmission-blocking activity with gametocyte prevalence, genetic variation and anti-rPfs48/45.10C antibody titers and will provide critical information to direct the further development of an effective transmission-blocking vaccine.

描述（由申请人提供）：为了成功消除疟疾，该疟疾仍负责五名儿童死亡的8％，需要新的疟疾控制策略，包括传输阻断（TXB）疫苗。为了实现这一目标，我们最近以正确的GMP生产（GMZ3）形式产生了正确折叠的恶性疟原虫配子体表面蛋白P48/45（PFS48/45）使用体外培养适应的寄生虫饲料。我们假设抗GMZ3抗体还将阻止天然寄生虫分离株感染蚊子的能力，并且自然获得的TXB免疫力将与识别GMZ3的抗体的存在相关，表明GMZ3表明它是良好的疫苗候选者。为了测试这一点，我们建议目标1）评估大鼠在大鼠中产生的抗GMZ3抗体阻断天然分离株对蚊子的感染性的能力。我们还将评估目标2和3）自然寄生虫暴露是否诱导PFS48/45/gmz3抗体，这些抗体有助于传播阻断免疫。 PFS48/45是四种疟原虫蛋白（PFS48/45和P230，P25和P28）之一，它们是单克隆抗体的靶标，它们有效地阻断了疟疾TX并已被靶向疫苗候选者。所有这些蛋白质相对富含半胱氨酸，具有多个二硫键，导致抗体表位，这些抗体取决于三级结构而不是线性氨基酸序列。只有p25已进入IA期临床试验，但是由于免疫原性有限和自然疟疾感染期间缺乏增强，进一步的发育速度很慢。 PFS48/45和PFS230均表示为寄生虫在人类宿主中经历性别分化为配子细胞，并且在暴露于疟疾后发现了自然发生的抗PFS48/45抗体。这表明对PFS48/45或基于PFS230的TXB疫苗的免疫反应在自然感染期间可以增强疫苗的功效。此处提出的项目将直接评估GMZ3作为针对天然分离株的疫苗候选者的潜力。它通过直接比较传播障碍活性与配子细胞患病率，遗传变异和抗RPFS48/45.10C抗体滴度来增强正在进行的流行病学和临床安全研究，并将提供关键信息，以指导有效的透射阻挡疫苗的进一步开发。