Chimeric hybrid transmission blocking vaccine for malaria

疟疾嵌合混合传播阻断疫苗

基本信息

批准号：
8424202
负责人：
Alberto Moreno
金额：
$ 22万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8424202
关键词：
Active Immunization Adjuvant Adverse event Adverse reactions Africa Americas Anopheles Genus Antibodies Antibody Affinity Antibody Formation Antigen Presentation Antigens Applications Grants Area Attention Biological Assay Blocking Antibodies CD4 Positive T Lymphocytes Carrier Proteins Categories Chemicals Chimeric Proteins Clinical Clinical Trials Clinical Trials Design Codon Nucleotides Conjugate Vaccines Culicidae Data Development Drug Formulations Drug resistance Emulsions Epidermal Growth Factor Epitopes Erythrocytes Escherichia coli Fertilization Future Genetic Geographic Distribution Glycine decarboxylase Goals Health Helper-Inducer T-Lymphocyte Human Hybrids Immune response Immune system Immunity Immunization In Vitro Infection Infection Control Lead Longevity Macaca mulatta Malaria Malaria Vaccines Measures Membrane Merozoite Surface Protein 1 Methodology Midgut Modeling Molecular Conformation Monitor Montanide ISA-51 Mus Nature Oils Parasites Passive Immunization Phase Plasmodium Plasmodium falciparum Plasmodium vivax Protein Fragment Proteins Publishing Reagent Recombinant Proteins Recombinants Regimen Reporting Research Research Proposals Resources Risk Safety Sexual Development Southeastern Asia Staging Structure Surface Synthetic Genes System T-Lymphocyte T-Lymphocyte Epitopes Testing Therapeutic Time Transgenic Organisms Trefoil Motif Vaccines Vivax Malaria Water Yeasts acquired immunity base comparative feeding fertilization antigen genetic linkage hybrid gene immunogenic immunogenicity improved in vitro Assay in vivo innovation novel prevent programs prophylactic research study resistant strain tool transmission process vaccine candidate vaccine evaluation vector zygote

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this R21 research proposal is to develop and evaluate the potential of a novel chimeric construct based on Pvs25 as an effective Plasmodium vivax transmission blocking vaccine (TBV). Given the emergence and spread of drug-resistant parasites, and the global malaria eradication agenda, the development of novel tools to control malaria transmission is an essential priority. Plasmodium vivax is the most prevalent of the human malaria parasites outside Africa with an estimated 80% of the cases in South and Southeast Asia and 70% in the Americas. Although Pvs25 vaccine constructs have reached a phase of clinical development, a main concern in the field is its poor immunogenicity. Strategies used to date to enhance the immunogenicity include changes in the delivery system and formulation. However, a clinical trial using a water- in-oil emulsion was halted due to severe systemic adverse events. New methodologies to improve safety and immunogenicity of Pvs25 are required. We have recently shown that the homospecific CD4+ help, provided by the genetic linkage of tandem Plasmodium promiscuous T cell epitopes to a merozoite vaccine candidate, improves efficacy by a direct effect on the quality of the antibody response. We hypothesized that this T helper module (HM) can be used as a carrier molecule to enhance the immunogenicity of Pvs25 and induce a robust transmission blocking immunity. We have genetically fused the synthetic gene encoding HM into a codon optimized synthetic gene encoding Pvs25. The hybrid gene has been successfully expressed in E. coli in a properly folded conformation. The studies proposed aim to (1) test in comparative experiments in mice the effect of a HM on Pvs25 immunogenicity and (2) assess the safety and immunogenicity of the novel chimeric construct in rhesus macaques. Transmission blocking immunity will be tested in vivo using a P. berghei transgenic parasite expressing Pvs25 and in vitro using standard membrane-feeding assays. These studies have the general goal of showing that a HM can be used as a carrier platform for poorly immunogenic malaria antigens. Given the dramatic impact of malaria with increasing attention on the widespread and severe nature of P. vivax, and the urgent need for novel control measures to reduce transmission, our proposal has the potential to serve as the framework for future development of effective multi-stage vaccines.

描述（由申请人提供）：该 R21 研究计划的总体目标是开发和评估基于 Pvs25 的新型嵌合构建体作为有效的间日疟原虫传播阻断疫苗 (TBV) 的潜力。鉴于耐药寄生虫的出现和传播以及全球根除疟疾议程，开发控制疟疾传播的新工具是当务之急。间日疟原虫是非洲以外最流行的人类疟疾寄生虫，估计 80% 的病例发生在南亚和东南亚，70% 发生在美洲。尽管 Pvs25 疫苗结构已进入临床开发阶段，但该领域的一个主要问题是其免疫原性差。迄今为止用于增强免疫原性的策略包括改变递送系统和制剂。然而，由于严重的全身不良事件，使用油包水乳剂的临床试验被停止。需要新的方法来提高 Pvs25 的安全性和免疫原性。我们最近表明，串联疟原虫混杂 T 细胞表位与候选裂殖子疫苗的遗传连锁所提供的同特异性 CD4+ 帮助，通过直接影响抗体反应的质量来提高功效。我们假设这种T辅助模块（HM）可以作为载体分子来增强Pvs25的免疫原性并诱导强大的传播阻断免疫。我们已将编码 HM 的合成基因基因融合到编码 Pvs25 的密码子优化的合成基因中。该杂交基因已在大肠杆菌中以正确折叠的构象成功表达。这些研究的目的是（1）在小鼠的比较实验中测试 HM 对 Pvs25 免疫原性的影响，以及（2）评估新型嵌合结构在恒河猴中的安全性和免疫原性。将使用表达 Pvs25 的伯氏疟原虫转基因寄生虫在体内测试传播阻断免疫，并使用标准膜喂养测定在体外测试。这些研究的总体目标是表明 HM 可用作免疫原性较差的疟疾抗原的载体平台。鉴于疟疾的巨大影响，人们越来越关注间日疟原虫的广泛性和严重性，以及迫切需要新的控制措施来减少传播，我们的建议有可能成为未来发展有效的多阶段的框架。疫苗。