Chimeric hybrid transmission blocking vaccine for malaria

疟疾嵌合混合传播阻断疫苗

• 批准号: 8243137
• 负责人: Alberto Moreno
• 金额: $ 26.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243137
• 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

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. PUBLIC HEALTH RELEVANCE: Malaria caused by P. vivax is a major worldwide health problem with likely annual infections estimated at 132 to 391 million of cases. P. vivax is characterized by its wider geographic distribution than P. falciparum with 2.6 billion of people at risk of infection. P. vivax malaria is resurging and now represents a serious threat in areas where it had been eradicated. The emergence and spread of P. vivax drug resistant strains has brought increased emphasis to the need for alternative prophylactic and therapeutic strategies to control this infection. An effective transmission blocking vaccine is an essential tool for a malaria elimination program.

描述（由申请方提供）：本R21研究提案的总体目标是开发和评价基于Pvs 25的新型嵌合构建体作为有效间日疟原虫传播阻断疫苗（TBV）的潜力。鉴于抗药性寄生虫的出现和传播，以及全球消灭疟疾议程，开发控制疟疾传播的新工具是一个重要的优先事项。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Pvs 25疫苗构建体已经达到临床开发阶段，但该领域的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，使用油包水乳剂的临床试验由于严重的全身不良事件而停止。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，同源特异性CD4+的帮助，提供了串联疟原虫混杂T细胞表位裂殖子疫苗候选人的遗传连锁，提高了抗体应答的质量的直接影响的效力。我们假设，这种辅助性T细胞模块（HM）可以用作载体分子，以增强Pvs 25的免疫原性，并诱导一个强大的传输阻断免疫。我们已经将编码HM的合成基因遗传融合到编码Pvs 25的密码子优化的合成基因中。该杂交基因已在大肠杆菌中成功表达。大肠杆菌中正确折叠的构象。所提出的研究旨在（1）在小鼠中的比较实验中测试HM对Pvs 25免疫原性的影响和（2）评估新嵌合构建体在恒河猴中的安全性和免疫原性。将使用表达Pvs 25的伯氏疟原虫转基因寄生虫在体内测试传播阻断免疫力，并使用标准膜饲养试验在体外测试传播阻断免疫力。这些研究的总体目标是显示HM可以用作免疫原性差的疟疾抗原的载体平台。考虑到疟疾的巨大影响以及对间日疟原虫广泛和严重性质的日益关注，以及迫切需要新的控制措施来减少传播，我们的建议有可能作为未来开发有效多阶段疫苗的框架。 公共卫生关系：由间日疟原虫引起的疟疾是一个主要的全球性健康问题，估计每年可能有1.32亿至3.91亿例感染病例。间日疟原虫的特点是其地理分布比恶性疟原虫更广泛，有26亿人面临感染风险。间日疟原虫疟疾正在死灰复燃，现在在已经根除的地区构成严重威胁。间日疟原虫耐药菌株的出现和传播使得人们越来越重视对控制这种感染的替代预防和治疗策略的需求。有效的传播阻断疫苗是消灭疟疾计划的重要工具。