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以及人们对间日疟的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，我们的建议有可能成为未来开发有效的多阶段疫苗的框架。 公共卫生相关性：由间日疟原虫引起的疟疾是全球范围内的一个主要健康问题，估计每年可能有 132 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。间日疟疾正在卷土重来，目前对已消灭疟疾的地区构成严重威胁。间日疟原虫耐药菌株的出现和传播日益强调需要替代性预防和治疗策略来控制这种感染。有效的传播阻断疫苗是消除疟疾计划的重要工具。