Chimeric hybrid transmission blocking vaccine for malaria

描述（由申请人提供）：本R21研究计划的总体目标是开发和评估基于Pvs25的新型嵌合结构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消灭疟疾议程，开发控制疟疾传播的新工具是一项至关重要的优先事项。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Pvs25疫苗结构已达到临床开发阶段，但该领域的一个主要问题是其免疫原性差。迄今用于增强免疫原性的策略包括改变给药系统和配方。然而，一项使用油包水乳剂的临床试验因严重的全身不良事件而中止。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merozoite候选疫苗的遗传连锁所提供的同源性CD4+帮助，通过直接影响抗体反应的质量来提高疗效。我们假设这种T辅助模块（HM）可以作为载体分子增强Pvs25的免疫原性，并诱导强大的传播阻断免疫。我们将编码HM的合成基因融合到编码Pvs25的密码子优化合成基因中。该杂交基因已成功地在大肠杆菌中以正确的折叠构象表达。本研究的目的是：(1)在小鼠实验中比较HM对Pvs25免疫原性的影响；(2)在恒河猴中评估新型嵌合结构的安全性和免疫原性。传播阻断免疫将在体内使用表达Pvs25的伯氏疟原虫转基因寄生虫进行测试，在体外使用标准的膜饲养试验进行测试。这些研究的总体目标是表明HM可以用作免疫原性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的多阶段疫苗的框架。

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.