EVALUATION OF A LYMPHATIC FILARIASIS VACCINE IN NON-HUMAN PRIMATES

在非人类灵长类动物中评价淋巴丝虫病疫苗

• 批准号: 9042921
• 负责人: RAMASWAMY KALYANASUNDARAM
• 金额: $ 61.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042921
• 关键词: Adjuvant; Agonist; Ancylostoma (genus); Antigens; Brugia malayi; Characteristics; Chimeric Proteins; Clinical Trials; Combined Vaccines; Country; Development; Disease; Economic Burden; Enlargement of lymph nodes; Equilibrium; Evaluation; Experimental Animal Model; Female; Filaria bancrofti; Filarial Elephantiases; Formulation; Hamsters; Health; Helminths; Hookworm Infections; Human; Immune response; Immunity; In Vitro; Incidence; Individual; Infection; Jird; Laboratories; Licensing; Life; Macaca; Macaca mulatta; Modeling; Parasites; Parasitic infection; Pathology; Pharmaceutical Preparations; Physically Handicapped; Preparation; Principal Investigator; Publishing; Recombinants; Regimen; Risk; Rodent; Rodent Model; Role; Safety; Sample Size; Sterility; TLR4 gene; Testing; Therapeutic; Therapeutic Effect; Time; Vaccination; Vaccine Antigen; Vaccine Clinical Trial; Vaccines; aluminum sulfate; base; clinically relevant; cost; disability burden; disability-adjusted life years; gastrointestinal; immunogenic; immunogenicity; male; nonhuman primate; novel; programs; prophylactic; public health relevance; research clinical testing; response; success; vaccine candidate; vaccine development; vaccine evaluation; vaccine safety; vaccine trial; vaccine-induced immunity

 DESCRIPTION (provided by applicant): The major objective of this proposal is to evaluate a multivalent fusion protein vaccine against lymphatic filariasis in a rhesus macaque model. Preliminary studies in macaque using a recombinant WbHAT vaccine plus alum showed that approximately 40% protection can be achieved against a challenge infection. Although this is significant, compared to our published findings using the same vaccine in rodent model, the values were substantially low. Vaccination trials using rBmHAT plus alum or rBmHAX plus alum in three rodent models showed that close to sterile immunity (95-97%) can be achieved. Thus, there is a significant difference in the degree of protection conferred following vaccination in th rhesus macaque and rodents. Analysis of the characteristics of the protective responses showed that in rhesus macaques the responses are predominantly Th2 with little or no Th1 response. A similar analysis in rodents and the human showed that balanced Th1/Th2 responses are critical for protection against lymphatic filariasis. This might explain the low protection observed in our rhesus macaque trial. In an effort to increase the Th1 responses towards the vaccine antigen and thus increase the rate of protection, in this application, we are proposing to use AL019 adjuvant, which is a combination of alum plus TLR4 agonist. Preliminary studies in rhesus macaque using AL019 as an adjuvant for rWbALT-2 showed that the adjuvant promotes both Th1 and Th2 responses and the rate of protection was doubled suggesting that AL019 is an excellent adjuvant for lymphatic filariasis vaccine in macaque. Therefore, in this application we are proposing an initial vaccination trial in macaque using rWbHAT and rWbHAX plus AL019 and down select the best formulation based on immunogenicity, safety, and correlates of protection. Selected vaccine candidate will be then further characterized and vaccination regimen will be optimized in a jird and hamster model. Finally the prophylactic and therapeutic potential of the selected vaccine formulation will be evaluated in detail in the macaque model. Several rounds of mass drug administration (MDA) have tremendously reduced the incidence of lymphatic filariasis in the endemic regions. Therefore, there is a need to maintain the momentum gained by MDA and leverage the success towards developing a sustained eradication strategy such as an effective vaccine for lymphatic filariasis. We have proposed three aims in this application. Specific Aim 1 is aimed at evaluating the immunogenicity of rWbHAT and rWbHAX in rhesus macaque and down select the best vaccine formulation for further development. Based upon our findings from rodent vaccination trial, either of the vaccines will be highly efficient as prophylactic vaccines. In Specific Aim 2 e will characterize the prophylactic and therapeutic potential of the down selected vaccines in a jird model. We decided to do these characterization studies in jirds mainly because of cost, time, repeatability, ability to accurately determine the parasite establishment, and the fact that bigger sample size are possible. Preliminary studies in the jirds showed that rWbHA, a major component of the two selected vaccine candidates have significant therapeutic activity. Thus, this aim will focus on characterizing the mechanism of the therapeutic activity and evaluate if combining the vaccine with anti-filarial treatment can achieve total clearance of the infection from infected jirds. Several studies show that hookworm infections coexist with lymphatic filariasis infection in the endemic regions. Therefore, this aim will also evaluate the effects of hookworm infections on the vaccine-induced immunity against lymphatic filariasis. Finally in Specific Aim 3 we will evaluate the prophylactic and therapeutic potential of the down selected and optimized multivalent vaccine formulation in rhesus macaque model. We will also test if combining anti-filarial treatment with the therapeutic vaccination is beneficial. Similarly we will also test the role of hookworm infection in the development of vaccine-induced immunity in macaques. Overall, these studies are aimed at selecting the most effective vaccine formulation for possible testing in the human clinical trials.

 描述（由适用提供）：该提案的主要目的是评估恒河猴模型中针对淋巴丝虫病的多价融合蛋白疫苗。使用重组WBHAT疫苗加上明矾的猕猴的初步研究表明，可以针对挑战感染实现约40％的保护。尽管这很重要，但是与我们在啮齿动物模型中使用相同疫苗的发布发现相比，这些值大大低。在三种啮齿动物模型中使用RBMHAT加上明矾或RBMHAX加上明矾的疫苗接种试验表明，可以实现接近无菌免疫释放性（95-97％）。这是恒河猴和啮齿动物接种后的保护程度有显着差异。对受保护反应的特征的分析表明，在恒河猕猴中，反应主要是Th2，而TH1反应很少或没有TH1。对啮齿动物和人类的类似分析表明，平衡的Th1/Th2反应对于防止淋巴丝虫病至关重要。这可能解释了我们猕猴试验中观察到的低保护。为了增加Th1对疫苗抗原的响应并因此增加了保护速率，在本应用中，我们建议使用AL019调整，这是Alum Plus TLR4激动剂的组合。使用AL019作为RWBALT-2调整的恒河猴的初步研究表明，调整促进了Th1和Th2响应，并且保护速度加倍，这表明AL019是猕猴中淋巴丝虫病疫苗的出色调整。因此，在此应用中，我们提出了使用RWBHAT和RWBHAX以及AL019及向下的猕猴中的初步疫苗试验选择基于免疫原性，安全性和保护性相关性的最佳配方。然后将进一步表征选定的疫苗候选者，并将在JIRD和仓鼠模型中优化疫苗方案。最后，将在猕猴模型中详细评估所选疫苗配方的预防性和治疗潜力。大规模药物给药（MDA）的几轮大大减少了内在区域淋巴丝虫病的入口。因此，有必要维持MDA获得的动力，并利用成功的目标1旨在评估RWBHAT和RWBHAX在Rhesus Macaque中的免疫原性，并为进一步开发的最佳疫苗配方选择。根据我们在Rod Avuumization试验中的发现，这两种疫苗都将作为抗抗性疫苗高效。在特定的目标2中，E将表征jird模型中下降选定疫苗的预防和治疗潜力。我们决定以jirds进行这些特征研究，主要是因为成本，时间，可重复性，准确确定寄生虫建立的能力以及更大的事实 样本量是可能的。 Jirds中的初步研究表明，RWBHA是两种选定疫苗候选物的主要组成部分具有显着的治疗活性。这是这个目标将集中在表征治疗活性的机制上，并评估是否将疫苗与抗抗疗法结合使用可以使感染的Jirds完全清除感染。几项研究表明，钩虫感染与内在区域中的淋巴丝虫病感染并存。因此，此目的还将评估钩虫感染对疫苗诱导的对淋巴丝虫病的免疫力的影响。最后，在特定的目标3中，我们将评估恒河猕猴模型中下降选定和优化的多价疫苗公式的预防和治疗潜力。我们还将测试是否将抗抗治疗与治疗疫苗相结合是有益的。同样，我们会的 还测试了钩虫感染在猕猴中疫苗诱导的免疫力发展中的作用。总体而言，这些研究旨在选择人类临床试验中可能测试的最有效的疫苗配方。