Evaluation of a Multivalent Vaccine against Lymphatic Filariasis in Rhesus macaque Model
Evaluation of a Multivalent Vaccine against Lymphatic Filariasis in Rhesus macaque Model
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DOI：
10.1371/journal.pone.0112982
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发表时间：
2014-11-17
期刊：
影响因子：
3.7
通讯作者：
Kalyanasundaram, Ramaswamy
中科院分区：
文献类型：
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作者：
Dakshinamoorthy, Gajalakshmi;von Gegerfelt, Agneta;Kalyanasundaram, Ramaswamy
淋巴丝虫病影响着全球1.2亿人，另有12亿人面临感染的风险。大规模给药的化疗大大降低了感染的发生率。然而，需要一种有效的疫苗来预防感染和根除疾病。先前我们报道了由小热休克蛋白12.6(HSP12.6)、丰富的幼虫转录本-2(ALT-2)和大胞外结构域(TSP LEL)组成的多价融合蛋白疫苗(RBmHAT)可以在小鼠和沙土鼠模型中对马来丝虫感染性幼虫(L3)的攻击感染提供95%的保护。在这项研究中，我们评估了rBmHAT融合蛋白疫苗在恒河猴模型中的免疫原性和有效性。我们的结果表明，rBmHAT对恒河猴具有高度的免疫原性。所有接种疫苗的猴子都产生了显著的抗原特异性抗体滴度(rBmHSP12.6为16,000)、rBmALT-2(24,000)和rBmTSP-LEL(16,000)。用免疫猴血清进行的体外抗体依赖细胞毒性(ADCC)试验表明，抗rBmHAT抗体对马来丝虫L3S的杀灭率为35%。接种疫苗的猴子外周血中也有抗原反应细胞。在用500只马来丝虫L3攻击猴子后，确定了疫苗诱导的保护作用。在攻击性感染后，5只接种疫苗的猕猴中有3只未能发生感染。这三只受保护的猕猴具有高滴度的IgG1抗体，它们的PBMC对疫苗抗原的反应显著地分泌高水平的干扰素-γ。感染的两只接种疫苗的猕猴抗体效价略低，它们的PBMC分泌高水平的IL-10。基于这些发现，我们得出结论，rBmHAT疫苗具有高度的免疫原性和安全性，可以显著保护猕猴免受攻击性感染。
Lymphatic filariasis affects 120 million people worldwide and another 1.2 billion people are at risk of acquiring the infection. Chemotherapy with mass drug administration is substantially reducing the incidence of the infection. Nevertheless, an effective vaccine is needed to prevent the infection and eradicate the disease. Previously we reported that a multivalent fusion protein vaccine (rBmHAT) composed of small heat shock proteins 12.6 (HSP12.6), abundant larval transcript-2 (ALT-2) and large extracellular domain of tetraspanin (TSP LEL) could confer >95% protection against the challenge infection with Brugia malayi infective larvae (L3) in mouse and gerbil models. In this study we evaluated the immunogenicity and efficacy of rBmHAT fusion protein vaccine in a rhesus macaque model. Our results show that rBmHAT is highly immunogenic in rhesus macaques. All the vaccinated monkeys developed significant titers of antigen-specific IgG antibodies against each of the component antigens (16,000 for rBmHSP12.6), (24,000 for rBmALT-2) and (16,000 for rBmTSP-LEL). An in vitro antibody dependent cellular cytotoxicity (ADCC) assay performed using the sera samples from vaccinated monkeys showed that the anti-rBmHAT antibodies are functional with 35% killing of B. malayi L3s. Vaccinated monkeys also had antigen responding cells in the peripheral blood. Vaccine-induced protection was determined after challenging the monkeys with 500 B. malayi L3. Following challenge infection, 3 out of 5 vaccinated macaques failed to develop the infection. These three protected macaques had high titers of IgG1 antibodies and their PBMC secreted significantly high levels of IFN-gamma in response to the vaccine antigens. The two vaccinated macaques that picked the infection had slightly low titers of antibodies and their PBMC secreted high levels of IL-10. Based on these findings we conclude that the rBmHAT vaccine is highly immunogenic and safe and can confer significant protection against challenge infections in rhesus macaques.