CAP: Trivalent Filovirus Vaccine for Pre- and Post-Exposure Vaccination

CAP：用于暴露前和暴露后疫苗接种的三价丝状病毒疫苗

• 批准号: 8946527
• 负责人: Heinrich Feldmann
• 金额: $ 25.14万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8946527
• 关键词: Address; Andes Virus; Angola; Animal Model; Antibodies; Antigenic Variation; Antigens; Attenuated; Attenuated Live Virus Vaccine; Case Fatality Rates; Categories; Cavia; Cell Culture Techniques; Centers for Disease Control and Prevention (U.S.); Clinical Trials; Data; Democratic Republic of the Congo; Disease Outbreaks; Ebola virus; Emerging Communicable Diseases; Family; Filoviridae; Filovirus; Frankfurt-Marburg Syndrome Virus; Genetic; Glycoproteins; Health Personnel; Human; Human Resources; Immune response; Immunization; In Vitro; Individual; Infection; Injection of therapeutic agent; Integral Membrane Protein; Intervention; Ivory Coast; Laboratories; Mediating; Mesocricetus auratus; Military Personnel; Modeling; Mono-S; National Institute of Allergy and Infectious Disease; Play; Proteins; Protocols documentation; Public Health; RNA Viruses; Recombinants; Recovery; Reston; Rodent Model; Role; Secondary Immunization; Sudan; Sudan Ebola virus; United States National Institutes of Health; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral Antigens; Virus; Work; animal rule; base; comparative efficacy; efficacy testing; forest; laboratory accident; meetings; nonhuman primate; pathogen; prophylactic; protective efficacy; recombinant virus vaccine; vaccine candidate; vector; vector vaccine; weapons

Our main vaccine platform is based on recombinant vesicular stomatitis virus (rVSVs), a live-attenuate vaccine approach. Over the years we have generated several rVSVs expressing the glycoproteins (GP) of representative isolates of all species of Ebola virus: Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Tai forest ebolavirus (TFEBOV), Bundibugyo ebolavirus (BEBOV) and Reston ebolavirus (REBOV). Additionally, we generated rVSVs expressing the GPs of two isolates of Marburg virus: Lake Victoria marburgvirus isolate Musoke (MARVmus) and Angola (MARVang). All vaccine vectors have been extensively characterized in cell culture and their protective efficacy has been evaluated in animal models against homologous challenges including nonhuman primates. In an effort to decipher the mechanism of protection of the rVSV vaccine vectors we used the rVSV/ZEBOVgp as a model. We could demonstrate in nonhuman primates that antibodies specific to the viral antigen play a critical role in protection. Ongoing work is investigating the mechanism of protection of the rVSV vaccine vector against MARV. Defining the mechanism(s) and correlate(s) of protection will be milestones for moving the rVSV platform into clinical trials. Cross-protection among the different Ebola virus species and even Marburg virus is an important consideration, but is thought to be difficult to achieve due to relatively high genetic and antigenic variability among genera in particular, but also among species within a single genus, and the general lack of cross-protective antibodies even among species. In a first attempt to address this issue we previously used a single-injection protocol with three blended vaccine vectors (rVSV/SEBOVgp, rVSV/ZEBOVgp and rVSV/MARVmusGP) and demonstrated complete protection against challenge with the three homologous virus species. We have also performed another proof-of-concept study, in which we evaluated cross-protection following immunization with a single vaccine vector (rVSV/ZEBOVgp or rVSV/CIEBOVgp) and demonstrated partial cross-protection against challenge with a heterologous virus species (BEBOV). This demonstrates that monovalent rVSV-based vaccines may be useful against a newly emerging species; however, heterologous protection across species remains challenging and may depend on enhancing the immune responses either through booster immunizations or through the inclusion of multiple immunogens. Overall, we can conclude that single monovalent rVSV vaccine vectors can provide partial cross-protection in cases of challenge virus species that are genetically more closely related. As mentioned above, one approach to overcome this limitation is the use of blended monovalent rVSV vaccine vectors, which provide broader protection against homologous and partial protection against certain heterologous challenges. Another approach to overcome the limitations in cross-protection is the use of multivalent rVSV vaccine vectors. In a proof-of-concept study protection against ZEBOV and Andes virus (ANDV) challenge was demonstrated using a single rVSV vector expressing both the ZEBOVgp and ANDV glycoprotein in the Syrian hamster model. This data showed that bivalent rVSV vectors are a feasible approach to vaccination against multiple pathogens. Further, this study demonstrated that the Syrian hamster is an adequate model to study rVSV-mediated protection prior to nonhuman primate work. Based on the results described above, we have in the past fiscal year generated more bivalent and trivalent rVSV vectors expressing two or three different filovirus GPs, one as a transmembrane protein (replacing the VSV glycoprotein) and one or two as soluble proteins that will be secreted during vector replication. Recovery of these recombinant vaccine viruses turned out to be difficult and in vitro characterization of the already rescued vectors is ongoing. Efficacy testing of these vectors will be performed initially using rodent models, mainly the Syrian hamster. The most promising vaccine vectors will be moved into efficacy testing in the nonhuman primate model for filovirus infections.

我们的主要疫苗平台基于重组水泡性口炎病毒（rVSV），这是一种减毒活疫苗方法。多年来，我们已经产生了几种表达埃博拉病毒所有物种的代表性分离株糖蛋白（GP）的rVSV：苏丹埃博拉病毒（SEBOV）、扎伊尔埃博拉病毒（ZEBOV）、泰森林埃博拉病毒（TFEBOV）、本迪布焦埃博拉病毒（BEBOV）和雷斯顿埃博拉病毒埃博拉病毒（REBOV）。此外，我们还生成了表达马尔堡病毒两种分离株 GP 的 rVSV：维多利亚湖马尔堡病毒分离株 Musoke (MARVmus) 和 Angola (MARVang)。所有疫苗载体都已在细胞培养物中进行了广泛的表征，并且已在动物模型中针对包括非人类灵长类动物在内的同源攻击评估了它们的保护功效。为了破译 rVSV 疫苗载体的保护机制，我们使用 rVSV/ZEBOVgp 作为模型。我们可以在非人类灵长类动物中证明，针对病毒抗原的特异性抗体在保护中发挥着关键作用。正在进行的工作是研究 rVSV 疫苗载体针对 MARV 的保护机制。定义保护机制和相关性将是 rVSV 平台进入临床试验的里程碑。 不同埃博拉病毒物种甚至马尔堡病毒之间的交叉保护是一个重要的考虑因素，但被认为很难实现，因为特别是属之间以及单个属内的物种之间相对较高的遗传和抗原变异性，并且即使在物种之间也普遍缺乏交叉保护性抗体。在解决这个问题的第一次尝试中，我们之前使用了具有三种混合疫苗载体（rVSV/SEBOVgp、rVSV/ZEBOVgp 和 rVSV/MARVmusGP）的单次注射方案，并证明了针对三种同源病毒物种攻击的完全保护。我们还进行了另一项概念验证研究，其中我们评估了使用单一疫苗载体（rVSV/ZEBOVgp 或 rVSV/CIEBOVgp）免疫后的交叉保护，并证明了针对异源病毒物种（BEBOV）攻击的部分交叉保护）。这表明基于 rVSV 的单价疫苗可能对新出现的物种有用；然而，跨物种的异源保护仍然具有挑战性，可能取决于通过加强免疫或通过包含多种免疫原来增强免疫反应。总体而言，我们可以得出结论，单一单价 rVSV 疫苗载体可以在遗传上更密切相关的攻击病毒物种的情况下提供部分交叉保护。 如上所述，克服这一限制的一种方法是使用混合单价 rVSV 疫苗载体，其提供针对同源攻击的更广泛保护和针对某些异源攻击的部分保护。克服交叉保护限制的另一种方法是使用多价 rVSV 疫苗载体。在一项概念验证研究中，使用表达 ZEBOVgp 和 ANDV 糖蛋白的单一 rVSV 载体在叙利亚仓鼠模型中证明了对 ZEBOV 和安第斯病毒 (ANDV) 攻击的保护作用。该数据表明二价 rVSV 载体是针对多种病原体进行疫苗接种的可行方法。此外，这项研究表明，叙利亚仓鼠是在非人类灵长类动物工作之前研究 rVSV 介导的保护的适当模型。 基于上述结果，我们在过去的财政年度中产生了更多的二价和三价 rVSV 载体，表达两种或三种不同的丝状病毒 GP，一种作为跨膜蛋白（取代 VSV 糖蛋白），一种或两种作为可溶性蛋白，将被在载体复制过程中分泌。事实证明，这些重组疫苗病毒的回收很困难，并且正在对已拯救的载体进行体外表征。这些载体的功效测试最初将使用啮齿动物模型（主要是叙利亚仓鼠）进行。最有前途的疫苗载体将进入非人灵长类动物模型中丝状病毒感染的功效测试。