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: 8745578
• 负责人: Heinrich Feldmann
• 金额: $ 81.17万
• 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/8745578
• 关键词: Andes Virus; Angola; Animal Model; Antibodies; Antigenic Variation; Antigens; Attenuated; Case Fatality Rates; Categories; Cavia; Cell Culture Techniques; Centers for Disease Control and Prevention (U.S.); Central Africa; 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; laboratory accident; meetings; nonhuman primate; pathogen; prophylactic; protective efficacy; recombinant virus vaccine; vaccine candidate; vector; vector vaccine; weapons

We have developed rVSVs expressing the glycoproteins (GP) of representative isolates of all species of Ebola virus: Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Cote d'Ivoire ebolavirus (CIEBOV), 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). Mainly the rVSV/ZEBOVgp, rVSV/SEBOVgp and rVSV/MARVmusGP vaccine vectors have been extensively characterized in cell culture and their protective efficacy has been evaluated in animal models against homologous challenges (Hoenen et al. 2012; Falzarano & Feldmann, 2013). Recently, we were able to demonstrate the protective efficacy of rVSV/BEBOVgp and rVSV/MARVangGP against homologous challenge in nonhuman primates (NHPs) (PLoS Negl Trop Dis, in revision). In an effort to decipher the mechanism of protection of the rVSV vaccine vector against ZEBOV, we were able to demonstrate in NHPs that antibodies specific to the viral antigen play a critical role (Marzi et al., 2013). 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 platform into clinical trials. Cross-protection among the different Ebola virus species and even Marburg virus is an important consideration and has been 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 this regard we have previously performed a proof-of-concept study using a single-injection protocol with a blended vaccine including rVSV/SEBOVgp, rVSV/ZEBOVgp and rVSV/MARVmusGP to see if a cross-protective vaccine could be developed against four human pathogenic filoviruses endemic in Central Africa. Challenge was performed four weeks after immunization with MARVmus, SEBOV, ZEBOV and CIEBOV resulting in protection against homologous challenges as well as a heterologous challenge (CIEBOV) indicating that cross-protective vaccines are feasible (Hoenen et al. 2012; Falzarano & Feldmann, 2013). More recently, we have performed another proof-of-concept study in which we evaluated cross-protection following immunization with a single vaccine vector (rVSV/ZEBOVgp or rVSV/CIEBOVgp). A single vaccination with the rVSV/ZEBOVgp provided cross-protection (75% survival) against a subsequent heterologous BEBOV challenge, whereas vaccination with the rVSV/CIEBOVgp resulted in no protection. 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 (Hoenen et al. 2012; Falzarano & Feldmann, 2013). Overall, we can conclude that single monovalent rVSV vaccine vectors can provide partial cross-protection in cases of challenge viruses that are genetically more closely related. One approach to overcome this limitation is the use of blended monovalent rVSV vaccine vectors, which provide broader cross-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) 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 (Hoenen et al. 2012; Falzarano & Feldmann, 2013). Based on the results described above, we have in the past fiscal year generated 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 and in vitro characterization are 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.

我们已经开发了所有表达所有埃博拉病毒的代表性分离株的RVSV：苏丹埃博拉病毒（SEBOV），Zaire Ebolavirus（Zebov），Cote d'Ivoire ebolavirus（Ciebov），Bundibugugyo Ebolavirus（bundibugyo ebolavirus（Bebbolavirus）和Repon（Rep）。此外，我们产生了表达两个马尔堡病毒分离株的GPS的RVSV：维多利亚湖Marburgvirus孤立的Musoke（Marvmus）和Angola（Marvang）。主要是RVSV/ZeboVGP，RVSV/SEBOVGP和RVSV/MARVMUSGP疫苗载体在细胞培养中已广泛特征，并且在针对同源挑战的动物模型中评估了它们的保护功效（Hoenen等人，2012; Falzarano＆Feldmann，2013年）。最近，我们能够证明RVSV/BEBOVGP和RVSV/MARVANGGP针对非人类灵长类动物（NHP）（NHPS）（修订版中的PLOS negl trop dis）的保护效果。 为了破译RVSV疫苗载体对Zebov的保护机理，我们能够在NHPS中证明对病毒抗原特有的抗体起着至关重要的作用（Marzi等，2013）。正在进行的工作正在研究保护RVSV疫苗载体免受MARV的保护机制。定义保护的机制和相关性将是将平台转移到临床试验中的里程碑。 不同的埃博拉病毒物种甚至马堡病毒之间的交叉保护是一个重要的考虑因素，并且由于属的遗传和抗原变异性相对较高，尤其是单一属中的物种，而且在物种之间，通常缺乏交叉保护抗体，因此很难实现。在这方面，我们先前使用单一注入方案进行了一项概念证明研究，其中包括RVSV/SEBOVGP，RVSV/ZEBOVGP和RVSV/MARVMUSGP，以查看是否可以针对四种人类病原体疫苗病毒疫苗在中部非洲开发交叉保护疫苗。挑战是在Marvmus，Sebov，Zebov和Ciebov进行免疫后四周进行的，导致防止同源挑战以及异源挑战（CIEBOV），表明交叉保护疫苗是可行的（Hoenen等人，2012年； Falzarano＆Feldmann，2013年）。最近，我们进行了另一项概念验证研究，其中我们用单个疫苗载体（RVSV/ZeboVGP或RVSV/CIEBOVGP）评估了交叉保护。 RVSV/ZeboVGP的一次疫苗接种可针对随后的异源Bebov挑战提供交叉保护（75％存活率），而使用RVSV/CIEBOVGP进行疫苗接种，没有任何保护。这表明基于RVSV的单价疫苗可能对新兴物种有用。然而，跨物种的异源保护仍然具有挑战性，可能取决于通过增强免疫或包含多种免疫原子来增强免疫反应（Hoenen等，2012; Falzarano＆Feldmann，2013）。总体而言，我们可以得出结论，在遗传上更紧密相关的挑战病毒的情况下，单一单价RVSV疫苗向量可以提供部分交叉保护。克服这一限制的一种方法是使用混合单价RVSV疫苗向量，该媒介为针对某些异源挑战提供了更广泛的交叉保护。 克服交叉保护局限性的另一种方法是使用多价RVSV疫苗向量。在对Zebov和Andes病毒（ANDV）的概念验证研究中，使用单个RVSV载体在叙利亚仓鼠模型中同时表达ZebovGP和ANDV糖蛋白。该数据表明，二价RVSV载体是针对多种病原体疫苗接种的可行方法。此外，这项研究表明，叙利亚仓鼠是研究RVSV介导的保护的适当模型（Hoenen等，2012； Falzarano＆Feldmann，2013）。 根据上述结果，在过去的财政年度中，我们产生了表达两种或三个不同的Filevirus GP的二价和三价RVSV载体，一种是跨膜蛋白（替换VSV糖蛋白），而在载体进行载体复制期间将被分泌的可溶蛋白。这些重组疫苗病毒的恢复和体外表征正在进行中。这些向量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。最有希望的疫苗向量将在非人类灵长类动物模型中转移到有效性的疫苗测试中。