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.

我们已经开发了表达所有埃博拉病毒物种的代表性分离株的糖蛋白（GP）的rVSV：苏丹埃博拉病毒（SEBOV）、扎伊尔埃博拉病毒（ZEBOV）、科特迪瓦埃博拉病毒（CIEBOV）、本迪布焦埃博拉病毒（BEBOV）和雷斯顿埃博拉病毒（REBOV）。此外，我们产生了表达两种马尔堡病毒分离株的GP的rVSV：维多利亚湖马尔堡病毒分离株Musoke（MARVmus）和安哥拉（MARVang）。主要地，rVSV/ZEBOVgp、rVSV/SEBOVgp和rVSV/MARVmusGP疫苗载体已经在细胞培养物中被广泛表征，并且已经在动物模型中评估了它们针对同源攻击的保护功效（Hoenen等人，2012; Falzarano & Feldmann，2013）。最近，我们能够证明rVSV/BEBOVgp和rVSV/MARVangGP对非人灵长类动物（NHP）同源攻击的保护作用（PLoS Negl Trop Dis，修订版）。 在努力破译rVSV疫苗载体针对ZEBOV的保护机制时，我们能够在NHP中证明对病毒抗原特异性的抗体起关键作用（Marzi et al.，2013年）。正在进行的工作是研究rVSV疫苗载体对MARV的保护机制。定义保护机制和相关性将是将平台转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，并且由于特别是在属之间，而且在单个属内的物种之间相对高的遗传和抗原变异性，以及甚至在物种之间普遍缺乏交叉保护性抗体而难以实现。在这方面，我们之前已经使用包括rVSV/SEBOVgp、rVSV/ZEBOVgp和rVSV/MARVmusGP的混合疫苗的单次注射方案进行了概念验证研究，以观察是否可以开发针对中非流行的四种人类致病性丝状病毒的交叉保护性疫苗。在用MARVmus、SEBOV、ZEBOV和CIEBOV免疫后四周进行攻击，导致针对同源攻击以及异源攻击（CIEBOV）的保护，表明交叉保护性疫苗是可行的（Hoenen等2012; Falzarano & Feldmann，2013）。最近，我们进行了另一项概念验证研究，其中我们评估了用单一疫苗载体（rVSV/ZEBOVgp或rVSV/CIEBOVgp）免疫后的交叉保护。用rVSV/ZEBOVgp的单次接种提供了针对随后的异源BEBOV攻击的交叉保护（75%存活率），而用rVSV/CIEBOVgp的接种不产生保护。这表明基于单价rVSV的疫苗可用于对抗新出现的物种;然而，跨物种的异源保护仍然具有挑战性，并且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应答（Hoenen等人，2012; Falzarano & Feldmann，2013）。总之，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的情况下提供部分交叉保护。克服这种限制的一种方法是使用混合的单价rVSV疫苗载体，其提供针对同源的更广泛的交叉保护和针对某些异源攻击的部分保护。 另一种克服交叉保护限制的方法是使用多价rVSV疫苗载体。在概念验证研究中，在叙利亚仓鼠模型中使用表达ZEBOVgp和ANDV糖蛋白的单一rVSV载体证明了针对ZEBOV和安第斯山脉病毒（ANDV）的保护。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，该研究表明叙利亚仓鼠是研究rVSV介导的保护作用的适当模型（Hoenen et al. 2012; Falzarano & Feldmann，2013）。 基于上述结果，我们在过去的财政年度中产生了表达两种或三种不同丝状病毒GP的二价和三价rVSV载体，一种作为跨膜蛋白（替代VSV糖蛋白），一种或两种作为可溶性蛋白，其将在载体复制期间分泌。这些重组疫苗病毒的回收和体外表征正在进行中。最初将使用啮齿动物模型（主要是叙利亚仓鼠）对这些载体进行有效性试验。最有前途的疫苗载体将在非人灵长类动物模型中进行丝状病毒感染的有效性测试。