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.

我们开发了表达埃博拉病毒所有物种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）、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（雷博夫）。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)。主要是 rVSV/ZEBOVgp、rVSV/SEBOVgp 和 rVSV/MARVmusGP 疫苗载体已在细胞培养中得到广泛表征，并在动物模型中针对同源攻击评估了它们的保护功效（Hoenen 等人，2012 年；Falzarano 和 Feldmann，2013 年）。最近，我们能够证明 rVSV/BEBOVgp 和 rVSV/MARVangGP 对非人灵长类动物 (NHP) 中同源攻击的保护功效（PLoS Negl Trop Dis，修订中）。 为了破译 rVSV 疫苗载体针对 ZEBOV 的保护机制，我们能够在 NHP 中证明病毒抗原特异性抗体发挥着关键作用（Marzi 等，2013）。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将平台转移到临床试验的里程碑。 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，但由于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以及普遍缺乏即使在物种之间也存在交叉保护性抗体。在这方面，我们之前使用单次注射方案和混合疫苗（包括 rVSV/SEBOVgp、rVSV/ZEBOVgp 和 rVSV/MARVmusGP）进行了一项概念验证研究，以了解是否可以开发针对四种人类的交叉保护疫苗致病性丝状病毒在中部非洲流行。在用 MARVmus、SEBOV、ZEBOV 和 CIEBOV 免疫后 4 周进行攻击，产生针对同源攻击以及异源攻击 (CIEBOV) 的保护，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，其中我们评估了使用单一疫苗载体（rVSV/ZEBOVgp 或 rVSV/CIEBOVgp）免疫后的交叉保护。 rVSV/ZEBOVgp 的单次疫苗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 rVSV/CIEBOVgp 的疫苗接种则没有产生任何保护作用。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（Hoenen 等人，2012 年；Falzarano 和 Feldmann，2013 年）。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的情况下提供部分交叉保护。克服这一限制的一种方法是使用混合单价 rVSV 疫苗载体，该载体提供更广泛的交叉保护以对抗同源攻击，并提供部分保护以对抗某些异源攻击。 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) 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研究 rVSV 介导的保护的适当模型（Hoenen 等人，2012 年；Falzarano 和 Feldmann，2013 年）。 基于上述结果，我们在上一财年生成了二价和三价 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），另一种或两种作为可分泌的可溶性蛋白在载体复制期间。这些重组疫苗病毒的回收和体外表征正在进行中。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。