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: 9354909
• 负责人: Heinrich Feldmann
• 金额: $ 12.17万
• 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/9354909
• 关键词: Achievement; Address; Africa; African; Andes Virus; Angola; Animal Model; Antibodies; 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; Development; Disease Outbreaks; Ebola virus; Epidemic; Family; Filoviridae; Filovirus; Frankfurt-Marburg Syndrome Virus; Genetic; Glycoproteins; Growth; Guinea; H5 hemagglutinin; Hamsters; Human; Immune response; Immunization; Immunoglobulin G; In Vitro; Individual; Influenza A Virus, H5N1 Subtype; Injection of therapeutic agent; Integral Membrane Protein; Ivory Coast; Liberia; Licensing; Mediating; Modeling; Mono-S; Mus; National Institute of Allergy and Infectious Disease; Outcome; Phase III Clinical Trials; Play; Proteins; Protocols documentation; Publishing; RNA Viruses; Recombinants; Recovery; Reporting; Reston; Rodent; Rodent Model; Role; Schedule; Secondary Immunization; Sierra Leone; Sudan; Sudan Ebola virus; Time; United States National Institutes of Health; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral; Virus; Work; animal rule; base; efficacy testing; forest; immunogenic; influenzavirus; nonhuman primate; pathogen; protective efficacy; recombinant virus vaccine; response; success; treatment strategy; 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 and Angola. All vaccine vectors have been extensively characterized in cell culture and their protective efficacy has been evaluated in animal models (rodents, nonhuman primates) against homologous challenges. 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 foreign immunogen play a critical role in protection. Recent similar work also confirmed a role of antibodies for the mechanism of protection mediated by the rVSV vaccine vector against MARV. Overall, we postulate that antibodies (total and neutralizing IgG) play a key role for the mechanism of protection for all rVSV-based vaccine candidates. In response to the recent Ebola outbreak in West Africa, the rVSV/ZEBOVgp vaccine candidate was fast-tracked and shown to be safe and immunogenic in humans. Phase III clinical trials with this vaccine candidate were initiated in Guinea, Sierra Leone and Liberia. To support the clinical trials we have shown that the GMP-produced rVSV/ZEBOVgp vaccine lot used in West Africa protects against challenge with a recent local isolate, a proof that had been missing at trial start. A recent preliminary report published in Lancet from the human trial in Guinea reports success of the rVSV/ZEBOVgp vaccine in a ring vaccination approach. This remarkable outcome is supported by another recent study of our group in nonhuman primates looking into the minimum time needed for protection. We could demonstrate complete protection when rVSV/ZEBOVgp was administered at least one week and partial protection when administered as close as three days prior to challenge. Overall, this is a milestone achievement in the development of Ebola countermeasures. Cross-protection among the different Ebola and Marburg virus species is an important consideration, but is thought to be difficult to achieve due to relatively high genetic variability and the general lack of cross-protective antibodies among genera in particular, but also among species within a single genus. 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/MARVgp) 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 filovirus 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 in rodent models protection against ZEBOV and Andes virus (ANDV) or ZEBOV and influenza virus (H5N1) challenge was demonstrated using a single rVSV vector expressing both the ZEBOVgp and the ANDV glycoprotein or ZEBOVgp and a H5 hemagglutinin, respectively. This data showed that the use of bivalent rVSV vectors are a feasible approach to vaccination against multiple pathogens. Based on the results described above, we have over the past two fiscal year successfully generated additional 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 glycoproteins that will be secreted during vector replication. Recovery of these recombinant vaccine viruses turned out to be difficult but has recently been successful. In vitro characterization of these vectors, including viral growth curves and verification of foreign immunogen expression has been completed. Efficacy testing in the Ebola and Marburg hamster models has resulted in promising results; nonhuman primate studies are scheduled.

我们的主要疫苗平台是基于重组水泡性口炎病毒（rVSV），一种减毒活疫苗方法。多年来，我们已经产生了几种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），Tai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（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和安哥拉。所有疫苗载体均已在细胞培养中进行了广泛表征，并已在动物模型（啮齿动物、非人灵长类动物）中评估了其针对同源攻击的保护效力。为了解释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，对外来免疫原具有特异性的抗体在保护中起着关键作用。最近的类似工作也证实了抗体对rVSV疫苗载体介导的针对MARV的保护机制的作用。总体而言，我们假设抗体（总IgG和中和IgG）在所有基于rVSV的候选疫苗的保护机制中发挥关键作用。 为了应对西非最近的埃博拉疫情，rVSV/ZEBOVgp候选疫苗被快速追踪，并显示在人类中是安全和免疫原性的。在几内亚、塞拉利昂和利比里亚启动了该候选疫苗的III期临床试验。为了支持临床试验，我们已经证明，在西非使用的GMP生产的rVSV/ZEBOVgp疫苗批次可以抵抗最近的当地分离株的攻击，这是试验开始时缺失的证据。最近发表在Lancet上的来自几内亚人体试验的初步报告报道了rVSV/ZEBOVgp疫苗在环接种方法中的成功。这一显著的结果得到了我们小组最近在非人类灵长类动物中进行的另一项研究的支持，该研究旨在研究保护所需的最短时间。我们可以证明，当rVSV/ZEBOVgp给药至少一周时，具有完全保护作用，而当在攻击前三天给药时，具有部分保护作用。总的来说，这是制定埃博拉对策方面的一个里程碑式的成就。 不同埃博拉病毒和马尔堡病毒物种之间的交叉保护是一个重要的考虑因素，但由于相对高的遗传变异性和特别是在属之间以及在单个属内的物种之间普遍缺乏交叉保护抗体，因此认为难以实现。在解决这个问题的第一次尝试中，我们之前使用了三种混合疫苗载体（rVSV/SEBOVgp、rVSV/ZEBOVgp和rVSV/MARVgp）的单次注射方案，并证明了对三种同源病毒种的攻击的完全保护。我们还进行了另一项概念验证研究，其中我们评价了用单一疫苗载体（rVSV/ZEBOVgp或rVSV/CIEBOVgp）免疫后的交叉保护，并证明了对异源病毒种（BEBOV）攻击的部分交叉保护。这表明基于单价rVSV的疫苗可用于对抗新出现的丝状病毒物种;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。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物种的情况下提供部分交叉保护。 如上所述，克服这种限制的一种方法是使用混合的单价rVSV疫苗载体，其提供针对同源攻击的更广泛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。在啮齿动物模型中的概念验证研究中，使用分别表达ZEBOVgp和ANDV糖蛋白或ZEBOVgp和H5血凝素的单一rVSV载体证明了针对ZEBOV和安第斯山脉病毒（ANDV）或ZEBOV和流感病毒（H5 N1）攻击的保护。该数据表明，使用二价rVSV载体是针对多种病原体进行疫苗接种的可行方法。 基于上述结果，我们在过去的两个财政年度中成功地产生了表达两种或三种不同丝状病毒GP的额外的二价和三价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糖蛋白，其将在载体复制期间分泌。这些重组疫苗病毒的回收原来是困难的，但最近已经成功。已经完成了这些载体的体外表征，包括病毒生长曲线和外源免疫原表达的验证。在埃博拉和马尔堡仓鼠模型中进行的功效测试已经产生了有希望的结果;非人类灵长类动物研究正在计划中。