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 和 Angola。所有疫苗载体均已在细胞培养物中进行了广泛表征，并在动物模型（啮齿动物、非人灵长类动物）中针对同源攻击评估了其保护功效。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，针对外源免疫原的特异性抗体在保护中发挥着关键作用。最近的类似工作也证实了抗体在 rVSV 疫苗载体针对 MARV 介导的保护机制中的作用。总体而言，我们假设抗体（总 IgG 和中和 IgG）对于所有基于 rVSV 的候选疫苗的保护机制发挥着关键作用。 为了应对最近在西非爆发的埃博拉疫情，rVSV/ZEBOVgp 候选疫苗得到了快速跟踪，并被证明对人类安全且具有免疫原性。该候选疫苗的 III 期临床试验已在几内亚、塞拉利昂和利比里亚启动。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 疫苗批次可以防止最近当地分离株的攻击，这一证据在试验开始时缺失。最近发表在《柳叶刀》上的一份关于几内亚人体试验的初步报告报告了 rVSV/ZEBOVgp 疫苗在环形疫苗接种方法中的成功。这一显着的结果得到了我们小组最近对非人类灵长类动物进行的另一项研究的支持，该研究探讨了保护所需的最短时间。当 rVSV/ZEBOVgp 施用至少一周时，我们可以证明完全保护，而当攻击前三天施用时，我们可以证明部分保护。总体而言，这是制定埃博拉对策的里程碑式成就。 埃博拉病毒和马尔堡病毒不同物种之间的交叉保护是一个重要的考虑因素，但由于遗传变异性相对较高，而且普遍缺乏交叉保护抗体，特别是属之间，而且同一物种内的物种之间，因此很难实现。单属。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，并证明了针对三种同源病毒种类攻击的完全保护。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，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。在一项啮齿动物模型概念验证研究中，使用表达ZEBOVgp和ANDV糖蛋白或表达ZEBOVgp和H5血凝素的单一rVSV载体证明了针对ZEBOV和安第斯病毒（ANDV）或ZEBOV和流感病毒（H5N1）攻击的保护作用， 分别。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年成功地产生了额外的二价和三价 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糖蛋白，将在载体复制过程中分泌。事实证明，回收这些重组疫苗病毒很困难，但最近取得了成功。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已经完成。埃博拉和马尔堡仓鼠模型的功效测试取得了有希望的结果；非人类灵长类动物研究已安排。