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: 9566740
• 负责人: Heinrich Feldmann
• 金额: $ 15.35万
• 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/9566740
• 关键词: Achievement; Address; Africa; African; Andes Virus; Angola; Animal Model; Antibodies; Antigens; Area; 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; Hamsters; Human; Immune response; Immunization; Immunoglobulin G; In Vitro; Individual; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Injection of therapeutic agent; Integral Membrane Protein; Liberia; Mediating; Modeling; Mono-S; Mus; National Institute of Allergy and Infectious Disease; Outcome; Phase III Clinical Trials; Play; Process; Protocols documentation; Publishing; RNA Viruses; Recombinants; Recovery; Reporting; Reston; Rodent; Rodent Model; Role; Schedule; Secondary Immunization; Sierra Leone; Sudan; Time; United States National Institutes of Health; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral; Virus; Work; Zika Virus; Zika virus vaccine; animal rule; base; efficacy testing; forest; immunogenic; nonhuman primate; pathogen; protective efficacy; recombinant virus vaccine; response; success; treatment strategy; vaccine candidate; vaccine trial; 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 ebolavirus species: Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Ta forest ebolavirus (TFEBOV), Bundibugyo ebolavirus (BEBOV) and Reston ebolavirus (REBOV). Additionally, we generated rVSVs expressing the GPs of two isolates of MARV, 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-ZEBOV 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-ZEBOV 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-ZEBOV vaccine lot used in West Africa protects against challenge with a recent local isolate, a proof that had been missing at trial start. A first preliminary report published in Lancet from the human trial in Guinea reports success of the rVSV-ZEBOV 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-ZEBOV 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 virus countermeasures. Cross-protection among the different Ebolavirus species and Marburgvirus 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-SEBOV, rVSV-ZEBOV and rVSV-MARV) 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-TFEBOV) 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) challenge was demonstrated using a single rVSV vector expressing both the ZEBOV GP and the ANDV glycoprotein. This data showed that the use of bivalent rVSV vectors are a feasible approach to vaccination against multiple pathogens. Therefore, we have developed a single vector expressing ZEBOV GP and influenza H5 hemaglutinin and are in the process of evaluating the protective efficacy against lethal H5N1 challenge. Additionally, we are also working towards rVSV-ZEBOV-based Zika virus (ZIKV) vaccine as both pathogens share overlapping endemic areas in Africa. In a fist study this vaccine was even further attenuated compared to rVSV-ZEBOV and protected mice from lethal ZIKV challenge. We are currently evaluating if this vaccine is still protective against ZEBOV infection. Based on the results described above, we have over the past fiscal years successfully generated additional bivalent and trivalent rVSV vectors expressing two or three different antigens, one as a transmembrane protein (replacing the VSV glycoprotein) and one or two as soluble antigens 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 antigen expression has been completed. Efficacy testing in the appropriate rodent 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，我们已经产生了表达所有埃博拉病毒物种代表性分离株的糖蛋白（GP）的几种rVSV：苏丹埃博拉病毒（SEBOV）、扎伊尔埃博拉病毒（ZEBOV）、塔森林埃博拉病毒（TFEBOV）、本迪布焦埃博拉病毒（BEBOV）和雷斯顿埃博拉病毒（雷博夫）。此外，我们还生成了表达 MARV 两种分离株（Musoke 和 Angola）GP 的 rVSV。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-ZEBOV 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-ZEBOV 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-ZEBOV 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。 《柳叶刀》上发表的第一份关于几内亚人体试验的初步报告报告了 rVSV-ZEBOV 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-ZEBOV 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，这是埃博拉病毒对策发展的里程碑式成就。 不同埃博拉病毒物种和马尔堡病毒之间的交叉保护是一个重要的考虑因素，但由于相对较高的遗传变异性和普遍缺乏交叉保护抗体，特别是在属之间，而且在单一物种内的物种之间，被认为很难实现属。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-SEBOV、rVSV-ZEBOV 和 rVSV-MARV）的单次注射方案，并证明了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-TFEBOV）免疫后的交叉保护，并证明了针对异源病毒种类（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。在啮齿动物模型的概念验证研究中，使用表达 ZEBOV GP 和 ANDV 糖蛋白的单一 rVSV 载体证明了对 ZEBOV 和安第斯病毒 (ANDV) 攻击的保护作用。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。因此，我们开发了一种表达ZEBOV GP和流感H5血凝素的单一载体，并且正在评估针对致命性H5N1攻击的保护功效。此外，我们还致力于开发基于 rVSV-ZEBOV 的寨卡病毒 (ZIKV) 疫苗，因为这两种病原体在非洲都有重叠的流行区。在第一项研究中，与 rVSV-ZEBOV 相比，这种疫苗的毒性甚至进一步减弱，并保护小鼠免受致命的 ZIKV 攻击。我们目前正在评估该疫苗是否仍能预防ZEBOV 感染。 基于上述结果，我们在过去的财政年度中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抗原，一种作为跨膜蛋白（取代 VSV 糖蛋白），另一种或两种作为可溶性抗原，将被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抗原表达的验证已经完成。在适当的啮齿动物模型中进行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。