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囊泡性口腔炎病毒（RVSV），这是一种活鉴定疫苗方法。多年来，我们已经生成了几种RVSV，这些RVSV表达了所有埃博拉病毒的代表性分离物的糖蛋白（GP）：苏丹埃博拉病毒（Sebov），Zaire Ebolavirus（Zebov），Tai Forest Ebolavirus（Tfebov），Bundibugyo Ebolavirus（Bundibugyo Ebolavirus）（budbolavirus）（Bebovirus）（bbolavirus）和埃博夫（Ebbolav）和埃博夫（Ebborirus）和RESON RESON（RESON）和RESON（RESON）（RESON）。此外，我们产生了表达两个马尔堡病毒分离株的GPS的RVSV：维多利亚湖Marburgvirus孤立的Musoke和Angola。所有疫苗向量均已在细胞培养中进行了广泛的特征，并且在动物模型（啮齿动物，非人类灵长类动物）中针对同源挑战进行了保护效果。为了破译RVSV疫苗向量的保护机理，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国免疫原具有特异性的抗体在保护中起着至关重要的作用。最近的类似工作还证实了抗体在RVSV疫苗载体针对MARV介导的保护机理中的作用。总体而言，我们假设抗体（总和中和IgG）对于所有基于RVSV的疫苗候选物的保护机理起着关键作用。 为了应对西非最近发生的埃博拉病毒爆发，RVSV/Zebovgp疫苗候选者被快速跟踪，并在人类中证明是安全且具有免疫原性的。在几内亚，塞拉利昂和利比里亚开始了使用该疫苗的III期临床试验。为了支持临床试验，我们已经表明，在西非使用的GMP生产的RVSV/Zebovgp疫苗批次可以通过最近的局部分离物来防止挑战，这一证明是在试验开始时缺少的。几内亚人类试验中发表在柳叶刀上的一份初步报告报告了RVSV/Zebovgp疫苗在环疫苗接种方法中的成功。这一显着的结果得到了我们小组在非人类灵长类动物中的另一项研究的支持，以研究保护所需的最低时间。当RVSV/ZebovGP至少一周和部分保护时，我们可以在挑战前三天接近时进行部分保护时，可以证明完全保护。总体而言，这是埃博拉对抗发展的里程碑成就。 不同的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，但由于遗传变异性相对较高，并且尤其是属之间的跨保护抗体，因此被认为难以实现，而在单一属中也很难实现。在解决此问题的首次尝试中，我们以前使用了三种混合疫苗向量（RVSV/SEBOVGP，RVSV/ZEBOVGP和RVSV/MARVGP）的单一注射方案，并显示出对三种同源病毒物种的挑战完全保护。我们还进行了另一项概念验证研究，在该研究中，我们评估了与单个疫苗载体（RVSV/ZeboVGP或RVSV/CIEBOVGP）免疫后进行的交叉保护，并通过异型病毒物种（Bebov）表现出对挑战的部分交叉保护。这表明基于RVSV的单价疫苗可能对新出现的丝状病毒物种有用。但是，跨物种的异源保护仍然具有挑战性，可能取决于通过增强免疫或包含多种免疫原子来增强免疫反应。总体而言，我们可以得出结论，单一单价RVSV疫苗向量可以在遗传上更紧密相关的挑战病毒物种的情况下提供部分交叉保护。 如上所述，一种克服该限制的方法是使用混合单价RVSV疫苗向量，该疫苗向量提供了更广泛的保护，以防止对某些异源挑战的同源和部分保护。克服交叉保护局限性的另一种方法是使用多价RVSV疫苗向量。在一项针对针对Zebov和Andes病毒（ANDV）或Zebov和Zebov和流感病毒（H5N1）挑战的啮齿动物模型保护的概念验证研究中，使用单个RVSV矢量表达ZebovGP和ANDV Glycoprotein或ZebovgP或ZebovgP和H5 Hymagglutinin clastection。该数据表明，使用二价RVSV载体是对多种病原体疫苗接种的可行方法。 根据上述结果，在过去的两个会计年度中，我们成功地产生了表达两种或三种不同的Filevirus GPS的其他二价和三价RVSV矢量，一种是跨膜蛋白（更换VSV糖蛋白），将其作为可溶性糖蛋白作为可溶性的糖蛋白，作为可溶性的糖蛋白，这些蛋白将在矢量重复中分泌。这些重组疫苗病毒的恢复很困难，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。埃博拉病毒和马堡仓鼠模型中的功效测试导致了令人鼓舞的结果。计划进行非人类灵长类研究。