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

基本信息

批准号：
10014207
负责人：
Heinrich Feldmann
金额：
$ 95.4万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/10014207
关键词：
Address Africa Africa South of the Sahara African Andes Virus Angola Animal Disease Models Animal Model Animals Antigens Attenuated Attenuated Live Virus Vaccine Case Fatality Rates Cavia Cell Culture Techniques Cells Clinical Trials Data Democratic Republic of the Congo Dendritic Cells Disease Disease Outbreaks E protein Ebola virus Emergency Situation Emerging Communicable Diseases Epidemic Family Family suidae Filovirus Frankfurt-Marburg Syndrome Virus Genetic Glycoproteins Hamsters Human Immune Immune response Immunization Immunize Influenza Hemagglutinin Injections Kyasanur Forest disease virus Lassa virus Livestock Modeling Mucins Nipah Virus Phase II Clinical Trials Phase III Clinical Trials Polysaccharides Protein Region Protocols documentation RNA Viruses Recombinants Reston Ebola virus Rodent Rodent Model Secondary Immunization Sudan Sudan Ebola virus Time Vaccination Vaccines Vesicular stomatitis Indiana virus Virus Wit Zaire Ebola virus Zika Virus base efficacy testing forest glycoprotein G human pathogen immunogenic macrophage monocyte nonhuman primate pathogen protective efficacy response tissue culture treatment strategy vaccin protein vaccine candidate vaccine efficacy vector vector vaccine vector-based vaccine

项目摘要

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, Zaire ebolavirus (EBOV), Ta Forest ebolavirus, Bundibugyo ebolavirus (BDBV) and Reston ebolavirus (RESTV). Additionally, we generated rVSVs expressing the GPs of two isolates of Marburg virus (MARV), Musoke and Angola. All vaccine vectors have been extensively characterized in cell culture and their protective efficacy has been evaluated at least in animal models (rodents, nonhuman primates) largely against homologous challenges. In response to the West African Ebola epidemic, rVSV-EBOV was fast-tracked and shown to be safe and immunogenic in humans. Human phase II and III clinical trials with rVSV-EBOV were initiated in West Africa. rVSV-EBOV is currently being used in the ongoing Ebola outbreak in the northeastern Democratic Republic of the Congo. (summarized in Suder et al. Hum Vaccin Immunother 2018). Cross-protection among the different filovirus species is an important consideration as endemicity zones may overlap in Sub-Saharan Africa. This, however, seems difficult to achieve due to relatively high genetic variability and therefore limited cross-protective immune responses among viruses of different species and genera. In a first attempt to address this issue, we previously used a single-injection protocol with three blended vaccine vectors and demonstrated complete protection against challenge with the three homologous virus species (Geisbert et al. J Virol 2009). We have also performed another proof-of-concept study, in which we evaluated cross-protection following immunization with a single vaccine vector (rVSV-EBOV) and demonstrated partial cross-protection against challenge with a heterologous virus species (BDBV) (Falzarano et al. J Infect Dis 2011). 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. This approach can be immediately implemented if needed. Another approach to overcome the limitations in cross-protection is the use of multivalent rVSV vaccine vectors. In a proof-of-concept study in hamsters protection against ZEBOV and Andes virus (ANDV) challenge was demonstrated using a single rVSV vector expressing both the ZEBOV GP and the ANDV glycoprotein (Tsuda et al. J Infect Dis 2011). This data showed that the use of bivalent rVSV vectors is a feasible approach to vaccination against multiple pathogens. EBOV GP provides targeting to important immune cells such as monocytes/macrophages and dendritic cells. Using this favorable targeting, we have generated further bivalent rVSV vaccines to proof the concept of immune enhancement through EBOV GP (Prescott et al., Vaccine 2015). We have developed rVSV-EBOV vectors expressing the Nipah virus glycoproteins (G and F) (de Buysscher et al Vaccine 2014; de wit et al., unpublished), the Zika virus preM and E proteins (Emanuel et al. Sci Rep 2018), the influenza hemagglutinin (H5) (Furuyama et al., in revision) and the preM and E proteins of Kyasanur Forest Disease virus (Bhatia et al., unpublished). In all cases we could demonstrate complete or nearly complete protection against homologous challenge in respective animal models. We postulate that vaccine vectors based on rVSV-EBOV will show enhanced protection due to favorable immune cell targeting. Following this concept, we recently have generated a rVSV-EBOV vector expressing the Lassa virus glycoprotein (GP); efficacy testing in animals is ongoing. To optimize the rVSV-EBOV vector for immune responses directed to a foreign antigen we have generated vectors carrying an EBOV GP deleted for its mucin-like domain as well as the mucin-like and glycan cap domains. These vectors will maintain the EBOV GP-driven cell targeting but are supposed to show reduced immune responses to EBOV GP as the main antigenic regions of the protein have been removed. We are currently characterizing and evaluating these new rVSV-EBOV vectors in tissue culture and animal models. Recently, we have evaluated rVSV-RESTV as a vaccine vector in a livestock species. Young Yorkshire cross pigs were immunized with a single shot of rVSV-RESTV 7 days prior to challenge. The vaccine provided 66% protection from disease in this new animal disease model. Further studies are planned to optimize vaccine administration to increase vaccine efficacy (Haddock et al., unpublished). Overall, this project has shown promise and should be continued as the rVSV approach has demonstrated efficacy for emergency vaccination. Vectors can be generated in a short period of time (1-2 months) and a vaccine product can be available in several months (6-9 months). Thus, this platform has potential for our response capabilities to counteract emerging infectious diseases.

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，我们已经产生了几种RVSV，这些RVSV表达了所有埃博氏菌的代表性分离株的糖蛋白（GP）：苏丹埃博拉病毒，Zaire Ebolavirus（EBOV），TA Forest Eybolavirus，Bundibugyo Ebolavirus（Bdbv）和Reston Ebolavirus（Reston Ebolavirus（Reston Ebolavirus）（Restv）（Restv）。此外，我们产生了表达两种Marburg病毒分离株（MARV），Musoke和Angola的GPS的RVSV。所有疫苗向量均在细胞培养中进行了广泛的特征，并且至少在动物模型（啮齿动物，非人类灵长类动物）中评估了它们的保护功效。为了应对西非埃博拉病毒的流行，RVSV-EBOV是快速跟踪的，并且在人类中证明是安全和免疫原性的。西非启动了RVSV-EBOV的人类II和III期临床试验。 RVSV-EBOV目前正在刚果东北民主共和国正在进行的埃博拉疫情中使用。（总结在Suder等人的HUM疫苗免疫2018中）。不同的丝状病毒物种之间的交叉保护是一个重要的考虑因素，因为撒哈拉以南非洲可能重叠。但是，由于遗传变异性相对较高，因此这似乎很难实现，因此在不同物种和属的病毒中有限的交叉保护免疫反应有限。在解决这个问题的首次尝试中，我们以前使用了一种与三个混合疫苗载体的单注射方案，并证明了针对三种同源病毒物种的挑战的完全保护（Geisbert等人，J Virol，2009年）。我们还进行了另一项概念验证研究，其中我们用单个疫苗载体（RVSV-EBOV）评估了交叉保护，并证明了针对异源性病毒物种（BDBV）（Falzarano et and of tagence挑战）的部分交叉保护。 Al。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。如果需要，可以立即实施此方法。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。在仓鼠概念证明的研究中，使用表达Zebov GP和ANDV糖蛋白的单个RVSV载体对Zebov和Andes病毒（ANDV）挑战进行了挑战（Tsuda等人Infect Dis 2011）。该数据表明，使用二价RVSV载体是一种对多种病原体疫苗接种的可行方法。 EBOV GP为重要的免疫细胞（例如单核细胞/巨噬细胞和树突状细胞）提供靶向。使用这种有利的靶向，我们已经生成了进一步的二价RVSV疫苗，以证明通过EBOV GP的免疫增强概念（Prescott等人，疫苗，2015年）。我们已经开发了表达NIPAH病毒糖蛋白（G和F）的RVSV-EBOV载体（De Buysscher等人疫苗2014； de Wit等，未发表），Zika病毒PERPER和E蛋白（Emanuel等人SCI REP 2018），流感hemagglutinin（H5）（Furuyama等人，在修订中）以及Kyasanur森林疾病病毒的PREM和E蛋白（Bhatia等人，未发表）。在所有情况下，我们都可以在各自的动物模型中证明完全或几乎完全保护对同源挑战。我们假设，由于有利的免疫细胞靶向，基于RVSV-EBOV的疫苗向量将显示出增强的保护。按照这个概念，我们最近产生了表达LASSA病毒糖蛋白（GP）的RVSV-EBOV载体。动物的功效测试正在进行中。为了优化针对异物抗原的免疫反应的RVSV-EBOV载体，我们已经生成了载有EBOV GP的载体，该载体用于其粘蛋白样结构域以及粘蛋白样和类似聚糖的帽域。这些向量将保持EBOV GP驱动的细胞靶向，但由于已去除蛋白质的主要抗原区域，因此应该显示出对EBOV GP的免疫反应降低。我们目前正在表征和评估组织培养和动物模型中这些新的RVSV-EBOV载体。最近，我们评估了RVSV-restv作为牲畜物种中的疫苗载体。在挑战前7天，Young Yorg Yorg Yorkshire Cross Pig用RVSV-Restv的一次镜头进行了免疫。在这种新的动物疾病模型中，该疫苗可提供66％的疾病保护。计划进一步研究以优化疫苗给药以提高疫苗功效（Haddock等，未发表）。总体而言，该项目已显示出希望，并且应该继续进行，因为RVSV方法已证明了紧急疫苗接种的功效。矢量可以在短时间内（1-2个月）生成，并且可以在几个月（6-9个月）内提供疫苗产品。因此，该平台具有我们应对新兴传染病的反应能力的潜力。