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疱性口炎病毒（rvss），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）和莱斯顿埃博拉病毒（REBOV）。此外，我们生成了表达两种马尔堡病毒分离株gp的rvsv：维多利亚湖马尔堡病毒分离株Musoke和安哥拉。所有疫苗载体已在细胞培养中进行了广泛的表征，并在动物模型（啮齿动物、非人灵长类动物）中评估了其对同源攻击的保护功效。为了破译rVSV疫苗载体的保护机制，我们使用rVSV/ZEBOVgp作为模型。我们可以在非人灵长类动物中证明，针对外来免疫原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在rVSV疫苗载体介导的针对MARV的保护机制中的作用。总之，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起关键作用。