Rapid Development of Vaccines for Emerging Viruses

新兴病毒疫苗的快速开发

• 批准号: 10497747
• 负责人: Barney Graham
• 金额: $ 160.49万
• 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/10497747
• 关键词: Acute; Americas; Amino Acids; Animal Model; Animals; Antibodies; Antibody Response; Antigens; Asia; Attenuated Vaccines; Childhood; Chimera organism; Chimeric Proteins; Clinical Trials; DNA Vaccines; Disease Outbreaks; Dose; E protein; Enterovirus; Enterovirus 68; Evaluation; Exposure to; Far East; Female of child bearing age; Ferrets; Flavivirus; French Polynesia; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Generations; Genes; Genetic Techniques; Goals; Hendra Virus; Human; Immune response; Immunization; Immunologics; India; Infection prevention; Knowledge; Lead; Macaca mulatta; Measles; Messenger RNA; Microcephaly; Modeling; Monoclonal Antibodies; Mothers; Mumps; Mus; Myelitis; Nipah Virus; Paramyxovirus; Population; Pregnancy; Proteins; RNA vaccine; Risk; Route; Serum; South America; Structural Protein; Structure; Testing; Time; Transfection; Vaccine Design; Vaccines; Viremia; Virus; West Nile virus; Work; ZIKA; ZIKV infection; Zika Virus; Zika virus vaccine; base; clinical development; combat; congenital infection; congenital zika syndrome; design; efficacy evaluation; immunogenic; immunogenicity; improved; nervous system disorder; neutralizing antibody; particle; respiratory; stem; success; vaccine candidate; vaccine development

While the outbreak of ZIKV in the Americas has subsided, there is an ongoing risk of congenital Zika syndrome in babies born to mothers exposed to ZIKV during pregnancy. There is no licensed vaccine or treatment to combat ZIKV infection. Because of the urgent need for a ZIKV vaccine, and a finite time in which efficacy could be demonstrated in the current outbreak, we focused on developing a DNA vaccine which can be rapidly produced and can easily modified using genetic techniques. The first generation DNA vaccines are based on prior success in West Nile Virus. We designed and evaluated two lead DNA vaccine candidates which produce subviral particles (SVP) after transfection. The first candidate (VRC5283) expresses the prM and E proteins from the ZIKV French Polynesia 2014 strain. The other (VRC5288) is a ZIKV/JEV chimera virus and was designed with the final 98 amino acids of (comprising the transmembrane and stem domains from JEV) swapped for the corresponding regions from ZIKV which has been demonstrated to improve SVP secretion for other flaviviruses. Immunization with these constructs generated robust neutralizing antibody responses in mice and rhesus macaques. Two doses of DNA vaccine candidates expressing the prM and E proteins of Zika virus protected 17 out of 18 rhesus macaques from viremia after Zika virus challenge. This protection was correlated with serum neutralizing activity. A single dose of DNA vaccine did not completely prevent infection, but significantly reduced the level of viremia in Zika virus challenged rhesus macaques. Subsequently, we have continued to study the two DNA vaccines by performing dose de-escalation studies to determine the neutralizing antibody threshold of protection, and correlates of protection. Additionally, we have collaborated with multiple groups to help develop alternative ZIKV vaccines, including mRNA-based and live-attenuated vaccines. Nipah Virus (NiV) circulates in animal reservoirs and has caused sporadic outbreaks in humans in India and South East Asia. NiV is transmitted by the respiratory route, but can develop into a highly fatal neurologic disease. There is no licensed vaccine or treatment for NiV, although a G protein vaccine, and mAb from the related Hendra virus are currently being developed for Nipah. We have begun to use structure-based design to stabilize the fusion protein in its prefusion confirmation to use as a vaccine immunogen. Based on the establishment of G antibodies as a correlate of protection for Hendra virus, we also developed oligomeric G protein vaccines and chimeric vaccine that expresses the Pre-F and G protein. These vaccines are highly immunogenic in the protein and mRNA platforms and mRNA vaccines expressing these antigens are currently being evaluated in a ferret challenge model and advancing toward clinical trial testing. We are taking the same approach to develop subunit and gene-based vaccines for other paramyxoviruses (measles and mumps), and are evaluating candidates in animal models. Enterovirus D68 causes biannual respiratory illnesses in pediatric populations, and has been temporally related to outbreaks of acute flacid myelitis (AFM). We have begun efforts to develop a VLP vaccine that expresses the structural proteins of EV-D68. We have demonstrated immunogenicity of B1 subclade VLP and cross-neutralization of B3 and A2 subclade viruses. We are continuing to develop challenge models in immunodeficient AG129 mice, and mouse adapting B3 and A2 subclade viruses to evaluate the efficacy of VLP-elicited immune responses. We aim to apply the knowledge from this project to develop an enterovirus vaccine platform that can be used for vaccines against related enteroviruses.

虽然美洲寨卡病毒的暴发已经平息，但孕期接触寨卡病毒的母亲所生婴儿仍有患先天性寨卡综合征的风险。目前还没有获得许可的疫苗或治疗方法来对抗寨卡病毒感染。由于对ZIKV疫苗的迫切需求，以及在当前疫情中能够展示效力的有限时间，我们专注于开发一种可以快速生产并可以很容易地利用基因技术进行修饰的DNA疫苗。第一代DNA疫苗是基于先前在西尼罗河病毒上取得的成功。我们设计并评价了两种主要的DNA疫苗候选疫苗，它们在转染后产生亚病毒颗粒(SVP)。第一个候选(VRC5283)表达来自ZIKV法属波利尼西亚2014株的PrM和E蛋白。另一株(VRC5288)是一种ZIKV/JEV嵌合体病毒，其最终98个氨基酸(包括JEV的跨膜和茎结构域)与ZIKV的相应区域互换，这已被证明可以改善其他黄病毒的SVP分泌。用这些构建物免疫小鼠和恒河猴产生了强大的中和抗体反应。在寨卡病毒攻击后，表达寨卡病毒PrM和E蛋白的两剂候选DNA疫苗保护了18只恒河猴中的17只免受病毒血症的影响。这种保护作用与血清中和活性有关。单剂DNA疫苗不能完全预防感染，但显著降低了寨卡病毒挑战恒河猴的病毒血症水平。随后，我们继续研究这两种DNA疫苗，进行剂量降级研究，以确定保护的中和抗体阈值，以及保护的相关性。此外，我们还与多个小组合作，帮助开发替代ZIKV疫苗，包括基于mRNA的疫苗和减毒活疫苗。 尼帕病毒(Nipah Virus，NIV)在动物宿主中传播，并已在印度和东南亚的人类中造成零星疫情。新城疫通过呼吸道传播，但可发展为一种高度致命的神经系统疾病。目前还没有获得许可的新城疫疫苗或治疗方法，尽管目前正在为新城疫开发G蛋白疫苗和相关Hendra病毒的单抗。我们已经开始使用基于结构的设计来稳定融合蛋白，在其灌流确认后用作疫苗免疫原。在建立了与Hendra病毒保护相关的G抗体的基础上，我们还研制了表达前F蛋白和G蛋白的寡聚G蛋白疫苗和嵌合疫苗。这些疫苗在蛋白质和信使核糖核酸平台上具有高度的免疫原性，表达这些抗原的信使核糖核酸疫苗目前正在雪貂挑战模型中进行评估，并进入临床试验测试。我们正在采取同样的方法来开发针对其他副粘病毒(麻疹和腮腺炎)的亚单位和基于基因的疫苗，并正在动物模型中评估候选疫苗。 肠道病毒D68每年在儿童人群中引起两年一次的呼吸系统疾病，并与急性氟化性脊髓炎(AFM)的爆发暂时相关。我们已经开始努力开发一种表达EV-D68结构蛋白的VLP疫苗。我们已经证明了B1亚型VLP的免疫原性以及B3和A2亚型病毒的交叉中和作用。我们正在继续开发免疫缺陷AG129小鼠的挑战模型，并使小鼠适应B3和A2亚型病毒，以评估VLP诱导的免疫反应的有效性。我们的目标是应用这个项目的知识来开发一个可以用于相关肠道病毒疫苗的肠道病毒疫苗平台。