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.

尽管美洲的Zikv爆发已经消退，但在怀孕期间暴露于Zikv的母亲出生的婴儿出生的先天性Zika综合征的风险持续。没有许可的疫苗或治疗以对抗ZIKV感染。由于迫切需要进行ZIKV疫苗，并且在当前爆发中可以证明疗效的有限时间，因此我们专注于开发可以快速生产的DNA疫苗，并可以使用遗传技术轻松地修饰。第一代DNA疫苗基于西尼罗河病毒的先前成功。我们设计并评估了两种铅DNA疫苗候选物，它们在转染后产生亚病毒颗粒（SVP）。 第一个候选者（VRC5283）从2014年ZIKV French Polynesia菌株中表达PRM和E蛋白。 另一个（VRC5288）是一种ZIKV/JEV嵌合体病毒，其设计为最终的98个氨基酸（包括JEV的跨膜和茎结构域），该氨基酸已交换为ZIKV的相应区域，该区域已被证明是为了改善其他Flaviviviruses的SVP分泌。用这些构建体的免疫产生了小鼠和恒河猕猴的鲁棒中和抗体反应。 在寨卡病毒挑战后，两种表达寨卡病毒PRM和E蛋白的DNA疫苗候选者在18种恒河猕猴中保护了17个蛋白质。 该保护与血清中和活性相关。 单剂量的DNA疫苗并不能完全防止感染，但显着降低了寨卡病毒挑战猕猴的病毒血症水平。 随后，我们继续通过进行剂量推动研究来研究两种DNA疫苗，以确定保护的中和抗体阈值和保护的相关性。 此外，我们已经与多个组合作，以帮助开发替代性ZIKV疫苗，包括基于mRNA的疫苗和实时销售疫苗。 Nipah病毒（NIV）在动物水库中循环，并引起了印度和东南亚人类零星的爆发。 NIV通过呼吸道传播，但可以发展为高度致命的神经系统疾病。尽管G蛋白疫苗和相关Hendra病毒的MAB目前正在为NIPAH开发，但没有持牌疫苗或NIV治疗。 我们已经开始使用基于结构的设计来稳定融合蛋白的融合蛋白确认，以用作疫苗免疫原。 基于建立G抗体作为Hendra病毒保护的相关性，我们还开发了表达前F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mRNA平台中具有高度免疫原性，而表达这些抗原的mRNA疫苗目前正在雪貂挑战模型中进行评估，并朝着临床试验测试前进。我们正在采用相同的方法来开发用于其他帕托病毒（麻疹和腮腺炎）的基于亚基和基因的疫苗，并正在评估动物模型中的候选物。 肠病毒D68在小儿群体中引起双年性呼吸道疾病，并且与急性易脆性脊髓炎（AFM）的爆发有关。 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子基团VLP的免疫原性以及B3和A2子基种病毒的交叉中和化。我们将继续在免疫缺陷的AG129小鼠中开发挑战模型，以及小鼠适应B3和A2子基类病毒，以评估VLP引用的免疫反应的疗效。我们旨在运用该项目的知识来开发可用于针对相关肠病毒的疫苗的肠病毒疫苗平台。