A dual vaccine strategy against filovirus infection

针对丝状病毒感染的双重疫苗策略

• 批准号: 8463750
• 负责人: RICHARD W COMPANS
• 金额: $ 94.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463750
• 关键词: Amino Acid Sequence; Animal Model; Antibodies; Antibody Formation; Arenavirus; Baculovirus Expression System; Biological; Biomedical Research; Bioterrorism; Cells; Cessation of life; Chemicals; Coma; DNA; Development; Disease; Disease Outbreaks; Drug Formulations; Ebola virus envelope glycoprotein; Employment; Encapsulated; Epidemic; Exhibits; Family; Feedback; Fever; Filoviridae; Filovirus; Flavivirus; Foundations; Future; Glycoproteins; Hemorrhage; Human; Immune; Immune response; Immunity; Immunization; Individual; Infection; Insecta; Institutes; Intramuscular Injections; Investigation; Laboratory Animal Models; Mediating; Muscle Fatigue; Myalgia; Non-Viral Vector; Orthobunyavirus; Outcome; Persons; Production; Property; Public Health; Recombinants; Research Personnel; Seizures; Severity of illness; Shock; Symptoms; T cell response; Technology; Temperature; Universities; Vaccine Design; Vaccines; Viral Hemorrhagic Fevers; Virus; Virus Diseases; base; cost effective; design; effective therapy; immunogenicity; improved; influenza virus vaccine; member; mortality; nonhuman primate; novel; novel vaccines; protective efficacy; public health relevance; response; technology development; transmission process; vaccine candidate; vaccine delivery; vaccine development; vector-based vaccine

DESCRIPTION (provided by applicant): This project focuses on development of an effective vaccine for filovirus infection, which is an etiologic agent of highly lethal hemorrhagic fever and can be transmitted via person-to-person contact, thus posing a high threat of an epidemic outbreak. We have studied the development of VLP vaccines against virus infection, and have shown that EBOV VLPs produced in insect cells using the recombinant baculovirus expression system, which gives high VLP production yield, exhibit DC-stimulating activity and induce strong antibody responses that neutralize EBOV GP mediated virus infection, indicating that such VLPs could be safe and effective vaccines to induce protective immunity against EBOV infection. We also found that immunization with a mixture of DNA and VLP vaccines (DNA/VLP) induced higher levels of both antibody and cellular immune responses in comparison to immunization with either alone. We hypothesize that the novel DNA/VLP vaccine will elicit strong cellular and antibody responses against filovirus infection and that the employment of a new vaccine delivery technology will further augment induction of such responses, with the aim to obtain a vaccine strategy that can confer rapid and long lasting protection against filovirus infection. Specific Aim 1. To improve the immunogenicity of DNA and VLP vaccines for eliciting more potent and durable protective immunity against pan-filovirus infection. We will explore different strategies to modify filovirus DNA and VLP vaccines to enhance their immunogenicity for inducing both antibody and T cell responses as well as their production yield and will determine the immune responses that contribute to and are critical for achieving long lasting protection against filovirus infection. Specific Aim 2. To evaluate the microneedle (MN) technology for filovirus vaccine delivery. We will develop the technology to encapsulate filovirus DNA and VLP vaccines into bio-absorbable MNs and investigate the biological property, stability, and immunogenicity of encapsulated vaccines and investigate different geometrical designs and chemical formulations to further improve the MN vaccine delivery technology for achieving more efficient and reproducible vaccine encapsulation, and improved vaccine stability. Specific Aim 3. To compare the protective efficacy of different vaccine approaches and determine the immune correlates for protection against filovirus infection. We will compare immune responses induced by different vaccine formulations using both conventional intramuscular injection as well as the novel MN vaccine delivery technology and evaluate their protective efficacy against lethal filovirus challenge in small laboratory animal models as well as non-human primates and will determine the correlates of immune responses that are important for achieving long lasting protection against filovirus infection. The results will set the foundation for selection of the most effective candidate vaccine strategy for GMP production and human trials. The successful development of this vaccine strategy may also be readily applied to vaccines against other viral hemorrhagic fevers which still lack effective vaccines.

描述（由申请人提供）：该项目的重点是开发用于丝状病毒感染的有效疫苗，该疫苗是高度致命的出血热的病因学药，可以通过人与人之间的接触来传播，从而对流行病爆发构成高威胁。我们已经研究了针对病毒感染的VLP疫苗的开发，并表明使用重组杆状病毒表达系统在昆虫细胞中产生的EBOV VLP，从而产生高VLP产生的产量，表现出DC刺激活性并诱导EBOV GP GP GP介导的eBIDIAD INCTICTION的强大抗体反应，表明对VICTICT进行了侵害，表明对VITPS进行了侵害，并有助于施加过度，并有助于触发过度，并有助于造成效果。我们还发现，与单独使用任何一种单独免疫相比，与DNA和VLP疫苗（DNA/VLP）的混合物免疫可诱导较高水平的抗体和细胞免疫反应。我们假设新型DNA/VLP疫苗将引起针对丝病毒感染的强细胞和抗体反应，并且使用新的疫苗输送技术将进一步增强此类反应的诱导，以获得疫苗策略，以获取可以快速且持久的针对FILOVIRECTICT的疫苗策略。具体目的1。提高DNA和VLP疫苗的免疫原性，以引起对泛 - 细胞病毒感染的更有效和耐用的保护性免疫。我们将探索不同的策略，以修改丝状病毒DNA和VLP疫苗，以增强其免疫原性，以诱导抗体和T细胞反应以及其生产率，并确定对实现持久的持续保护侵害FILOVIRUS感染的免疫反应，并至关重要。具体目的2。评估用于丝状病毒疫苗的微针（MN）技术。我们将开发该技术，以将丝状病毒DNA和VLP疫苗封装到可吸收的MN中，并研究包裹疫苗的生物学特性，稳定性和免疫原性，并研究不同的几何设计和化学配方，以进一步提高MN疫苗的递送技术，以提高有效的疫苗和改善疫苗，并改善了疫苗，并改善了疫苗。具体目的3。比较不同疫苗方法的保护效果，并确定免疫相关性以防止丝状病毒感染。我们将使用常规的肌内注射以及新型的MN疫苗输送技术来比较不同的疫苗配方诱导的免疫反应，并评估其针对小型实验室动物模型以及非人类灵长类动物的致命性丝状病毒挑战的保护性疗效，并将确定对终于可以抗衡的免疫反应的重要反应，并确定对终于终止的保护的相关性。结果将为选择GMP生产和人类试验的最有效候选疫苗策略奠定基础。该疫苗策略的成功开发也很容易地用于针对仍然缺乏有效疫苗的其他病毒出血狂热的疫苗。