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: 8076663
• 负责人: RICHARD W COMPANS
• 金额: $ 96.61万
• 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/8076663
• 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. Public Health Relevance: Filoviruses are etiologic agents that cause highly lethal hemorrhagic fevers and can be transmitted via person-to-person contact, thus posing a high threat to public health. We have recently demonstrated the combined benefit of two non-viral-vector based vaccine platforms and its potential for the development of an efficacious vaccine against EBOV infection. In this project we will further develop the novel DNA/VLP vaccine strategy for eliciting strong cellular and antibody responses against EBOV infection and develop a new vaccine delivery technology to further augment induction of such responses.

描述（由申请人提供）：该项目的重点是开发一种有效的丝状病毒感染疫苗，丝状病毒是高致死性出血热的病原体，可以通过人与人之间的接触传播，因此对流行病爆发构成高度威胁。我们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具有高VLP产量，表现出DC刺激活性并诱导强烈的抗体反应，从而中和EBOV GP介导的病毒感染，表明此类VLP可能是安全有效的疫苗，可诱导针对EBOV感染的保护性免疫。我们还发现，与单独使用任何一种疫苗相比，使用 DNA 和 VLP 疫苗（DNA/VLP）混合疫苗进行免疫可诱导更高水平的抗体和细胞免疫反应。我们假设新型DNA/VLP疫苗将引发针对丝状病毒感染的强烈细胞和抗体反应，并且采用新的疫苗递送技术将进一步增强这种反应的诱导，目的是获得一种能够针对丝状病毒感染提供快速且持久的保护的疫苗策略。具体目标 1. 提高 DNA 和 VLP 疫苗的免疫原性，以引发针对泛丝状病毒感染的更有效和持久的保护性免疫。我们将探索修改丝状病毒 DNA 和 VLP 疫苗的不同策略，以增强其诱导抗体和 T 细胞反应的免疫原性及其产量，并将确定有助于实现针对丝状病毒感染的长期保护且至关重要的免疫反应。具体目标 2. 评估用于丝状病毒疫苗递送的微针 (MN) 技术。我们将开发将丝状病毒DNA和VLP疫苗封装到生物可吸收MN中的技术，研究封装疫苗的生物学特性、稳定性和免疫原性，并研究不同的几何设计和化学配方，以进一步改进MN疫苗递送技术，以实现更高效和可重复的疫苗封装，并提高疫苗稳定性。具体目标 3. 比较不同疫苗方法的保护功效，并确定预防丝状病毒感染的免疫相关性。我们将比较使用传统肌肉注射和新型 MN 疫苗递送技术的不同疫苗配方诱导的免疫反应，并评估它们在小型实验动物模型和非人灵长类动物中对致命丝状病毒攻击的保护功效，并将确定免疫反应的相关性，这对于实现针对丝状病毒感染的持久保护非常重要。结果将为 GMP 生产和人体试验选择最有效的候选疫苗策略奠定基础。这种疫苗策略的成功开发也可以很容易地应用于针对仍缺乏有效疫苗的其他病毒性出血热的疫苗。 公共卫生相关性：丝状病毒是引起高度致命的出血热的病原体，可以通过人与人之间的接触传播，从而对公众健康构成高度威胁。我们最近展示了两种基于非病毒载体的疫苗平台的综合优势及其开发针对埃博拉病毒感染的有效疫苗的潜力。在这个项目中，我们将进一步开发新型 DNA/VLP 疫苗策略，以引发针对 EBOV 感染的强烈细胞和抗体反应，并开发一种新的疫苗递送技术，以进一步增强此类反应的诱导。