Human Coronaviruses as Multigene Mucosal Vaccine Vectors for HIV

人类冠状病毒作为艾滋病毒多基因粘膜疫苗载体

• 批准号: 7629736
• 负责人: AMY C SIMS
• 金额: $ 19.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629736
• 关键词: Address; Animals; Antigens; Attenuated; Attenuated Live Virus Vaccine; CD4 Lymphocyte Count; Capsid; Cell Culture Techniques; Clinical; Common Cold; Communicable Diseases; Complementary DNA; Coronavirus; Development; Disease Progression; Elements; Engineering; Evaluation; Foundations; Gagging; Gene Expression; Genes; Genetic Recombination; Genetic Transcription; Genome; HIV; HIV Antigens; HIV vaccine; HIV-1; HIV-1 vaccine; Heterophile Antigens; Human Coronavirus OC43; Immune response; Immunity; In Vitro; Length; Life; Macaca; Measures; Methods; Modeling; Molecular; Monitor; Mucosal Immune Responses; Mucous Membrane; Mus; Nature; Pathology; Peripheral; Phase; Pilot Projects; RNA; Reporter Genes; Resistance; SIV; Safety; Series; Site; Surface; System; Upper Respiratory Infections; Vaccinated; Vaccine Design; Vaccines; Vertebral column; Viral; Viral Antigens; Viral Load result; Virus; Virus Replication; Virus Shedding; brain tissue; cost; expression vector; gag Gene Products; human coronavirus; human coronavirus spike glycoprotein; immunogenicity; in vivo; inflammatory marker; innovation; meetings; mucosal site; mucosal vaccine; neurovirulence; neutralizing antibody; positional cloning; public health relevance; research study; transmission process; vaccine development; vaccine efficacy; vector; vector genome; vector vaccine; vector-based vaccine; viral RNA

DESCRIPTION (provided by applicant): An effective HIV-1 vaccine approach not only will need to induce broadly reactive neutralizing antibody and cellular immune responses at systemic and mucosal sites, but the vaccine also will have to be feasible for distribution to parts of the world that need it most in terms of safety, manufacturing cost, number of inoculations, and ease of administration. The common cold human coronavirus (HCoV) OC43 is attractive as a vaccine vector for HIV, and recent breakthroughs in coronavirus reverse genetics have now made it feasible for their exploitation as vaccine vectors. Coronavirus genomes are the largest RNA genomes in nature (~30kb), and contain multiple genes that are not essential for viral replication, theoretically allowing the insertion of multiple heterologous genes into a single virus with a packaging capacity much larger than most other vector systems. Because HCoV OC43 causes only a mild upper respiratory tract infection, it is anticipated to be relatively safe as a vaccine vector, allowing for replication competent viruses to be used to present heterologous antigen at mucosal surfaces for multiple rounds of vector replication, much like a live attenuated vaccine. Coronavirus genomes also can be engineered such that recombination with naturally circulating strains yields a dead virus. We recently completed the development of a reverse genetics system for HCoV OC43, which now makes it technically feasible to develop a HCoV OC43-based vaccine vector. In this phased innovation R21/R33 project we propose to engineer the HCoV OC43 genome as a multiple heterologous gene expression vector for SIV, which we will assess using the SIVsmE660/macaque model. In the R21 proof-of-concept phase we will: (i) engineer HCoV OC43 to express the SIVsmH4 matrix/capsid (MA/CA) gene from different regions of the vector genome, and (ii) evaluate the systemic, mucosal, and cellular immunogenicity of MA/CA-expressing HCoV OC43 vectors in mice. In the R33 phase we will: (i) characterize infectivity of HCoV OC43 in macaques, (ii) engineer and validate a recombination-resistant HCoV OC43 construct to express up to four SIVsmH4 proteins-Gag, Env, Nef and Vif, and (iii) vaccinate macaques with the multigene HCoV OC43 vector and assess vaccine efficacy by mucosal challenge with SIVsm E660. This project will provide the first critical evaluation of the potential use of common cold human coronaviruses as live mucosal vaccine vectors for HIV. PUBLIC HEALTH RELEVANCE: In the proposed study we will develop human coronaviruses, which cause about one- third of all common colds, as vaccine vectors to deliver HIV antigens. There are several potential attractive features of coronavirus vectors as vaccines for HIV, such as safety, simplicity in manufacturing, the ability to induce immune responses in sites of HIV transmission, and the ability to induce immune responses with a limited number of inoculations. We will evaluate the potential use of coronaviruses as HIV vaccine vectors using the SIV/macaque model.

描述（由申请人提供）：有效的HIV-1疫苗方法不仅需要在全身和粘膜部位诱导广泛反应性中和抗体和细胞免疫应答，而且疫苗还必须在安全性、生产成本、接种次数和易于接种方面能够分发到世界上最需要它的地区。普通感冒人类冠状病毒（HCoV）OC 43作为HIV的疫苗载体是有吸引力的，并且冠状病毒反向遗传学的最新突破现在使其作为疫苗载体的开发成为可能。冠状病毒基因组是自然界中最大的RNA基因组（约30 kb），包含多个对病毒复制不必要的基因，理论上允许将多个异源基因插入单个病毒中，其包装容量比大多数其他载体系统大得多。由于HCoV OC 43仅引起轻度上呼吸道感染，因此预期其作为疫苗载体是相对安全的，允许复制能力病毒用于在粘膜表面呈递异源抗原以进行多轮载体复制，非常像活减毒疫苗。冠状病毒基因组也可以被改造，使得与自然传播的毒株重组产生死病毒。我们最近完成了HCoV OC 43的反向遗传学系统的开发，这使得开发基于HCoV OC 43的疫苗载体在技术上是可行的。在这个分阶段的创新R21/R33项目中，我们建议将HCoV OC 43基因组作为SIV的多异源基因表达载体，我们将使用SIVsmE 660/猕猴模型进行评估。在R21概念验证阶段，我们将：（i）改造HCoV OC 43，以表达来自载体基因组不同区域的SIVsmH 4基质/衣壳（MA/CA）基因，以及（ii）在小鼠中评估表达MA/CA的HCoV OC 43载体的全身、粘膜和细胞免疫原性。在R33阶段，我们将：（i）表征HCoV OC 43在猕猴中的感染性，（ii）设计并验证重组抗性HCoV OC 43构建体以表达多达四种SIVsmH 4蛋白-Gag、Env、Nef和Vif，以及（iii）用多基因HCoV OC 43载体接种猕猴并通过用SIVsm E660粘膜攻击来评估疫苗效力。该项目将首次对普通感冒人类冠状病毒作为HIV活粘膜疫苗载体的潜在用途进行关键性评估。公共卫生相关性：在拟议的研究中，我们将开发人类冠状病毒，这种病毒引起约三分之一的普通感冒，作为疫苗载体来递送艾滋病毒抗原。冠状病毒载体作为HIV疫苗有几个潜在的吸引人的特征，例如安全性、制造简单、在HIV传播部位诱导免疫应答的能力以及用有限数量的接种诱导免疫应答的能力。我们将使用SIV/猕猴模型评估冠状病毒作为HIV疫苗载体的潜在用途。