Virus-Like Particle Vaccine for SARS-CoV

SARS-CoV 病毒样颗粒疫苗

• 批准号: 7218604
• 负责人: RAPHAEL Paul VISCIDI
• 金额: $ 39.78万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218604
• 关键词: Amino Acids; Animals; Antibodies; Antibody Formation; Baculoviruses; Biological; Biological Assay; Calculi; Capsid; Capsid Proteins; Cells; Class; Clinical Trials; Coronavirus; Cultured Cells; DNA Vaccines; Data; Disease; E protein; Emerging Communicable Diseases; Enzyme-Linked Immunosorbent Assay; Epitopes; Ferrets; Future; Genes; Goals; Human Coronavirus OC43; Immune Sera; Immunization; Inbred BALB C Mice; Infection; Insecta; Intervention; Life; Measures; Mediating; Membrane; Methods; Mus; Mutation; Oryctolagus cuniculus; Particulate; Predisposition; Production; Range; Recombinants; Resistance; Serotyping; Serum; Severe Acute Respiratory Syndrome; Supervision; System; United States Food and Drug Administration; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Viral; Viral Genome; Virion; Virus; Virus-like particle; Work; Yang; base; biosafety level 3 facility; immunogenic; immunogenicity; neutralizing antibody; pandemic disease; pathogen

DESCRIPTION (provided by applicant): A Severe Acute Respiratory Syndrome (SARS) pandemic, caused by re-emergence of the causative coronavirus (CoV) from an animal reservoir, is a serious threat. Induction of protective antibody by vaccination has proven the most effective intervention for highly contagious viral pathogens. The capsid proteins of viruses typically self-assemble into empty capsids known as virus-like particles (VLPs). VLPs resemble native virions immunologically. As vaccine candidates, VLPs have the advantage of being non-replicating and non-pathogenic, and of presenting host protective epitopes in a particulate and multimeric form. We have generated SARS-CoV VLPs by expression of the spike (S), membrane (M) and small envelope (E) proteins in the baculovirus/insect cell system and shown that VLP are immunogenic in rabbits. We now propose: (1) to develop efficient methods for production of highly purified SARS-CoV M+E and M+E+S VLPs from insect cell cultures, (2) to characterize the immunogenicity of SARS-CoV VLP vaccines in BALB/c mice; and (3) to determine the potency of a VLP vaccine to protect BALB/c mice and ferrets challenged with live SARS-CoV. Recent studies have shown that amino acids changes in S can mediate increased resistance to neutralization and enhancement of S pseudotype virus entry. The conserved C terminus of coronaviruses contains epitopes that contribute to enhancement. Thus, our final specific aim (4) is to determine the cross neutralizing/enhancing capacity of antisera raised in mice against VLPs of SARS-CoV strains and the human coronaviruses, OC43 and 229E. The successful implementation of the proposed studies would provide a stepping-stone toward future clinical trials with a VLP-based SARS-CoV vaccine.

描述（由申请人提供）：严重急性呼吸系统综合征（SARS）大流行，由病原性冠状病毒（CoV）从动物宿主中重新出现引起，是一种严重的威胁。通过接种疫苗诱导保护性抗体已被证明是对高度传染性病毒病原体最有效的干预措施。病毒的衣壳蛋白通常自组装成称为病毒样颗粒（VLP）的空衣壳。VLP在免疫学上类似于天然病毒体。作为候选疫苗，VLP具有非复制性和非致病性的优点，并且可以以颗粒和多聚体形式呈现宿主保护性表位。我们已经通过在杆状病毒/昆虫细胞系统中表达刺突（S）、膜（M）和小包膜（E）蛋白来产生SARS-CoV VLP，并且显示VLP在兔中具有免疫原性。我们现在提议：（1）开发从昆虫细胞培养物中生产高度纯化的SARS-CoV M+E和M+E+S VLP的有效方法，（2）表征SARS-CoV VLP疫苗在BALB/c小鼠中的免疫原性;和（3）确定VLP疫苗保护用活SARS-CoV攻击的BALB/c小鼠和雪貂的效力。最近的研究表明，S中的氨基酸变化可以介导增加对中和的抗性和增强S假型病毒进入。冠状病毒的保守C末端含有有助于增强的表位。因此，我们最终的具体目标（4）是确定在小鼠中产生的抗血清对SARS-CoV毒株和人冠状病毒OC 43和229 E的VLP的交叉中和/增强能力。这些研究的成功实施将为未来基于VLP的SARS-CoV疫苗的临床试验提供一块垫脚石。