Virus-Like Particle Vaccine for SARS-CoV

SARS-CoV 病毒样颗粒疫苗

• 批准号: 7388873
• 负责人: RAPHAEL Paul VISCIDI
• 金额: $ 39.05万
• 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/7388873
• 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）：由动物宿主中重新出现的致病冠状病毒（CoV）引起的严重急性呼吸系统综合症（SARS）大流行是一种严重威胁。通过疫苗接种诱导保护性抗体已被证明是针对高传染性病毒病原体的最有效干预措施。病毒的衣壳蛋白通常自组装成空衣壳，称为病毒样颗粒（VLP）。 VLP 在免疫学上类似于天然病毒颗粒。作为候选疫苗，VLP 具有非复制性和非致病性的优点，并且以颗粒和多聚体形式呈现宿主保护性表位。我们通过在杆状病毒/昆虫细胞系统中表达刺突蛋白 (S)、膜蛋白 (M) 和小包膜蛋白 (E) 来生成 SARS-CoV VLP，并表明 VLP 在兔子中具有免疫原性。我们现在建议：（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； (3) 确定 VLP 疫苗保护受到活 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对中和的抵抗力的增加和 S 假型病毒进入的增强。冠状病毒的保守 C 末端含有有助于增强的表位。因此，我们的最终具体目标 (4) 是确定小鼠体内针对 SARS-CoV 毒株和人类冠状病毒 OC43 和 229E VLP 的抗血清的交叉中和/增强能力。拟议研究的成功实施将为未来基于 VLP 的 SARS-CoV 疫苗临床试验奠定基础。