A novel lactic acid bacteria-based norovirus vaccine

一种新型乳酸菌诺如病毒疫苗

• 批准号: 9441705
• 负责人: Prosper N Boyaka
• 金额: $ 59.78万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-10 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9441705
• 关键词: Acute; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antiviral Agents; Attenuated Live Virus Vaccine; Attenuated Vaccines; Binding; Calicivirus; Categories; Cell Culture System; Cellular Immunity; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical Trials; Communicable Diseases; Data; Dendritic Cells; Development; Diarrhea; Disease; Disease Outbreaks; Disinfectants; Domestic Animals; Economics; Enteral; Environment; Epidemic; Event; Family suidae; Food; Future; Gastroenteritis; Gastrointestinal tract structure; Genotype; Gnotobiotic; Goals; Hospitalization; Human; Humoral Immunities; Immune; Immune response; Immunity; In Vitro; Individual; Infection; Japan; Lactococcus lactis; Lead; Medical center; Microencapsulations; Modeling; Mucosal Immunity; Mucous Membrane; National Institute of Allergy and Infectious Disease; Natural Immunity; Norovirus; Ohio; Oral; Pathogenesis; Pathogenicity; Pediatric Hospitals; Peptides; Prevention; Price; Probiotics; Production; Recombinants; Reporting; Research; Research Personnel; Resistance; Site; Syndrome; Universities; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccines; Viral Antigens; Virulent; Virus; Virus Diseases; Virus-like particle; Water; Weaning; Zoonoses; adaptive immune response; base; biodefense; efficacy testing; foodborne illness; foodborne outbreak; human model; immunogenic; immunogenicity; improved; in vivo; interest; lactic acid bacteria; mortality; nonhuman primate; novel; novel vaccines; particle; pathogen; public health relevance; time interval; uptake; vaccine candidate; vaccine development; vaccine-induced immunity; vector

 DESCRIPTION (provided by applicant): Human norovirus (HuNoV) infections are responsible for more than 95% of the non-bacterial acute gastroenteritis worldwide and more than 60% of all food-borne illnesses in the US. Evidence suggests that HuNoVs and porcine norovirus (PoNoV) possess high zoonotic potential and, since PoNoV shares the highest identity to HuNoV GII strains, suggesting that swine may serve as reservoirs HuNoV and for emergence of novel HuNoVs and porcine/human GII recombinants. Despite the major efforts, vaccines or antiviral drugs are not available. This is due in major part to the lack of a cell culture system or a small animal model for HuNoV pathogenesis. The overall goal of this proposal is to develop a Lactococcus lactis or lactic acid bacteria (LAB) as the vector to deliver NoV virus-like particles (VLPs) and protrusion (P) particles, and to develop LAB-based "live" NoV vaccines for clinical trials. We have shown that LAB strains expressing VLP and P particles derived from HuNoV-GII.4 induced strong protective immune responses when orally inoculated into gnotobiotic (GN) piglets, the only nonprimate animal model that accurately replicates HuNoV disease. Using this unique animal model, we will determine the dynamics of LAB colonization and the expression, uptake of the NoV VLP and P particles in gastrointestinal tract, and innate immunity induced by LAB-based vaccines. We will determine if LAB- based vaccines provide protection against challenge with homologous (HuNoV-GII) or heterologous (PoNoV-GII) viruses. Subsequently, we will determine the mechanism by which LAB-based vaccine induces NoV-specific mucosal, humoral, and cellular immune responses, and define immune correlates of homologous and heterologous protection against NoV strains. Finally, we will determine if microencapsulation and a dendritic cell (DC) targeting peptide that specifically binds mucosal antigen- presenting cells (APCs) will enhance the immunogenicity of LAB-based NoV vaccines and will protect GN piglets from virulent virus challenge. Successful completion of these studies will result in development of safe, stable and efficacious vaccine(s) for the prevention of HuNoV/PoNoV gastroenteritis in humans and swine. This project will also provide a new avenue for vaccine development for other non-cultivable food- and water-borne viruses of human and domestic animal significance.

 描述（由适用提供）：人类诺如病毒（Hunov）感染负责全球超过95％的非细菌急性胃肠炎，而美国所有食物传播疾病的60％以上。有证据表明，霍诺夫和牛肝菌（Ponov）具有高的人畜共患潜力，并且由于Ponov具有与Hunov GII菌株具有最高的身份，这表明猪可以用作霍诺夫的储层，并且出现了新型的Hunovs和新型的Hunovs和Porcine/Porcine/Hunder Gii重组。尽管做出了重大努力，但仍未使用疫苗或抗病毒药。这在主要部分是由于缺乏细胞培养系统或用于霍诺夫发病机理的小动物模型。该提案的总体目标是开发乳酸菌或乳酸细菌（LAB）作为载体，以提供NOV病毒样颗粒（VLP）和蛋白质（P）颗粒，并开发基于LABS的“实时” NOOV疫苗用于临床试验。我们已经表明，表达源自Hunov-GII的VLP和P颗粒的实验室菌株。4当口服将口服接种到Gnotobiotic（GN）Piglets中时，诱导了强烈的受保护的免疫复杂，这是唯一准确地复制Hunov疾病的唯一非高级动物模型。使用这种独特的动物模型，我们将确定胃肠道中实验室定植的动力学以及表达，摄取NOV VLP和P颗粒的动力学，以及由基于实验室的疫苗进行的先天免疫。我们将确定基于实验室的疫苗是否提供了与同源（Hunov-GII）或异源（Ponov-GII）病毒的挑战的保护。随后，我们将确定基于实验室的疫苗影响NOV特异性粘膜，体液和细胞免疫调查的机制，并定义针对NOV菌株的同源和异源保护的免疫原子。最后，我们将确定针对特异性结合粘膜抗原细胞（APC）的肽的微囊囊和树突状细胞（DC）是否会增强基于实验室的NOV疫苗的免疫原性，并将保护GN Piglets免受病毒攻击。这些研究的成功完成将导致开发安全，稳定和有效的疫苗，以预防人类和猪的Hunov/Ponov胃肠炎。该项目还将为其他不可培养的食品和水传播人类和家养动物意义的病毒提供疫苗开发的新途径。