Preclinical Studies of Vaccines for Pandemic Influenza

大流行性流感疫苗的临床前研究

• 批准号: 8745407
• 负责人: Kanta Subbarao
• 金额: $ 190.15万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745407
• 关键词: Animal Sources; Animals; Antibodies; Antibody Formation; Attenuated; Attenuated Live Virus Vaccine; Avian Influenza A Virus; Base Sequence; Birds; Blood Circulation; Canis familiaris; Clinical Trials; Cooperative Research and Development Agreement; Development; Disease; Disease Outbreaks; Domestic Fowls; Epidemic; Equilibrium; Equus caballus; Evaluation; Event; Exhibits; Experimental Animal Model; Family suidae; Felis catus; Ferrets; Formalin; Genes; Goals; Hemagglutinin; Human; Human Influenza A Virus; Immune response; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Kinetics; Licensure; Life; Lower respiratory tract structure; Lung; Mammals; Membrane Glycoproteins; Mus; Mutation; Nature; Needles; Neuraminidase; Phenotype; Plasmids; Population; Proteins; Public Health; Safety; Scientist; Specific qualifier value; Temperature; Upper respiratory tract; Vaccinated; Vaccines; Virus; aquatic bird; attenuation; base; cross reactivity; immunogenicity; influenza virus vaccine; influenzavirus; pandemic disease; pandemic influenza; pandemic preparedness; positional cloning; preclinical study; programs; response; seal; vaccine candidate; vaccine development

LID scientists are collaborating with scientists from MedImmune under a CRADA to generate candidate vaccines against avian influenza viruses of each subtype. The vaccines were generated using plasmid based reverse genetics and each contains the hemagglutinin and neuraminidase genes from an avian influenza virus and six internal gene segments from the AA ca virus. Since 1968, human H3N2 influenza viruses have been circulating worldwide, and the population has been infected by and/or vaccinated against these viruses. However, H3 subtype influenza viruses have been isolated from humans, pigs, horses, dogs, cats, seals, and numerous avian species, and these viruses are antigenically and genetically distinct from human H3 viruses. Swine, equine, and avian H3 influenza viruses all have crossed the species barrier to mammals, including humans, dogs, and seals. Very little information is available on the kinetics of replication and cross-reactivity of the immune response of swine, equine, and avian H3 influenza viruses in experimental animal models. Based on the emergence of a swine-origin H1N1 virus as a pandemic strain in 2009 despite the ongoing circulation of human H1viruses, we believe it is necessary to consider the development of H3 animal influenza vaccines. We selected 11 swine, equine, and avian H3 influenza viruses and evaluated their kinetics of replication and ability to induce a broadly cross-reactive antibody response in mice and ferrets. The swine and equine viruses replicated well in the upper respiratory tract of mice. With one exception of an avian virus that replicated poorly in the lower respiratory tract, all of the viruses replicated in mouse lungs. In ferrets, all of the viruses replicated well in the upper respiratory tract, but the equine viruses replicated poorly in the lungs. Extrapulmonary spread was not observed in either mice or ferrets. No single virus elicited antibodies that cross-reacted with viruses from all three animal sources. Avian and equine H3 viruses elicited broadly cross-reactive antibodies against heterologous viruses isolated from the same or other species, but the swine viruses did not. We selected an equine and an avian H3 influenza virus for further development as vaccines.

LID的科学家正在与MedImmune的科学家合作，根据CRADA生产针对每种亚型禽流感病毒的候选疫苗。使用基于质粒的反向遗传学产生疫苗，并且每个疫苗含有来自禽流感病毒的血凝素和神经氨酸酶基因以及来自AA ca病毒的六个内部基因片段。 自1968年以来，人H3 N2流感病毒已在世界范围内传播，并且人群已被这些病毒感染和/或接种了针对这些病毒的疫苗。然而，H3亚型流感病毒已从人、猪、马、狗、猫、海豹和许多鸟类物种中分离出来，并且这些病毒在抗原性和遗传学上与人H3病毒不同。猪、马和禽H3流感病毒都已跨越物种屏障，感染到哺乳动物，包括人类、狗和海豹。关于猪、马和禽H3流感病毒在实验动物模型中的复制动力学和免疫反应的交叉反应性的信息非常少。尽管人类H1病毒正在传播，但2009年猪源H1N1病毒作为大流行毒株出现，我们认为有必要考虑开发H3动物流感疫苗。我们选择了11个猪，马，禽H3流感病毒，并评估其复制动力学和能力，以诱导广泛的交叉反应性抗体反应的小鼠和雪貂。猪和马病毒在小鼠的上呼吸道中复制良好。除了一种在下呼吸道复制能力差的禽流感病毒外，所有病毒都在小鼠肺中复制。在雪貂中，所有病毒在上呼吸道复制良好，但马病毒在肺部复制较差。在小鼠或雪貂中均未观察到肺外扩散。没有一种单一的病毒引起抗体与所有三种动物来源的病毒发生交叉反应。禽和马H3病毒引起广泛的交叉反应抗体对异源病毒分离自相同或其他物种，但猪病毒没有。我们选择了马和禽H3流感病毒作为疫苗进行进一步的开发。