A Miniature Pig Model for the Study of Host-Immune Responses Against Influenza A Virus

用于研究甲型流感病毒宿主免疫反应的小型猪模型

• 批准号: 10216937
• 负责人: Juergen A Richt
• 金额: $ 19.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216937
• 关键词: Animal Model; Animals; B-Lymphocytes; Cessation of life; Clinical; Clinical Research; Complement; Containment; Development; Development Plans; Disease; Dose; Economics; Enzyme-Linked Immunosorbent Assay; Epidemic; Exposure to; Family suidae; Haplotypes; Healthcare Systems; Homo; Hospitalization; Human; Immune; Immune response; Immunity; Immunologic Monitoring; Immunologics; Inactivated Vaccines; Inbreeding; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza vaccination; Knowledge; Longitudinal Studies; Lung diseases; Membrane Proteins; Modeling; Monitor; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Outcome; Pathology; Population; Public Health; Publishing; Respiratory Tract Infections; Seasons; Strategic Planning; Stress; Study models; Symptoms; T-Lymphocyte; Testing; Time; Upper Respiratory Infections; Vaccinated; Vaccination; Vaccines; Viral Proteins; Virulent; Virus; Virus Diseases; Virus Replication; Weight Gain; Work; age group; cost; economic cost; experimental study; feasibility testing; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; mouse model; neutralizing antibody; novel; pandemic disease; porcine model; tool; universal influenza vaccine; universal vaccine; vaccination strategy; vaccine development; vaccine evaluation; vaccine response; vaccine trial

Influenza viruses cause infections of the respiratory tract in both humans and pigs. Antigenic drift allows viruses to escape pre-existing immunity present in the human population and cause annual epidemics that results in significant morbidity, economic loss, and an estimated 250,000 deaths per year worldwide. Antigenic shift allows the creation of new influenza viruses with novel surface proteins that are antigenically unrelated to surface proteins of viruses that circulated in previous seasons. Currently licensed vaccines aim at the induction of neutralizing antibodies and their efficacy depends on accurate prediction of the influenza strains that will circulate in the next season. Protection provided by current vaccines is limited in time since antigenic drift and shift allow influenza viruses to escape vaccine-induced neutralizing antibodies, and there is a critical need for broad and long-lasting vaccines that provide protection against influenza viruses of different subtypes in all age groups. The development of such universal influenza vaccines is of public health importance and the outlines of a strategic plan have been published recently by the National Institute of Allergy and Infectious Diseases. One of the action items is to develop animal models that recapitulate human immunity to influenza virus infection and vaccination. In this project proposal, we plan to further develop the miniature pig model for the study of host-immune responses to influenza A virus infection and vaccination. We choose to work with miniature pigs because they are natural influenza hosts, easier to handle and to obtain seronegative animals than with conventional pigs and because haplotyped inbred animals are available. In the first part of the project we will focus on the establishment of an influenza A infection and re-infection model with miniature pigs to complement clinical studies previously performed in humans and the conventional pig influenza model. Immune responses induced by the first influenza infection will be monitored and correlated with protection against re-infection with a heterosubtypic influenza virus. In the second part of the project we will focus on the establishment of an influenza A vaccine model with miniature pigs to evaluate universal vaccine approaches and compare them to a conventional influenza vaccine. We will also investigate if the miniature pig influenza model is suitable for the study of vaccine-associated enhancement of disease, as is described for conventional pigs. This project will allow to define correlates of protective immunity against influenza A viruses of different subtypes and is crucial to close knowledge gaps in the current models for universal influenza vaccine studies.

流感病毒会引起人类和猪的呼吸道感染。抗原漂移使病毒能够逃脱人群中存在的预先存在的免疫，并引起每年的流行病，造成重大发病率和经济损失，估计全世界每年有25万人死亡。抗原转移允许产生具有新的表面蛋白的新流感病毒，这些表面蛋白在抗原性上与前几个季节传播的病毒表面蛋白无关。目前获得许可的疫苗旨在诱导中和抗体，其有效性取决于对下一季将流行的流感毒株的准确预测。目前疫苗提供的保护在时间上是有限的，因为抗原漂移和转移使流感病毒逃脱疫苗诱导的中和抗体，并且迫切需要广泛和持久的疫苗，以提供对所有年龄组不同亚型流感病毒的保护。研制这种通用流感疫苗对公共卫生具有重要意义，国家过敏和传染病研究所最近公布了一项战略计划纲要。其中一个行动项目是开发能够概括人类对流感病毒感染和疫苗接种免疫的动物模型。在本课题中，我们计划进一步开发小型猪模型，用于甲型流感病毒感染和疫苗接种的宿主免疫应答研究。我们之所以选择小型猪作为研究对象，是因为它们是天然的流感宿主，与传统猪相比，它们更容易处理和获得血清阴性动物，而且单倍型近交系动物也是可用的。在该项目的第一部分，我们将重点建立小型猪甲型流感感染和再感染模型，以补充先前在人类和传统猪流感模型中进行的临床研究。将监测由首次流感感染引起的免疫反应，并将其与防止异亚型流感病毒再次感染的保护联系起来。在该项目的第二部分，我们将重点建立小型猪甲型流感疫苗模型，以评估通用疫苗方法，并将其与传统流感疫苗进行比较。我们还将调查微型猪流感模型是否适合研究疫苗相关的疾病增强，就像对传统猪所描述的那样。这一项目将使我们能够确定针对不同亚型甲型流感病毒的保护性免疫的相关因素，对于填补目前通用流感疫苗研究模型中的知识空白至关重要。

项目成果

Lipid nanoparticle composition for adjuvant formulation modulates disease after influenza virus infection in QIV vaccinated mice.

用于佐剂制剂的脂质纳米颗粒组合物在QIV疫苗接种的小鼠中调节流感病毒感染后的疾病。

• DOI: 10.1101/2024.01.14.575599
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Jangra,Sonia;Lamoot,Alexander;Singh,Gagandeep;Laghlali,Gabriel;Chen,Yong;Yz,Tingting;García-Sastre,Adolfo;DeGeest,BrunoG;Schotsaert,Michael
• 通讯作者: Schotsaert,Michael