Disease Modeling of Influenza and Other Emerging Respiratory Viral Pathogens

流感和其他新出现的呼吸道病毒病原体的疾病模型

• 批准号: 10272159
• 负责人: Heinrich Feldmann
• 金额: $ 85.65万
• 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/10272159
• 关键词: 2019-nCoV; Acute; African Green Monkey; Animal Disease Models; Animal Diseases; Animal Model; Animals; Antibodies; Antibody Response; Antiviral Agents; Avian Influenza; Avian Influenza A Virus; Bangladesh; COVID-19; Callithrix jacchus jacchus; Cessation of life; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Containment; Control Animal; Coronavirus Infections; Data; Development; Disease; Disease Outbreaks; Disease model; Dose; Drug Screening; Emergency Situation; Emerging Communicable Diseases; Epidemic; Fostering; Functional disorder; Funding; GTP-Binding Proteins; Genotype; Goals; H5 influenza virus; Hantavirus; Hantavirus Pulmonary Syndrome; Hemagglutinin; Hendra Virus; Henipavirus; Human; Hydroxychloroquine; Immune response; Immunoglobulin G; In Vitro; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; International; Intramuscular Injections; Kinetics; Lead; Length; Lesion; Lipids; Lower respiratory tract structure; Lung; Lung diseases; Macaca fascicularis; Macaca mulatta; Malaria; Malaysia; Manuscripts; Mesocricetus auratus; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Modeling; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Nipah Virus; Oseltamivir; Outcome; Pathogenesis; Pathogenicity; Pathologic; Patients; Preparation; Prophylactic treatment; Proteins; Public Health; RNA; Recombinants; Replicon; Research; Resistance; SARS coronavirus; Severities; T cell response; Testing; Therapeutic; Tissues; Treatment Efficacy; Treatment Protocols; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral; Virulence; Virulent; Virus; Virus Diseases; Virus Replication; Wit; Work; anti-viral efficacy; antimicrobial; base; burden of illness; coronavirus disease; design; disease transmission; drug efficacy; efficacy testing; human pathogen; immunogenic; immunogenicity; in vivo evaluation; influenza virus vaccine; influenzavirus; innovation; inorganic phosphate; intravenous administration; mutant; nanoparticle; nonhuman primate; novel; pandemic disease; pathogenic virus; pre-clinical; prevent; prophylactic; remdesivir; respiratory; response; vaccination strategy; vaccine candidate; vaccine response; vector; vector vaccine

Over the past fiscal year, we have performed studies on four viral pathogens causing respiratory disease in humans, Nipah virus, influenza virus, Middle East Respiratory Syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). From February to July 2020, only work on SARS-CoV-2 was permitted. (1)Nipah virus: We have continued work on two main projects, efficacy of the antiviral drug remdesivir and prophylactic efficacy of the VSV-based vaccine (VSV-Nipah) against Nipah virus infection. We tested the efficacy of remdesivir against Nipah virus (Bangladesh genotype) in African green monkeys. In contrast to control animals, which all succumbed to the infection, all GS-5734-treated animals survived the lethal challenge, indicating that GS-5734 is a promising antiviral treatment for Nipah virus infection (Lo et al. Sci Transl Med 2019). We also tested the efficacy of VSV-Nipah in African green monkeys against Nipah virus (Malaysia and Bangladesh genotypes) challenge. In contrast to control animals, which all succumbed, all vaccinated animals were completely protected against both challenges. The vaccine expressing the Nipah virus G protein performed slightly better in regard to the immunological responses than that vaccine expressing the Nipah virus F protein (de Wit et al., manuscript in preparation). VSV-Nipah (expressing G protein) will now be evaluated under CEPI funding in collaboration with Public Health Vaccines and moved into clinical trials. (2)Influenza virus: The observed virulence of the 1918 influenza virus substantiates the need for evaluating antiviral options against infections with this virulent human pathogen. Here we demonstrate that oseltamivir phosphate is effective in preventing severe disease in cynomolgus macaques if given prophylactically. Efficacy was reduced in a treatment regimen through emergence of oseltamivir-resistant mutants that lead to death of one of four animals. This emphasizes the importance of implementing combination therapy and vaccination strategies early in an epidemic or pandemic. (Feldmann et al., mBio 2019). The avian influenza virus outbreak in 1997 highlighted the potential of the highly pathogenic H5N1 virus to cause severe disease in humans. Therefore, effective vaccines against H5N1 viruses are needed to counter the potential threat of a global pandemic. We generated recombinant VSV-based H5N1 influenza virus vectors to demonstrate the feasibility of this platform for a fast-acting pan-H5 influenza virus vaccine. We found that a single dose of VSV vectors expressing full-length hemagglutinin (HAfl) were sufficient to provide 100% protection. The vaccine vectors were fast-acting as demonstrated by uniform protection when administered 3 days prior to lethal challenge. Moreover, single vaccination induced cross-protective H5-specific antibodies and protected mice against lethal challenge with various H5 clade 2 viruses, highlighting the potential of the VSV-based HAfl as a pan-H5 influenza virus emergency vaccine. (3)Middle East Respiratory Syndrome coronavirus (MERS-CoV): We performed two major therapeutic projects, efficacy of antibody and remdesivir treatment. We tested the prophylactic efficacy of the monoclonal antibody LCA60 in the common marmoset model of MERS-CoV infection. Intravenous administration of LCA60 one day before virus challenge resulted in a moderate clinical benefit of treatment including reduced respiratory involvement. Although viral lung loads were not reduced in LCA60-treated animals as compared to controls, there were fewer pathological changes in the lungs. Thus, prophylactic LCA60 treatment could be implemented to reduce disease burden in contacts of confirmed MERS-CoV patients. Furthermore, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in the rhesus macaque model of MERS-CoV infection. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV-induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h post inoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. (4)Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2): Since February 2020 we have been mainly working on COVID projects. We have established the Syrian hamster disease model for pathogenesis studies and countermeasure development (Rosenke et al., manuscript in preparation). We have established an in vitro drug screening pipeline that will feed promising candidates into in vivo testing using the Syrian hamster model (Jarvis et al., Antivir Ther 2020; Rosenke et al., J Antimicrobial Chemotherap, submitted). These studies are ongoing. We further assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ) in two animal disease models. The standard human malaria HCQ prophylaxis and treatment did not significantly benefit clinical outcome nor reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. Similarly, when used for prophylaxis or treatment neither the standard human malaria dose nor a high dose of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Results from these two preclinical animal models may prove helpful in guiding clinical use of HCQ for prophylaxis/treatment of COVID-19. Finally, we have rapidly developed repRNA-CoV2S, a stable and highly immunogenic vaccine candidate comprised of an RNA replicon formulated with a novel Lipid InOrganic Nanoparticle (LION) designed to enhance vaccine stability, delivery, and immunogenicity. We have shown that intramuscular injection of LION/repRNA-CoV2S elicited robust anti-SARS-CoV-2 spike protein IgG antibody isotypes indicative of a Type 1 T helper response as well as potent T cell responses in mice. Importantly, a prime-only administration in nonhuman primates elicited antibody responses that potently neutralized SARS-CoV-2 as well as T cell responses indicative of a Type 1 T helper response. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection from SARS-CoV-2 infection (Erasmus et al., Sci Transl Med 2020).

在过去的财政年度，我们对导致人类呼吸道疾病的四种病毒性病原体进行了研究，即尼帕病毒、流感病毒、中东呼吸综合征冠状病毒（MERS-CoV）和严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）。从2020年2月到7月，只允许进行SARS-CoV-2的工作。