Human Monoclonal Antibodies for Encephalitic Alphaviruses

脑炎甲病毒的人单克隆抗体

• 批准号: 10669266
• 负责人: James E Crowe
• 金额: $ 81.03万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-20 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669266
• 关键词: Active Biological Transport; Aedes; Aerosols; Affect; Affinity; Alanine; Alphavirus; Alphavirus Infections; Animal Model; Animals; Antibodies; Antigens; Arboviruses; Binding; Biological Assay; Biological Models; Biological Products; Biological Warfare; Bioterrorism; Birds; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain region; Cell Culture Techniques; Cells; Central Nervous System; Characteristics; Charge; Clinical; Community Hospitals; Coupled; Culex (Genus); Culicidae; Development; Diagnosis; Diamond; Disease; Eastern Equine Encephalitis Virus; Engineering; Epitope Mapping; Epitopes; Equus caballus; Escape Mutant; FDA approved; Family; Frequencies; Future; Genes; Genetic; Goals; Human; Imaging Techniques; Immune response; Immunity; Immunoglobulin G; Immunologics; In Vitro; Infection; Knowledge; Laser Scanning Confocal Microscopy; Measurement; Measures; Mediating; Membrane Fusion; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Morbidity - disease rate; Mutagenesis; Mutation; Nature; Neurologic; Pathogenesis; Pathogenicity; Predisposition; Prevention; Property; Prophylactic treatment; Proteomics; Reporting; Research; Research Personnel; Resistance; Resolution; Role; Route; Scanning; Scientist; Secondary to; Site; Somatic Mutation; Specificity; Structure; Survivors; Testing; Therapeutic; Therapeutic Effect; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Togaviridae; Translating; Treatment Efficacy; United States; Vaccine Design; Vaccines; Variant; Viral; Virus; Virus Diseases; Work; antibody engineering; blood-brain barrier crossing; climate change; disease transmission; effective therapy; env Gene Products; enzootic; experience; experimental study; human monoclonal antibodies; in vivo; in vivo imaging; inhibiting antibody; innovation; insight; medical countermeasure; mortality; mosquito-borne; neutralizing antibody; neutralizing monoclonal antibodies; new technology; next generation sequencing; novel; pathogen; prevent; prophylactic; rational design; receptor; rural setting; synergism; transmission process; vector; viral fitness; viral resistance

SUMMARY: Eastern equine encephalitis virus (EEEV) is a re-emerging mosquito-borne alphavirus that causes a debilitating encephalitic illness in humans. About a third of human cases of EEEV infection die and many survivors have long-term, debilitating neurologic problems. The virus is maintained in an enzootic cycle between Culiseta melanura mosquitoes and avian hosts but can be transmitted to humans and horses by some Aedes, Coquillettidia, and Culex species. The infection is unusual in humans but increasing in frequency in recent years, likely secondary to climate changes, vector expansion, and other uncharacterized factors. EEEV also is regarded as a potential bioterrorism threat due to spread via aerosol route. Despite the highly pathogenic nature of the virus, no specific treatment or vaccine for EEEV is available. A primary goal of this project is to define the molecular, genetic, immunologic, and structural characteristics of ultra-potent neutralizing human mAbs with broad activity in vivo against EEEV. Additional goals include defining the mechanistic correlates of protection by these ultra-potent neutralizing mAbs and determining ways to optimize function and deliver to the brain. In these studies, we will elucidate how antiviral Abs with exceptional inhibitory activity exert their action in cell culture and in vivo. The approach will include high efficiency isolation of human mAbs, coupled with innovative antibody gene repertoire studies based on next-gen sequencing. Several hypotheses will be tested, including the concept that ultra-potent neutralizing activity results from features of both the antibodies (selection of optimal V-D-J clonotypes and accumulation of critical somatic mutations) and the antigen (binding to quaternary epitopes on multiple adjacent envelope proteins and blockade of structural transitions critical for virus entry or release). We also will apply new technologies for receptor-mediated transfer of molecules across the blood-brain barrier using engineered sequence changes in the Fc region. Although our focus is to understand how and why ultra-potent human mAbs inhibit EEEV, the studies likely will be relevant to general principles of antibody neutralization of many different encephalitic viruses. In addition to defining the molecular and structural basis of Ab neutralization of EEEV and deploying new strategies for delivery of biologics to the brain, these studies will generate a group of fully human mAbs that can prevent and treat EEEV infection, which could be developed in the near future as a possible therapeutic for humans. Studies in this project, while targeted against EEEV, likely will inform future Ab-based and/or vaccine efforts against other arboviruses that cause human brain infections. We have assembled a unique group of investigators, including a human Ab expert, a molecular virologist with experience in Ab-virus interactions, an animal model and pathogenesis expert with specific expertise in encephalitic alphaviruses, including EEEV, and brain-targeting scientists to pursue these studies.

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