Understanding and optimizing antibody-based interventions against neonatal HSV infection

了解和优化针对新生儿 HSV 感染的抗体干预措施

基本信息

批准号：
10752835
负责人：
Margaret E Ackerman
金额：
$ 80.16万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-14 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752835
关键词：
Active Biological Transport Acyclovir Adult Affinity Antibodies Antibody Therapy Antibody-mediated protection Automobile Driving Behavioral Binding Biological Models Birth Central Nervous System Cessation of life Clinical Communicable Diseases Complex Congenital herpes simplex Coupled Data Development Disease Economic Burden Encephalitis Epidemiology Evaluation Fc Receptor Fc domain Fetal Tissues Fetal health Fetus Glycoproteins Goals Herpes Simplex Infections Herpes Simplex Virus Vaccines Herpesviridae Herpesvirus 1 Human Human Herpesvirus 2 Humoral Immunities Immune Evasion Immunization Immunoglobulin G In Vitro Infant Infection Inherited Innate Immune System Intervention Knowledge Life Longevity Maternal antibody Modeling Monoclonal Antibodies Monoclonal Antibody Therapy Morbidity - disease rate Mothers Neonatal Neonatal Mortality Neurologic Newborn Infant Outcome Pathology Placenta Play Population Pregnant Women Prevention Regimen Reporting Risk Role Simplexvirus Testing Therapeutic Therapeutic antibodies Vaccine Design Viral Viral Load result Virus Virus Diseases Vulnerable Populations Work aggressive therapy antibody engineering antibody transfer clinical investigation design fetal fetal infection improved in vivo infection risk inhibiting antibody innate immune function innovation insight maternal immune system mortality mouse model neonatal health neonatal period neonate neural next generation novel novel therapeutics novel vaccines pathogen placental transfer postnatal period preclinical study prevent prophylactic receptor function seropositive vaccine development vaccine-induced antibodies

项目摘要

ABSTRACT The fetal/neonatal period represents a unique period of vulnerability to viral infections. While Herpesviruses such as herpes simplex virus (HSV) are highly prevalent and typically non life-threatening infections among healthy adults, they are among the most consequential viral infections of early life. HSV infection during parturition or the early postnatal period results in disseminated disease or encephalitis in up to 50% of infected newbowns. Without treatment, mortality is high and an estimated 70% of surviving infants with central nervous system (CNS) involvement suffer long-term neurodevelopmental sequelae despite aggressive treatment with acyclovir. Fortunately, newborns in our pathogen-rich world inherit some of the protection provided by the maternal immune system in the form of transferred antibodies (Ab). For HSV, maternal Ab seropositivity, resulting in placental transfer of Ab capable of directly neutralizing virus and eliciting the diverse effector functions of the innate immune system, is associated with dramatically decreased risk of nHSV. There is no currently approved HSV vaccine whereby maternal Abs could be induced among seronegative mothers. As an alternative, our previous work has demonstrated that maternal Ab readily accesses neural tissues of the fetus and is sufficient to prevent nHSV. Preliminary data now demonstrate a novel mouse model system whereby we can model not only mortality and viral burden, but also behavioral pathologies that are frequent and lifelong in humans following nHSV. The central hypothesis of this proposal is that the development of effective vaccines and therapeutic antibodies for nHSV infections will benefit from careful in vivo and in vitro evaluation of antibody mechanism(s) of action. Presently, there is a critical gap in knowledge of the mechanisms whereby Ab-based interventions provide benefit in the context of nHSV infection, and how these interventions might be optimized in order to best prevent this devastating disease. Our objective is to define and refine the means by which monoclonal antibodies (mAbs) can be used to prevent or reduce nHSV morbidity and mortality. We hypothesize that while Ab effector functions contribute to direct neutralization activity, they are modulated by the viral Fc Receptor (vFcR), glycoprotein E (gE/gI complex). Guided by strong preliminary data, the project goals will be achieved though completion of two Specific Aims: 1) Define the mechanism(s) of action of mAbs that prevent nHSV, and 2) Define the role of the viral Fc receptor (gE/gI) in influencing antiviral mAb activity.

抽象的胎儿/新生儿期是一个容易受到病毒感染的独特时期。尽管单纯疱疹病毒 (HSV) 等疱疹病毒非常流行，通常不会危及生命健康成年人中的感染，它们是生命早期最严重的病毒感染之一。单纯疱疹病毒分娩期间或产后早期感染可导致播散性疾病或脑炎 50%的新冠感染者。如果不进行治疗，死亡率很高，估计 70% 的幸存婴儿患有此病尽管积极治疗，但中枢神经系统（CNS）受累仍会遭受长期的神经发育后遗症用阿昔洛韦治疗。幸运的是，在病原体丰富的世界中，新生儿继承了所提供的一些保护由母体免疫系统以转移抗体 (Ab) 的形式产生。对于 HSV，母体抗体血清阳性，导致胎盘转移能够直接中和病毒并引发多种效应功能的抗体的先天免疫系统，与显着降低的 nHSV 风险相关。目前尚无批准的 HSV 疫苗可在母体中诱导产生抗体。血清阴性的母亲。作为替代方案，我们之前的工作表明母体抗体很容易获得胎儿的神经组织，足以预防 nHSV。初步数据现在展示了一种新型小鼠模型系统，我们不仅可以模拟死亡率和病毒负荷，还可以模拟行为病理学在人类感染 nHSV 后，该病很常见且终生。该提案的中心假设是针对 nHSV 感染的有效疫苗和治疗性抗体的开发将受益于仔细的体内研究以及抗体作用机制的体外评估。目前，人们对这方面的认识存在着严重的差距。基于抗体的干预措施在 nHSV 感染情况下提供益处的机制，以及这些机制如何可以优化干预措施，以最好地预防这种毁灭性疾病。我们的目标是定义和完善单克隆抗体 (mAb) 的使用方法预防或降低 nHSV 发病率和死亡率。我们假设虽然 Ab 效应子功能有助于为了指导中和活性，它们受到病毒 Fc 受体 (vFcR)、糖蛋白 E (gE/gI) 的调节复杂的）。在强有力的初步数据的指导下，项目目标将通过完成两个项目来实现具体目标： 1) 定义单克隆抗体预防 nHSV 的作用机制，以及 2) 定义单克隆抗体的作用病毒 Fc 受体 (gE/gI) 影响抗病毒 mAb 活性。