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

• 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
• 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

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/新生儿时期代表了一个独特的病毒感染脆弱时期。尽管 疱疹病毒（例如单纯疱疹病毒（HSV））非常普遍，通常不威胁生命 健康成年人的感染是早期生命中最重要的病毒感染之一。 HSV 分娩期间或产后早期的感染导致传播疾病或脑炎 50％的被感染新班子。没有治疗，死亡率很高，估计有70％的尚存婴儿 中枢神经系统（CNS）的参与遭受了长期神经发育后遗症 Acyclovir治疗。幸运的是，我们病原体富裕世界中的新生儿继承了一些保护 由母体免疫系统以转移的抗体（AB）的形式形式。对于HSV，母体AB血清阳性， 导致AB的胎盘转移能够直接中和病毒并引起各种效应子功能 先天性免疫系统的中，与NHSV的风险大大降低有关。 目前尚无批准的HSV疫苗，可以在该疫苗中引起母体ABS 血清神经母亲。作为替代方案，我们以前的工作表明，母亲很容易访问 胎儿的神经组织足以预防NHSV。初步数据现在证明了一种新型鼠标 模型系统，我们不仅可以对死亡率和病毒负担进行建模，还可以对行为病理进行建模 在NHSV之后，人类频繁且终生。该提议的核心假设是 开发NHSV感染的有效疫苗和治疗抗体将受益于仔细的体内 以及对作用的抗体机制的体外评估。目前，了解 基于AB的干预措施在NHSV感染的背景下提供好处的机制，以及如何 可以优化干预措施，以便最好地防止这种毁灭性疾病。 我们的目标是定义和完善可以使用单克隆抗体（mAb）的手段 预防或减少NHSV的发病率和死亡率。我们假设虽然AB效应功能有助于 为了直接中和活性，它们由病毒FC受体（VFCR），糖蛋白E（GE/GI）调节 复杂的）。在强大的初步数据的指导下，将实现两个项目目标 具体目的：1）定义防止NHSV的mAb的作用机制，以及2）定义 病毒FC受体（GE/GI）在影响抗病毒MAB活性的情况下。