Maternal and infant immunization to eliminate breast milk transmission of HIV-1

母婴免疫接种以消除 HIV-1 母乳传播

基本信息

批准号：
8897735
负责人：
Sallie R. Permar
金额：
$ 244.03万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897735
关键词：
Active Immunization Acute Adherence Adjuvant Anti-Retroviral Agents Antibodies Antibody Response Antigens B-Lymphocytes Birth Breast Feeding Child Childhood Chronic Clinical Trials Development Dose Effectiveness Epidemic Evaluation Exposure to Gastrointestinal tract structure Generations Goals Grant HIV HIV-1 Health Hepatitis B Human Milk Humoral Immunities Immune Immune response Immunity Immunization Immunoglobulin A Immunoglobulin G Infant Infection Influenza Interruption Intervention Intramuscular Lactation Macaca mulatta Maternal antibody Milk Modeling Monkeys Mothers Neonatal Oral Poxviridae Pregnancy Prevention Prevention strategy Program Research Project Grants Prophylactic treatment Proteins Public Health Regimen Risk SIV Safety Solutions Testing Tetanus Time Vaccinated Vaccination Vaccines Vertical Disease Transmission Virus Virus Diseases Work base design drug resistant virus env Gene Products immunogenic immunogenicity infancy member mucosal vaccination neutralizing antibody nonhuman primate novel strategies pathogen postnatal prevent programs protective efficacy response scale up simian human immunodeficiency virus transmission process vaccination strategy vaccine trial vector

项目摘要

DESCRIPTION (provided by applicant): Overall With over 250,000 children newly-infected each year, the worldwide HIV-1 epidemic remains an imperative public health challenge for children. Specifically, mother to child transmission (MTCT) of HIV-1 continues to occur at this alarming rate, despite the global scale-up of antiretroviral (ARV)-based prophylaxis during pregnancy and breastfeeding. The inability of ARV-based interventions, alone, to eliminate pediatric HIV-1 infections is due to several challenges, including ARV access/adherence, acute infection of mothers, and the development of drug resistant virus strains. Thus, elimination of pediatric HIV-1 depends on the development of alternate strategies to interrupt MTCT. Strategies involving combined maternal and infant immune-based interventions have been effective against other neonatal pathogens, including hepatitis B and tetanus. In the case of HIV/SIV, previous maternal-infant nonhuman primate vaccine studies from our team members have achieved both partial protection of infants against oral SIV infection and robust, functional neutralizing maternal antibody responses in breast milk. Extending this work, this Program Project grant will test the hypothesis that infant HIV-1 acquisition via breastfeeding can be reduced by an approach combining maternal immunization, to passively immunize the infant with HIV-1 Env-specific antibody (Project 1) and active immunization of the infant (Project 2). Specifically, we will evaluate whether vaccination of mothers and infants with a nonreplicating MVA prime and combined systemic and mucosal transmitted/founder Envelope protein immunogens boost vaccine regimen produced and tested for immunogenicity by Core 1 (Immunogenicity and Vector Development Core) can reduce virus acquisition in a neonatal monkey oral low dose Simian-Human Immunodeficiency Virus (SHIV) challenge model developed by Core 3 (NHP Core). This work will determine if combined maternal and infant immunization can reduce oral virus acquisition in the settings of both acute maternal infection and chronic, ARV-treated maternal infection (Project 1 and 2). Moreover, our studies utilize novel strategies to assess the quality and quantity of Envelope-specific B cell responses in Core 2 (B Cell Core) to decipher the potentially-protective maternal and infant immune responses in this model. Together, the proposed studies will provide understanding of the efficacy and protective mechanisms of combined maternal and infant immunization-information that is crucial to the design of effective maternal and infant HIV-1 vaccines and necessary to end the pediatric HIV-1 epidemic and achieve an HIV-1-free generation.

描述（由申请人提供）：总体而言，每年有超过 250,000 名儿童新感染艾滋病毒，全球范围内的 HIV-1 流行仍然是儿童面临的一项紧迫的公共卫生挑战。具体而言，尽管全球在怀孕和母乳喂养期间扩大了基于抗逆转录病毒（ARV）的预防措施，但 HIV-1 母婴传播（MTCT）仍然以惊人的速度发生。仅基于抗逆转录病毒药物的干预措施无法消除儿童 HIV-1 感染，这是由于多项挑战造成的，包括抗逆转录病毒药物的获取/依从性、母亲的急性感染以及耐药病毒株的发展。因此，消除儿童 HIV-1 取决于开发替代策略来中断 MTCT。涉及母婴免疫干预的联合策略对其他新生儿病原体（包括乙型肝炎和破伤风）有效。就 HIV/SIV 而言，我们团队成员之前进行的母婴非人灵长类疫苗研究已经实现了对婴儿免受口腔 SIV 感染的部分保护，并在母乳中产生了强大的、功能性的中和母体抗体反应。为了扩展这项工作，该计划项目赠款将测试以下假设：通过母亲免疫、用 HIV-1 Env 特异性抗体（项目 1）对婴儿进行被动免疫和主动免疫相结合的方法，可以减少婴儿通过母乳喂养感染 HIV-1婴儿的情况（项目 2）。具体来说，我们将评估使用非复制 MVA 初免疫苗以及组合的系统性和粘膜传播/创始人包膜蛋白免疫原增强疫苗方案对母亲和婴儿进行疫苗接种，该疫苗方案是由核心 1（免疫原性和载体开发核心）生产并测试免疫原性的，可以减少病毒获得Core 3 (NHP Core) 开发的新生猴口服低剂量猿猴人类免疫缺陷病毒 (SHIV) 攻击模型。这项工作将确定孕产妇和婴儿联合免疫是否可以减少急性孕产妇感染和慢性抗逆转录病毒治疗孕产妇感染情况下的口腔病毒获得（项目 1 和 2）。此外，我们的研究利用新策略来评估 Core 2（B 细胞核心）中包膜特异性 B 细胞反应的质量和数量，以破译该模型中潜在的保护性母婴免疫反应。总之，拟议的研究将提供对孕产妇和婴儿联合免疫信息的功效和保护机制的了解，这对于设计有效的孕产妇和婴儿 HIV-1 疫苗至关重要，并且对于结束儿科 HIV-1 流行并实现无 HIV-1 的一代。