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

• 批准号: 9252353
• 负责人: Sallie R. Permar
• 金额: $ 226.33万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/9252353
• 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; HIV-1 vaccine; Hepatitis B; Human Milk; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunize; Immunoglobulin A; Immunoglobulin G; Infant; Infection; Influenza; Interruption; Intervention; Intramuscular; Lactation; Macaca mulatta; Maternal antibody; Milk; Modeling; Monkeys; Mother-to-child HIV transmission; Mothers; Neonatal; Oral; Poxviridae; Pregnancy; Prevention; Prevention strategy; Program Research Project Grants; Prophylactic treatment; Proteins; Public Health; Regimen; Resistance development; Risk; SIV; Safety; Testing; Tetanus; Time; Vaccinated; Vaccination; Vaccines; Vertical Disease Transmission; Virus; Virus Diseases; Work; base; design; drug development; drug resistant virus; env Gene Products; immunogenic; immunogenicity; infancy; maternal vaccination; member; mucosal vaccination; neutralizing antibody; nonhuman primate; novel strategies; oral HIV; pathogen; pediatric human immunodeficiency virus; placental transfer; postnatal; prevent; programs; public health relevance; response; scale up; simian human immunodeficiency virus; transmission process; vaccination strategy; vaccine trial; vector; viral transmission; virus development

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25万名新感染的儿童，全球HIV-1流行病仍然是儿童急需的公共卫生挑战。具体而言，尽管在怀孕和母乳喂养期间，基于抗逆转录病毒（ARV）基于抗逆转录病毒（ARV）的预防量进行了全球范围，但HIV-1儿童传播（MTCT）仍继续以这种惊人的速度发生。仅基于ARV的干预措施就无法消除小儿HIV-1感染，这是由于几个挑战，包括ARV访问/依从性，母亲的急性感染以及耐药性病毒菌株的发展。因此，消除小儿HIV-1取决于开发中断MTCT的替代策略。涉及孕产妇和婴儿免疫干预措施的策略对其他新生儿病原体（包括乙型肝炎和破伤风）有效。就艾滋病毒/SIV而言，我们团队成员的先前孕产妇非人类灵长类动物疫苗的研究已经对婴儿的口服SIV感染和强大的功能性中和母乳中和鲁棒的孕产妇抗体反应进行了部分保护。扩展了这项工作，该计划项目赠款将测试以下假设：通过结合母体免疫接种的方法可以通过母乳喂养获取婴儿HIV-1，从而降低婴儿免疫接种，以将婴儿与HIV-1 ENV特异性抗体（项目1）和婴儿的主动免疫接种（项目2）。具体而言，我们将评估对母亲和婴儿的疫苗接种，具有未复制的MVA Prime以及联合全身和粘膜传播/创建者的包膜蛋白免疫促进疫苗治疗方案会增强疫苗治疗方案，并通过核心1通过核心1（核心核心核心核心）降低了核心1的免疫原性，可以降低病毒性的含量，以降低病毒性的含量，可降低病毒性的含量，或者可以降低病毒性的含量。 （SHIV）由Core 3（NHP Core）开发的挑战模型。这项工作将确定在急性母体感染和经过慢性ARV治疗的母体感染的情况下，在孕产妇和婴儿免疫中是否可以减少口腔病毒的获取（项目1和2）。此外，我们的研究利用新颖的策略来评估Core 2（B细胞核）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保护的孕妇和婴儿免疫反应。共同的研究将提供对孕产妇和婴儿免疫信息的疗效和保护机制的理解，这对于设计有效的母体和婴儿HIV-1疫苗至关重要，这对于结束儿科HIV-1流行并实现HIV-1无生成的生成至关重要。