Subingual-parenteral Vaccination to Prevent Oral HIV Transmission in Infants

舌下注射疫苗预防婴儿经口艾滋病毒传播

• 批准号: 10425465
• 负责人: Kristina De Paris
• 金额: $ 91.17万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-06 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425465
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Acute; Adherence; Adjuvant; Adult; Africa South of the Sahara; Agonist; Antibodies; Antibody Response; Antigen-Presenting Cells; Antigens; Avidity; Breast Feeding; CD8-Positive T-Lymphocytes; Cells; Child; Childhood; Clinical Trials; DNA; Dendritic Cells; Development; Diagnosis; Disease; Drug resistance; Frequencies; Generations; Goals; Growth; HIV; HIV Envelope Protein gp120; HIV diagnosis; HIV envelope protein; HIV vaccine; HIV-1; Human; Human Milk; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunize; Immunoglobulin A; Immunoglobulin G; Infant; Infection; Intestines; Intramuscular; Lymphatic System; Macaca; Mediating; Molecular Profiling; Mother-to-child HIV transmission; Mothers; Mucosal Immune Responses; Mucous Membrane; Newborn Infant; Oral; Oral mucous membrane structure; Outcome; Pathway interactions; Perinatal; Plasma; Poly I-C; Pregnancy; Prevention; Preventive measure; Proteins; Regimen; Risk; Route; SIV; Saliva; Secondary Immunization; Site; Specimen; T cell response; T-Lymphocyte; TLR3 gene; TLR7 gene; Testing; Time; Vaccinated; Vaccination; Vaccines; Vertical Disease Transmission; Viral; Virus; Virus Replication; acute infection; adaptive immune response; aluminum sulfate; antiretroviral therapy; base; clinically relevant; cytotoxic; design; env Gene Products; in utero; infant infection; infection risk; lymph nodes; neutralizing antibody; nonhuman primate; novel; oral HIV; oral infection; oral vaccine; pediatric human immunodeficiency virus; pediatric human immunodeficiency virus infection; poxvirus vectors; preclinical trial; prevent; rational design; simian human immunodeficiency virus; subcutaneous; tool; translational potential; transmission process; vaccine acceptance; vaccine delivery; vaccine strategy; vaccine trial

ABSTRACT Every day, about 400 infants acquire HIV-1 globally, the vast majority by breast milk transmission. Late HIV-1 diagnosis in pregnancy, lack of adherence, and acute HIV-1 infection during the breastfeeding period remain significant hurdles in the prevention of mother-to-child-transmission (MTCT). Thus, to achieve the goal of an AIDS-free generation, we need preventive measures in addition to antiretroviral therapy (ART). An HIV vaccine represents a core component of these efforts. Our long-term goal is the development of a pediatric HIV vaccine to protect against breastmilk transmission of HIV. Despite HIV being transmitted primarily by mucosal routes, few vaccine strategies explored mucosal routes of immunization to induce protective immune responses at potential mucosal entry sites, including the oral mucosa in infants. To close these gaps, we started to explore the potential of oral vaccination in the protection against breastmilk transmission of HIV. Newborn macaques vaccinated with a combined oral (PO) and intramuscular (IM) DNA-SIV prime and boosted by combined sublingual (SL) and IM MVA-SIV had a significantly reduced per-exposure-risk of oral SIV infection compared to infants receiving the same vaccine by the IM route alone. Reduced infection risk was associated with higher SIV Env gp120 and V1V2 specific IgG antibodies in fecal specimens. Based on this premise, we present the central hypothesis that a rationally designed combined SL+parental vaccine regimen can prevent oral HIV acquisition in infants. The rich regional lymphatic network of the Waldeyer’s Ring provides an easy and non- invasive portal for oral vaccine uptake, and, as an intrinsic part of the systemic lymphatic network, enables the induction of local and systemic protective immune responses by oral vaccines. The objective of the proposed studies is to optimize our pediatric vaccine through rational selection of adjuvants and HIV Env immunogens that can induce Env-specific IgG and IgA antibodies in plasma and at mucosal entry sites, such as the oral mucosa and the intestine. We will immunize infants by the SL and subcutaneous (SC) route with MVA expressing SIVgag, pol and the clade C HIV C.1086 envelope (Env) NFL trimer plus Env NFL trimer protein and test the hypothesis that a combined SL+SC vaccine regimen provides superior efficacy against oral SHIV CH848 challenge compared to vaccination by only the SC route (Aims 1 and 2). Both Env immunogen and challenge virus contain Envs of HIV clade C, the clade most prevalent in sub-Saharan Africa where the majority of pediatric HIV infections occur, emphasizing the clinical relevance of our studies. We further test novel adjuvants that were selected to specifically enhance mucosal immune responses and the priming function of infant dendritic cells. To identify pathways that are essential for the generation of highly functional antibody responses in infants and are associated with protection against oral SHIV CH848 challenge in infant macaques, we will define oral innate molecular signatures that determine vaccine-induced adaptive immune responses at the time of challenge and are correlated with challenge outcome (Aim 3).

抽象的 全球每天约有 400 名婴儿感染 HIV-1，其中绝大多数是通过母乳传播。晚期HIV-1 妊娠期诊断、缺乏依从性以及母乳喂养期间急性 HIV-1 感染仍然存在 预防母婴传播（MTCT）的重大障碍。因此，要达到一个目标 没有艾滋病的一代，除了抗逆转录病毒治疗（ART）之外，我们还需要预防措施。艾滋病毒疫苗 是这些努力的核心组成部分。我们的长期目标是开发儿童艾滋病毒疫苗 以防止艾滋病毒母乳传播。尽管艾滋病毒主要通过粘膜途径传播， 很少有疫苗策略探索粘膜免疫途径以诱导保护性免疫反应 潜在的粘膜进入部位，包括婴儿的口腔粘膜。为了缩小这些差距，我们开始探索 口服疫苗接种在预防艾滋病毒母乳传播方面的潜力。新生猕猴 联合口服 (PO) 和肌内 (IM) DNA-SIV 初免疫苗接种，并通过联合疫苗加强 与舌下含服 (SL) 和 IM MVA-SIV 相比，每次接触口腔 SIV 感染的风险显着降低 仅通过 IM 途径接受相同疫苗的婴儿。感染风险降低与更高的感染风险相关 粪便样本中的 SIV Env gp120 和 V1V2 特异性 IgG 抗体。基于这个前提，我们提出 中心假设：合理设计的 SL+亲本疫苗联合方案可以预防口服 HIV 婴儿获得。瓦氏环丰富的区域淋巴网络提供了一种简单且非 口服疫苗摄取的侵入性门户，并且作为全身淋巴网络的固有部分，使得 通过口服疫苗诱导局部和全身保护性免疫反应。拟议的目标 研究的目的是通过合理选择佐剂和HIV包膜免疫原来优化我们的儿科疫苗 可以在血浆和粘膜入口部位（例如口腔）诱导 Env 特异性 IgG 和 IgA 抗体 粘膜和肠道。我们将通过 SL 和皮下 (SC) 途径使用 MVA 对婴儿进行免疫接种 表达 SIVgag、pol 和进化枝 C HIV C.1086 包膜 (Env) NFL 三聚体加上 Env NFL 三聚体蛋白 并检验以下假设：SL+SC 联合疫苗方案可提供针对口服 SHIV 的卓越功效 CH848 攻击与仅通过 SC 途径进行疫苗接种进行比较（目标 1 和 2）。 Env 免疫原和 挑战病毒含有 HIV 分支 C 的包膜，该分支在撒哈拉以南非洲地区最流行，在那里 大多数儿童艾滋病毒感染都会发生，这强调了我们研究的临床相关性。我们进一步测试 选择专门增强粘膜免疫反应和启动的新型佐剂 婴儿树突状细胞的功能。确定生成高功能物质所必需的途径 婴儿体内的抗体反应，并与婴儿免受口服 SHIV CH848 攻击的保护有关 猕猴，我们将定义口腔先天分子特征，以确定疫苗诱导的适应性免疫 挑战时的反应并与挑战结果相关（目标 3）。