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

基本信息

批准号：
10172886
负责人：
Kristina De Paris
金额：
$ 92.08万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-06 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172886
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 Antiviral Agents 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 simian human immunodeficiency virus subcutaneous tool transmission process vaccine acceptance vaccine delivery vaccine trial

项目摘要

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).

抽象的每天，大约有400名婴儿在全球获得HIV-1，这是母乳传播的绝大多数。 HIV-1晚期在母乳喂养期间，怀孕，缺乏依从性和急性HIV-1感染的诊断仍然存在预防母亲到儿童传播（MTCT）方面的巨大障碍。这是为了实现一个目标无艾滋病生成，除抗逆转录病毒疗法（ART）外，我们还需要采取预防措施。 HIV疫苗代表了这些努力的核心组成部分。我们的长期目标是开发小儿艾滋病毒疫苗防止母乳传播艾滋病毒。尽管艾滋病毒主要是通过粘膜路线传播的很少有疫苗策略探讨了免疫抑制的粘膜途径，以诱导受保护的免疫复杂潜在的粘膜进入部位，包括婴儿的口腔粘膜。要缩小这些差距，我们开始探索口服疫苗接种可防止艾滋病毒的母乳传播的潜力。新生儿猕猴用肌肉（PO）和肌肉内（IM）DNA-SIV疫苗接种，并通过联合加强相比仅靠IM路线接收同一疫苗的婴儿。降低的感染风险与较高有关粪便标本中的SIV Env GP120和V1V2特异性IgG抗体。基于这个前提，我们介绍中心假设是合理设计的SL+亲代疫苗方案可以预防口服HIV 婴儿的收购。瓦尔德（Waldeyer）环的丰富区域淋巴网络提供了一个简单而非 - 口服疫苗摄取的入侵门户，作为系统性淋巴网络的内在部分，通过口服疫苗诱导局部和全身受保护的免疫反应。提议的目标研究是通过合理选择调节器和HIV ENV免疫来优化我们的小儿疫苗可以诱导血浆和粘膜进入位点的ENV特异性IgG和IgA抗体，例如口服粘膜和肠。我们将通过SL和皮下（SC）途径与MVA免疫婴儿表达sivgag，pol和进化枝C HIV C.1086信封（Env）NFL Trimer Plus Env NFL Trimer蛋白并检验以下假设：合并的SL+SC疫苗方案可为口服SHIV提供较高的效率与仅SC路线接种疫苗相比，CH848的挑战（目标1和2）。 env Immunogen和挑战含有艾滋病毒进化枝C的病毒C，在撒哈拉以南非洲最普遍的进化枝C 大多数小儿艾滋病毒感染发生，强调我们研究的临床相关性。我们进一步测试被选中以特异性增强粘膜免疫反应和启动的新型调节器婴儿树突状细胞的功能。确定对于高度功能的生成必不可少的途径婴儿的抗体反应，并与婴儿的口服SHIV CH848挑战有关猕猴，我们将定义确定疫苗诱导的适应性免疫的口服先天分子特征在挑战时的反应，并与挑战结果相关（AIM 3）。