Vitamin A adjuvant to enhance gut immunity and rotavirus vaccines in neonates

增强新生儿肠道免疫力的维生素 A 佐剂和轮状病毒疫苗

• 批准号: 7706606
• 负责人: Linda J. Saif
• 金额: $ 21.78万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706606
• 关键词: Acute; Address; Adjuvant; Adoption; Adult; Adverse effects; Africa; African; Age; All-Trans-Retinol; Anatomy; Animal Model; Animals; Antibodies; Antigens; Asia; Asians; Attenuated; B-Lymphocytes; CCR9 gene; Cell Maturation; Cells; Cessation of life; Child; Child health care; Childhood; Cholera Toxin; Clinical Research; Communicable Diseases; Country; Data; Dendritic Cells; Developed Countries; Developing Countries; Development; Diarrhea; Disease; Disease model; Dose; Double-Stranded RNA; Down-Regulation; Effectiveness; Enterocytes; Enzymes; Eragrostis; Family suidae; Food; Gastrointestinal Physiology; Gnotobiotic; Goals; HIV; Homing; Human; Immune; Immune response; Immune system; Immunity; Immunization Programs; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin-Secreting Cells; Immunologics; Immunosuppression; Inbred Mouse; Infant; Infection; Inflammation Mediators; Inflammatory; Influenza; Interferon-alpha; Interferons; Intestines; Lesion; Licensing; Life; Ligands; Link; Lymphocyte; Malnutrition; Measles Vaccine; Mediating; Mediator of activation protein; Metabolism; Micronutrients; Modeling; Mucosal Immune Responses; Mucosal Immunity; Natural Killer Cells; Neonatal; Nutrient; Nutritional Requirements; Oral; Outcome; Parasites; Pathway interactions; Poliomyelitis; Poly C; Population Heterogeneity; Predisposition; Prevalence; Production; Risk; Role; Rotavirus; Rotavirus Vaccines; Serum; Signal Transduction; Signaling Molecule; Structure; Supplementation; T-Lymphocyte; TLR3 gene; Target Populations; Testing; Tretinoin; Up-Regulation; Vaccine Adjuvant; Vaccines; Villous Atrophy; Villus; Viral Gastroenteritis; Virulence; Virulent; Virus-like particle; Vitamin A; Vitamin A Deficiency; base; combat; cost; cytokine; cytotoxic; design; enteric pathogen; gut microflora; immunogenicity; imprint; improved; in vivo; innovation; micronutrient deficiency; migration; mortality; mucosal vaccine; neonate; novel; novel strategies; oral vaccine; particle; receptor; response; vaccine development; vaccine effectiveness; vaccine efficacy

DESCRIPTION (provided by applicant): Rotavirus (RV) causes diarrhea in infants worldwide with most deaths in Africa and Asia. Newly licensed oral RV vaccines have unproven or lower efficacies in infants in impoverished countries. Their high costs remain obstacles to universal adoption. In developing countries, widespread vitamin A deficiencies (VAD) compromise children's health, gut immune responses and vaccine effectiveness. WHO has linked vitamin A (VitA) supplementation in infants to immunization programs to reduce VAD and increase vaccine coverage. The impact of VitA supplementation on RV vaccines is unknown. Our innovative and novel strategy is to use supplemental VitA as an adjuvant with oral vaccines in neonates. New discoveries have revealed that VitA is a key regulator of intestinal immune responses and that VAD impairs gut immune responses. Gut dendritic cells (DCs) convert dietary VitA to retinoic acid (RA) and DCs and/or RA in concert with key signaling molecules (cytokines, inflammatory mediators), imprint gut homing (CCR9, a4¿7) on T and B cells, promote isotype switching to IgA and enhance IgA production. In infants and piglets, fecal or serum IgA antibodies or IgA antibody secreting cells in the gut correlate with protection against RV diarrhea. Gut DCs orchestrate critical upregulation of intestinal immune responses (via Teffector, B cells and mediators) to enteric pathogens or downregulation (via immunoregulatory T cells and mediators like TGF¿) to food antigens and commensals. We hypothesize that "danger signals" consisting of inflammatory or TLR signaling are essential to activate DCs to overcome intestinal downregulation and increase immune responses to oral vaccines. To test this, we will use attenuated RV that replicates in enterocytes, (increase proinflammatory, decrease TGF¿ cytokines) as oral vaccine with VitA adjuvant to enhance gut IgA responses. Alternatively nonreplicating rotavirus-like-particle (VLP) vaccines may require TLR signals (polyinosine-polycytidylic acid synthetic dsRNA, TLR3 ligand) with VitA to mimic the effect of RV dsRNA. Using VitA as adjuvant, we will compare immune responses to live attenuated (Aim 1) with VLP (Aim 2) oral RV vaccines. Vaccine efficacy will be tested in VAD versus VitA replete neonatal gnotobiotic (Gn) pigs challenged with virulent human RV (Aim 3). Neonatal Gn piglets mimic infants in their gastrointestinal physiology, mucosal immune responses and susceptibility to human RV diarrhea. Pigs metabolize VitA like humans and VitA levels can be manipulated to mimic VAD in infants. To elucidate immune mechanisms, we will assess innate (DCs, NK/NKT cells, IFNa, inflammatory cytokines) and adaptive T (Teff/Treg ratio) and B cell (IgA) intestinal immune responses, including gut DC and cytokine profiles and their correlation with protection. Understanding the impact of VAD on gut immunity is critical to improve oral vaccine efficacy in VAD infants in developing countries. If successful, strategic implementation of supplemental VitA in infants (as recommended by WHO) with existing RV oral vaccines may be feasible and could provide more cost-effective vaccines (lower, fewer doses) in developing countries. An innovative outcome would be universal application of VitA adjuvants not only to RV vaccines, but also to other mucosal vaccines such as for HIV. RELEVANCE: Rotavirus (RV) causes 660,000 childhood deaths annually worldwide, with most (90%) in Africa and Asia. Although live oral rotavirus vaccines are licensed, their unproven or lower effectiveness in infants in impoverished countries, where they are most needed, and high costs remain obstacles to their universal adoption. In developing countries, widespread malnutrition with micronutrient deficiencies (vitamin A, etc) and multiple concurrent infections compromise children's health, gut immune responses and vaccine effectiveness. New discoveries have revealed that vitamin A is a key regulator of intestinal immune responses and that vitamin A deficiency impairs gut immune responses. We will test supplemental vitamin A as adjuvant with live or nonreplicating oral rotavirus vaccines in vitamin A deficient versus vitamin A replete neonatal gnotobiotic pigs. Our studies will elucidate the immune responses and correlates of protection to challenge with virulent human rotavirus. Neonatal gnotobiotic piglets will be used as a disease model because they are the only animal susceptible to human rotavirus diarrhea. Moreover they are similar to infants in anatomy, gastrointestinal physiology, nutrient requirements/metabolism, and development of mucosal immunity. Also swine metabolize retinol comparable to humans. Thus the effects of vitamin A on the porcine immune system most closely mimic that in humans, and piglets best mirror responses of infants to rotavirus diarrhea and vaccines. An understanding of impacts of vitamin A deficiency on gut immune responses is critical to improve oral vaccine efficacy in vitamin A compromised infants in developing countries. If successful, immediate implementation of supplemental vitamin A in infants (as recommended by WHO) with the existing RV vaccines may be feasible and could provide more cost-effective vaccines (lower, fewer doses) in developing countries. Vitamin A adjuvants may be universally applicable, not only to rotavirus vaccines, but also to other mucosal vaccines for humans such as HIV.

描述（由申请人提供）：轮状病毒 (RV) 会导致全球婴儿腹泻，其中大多数死亡发生在非洲和亚洲。新获得许可的口服 RV 疫苗对贫困国家的婴儿的疗效尚未得到证实或较低，但其高昂的成本仍然是其普遍采用的障碍。在发展中国家，普遍存在的维生素 A 缺乏症 (VAD) 会损害儿童的健康、肠道免疫反应和疫苗的有效性，世卫组织已将婴儿维生素 A (VitA) 补充剂与减少 VAD 的免疫计划联系起来。补充 VitA 对 RV 疫苗的影响尚不清楚，我们的创新策略是使用补充 VitA 作为新生儿口服疫苗的佐剂。 VAD 会损害肠道免疫反应，肠道树突状细胞 (DC) 将饮食中的 VitA 转化为视黄酸 (RA)，并且 DC 和/或 RA 与关键信号分子（细胞因子、在婴儿和仔猪中，粪便或血清中的 IgA 抗体或肠道中的 IgA 抗体分泌细胞与 T 细胞和 B 细胞上的肠道归巢（CCR9、a4¿7）相关，促进同种型转换为 IgA 并增强 IgA 的产生。肠道 DC 协调肠道免疫反应（通过 T 效应器、B 细胞和介质）对肠道病原体的关键上调或下调（通过免疫调节 T 细胞）。以及 TGF 等介体?? ）到食物抗原和共生体，我们发现由炎症或 TLR 信号传导组成的“危险信号”对于激活 DC 克服肠道下调并增加对口服疫苗的免疫反应至关重要。为了测试这一点，我们将使用在肠细胞中复制的减毒 RV。 ，（增加促炎性，减少 TGF¿ 细胞因子）作为含有 VitA 佐剂的口服疫苗，以增强肠道 IgA 反应，或者可能需要非复制型轮状病毒样颗粒 (VLP) 疫苗。 TLR 信号（聚肌苷-聚胞苷酸合成 dsRNA，TLR3 配体）与 VitA 一起模拟 RV dsRNA 的效果。使用 VitA 作为佐剂，我们将比较减毒活疫苗 (目标 1) 与 VLP (目标 2) 口服 RV 疫苗的免疫反应。将在 VAD 与充满 VitA 的新生无菌 (Gn) 猪中测试疫苗功效，并用有毒人类 RV 进行攻击（目标 3）。新生 Gn 仔猪的胃肠道生理、粘膜免疫反应和对人类 RV 腹泻的易感性相似，猪像人类一样代谢 VitA，并且可以通过控制 VitA 水平来模拟婴儿的 VAD。先天性（DC、NK/NKT 细胞、IFNa、炎症细胞因子）和适应性 T（Teff/Treg 比率）和 B 细胞(IgA) 肠道免疫反应，包括肠道 DC 和细胞因子谱及其与保护的相关性，了解 VAD 对肠道免疫的影响对于提高发展中国家 VAD 婴儿口服疫苗的功效至关重要。婴儿（按照世卫组织的建议）接种现有的 RV 口服疫苗可能是可行的，并且可以在发展中国家提供更具成本效益的疫苗（更低、更少的剂量），一个创新成果是不仅将 VitA 佐剂普遍应用于 RV 疫苗，而且还可以在 RV 疫苗中普遍应用 VitA 佐剂。也对其他人粘膜疫苗，例如艾滋病毒疫苗。 相关性：轮状病毒 (RV) 每年导致 660,000 名儿童死亡，其中大多数 (90%) 发生在非洲和亚洲，尽管口服轮状病毒活疫苗已获得许可，但其在最需要疫苗的贫困国家的婴儿中的有效性尚未得到证实或较低，且效果较高。在发展中国家，普遍的营养不良和微量营养素缺乏（维生素 A 等）和多种并发感染损害了儿童的健康、肠道免疫反应和疫苗。新发现表明，维生素 A 是肠道免疫反应的关键调节剂，维生素 A 缺乏会损害肠道免疫反应。我们将在缺乏维生素 A 和补充维生素 A 的情况下测试补充维生素 A 与活或非复制口服轮状病毒疫苗的佐剂。我们的研究将阐明对有毒人类轮状病毒的免疫反应和保护的相关性，因为它们是疾病模型。猪是唯一易患人类轮状病毒腹泻的动物，而且它们在解剖学、胃肠道生理学、营养需求/代谢和粘膜免疫发育方面与婴儿相似，因此维生素 A 对猪免疫系统的影响也与人类相似。最接近人类的情况，仔猪最能反映婴儿对轮状病毒腹泻和疫苗的反应。了解维生素 A 缺乏对肠道免疫反应的影响对于提高口服疫苗的功效至关重要。如果成功，立即在婴儿中补充维生素 A（按照世界卫生组织的建议）和现有的 RV 疫苗可能是可行的，并且可以在发展中国家提供更具成本效益的疫苗（更低、更少的剂量）。维生素A佐剂可能普遍适用，不仅适用于轮状病毒疫苗，还适用于其他人类粘膜疫苗，例如艾滋病毒。