Development of a vaccine for prevention of Haemophilus influenzae otitis media

预防流感嗜血杆菌中耳炎疫苗的研制

基本信息

批准号：
8193934
负责人：
Stephen J. Barenkamp
金额：
$ 30万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8193934
关键词：
Acute Address Adenovirus Vector Adenoviruses Adhesions Adult Affinity Amino Acid Sequence Animals Antibodies Antibody Formation Antigens Bacteria Bacterial Adhesins Bacterial Antigens Bacterial Proteins Biological Assay Bordetella pertussis Child Chinchilla (genus)Collection Data Development Disease Epithelial Cells Epitopes Eukaryotic Cell Experimental Models Family Genes Goals Grant Haemophilus Vaccines Haemophilus influenzae Health Hemagglutinin Hemophilus Human Immune Sera Immune response Immunization Infection Laboratories Maps Mediating Modeling Molecular Weight Monoclonal Antibodies Nontypable Haemophilus influenza Otitis Otitis Media Pertussis Predisposition Preparation Prevention Protein Family Proteins Recombinant Fusion Proteins Recombinant Vaccines Recombinants Role Serum Serum Proteins Surface Vaccine Antigen Vaccines Work bactericide base defined contribution disorder prevention domain mapping ear infection immunogenic immunogenicity innovation killings novel prototype vaccine candidate vaccine development vector

项目摘要

DESCRIPTION (provided by applicant): Otitis media and other illnesses caused by nontypeable Haemophilus influenzae (NTHi) remain significant health problems for children and a vaccine for prevention of disease is much needed. Our long-term objectives are to identify surface-exposed antigens of NTHi that are important in a protective immune response, and ultimately, to determine whether a vaccine composed of such antigens would be protective against NTHi disease. In early work, we identified the HMW1/HMW2 and Hia families of proteins as major targets of the human antibody response following natural infection. We later demonstrated a critical role for both protein families in adhesion of NTHi to human eukaryotic cells. Virtually all NTHi express either HMW/HMW2-like or Hia-like adhesins. We later demonstrated the vaccine potential of prototype HMW1/HMW2 proteins in immunization studies in which chinchillas immunized parenterally were protected against NTHi otitis media caused by the homologous strain. We also demonstrated that naturally-acquired human antibodies specific for the HMW1/HMW2-like proteins and polyclonal antisera raised against these proteins are opsonophagocytic for both homologous and heterologous HMW1/HMW2-expressing strains. In more recent work on the Hia proteins, we demonstrated that antibodies specific for the Hia-like proteins are also opsonophagocytic for homologous and heterologous Hia-expressing NTHi. Taken together, these data suggest that proteins from both the HMW1/HMW2 and Hia families, most likely in combination, deserve serious consideration as vaccine candidates for prevention of NTHi disease. Direct mucosal immunization is thought by many experts in the field to be critical to development of a successful otitis media vaccine. In our very recent work, we constructed recombinant adenovirus vectors expressing either HMW1/HMW2 or Hia proteins and demonstrated the immunogenicity of these constructs in the chinchilla otitis model. In the proposed work, we will build upon these earlier studies and determine whether the HMW1/HMW2- and Hia-like proteins can move forward as viable NTHi vaccine candidates. First, we will define the contribution of human antibodies produced against the HMW1/HMW2- and Hia-like proteins to the opsonophagocytic activity that develops in convalescent sera of children with acute NTHI otitis media. Next, we will map the regions of the HMW1/HMW2- and Hia-like proteins that express epitopes recognized by antibodies capable of mediating opsonophagocytic activity against both homologous and heterologous NTHi. Finally, we will assess the ability of recombinant adenovirus vectors expressing the HMW1/HMW2- or Hia-like proteins to provide protection against NTHi disease in the chinchilla model of experimental otitis media. Our proposed studies are innovative for the field both in terms of the promising vaccine antigens under study and in terms of the novel mucosal immunization strategy being investigated. The resulting information will move us further towards our ultimate goal of developing effective vaccines for prevention of NTHi otitis media and other diseases in young children. PUBLIC HEALTH RELEVANCE: Ear infections caused by nontypeable Haemophilus influenzae bacteria are a major problem for children everywhere. The objective of our work is to develop a vaccine for prevention of these Haemophilus ear infections. We previously identified two related bacterial proteins that are very promising vaccine candidates and we will further assess their vaccine potential in the studies proposed in this grant.

描述（由申请人提供）：由不可分型流感嗜血杆菌（NTHi）引起的中耳炎和其他疾病仍然是儿童的重大健康问题，因此非常需要用于预防疾病的疫苗。我们的长期目标是鉴定对保护性免疫反应很重要的 NTHi 表面暴露抗原，并最终确定由此类抗原组成的疫苗是否能够预防 NTHi 疾病。在早期工作中，我们确定 HMW1/HMW2 和 Hia 蛋白家族是自然感染后人类抗体反应的主要靶标。我们后来证明了这两个蛋白家族在 NTHi 与人类真核细胞粘附中的关键作用。几乎所有 NTHi 都表达 HMW/HMW2 样或 Hia 样粘附素。我们后来在免疫研究中证明了原型 HMW1/HMW2 蛋白的疫苗潜力，其中肠胃外免疫的龙猫可以免受同源菌株引起的 NTHi 中耳炎的影响。我们还证明，天然获得的 HMW1/HMW2 样蛋白特异性人类抗体和针对这些蛋白产生的多克隆抗血清对于同源和异源 HMW1/HMW2 表达菌株均具有调理吞噬作用。在最近对 Hia 蛋白的研究中，我们证明了对 Hia 样蛋白具有特异性的抗体对于同源和异源表达 Hia 的 NTHi 也具有调理吞噬作用。总而言之，这些数据表明，来自 HMW1/HMW2 和 Hia 家族的蛋白质（很可能是组合）值得认真考虑作为预防 NTHi 疾病的候选疫苗。该领域的许多专家认为直接粘膜免疫对于成功开发中耳炎疫苗至关重要。在我们最近的工作中，我们构建了表达 HMW1/HMW2 或 Hia 蛋白的重组腺病毒载体，并在龙猫中耳炎模型中证明了这些构建体的免疫原性。在拟议的工作中，我们将在这些早期研究的基础上确定 HMW1/HMW2 和 Hia 样蛋白是否可以作为可行的 NTHi 候选疫苗继续发展。首先，我们将定义针对 HMW1/HMW2 和 Hia 样蛋白产生的人类抗体对急性 NTHI 中耳炎儿童恢复期血清中形成的调理吞噬活性的贡献。接下来，我们将绘制 HMW1/HMW2 和 Hia 样蛋白的区域图，这些蛋白表达由能够介导针对同源和异源 NTHi 的调理吞噬活性的抗体识别的表位。最后，我们将评估表达 HMW1/HMW2 或 Hia 样蛋白的重组腺病毒载体在实验性中耳炎模型中提供针对 NTHi 疾病的保护的能力。我们提出的研究无论是在正在研究的有前途的疫苗抗原方面还是在正在研究的新型粘膜免疫策略方面都是该领域的创新。由此产生的信息将推动我们进一步实现开发有效疫苗来预防幼儿 NTHi 中耳炎和其他疾病的最终目标。公共卫生相关性：由无法分型的流感嗜血杆菌引起的耳部感染是世界各地儿童的一个主要问题。我们工作的目标是开发一种疫苗来预防这些嗜血杆菌耳部感染。我们之前发现了两种相关的细菌蛋白，它们是非常有前途的候选疫苗，我们将在本次拨款中提出的研究中进一步评估它们的疫苗潜力。