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

• 批准号: 8452682
• 负责人: Stephen J. Barenkamp
• 金额: $ 28.2万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 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/8452682
• 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; public health relevance; vaccine candidate; vaccine development; vector

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.

描述（由申请人提供）：急需需要儿童的不可能的嗜血杆菌（NTHI）引起的中耳炎和其他疾病，对于儿童来说仍然是重大健康问题，并且需要预防疾病的疫苗。我们的长期目标是确定在保护性免疫反应中很重要的表面暴露的抗原，并最终确定由这种抗原组成的疫苗是否对NTHI疾病有保护。在早期工作中，我们确定了蛋白质的HMW1/HMW2和HIA家族是自然感染后人类抗体反应的主要靶标。后来，我们证明了两个蛋白质家族在NTHI粘附到人真核细胞中的关键作用。实际上，所有NTHI表达HMW/HMW2状或类似HIA的粘附素。后来，我们在免疫研究中证明了原型HMW1/HMW2蛋白原型的疫苗潜力，在该研究中，龙猫免疫肉交受到保护，以保护由同源菌株引起的NTHI耳炎培养基。我们还证明，针对这些蛋白质升高的HMW1/HMW2样蛋白和多克隆抗血清的自然人类抗体是同源性和异源HMW1/HMW2表达表达菌株的opsonoponopytic。在有关HIA蛋白的最新研究中，我们证明了针对HIA样蛋白的抗体对于同源性和异源HIA表达NTHI也是op子型蛋白质。综上所述，这些数据表明，来自HMW1/HMW2和HIA家族的蛋白质（最有可能结合使用）值得认真考虑作为预防NTHI疾病的疫苗候选者。该领域的许多专家认为，直接粘膜免疫对于成功开发了成功的中耳炎媒体疫苗至关重要。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Chinchilla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，我们将基于这些较早的研究，并确定HMW1/HMW2-和HIA样蛋白是否可以作为可行的NTHI疫苗候选者前进。首先，我们将定义针对HMW1/HMW2-和类似HIA样蛋白的人类抗体的贡献，对近代性NTHI耳炎培养基的儿童的疗养血清中发展。接下来，我们将绘制HMW1/HMW2-和HIA样蛋白的区域，这些区域表达了能够介导对同源性和异源NTHI的opsonophopytic活性识别的表达表位。最后，我们将评估表达HMW1/HMW2-或类似HIA的蛋白质的重组腺病毒载体在实验性冲突介质的Chinchilla模型中提供保护NTHI疾病的能力。我们所提出的研究在研究的有希望的疫苗抗原以及正在研究的新型粘膜免疫策略方面对该领域都是创新的。由此产生的信息将进一步迈向我们开发有效疫苗以预防幼儿中nthi ni症状和其他疾病的最终目标。