Vaccine and therapeutic antibodies against Group A Streptococcus

针对 A 组链球菌的疫苗和治疗抗体

• 批准号: 8371028
• 负责人: BENFANG LEI
• 金额: $ 21.6万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371028
• 关键词: Active Immunization; Acute Pharyngitis; Adjuvant; Amino Acids; Antibiotics; Antibodies; Antibody Therapy; Antigens; Attenuated; Biological Assay; Blood Platelets; C-terminal; Chimeric Proteins; Clinical; Communities; Data; Development; Disease; Drug Formulations; Future; Gene Deletion; Generations; Genes; Goals; Human; Hybridomas; Immune; Immunization; Immunotherapy; Infection; Interleukin-1; Lead; Licensing; Life; Mediating; Medical; Monoclonal Antibodies; Mus; Necrotizing fasciitis; Neutrophil Infiltration; Passive Immunization; Peptides; Pharyngeal structure; Pharyngitis; Phase; Publishing; Research; Serotyping; Skin; Streptococcal Infections; Streptococcus pyogenes; Streptococcus vaccine; Subcutaneous Tissue; Technology; Testing; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; United States; Vaccines; Variant; Virulence; Virulence Factors; base; effective therapy; efficacy testing; esterase; immunogenicity; mouse model; mutant; neutralizing monoclonal antibodies; neutrophil; novel strategies; pathogen; prevent; response; soft tissue; streptolysin S; subcutaneous; vaccine candidate; vaccine evaluation

DESCRIPTION (provided by applicant): Group A Streptococcus (GAS) is a major human pathogen that causes a variety of diseases, including relatively mild pharyngitis and severe invasive infections, such as necrotizing fasciitis. Unfortunately, there is no licensed GAS vaccine, and severe invasive infections are difficult to treat with conventional antibiotics. The goals of this project are to develop a candidate vaccine for GAS diseases and protective monoclonal antibodies for future development of immunotherapy to treat severe invasive infections. The endeavors of several decades made by academic and industrial communities have demonstrated that any of the vaccine candidates tested yet is not sufficient for a broad, efficacious GAS vaccine due to sequence variation or limited capacity of protection of protective antigens. As a new strategy to tackle the problems in development of GAS vaccine and treatment, we will target both the secreted esterase of GAS (designated SsE) and streptolysin S (SLS). The sse gene is required for the virulence and dissemination of a hypervirulent serotype M1 strain in a mouse model of necrotizing fasciitis. Active and passive immunizations with SsE significantly protects mice against subcutaneous GAS infection and bacterial spreading in the subcutis. Our preliminary data shows that the sse gene is also required for GAS virulence and throat colonization in intranasal infection of mice. The SsE gene is required for inhibition of neutrophil recruitment. These findings indicate that SsE is involved in the innate immune evasion by GAS and is a critical virulence factor and protective antigen. However, SsE is not a sufficiently protective antigen for some clinical strains. Our preliminary data suggest that SsE and SLS function in tandem to block neutrophil functions in subcutaneous infection of mice with a hypervirulent serotype M3 strain and that SLS is critical for GAS virulence and throat colonization. It is known that antibodies can be raised against the C-terminal fragment of SagA, the peptide component of SLS, and neutralize the hemolytic activity of SLS. We hypothesize that we can develop an efficacious, broad GAS vaccine based on SsE and SagA. We also hypothesize that monoclonal antibodies (mAbs) neutralizing the activity of SsE and SLS can be used to treat severe GAS infections. We will test the efficacy of SsE and SagA -based vaccine formulations against GAS infections using mouse models of intranasal and subcutaneous infections in Aim 1. In Aim 2, we will generate SsE- and SagA-specific inhibitory mAbs and test whether inhibitory mAbs protect mice against subcutaneous GAS infection in passive immunization. The project has the potential to lead to the development of a broad vaccine against GAS diseases and an antibody therapy to treat severe GAS infections. PUBLIC HEALTH RELEVANCE: Medical significance: Group A Streptococcus (GAS) is a major cause of acute pharyngitis and severe invasive infections in humans. Unfortunately, no licensed GAS vaccine is available, and severe invasive GAS infections are difficult to treat. This project will test the potential of two virulence factors as the targets for the development of a ne GAS vaccine and generation of protective monoclonal antibodies. If realized, the findings may lead to the further development of a broad, efficacious vaccine against GAS diseases and an immunotherapy against severe GAS infections.

描述（由申请人提供）：A组链球菌（气）是一种主要的人类病原体，可引起各种疾病，包括相对轻度的咽炎和严重的侵入性感染，例如坏死性筋膜炎。不幸的是，没有许可的气体疫苗，严重的侵入性感染很难用常规抗生素治疗。该项目的目标是开发一种用于气体疾病的候选疫苗和保护性的单克隆抗体，用于未来开发免疫疗法以治疗严重的侵入性感染。学术和工业社区几十年来的努力表明，由于序列变化或保护性抗原的保护能力有限，经过测试的任何候选疫苗候选者都不足以进行广泛的，有效的天然气疫苗。作为解决气体疫苗和治疗发展问题的新策略，我们将针对天然气的分泌酯酶（指定的SSE）和链霉菌素S（SLS）。 SSE基因是在坏死性筋膜炎小鼠模型中毒力和传播高毒性血清型M1菌株所必需的。用SSE进行主动和被动免疫可显着保护小鼠免受皮下的皮下气体感染和细菌扩散。我们的初步数据表明，在小鼠鼻内感染中，气体毒力和喉咙定殖也需要SSE基因。 SSE基因是抑制中性粒细胞募集所必需的。这些发现表明，SSE参与了气体的先天免疫逃避，是关键的毒力因子和保护性抗原。但是，对于某些临床菌株，SSE并不是足够的保护性抗原。我们的初步数据表明，SSE和SLS在串联中的功能可以阻止具有高毒性血清型M3菌株的小鼠皮下感染中嗜中性粒细胞的功能，而SLS对于气体毒力和喉咙定殖至关重要。众所周知，可以针对SAGA的C末端片段（SLS的肽成分）提出抗体，并中和SLS的溶血活性。我们假设我们可以根据SSE和SAGA开发有效的，广泛的气体疫苗。我们还假设单克隆抗体（mAb）中和SSE和SLS的活性可用于治疗严重的气体感染。我们将使用鼻内和皮下感染的小鼠模型在AIM 1中测试SSE和基于SAGA的疫苗配方对气体感染的功效。在AIM 2中，我们将产生SSE和SAGA特异性抑制性mAbs和抑制性MABS并测试抑制性MAB是否保护小鼠是否保护抗皮下气体感染的无质量感染。该项目有可能导致开发针对气体疾病的广泛疫苗和治疗严重气体感染的抗体疗法。 公共卫生相关性：医学意义：A组链球菌（气）是人类急性咽炎和严重侵入性感染的主要原因。不幸的是，没有许可的气体疫苗可用，严重的侵入性气体感染很难治疗。该项目将测试两个毒力因子的潜力，作为开发NE气体疫苗和生成保护性单克隆抗体的靶标。如果意识到，这些发现可能会导致针对气体疾病的广泛，有效的疫苗进一步开发，并对严重的气体感染进行免疫疗法。