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（申请人提供）：A组链球菌（GAS）是一种主要的人类病原体，可引起多种疾病，包括相对轻微的咽炎和严重的侵袭性感染，例如坏死性筋膜炎。不幸的是，目前还没有获得许可的 GAS 疫苗，并且严重的侵袭性感染很难用常规抗生素治疗。该项目的目标是开发针对 GAS 疾病的候选疫苗和保护性单克隆抗体，以用于未来开发治疗严重侵袭性感染的免疫疗法。学术界和工业界几十年来的努力表明，由于序列变异或保护性抗原的保护能力有限，任何尚未测试的候选疫苗都不足以成为广泛、有效的 GAS 疫苗。作为解决GAS疫苗和治疗开发中的问题的新策略，我们将针对GAS的分泌酯酶（指定为SsE）和链球菌溶血素S（SLS）。 sse 基因是高毒力血清型 M1 菌株在坏死性筋膜炎小鼠模型中的毒力和传播所必需的。 SsE 主动和被动免疫可显着保护小鼠免受皮下 GAS 感染和皮下细菌扩散。我们的初步数据表明，sse 基因也是小鼠鼻内感染中 GAS 毒力和喉咙定植所必需的。 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 GAS 的先天免疫逃避，是一种关键的毒力因子和保护性抗原。然而，SsE 对于某些临床菌株来说并不是足够的保护性抗原。我们的初步数据表明，SsE 和 SLS 协同作用，阻断高毒力血清型 M3 菌株皮下感染小鼠的中性粒细胞功能，并且 SLS 对于 GAS 毒力和喉咙定植至关重要。众所周知，可以针对SagA（SLS 的肽成分）的C 端片段产生抗体，并中和SLS 的溶血活性。我们假设我们可以开发一种基于 SsE 和 SagA 的有效、广泛的 GAS 疫苗。我们还假设中和 SsE 和 SLS 活性的单克隆抗体 (mAb) 可用于治疗严重的 GAS 感染。在目标 1 中，我们将使用小鼠鼻内和皮下感染模型来测试基于 SsE 和 SagA 的疫苗制剂对 GAS 感染的功效。在目标 2 中，我们将生成 SsE 和 SagA 特异性抑制性单克隆抗体，并测试抑制性单克隆抗体是否可以保护小鼠被动免疫中对抗皮下GAS感染。该项目有可能开发出针对 GAS 疾病的广泛疫苗和治疗严重 GAS 感染的抗体疗法。 公共卫生相关性：医学意义：A 族链球菌 (GAS) 是人类急性咽炎和严重侵袭性感染的主要原因。不幸的是，目前还没有获得许可的 GAS 疫苗，严重的侵袭性 GAS 感染很难治疗。该项目将测试两种毒力因子作为开发新 GAS 疫苗和生成保护性单克隆抗体的目标的潜力。如果实现，这些发现可能会导致进一步开发针对 GAS 疾病的广泛、有效的疫苗和针对严重 GAS 感染的免疫疗法。