Antibody therapy for pneumococcal disease

肺炎球菌疾病的抗体治疗

• 批准号: 10053301
• 负责人: Liise-anne Pirofski
• 金额: $ 41.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-10 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053301
• 关键词: AIDS/HIV problem; Address; Adult; Agglutination; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Response; Antibody Therapy; Antibody-mediated protection; Antigens; Apoptosis; B-Lymphocytes; Binding; Biological Assay; Child; Childhood; Clinical Medicine; Conjugate Vaccines; Data; Drug resistance; Elderly; Empyema; Epitopes; Equilibrium; Gene Expression; Gene Expression Profiling; Goals; Herd Immunity; Human; Immunity; Immunization; Immunotherapy; In Vitro; Infant; Infection; Inflammation; Inflammation Mediators; Knowledge; Learning; Lung; Lung Inflammation; Mediating; Modeling; Monoclonal Antibodies; Mus; Oligosaccharides; Passive Immunotherapy; Patients; Phagocytes; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumococcal vaccine; Pneumonia; Polysaccharides; Pre-Clinical Model; Prevention; Public Health; Risk; Sepsis; Serotyping; Specificity; Streptococcus pneumoniae; Testing; Transgenic Mice; Transgenic Organisms; Vaccines; Work; base; community acquired pneumonia; disorder risk; high risk; human monoclonal antibodies; immunogenic; improved; in vitro activity; in vivo; innovation; interest; macrophage; mortality; mortality risk; novel; novel strategies; pathogen; prevent; response; vaccine efficacy

ABSTRACT Pneumococcal polysaccharide (PPS conjugate vaccines (PCV) have had remarkable impact in preventing invasive pneumococcal disease (IPD), but there is still a gap in treatment and prevention of pneumococcal disease as current vaccines are less effective for pneumonia than IPD and less immunogenic in patients most at risk for disease. My group has a longstanding interest in vaccine-elicited PPS antibodies and how they work. We made the paradigm-shifting discovery that while some PPS3 monoclonal antibodies (MAbs) that protect mice from serotype 3 (ST3) pneumococcus mediate phagocyte killing of ST3 in vitro (opsonic), others do not (non-opsonic). These MAb types have distinct PPS3 specificities and require different effectors and FcγRs to protect mice from ST3 pneumonia. Opsonic antibodies induce early lung bacterial clearance, but non-opsonic MAbs do not, instead they reduce lung inflammation. These findings challenge prevailing dogma that vaccine efficacy is solely a function of opsonic antibodies and show there is still much to learn about how PPS antibodies mediate protection. The goal of this application is to make human monoclonal antibodies (huMAbs) to treat ST3 pneumonia. Ultimately, we wish to develop a multi-ST huMAb cocktail, but ST3 will be our first target as PCV13 is less effective for ST3, an important cause of pneumonia that still carries higher risk of death than other STs. We hypothesize huMAbs that balance ST3 clearance and control of host inflammation will provide the most protection. We will generate PPS3 huMAbs from pneumococcal vaccine recipients, use a novel ST3 glycan array to identify huMAb PPS3 epitopes, and determine their functional activities in vitro and efficacies against ST3 in vivo in colonization, pneumonia, and sepsis models in normal and human (hu)FcγR transgenic mice. This will identify candidate huMAbs to advance for therapy, reveal potentially new correlates of protection, and identify potential adjunctive PPS3 antigens to enhance vaccine efficacy for pneumonia. This project will advance understanding of mechanisms of antibody action and have a major impact on clinical medicine and public health by removing roadblocks to prevention and treatment of pneumococcal pneumonia with ideas and an approach that can be applied to any pathogen.

摘要 肺炎球菌多糖结合疫苗（pneumococcal polysaccharide conjugate vaccines，PCV）在预防肺炎方面有显著效果 侵袭性肺炎球菌病（IPD），但在治疗和预防肺炎球菌感染方面仍存在差距。 由于目前的疫苗对肺炎的效果不如IPD， 有患病的风险。我的团队对疫苗引发的PPS抗体及其工作原理有着长期的兴趣。 我们做出了范式转变的发现，虽然一些PPS 3单克隆抗体（MAbs），保护 来自血清3型（ST3）肺炎球菌的小鼠在体外介导了ST3的吞噬细胞杀伤（调理剂），其他小鼠则没有 （非调理素）。这些单克隆抗体类型具有不同的PPS 3特异性，需要不同的效应子和Fcγ R， 保护小鼠免受ST3肺炎。调理素抗体诱导早期肺细菌清除，但非调理素抗体 单克隆抗体不会，相反，它们会减少肺部炎症。这些发现挑战了流行的教条， 功效仅仅是调理素抗体的功能，这表明关于PPS如何 抗体介导保护。本申请的目标是制备人单克隆抗体（huMAbs） 治疗ST3肺炎最终，我们希望开发多ST huMAb鸡尾酒，但ST 3将是我们的第一个。 靶向为PCV 13对ST 3效果较差，ST 3是肺炎的重要原因，仍然具有较高的死亡风险 其他ST我们假设平衡ST3清除和宿主炎症控制的huMAb将 提供最大的保护。我们将从肺炎球菌疫苗接受者中产生PPS 3 huMAb，使用 新的ST3聚糖阵列，以鉴定huMAb PPS3表位，并确定其体外功能活性， 在正常和人（hu）FcγR的定植、肺炎和脓毒症模型中，体内抗ST3的疗效 转基因小鼠这将鉴定候选huMAb以推进治疗，揭示潜在的新相关性， 的保护，并确定潜在的免疫PPS 3抗原，以提高疫苗的肺炎疗效。这 该项目将促进对抗体作用机制的理解，并对临床产生重大影响。 消除预防和治疗肺炎球菌性肺炎的障碍， 可以应用于任何病原体的想法和方法。

项目成果

Post-severe Acute Respiratory Syndrome Coronavirus 2 Monoclonal Antibody Treatment Hospitalizations as a Sentinel for Emergence of Viral Variants in New York City.

• DOI: 10.1093/ofid/ofab313
• 发表时间: 2021-08
• 期刊: Open forum infectious diseases
• 影响因子: 4.2
• 作者: Cowman K;Guo Y;Pirofski LA;Wong D;Bao H;Chen V;Hopkins U;Andrews E;Hamel J;Keller M;Bellin E;Thota R;Davis P;Rodriguez ET;Suthar P;Allen L;Rossi J;Haviland A;Orner E;Szymczak W;Shujauddin S;McCarthy J;Binder B;Pushparaj V;Bard L;Pierino VF;Alsina L;Esses D;McCaskie A;Campbell C;Madzura T;Wollowitz A;Basset K;White D;Ruiz R;Sosnowski F;Nori P
• 通讯作者: Nori P

Understanding vaccine hesitancy in COVID-19.

• DOI: 10.1016/j.medj.2021.04.002
• 发表时间: 2021-05-14
• 期刊: Med (New York, N.Y.)
• 作者: Trogen B;Pirofski LA
• 通讯作者: Pirofski LA

Isolation and Characterization of Human Monoclonal Antibodies to Pneumococcal Capsular Polysaccharide 3.

• DOI: 10.1128/spectrum.01446-21
• 发表时间: 2021-12-22
• 期刊: Microbiology spectrum
• 影响因子: 3.7
• 作者: Babb R;Doyle CR;Pirofski LA
• 通讯作者: Pirofski LA