Antibody therapy for pneumococcal disease

肺炎球菌疾病的抗体治疗

基本信息

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
项目类别：
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

项目摘要

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.

抽象的肺炎球菌多糖（PPS结合疫苗（PCV）对防止侵入性肺炎球菌疾病（IPD），但治疗和预防肺炎球菌仍然存在差距疾病作为当前的疫苗对肺炎的有效性低于IPD，而对大多数患者的免疫原性较低有疾病的风险。我的小组对疫苗吸引的PPS抗体及其工作方式有很长的兴趣。我们做出了范式转移的发现，虽然有些PPS3单克隆抗体（mAb）可以保护血清型3（ST3）肺炎球菌介导ST3的吞噬细胞的小鼠体外（Opsonic）（非上语）。这些MAB类型具有不同的PPS3规格，需要不同的效果，FcγRS 保护小鼠免受ST3肺炎。 Opsonic抗体诱导早期肺细菌清除率，但非上型 mabs不会，而是减少了肺部注射。这些发现挑战了疫苗的盛行教条功效仅是opsonic抗体的函数，并且表明仍然有很多要了解PPS的功能抗体介导保护。该应用的目的是制造人类的单克隆抗体（Humabs）治疗ST3肺炎。最终，我们希望开发一种多st Humab鸡尾酒，但ST3将是我们的第一个 TARGET作为PCV13对ST3的有效性较小，ST3的肺炎的重要原因仍然具有更高的死亡风险比其他ST。我们假设Humab是平衡ST3的清除和控制宿主注入的人提供最大的保护。我们将从肺炎球菌疫苗接受者中生成PPS3 Humabs，请使用新型的ST3聚糖阵列以识别Humab PPS3表位，并在体外确定其功能活动在正常和人（HU）FcγR中对ST3体内抗体内的Efucicacies 转基因小鼠。这将确定候选Humabs进行治疗，揭示潜在的新相关性保护并确定潜在的辅助PPS3抗原，以提高肺炎的疫苗效率。项目将提高对抗体作用机制的理解，并对临床产生重大影响医学和公共卫生通过拆除障碍性肺炎肺炎的障碍和治疗有了想法和可以应用于任何病原体的方法。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Disease Severity and Durability of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Response: A View Through the Lens of the Second Year of the Pandemic.

DOI：
10.1093/cid/ciab374
发表时间：
2021-09-15
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
0
作者：
Pirofski LA
通讯作者：
Pirofski LA

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

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