Accelerating Malaria Vaccines with a Custom Preclinical Humanized Mouse Model Platform

利用定制的临床前人源化小鼠模型平台加速疟疾疫苗的研发

• 批准号: 10581697
• 负责人: Facundo Damian Batista
• 金额: $ 70.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581697
• 关键词: 5 year old; Acceleration; Affinity; Animal Model; Anti-malarial drug resistance; Antibodies; Antigens; Automobile Driving; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Cell Separation; Cells; Cessation of life; Child; Clinical; Clinical Trials; Communities; Custom; Data; Development; Drug Controls; Engineering; Epitopes; Erythrocytes; Etiology; Evaluation; Frequencies; Generations; Genetically Engineered Mouse; Goals; Growth; HIV-2; Health Priorities; Human; Humoral Immunities; Immune; Immune response; Immunization; Immunoglobulin Somatic Hypermutation; Infection; Insecticides; Knock-in; Knock-in Mouse; Length; Malaria; Malaria Vaccines; Modeling; Monoclonal Antibodies; Mus; Pathway interactions; Peptides; Persons; Physiological; Plasmodium falciparum; Preclinical Testing; Protein Region; Proteins; Resources; Series; Site; Sporozoites; Structure of germinal center of lymph node; Surface; Therapeutic; Time; Titrations; Vaccine Design; Vaccine Research; Vaccines; Validation; Variant; candidate validation; circumsporozoite protein; experimental study; global health; humanized mouse; immunogenicity; improved; in vivo; innovation; mortality; mouse model; novel; pre-clinical; prevent; protective allele; response; screening; single cell sequencing; success; technological innovation; tool; vaccination strategy; vaccine candidate; vaccine evaluation; vaccine immunogenicity; vector control; 5 year old; Acceleration; Affinity; Animal Model; Anti-malarial drug resistance; Antibodies; Antigens; Automobile Driving; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Cell Separation; Cells; Cessation of life; Child; Clinical; Clinical Trials; Communities; Custom; Data; Development; Drug Controls; Engineering; Epitopes; Erythrocytes; Etiology; Evaluation; Frequencies; Generations; Genetically Engineered Mouse; Goals; Growth; HIV-2; Health Priorities; Human; Humoral Immunities; Immune; Immune response; Immunization; Immunoglobulin Somatic Hypermutation; Infection; Insecticides; Knock-in; Knock-in Mouse; Length; Malaria; Malaria Vaccines; Modeling; Monoclonal Antibodies; Mus; Pathway interactions; Peptides; Persons; Physiological; Plasmodium falciparum; Preclinical Testing; Protein Region; Proteins; Resources; Series; Site; Sporozoites; Structure of germinal center of lymph node; Surface; Therapeutic; Time; Titrations; Vaccine Design; Vaccine Research; Vaccines; Validation; Variant; candidate validation; circumsporozoite protein; experimental study; global health; humanized mouse; immunogenicity; improved; in vivo; innovation; mortality; mouse model; novel; pre-clinical; prevent; protective allele; response; screening; single cell sequencing; success; technological innovation; tool; vaccination strategy; vaccine candidate; vaccine evaluation; vaccine immunogenicity; vector control

Project Abstract There were 229 million cases of malaria in 2019, leading to 409,000 deaths; effective vaccines are a global health priority. Animal models capable of prefiguring the human immune response are a vital component of the preclinical testing of vaccines. The major goal of this proposal is to apply the Batista lab's technical innovations in the rapid generation of mice with B cells bearing human B cell receptors (BCRs) to create new platforms for malaria immunogen screening and development. Vaccines targeting the infectious sporozoite stage could inhibit the establishment of clinical malaria, and sporozoite surfaces are densely covered by circumsporozoite protein (CSP); the most advanced current vaccines in human trials display regions of this protein, and we intend to use our mouse platforms to improve their targeting. For Aim 1, we will use our existing mouse model, which expresses the inferred germline version of a potent monoclonal antibody (mAb) currently in clinical trials, CIS43. Using an immunofocused approach, presenting a conserved junctional epitope between the N-terminus and the central repeat region of CSP, we have not only recapitulated the ontogeny of this potent mAb, but have also elicited variant antibodies that are even more effective in malaria challenge experiments. We intend to deep mine this effective platform with immunizations by variable-length junctional epitope peptides to 1) identify the most promising candidate junctional epitope immunogens for inclusion in vaccine design and 2) identify protective matured antibodies with potential clinical utility. In our models, B cells bearing humanized BCRs are titrated to low levels to mimic human physiological conditions. For Aim 2, we will use the CSP full-length and partial probes we have developed for characterizing our mouse models, in tandem with single-cell sequencing, to explore the frequencies of precursor B cells in humans. We will use these numbers to improve the precision of our mouse platform, titrating the humanized cells to more exactingly accurate levels. Finally, in Aim 3, we will take this immunofocusing approach to other regions of the CSP protein by creating a new series of mice expressing the precursor sequences of human antibodies to other subdomains of CSP. We will use this mouse platform to study the immunogenicity of peptides consisting of various sections of the CSP protein, with the goal of identifying the ideal epitope, or combination of epitopes, to elicit robust immune responses. We will enhance our models by moving multiple strains of KI B cells to the same host to try immunogens against “mini-repertoires” of humanized B cells. By creating these new precision platforms for malaria, we intend to cut the time needed to validate potential vaccine candidates.

项目摘要 2019年有2.29亿例疟疾病例，导致409,000例死亡；有效的疫苗 是全球健康优先事项。能够预先配置人免疫反应的动物模型 是疫苗临床前测试的重要组成部分。该提议的主要目标是 将Batista实验室的技术创新应用于带有B细胞的快速生成小鼠 人类B细胞受体（BCR）为疟疾免疫原筛查和 发展。针对感染性孢子岩阶段的疫苗可能会抑制建立 临床疟疾和孢子岩表面被电路孢子蛋白覆盖 （CSP）;人类试验中最先进的当前疫苗显示该蛋白质的区域，我们 打算使用我们的鼠标平台来改善其目标。对于AIM 1，我们将使用现有的 鼠标模型，表达有效的单克隆抗体的推断种系版本 （MAB）目前正在临床试验中，顺式43。使用免疫局限器的方法，呈现 N末端与CSP的中央重复区域之间的保守连接发作，我们 不仅概括了该电势mAb的个体发育，还引起了变体 在疟疾挑战实验中更有效的抗体。我们打算深我 这个有效的平台通过可变的长度连接表位肽进行免疫接种至1） 确定最有前途的候选交叉发作免疫剂，用于纳入疫苗 设计和2）鉴定具有潜在临床实用性的受保护的成熟抗体。在我们的模型中，b 携带人源化BCR的细胞被滴定到模拟人类生理状况的低水平。 对于AIM 2，我们将使用我们开发的CSP全长和部分问题来表征 我们的鼠标模型与单细胞测序同时探索前体的频率 人类的B细胞。我们将使用这些数字来提高鼠标平台的精度， 将人性化细胞滴定到更准确的水平。最后，在AIM 3中，我们将接受此操作 通过创建一系列新的小鼠，对CSP蛋白的其他区域进行免疫焦点的方法 表达对CSP其他亚域的人类抗体的前体序列。我们将 使用此鼠标平台研究辣椒的免疫原性，由各个部分组成 CSP蛋白，目的是识别理想的表位或表位的组合以引起 强大的免疫反应。我们将通过移动多个Ki B细胞来增强我们的模型 对同一宿主尝试对人源化B细胞的“迷你替代”的免疫原子。通过创建 这些新的疟疾精确平台，我们打算削减验证潜力所需的时间 候选疫苗。