Evaluating the Functional Impact of Genetic Diversity on Malaria Vaccine Candidates

评估遗传多样性对候选疟疾疫苗的功能影响

• 批准号: 10707438
• 负责人: Amy Kristine Bei
• 金额: $ 71.86万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707438
• 关键词: 5 year old; Acceleration; Africa; Africa South of the Sahara; Alleles; Antibodies; Antigenic Diversity; Antigens; Binding; Biochemical; Biological Assay; Blood; CD147 antigen; CRISPR/Cas technology; Cause of Death; Cessation of life; Child; Complex; Country; Credentialing; Development; Disease; Drug resistance; Epitopes; Evaluation; Evolution; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genomic approach; Genomics; Goals; Growth; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunoglobulins; In Vitro; Individual; Infection; Institution; Invaded; Kinetics; Knowledge; Longitudinal cohort; Malaria; Malaria Vaccines; Measures; Methods; Organism; Parasite resistance; Parasites; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Plasmodium; Plasmodium falciparum; Plasmodium genome; Play; Population; Positioning Attribute; Pregnant Women; Process; Public Health; Publishing; Recombinant Proteins; Research; Respiratory Burst; Role; Scientist; Specificity; Standardization; Structure; Surface Plasmon Resonance; Technology; Testing; Transgenic Organisms; Tropical Disease; Vaccine Design; Vaccines; Variant; Virus Diseases; attributable mortality; candidate validation; clinical development; cohesion; cost; fitness; genome editing; genome resource; genomic data; human monoclonal antibodies; insight; member; neutralizing antibody; neutrophil; next generation; next generation sequencing; novel; novel strategies; novel vaccines; phase II trial; phase III trial; protective efficacy; protein complex; receptor; receptor binding; structural biology; tool; transmission process; vaccine candidate; vaccine development; vaccine discovery; vaccine efficacy; vaccine formulation; vaccine trial; vaccine-induced immunity; vaccinology; volunteer

ABSTRACT Malaria caused by Plasmodium falciparum remains one of the leading causes of death globally of both children and pregnant women. The recent global stall in the reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been underprioritized in the evaluation of malaria vaccine candidates. This proposal will use genomic approaches to credential next generation malaria vaccine candidates. Reverse vaccinology is a method of identifying potential antigens for a vaccine that starts with the genomic sequence of an organism and uses that information to identify epitopes and antigens that might make suitable vaccine candidates. Since the genome sequence of Plasmodium falciparum was published, only four new potential candidate vaccines have entered clinical development, including PfRh5. The main objective of the proposed study is to use a reverse-vaccinology approach utilizing parasite genomic data directly from infected patients to identify and functionally interrogate the importance of diversity in these antigens. For these current and novel candidates, including PfRh5 and binding partners, we will test the role of genetic diversity on immune neutralization by creating transgenic parasites by using efficient CRISPR-Cas9 genome editing. These parasite lines will be used to assess the role of specific variants in immune evasion prior to Phase 2 clinical trials. We will use IgG from malaria-immune individuals, followed closely in long-term longitudinal cohorts, and IgG from subjects in vaccine trials to assess the degree of inhibition of replication of malaria parasites by growth inhibition assays, neutrophil respiratory burst, and opsonophagocytosis of merozoites. This approach requires the cohesion of genomic sequencing technologies to identify potential candidate antigens and naturally occurring diversity, well-characterized human longitudinal cohorts to follow evolution of infection and immunity, standardized assays to serve as in vitro correlates of immunity, structure-based approaches for vaccine design, and strong ties to both scientists and institutions in endemic countries. Our research team is uniquely positioned to combine these critical requirements to investigate the implications of parasite diversity on the development of protective immunity and vaccine efficacy, an essential factor to accelerate malaria vaccine discovery. This approach fills a critical need in the malaria vaccine development field in that it brings genetic diversity in candidate antigens to the forefront of vaccine candidate validation and credentialing. This study holds exceptional promise to discover new vaccine candidate combinations that will provide broadly neutralizing antibodies for inclusion in a globally effective vaccine, one that circumvents the parasite’s natural strategy to evade the immune system.

抽象的 由恶性疟原虫引起的疟疾仍然是全球导致人类死亡的主要原因之一 儿童和孕妇。最近全球在减少疟疾死亡方面停滞不前，使得 开发高效疫苗至关重要。开发有效疫苗的主要挑战 恶性疟原虫抗原的广泛多样性。虽然遗传多样性在其中发挥着重要作用 免疫逃避，并且是自然和疫苗诱导的保护性免疫发展的障碍， 在评估候选疟疾疫苗时，它没有得到优先重视。该提案将使用基因组 验证下一代疟疾候选疫苗的方法。反向疫苗学是一种方法 识别疫苗的潜在抗原，从生物体的基因组序列开始并使用 该信息可用于识别可能成为合适候选疫苗的表位和抗原。自从 恶性疟原虫基因组序列公布，仅有四种新的潜在候选疫苗 已进入临床开发，包括 PfRh5。拟议研究的主要目标是使用 反向疫苗学方法利用直接来自感染患者的寄生虫基因组数据来识别和 从功能上质疑这些抗原多样性的重要性。对于这些当前和新的候选人， 包括 PfRh5 和结合伴侣，我们将通过以下方式测试遗传多样性对免疫中和的作用： 通过使用高效的 CRISPR-Cas9 基因组编辑来创建转基因寄生虫。这些寄生线将 用于在二期临床试验之前评估特定变异在免疫逃避中的作用。我们将使用 IgG 来自疟疾免疫个体，在长期纵向队列中密切跟踪，以及来自受试者的 IgG 通过生长抑制测定评估疟疾寄生虫复制抑制程度的疫苗试验， 中性粒细胞呼吸爆发和裂殖子的调理吞噬作用。这种方法需要凝聚力 基因组测序技术来识别潜在的候选抗原和自然存在的多样性， 特征明确的人类纵向队列，以跟踪感染和免疫的进化，标准化 作为免疫体外相关性的测定、基于结构的疫苗设计方法以及强大的 与流行国家的科学家和机构的联系。我们的研究团队具有独特的定位 结合这些关键要求来研究寄生虫多样性对发育的影响 保护性免疫和疫苗功效的影响，这是加速疟疾疫苗发现的重要因素。这 该方法满足了疟疾疫苗开发领域的一个关键需求，因为它带来了遗传多样性 候选抗原处于候选疫苗验证和认证的最前沿。这项研究认为 发现新的候选疫苗组合的特殊承诺将提供广泛的中和作用 将抗体纳入全球有效的疫苗中，这种疫苗可以规避寄生虫的自然策略 逃避免疫系统。