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Developing a barcoded malaria parasite panel to assess broadly neutralizing antibodies

开发带条形码的疟原虫面板来评估广泛中和抗体

基本信息

批准号：
10511052
负责人：
Manoj T Duraisingh
金额：
$ 23.93万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-29 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10511052
关键词：
Affect Alleles Antibodies Antibody-mediated protection Antigen Targeting Antigenic Diversity Antigenic Variation Antigens Antimalarials Area Bar Codes Biological Biological Assay Blood COVID-19 pandemic CRISPR/Cas technology Cells Child Clinical Development Disease Drug Controls Epitopes Equilibrium Erythrocytes Evaluation Exhibits Falciparum Malaria Formulation Genetic Polymorphism Genetic Recombination Genomics Growth High-Throughput Nucleotide Sequencing Human Humoral Immunities Immune Targeting Immunization Immunologics In Vitro Individual Infection Insecticides Investments Malaria Malaria Vaccines Measurement Measures Mediating Methodology Modification Monoclonal Antibodies Natural Immunity Parasite resistance Parasites Pathogenicity Pathway interactions Phenotype Plasmodium falciparum Population Public Health Recommendation Research Resistance Resources Sampling Specificity Sporozoites Testing Vaccine Research Vaccines Variant World Health Organization base burden of illness combat cross immunity functional outcomes immunogenicity interest malaria infection neutralizing antibody neutralizing vaccine next generation sequencing novel vaccines parasite invasion pathogen prevent reverse genetics success tool vaccine development vector control

项目摘要

PROJECT SUMMARY Malaria remains a grave threat to global public health with concern that the limited drugs and vector control strategies at our disposal are becoming less effective. Recent progress and renewed interest in new vaccines targeting pathogens, including the Plasmodium falciparum malaria parasite, provide an opportunity to expand our toolkit to combat the disease. A highly efficacious vaccine for malaria, as for other eukaryotic parasites, has been elusive. Substantial effort has been invested in development of a pre-erythrocytic vaccine targeting the sporozoite form of the parasite, resulting in the recent recommendation by the World Health Organization for use in endemic areas. During the clinical blood-stage of malaria, many of the functional antigens that provide the parasite pathways for invasion into erythrocytes are known, and some naturally occurring antibodies are protective. Antigenic diversity and variation, among other factors, poses a major challenge for a broadly- neutralizing blood-stage vaccine, because many immune-targeted molecules for host cell entry are functionally redundant and sequence polymorphic. As antigens continue to be tested for immunogenicity, it will become a high-priority to identify those with the best potential for widespread protection against the breadth of antigenically diverse malaria parasites found across the world. We propose here to develop a platform for facile assessment of the broadly-neutralizing potential of anti-parasite antibodies. In Step 1, we will identify culture-adapted P. falciparum clonal lines that represent all major alleles of the parasite globally; and implement state-of-the-art CRISPR-Cas9 methodologies to introduce short, stably expressed barcode sequences to distinguish the lines. In Step 2, we will pool 90 barcoded lines and validate the use of Illumina-based amplicon-sequencing to deconvolute pools and measure the relative levels of the parasite lines. In Step 3, we will use the pooled assay to measure the strain-specificity of invasion inhibition and broadly-neutralizing potential of monoclonal antibodies targeting two antigens of interest for a blood-stage vaccine. The combination of population genomics, reverse genetic modification of parasites, and quantitative high- throughput sequencing, will permit us to analyze the functional outcomes of antigenic diversity at unprecedented scale and complexity; and will transform efforts to identify the most promising antigens for a potent, broadly- neutralizing malaria vaccine. We further anticipate that the approach will also be useful for non-vaccine related studies for P. falciparum, including analysis of parasite resistance to antimalarials.

项目总结