Large Scale systematic priorization of Plasmodium vivax blood stage vaccine antigens

间日疟原虫血期疫苗抗原的大规模系统优先级排序

基本信息

批准号：
10219142
负责人：
Julian Charles Rayner
金额：
$ 31.8万
依托单位：
UNIVERSITY OF CAMBRIDGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-14 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219142
关键词：
Africa Africa South of the Sahara Antibodies Antigen Receptors Antigenic Diversity Antigens Antimalarials Asia Attention Benign Binding Binding Proteins Bioinformatics Biological Biological Assay Biology Blocking Antibodies Blood Brazil Cells Child Clinical Clinical Data Clinical Trials Collaborations Communities Development Diagnosis Disease Erythrocytes Future Gene Expression Genome Genomics Geography Goals Growth India Infection Institutes Lead Length Libraries Liver Location Malaria Malaria Vaccines Methodology Morbidity - disease rate Parasitemia Parasites Phase II/III Trial Phenotype Plasmodium falciparum Plasmodium vivax Plasmodium vivax vaccine Play Price Proteins Public Health Public Health Schools Publishing Reagent Research Resistance Resources Role South America Southeastern Asia System Techniques Testing Transcend Vaccine Antigen Vaccine Research Vaccines Vivax Malaria Work antibody test base biophysical properties burden of illness case control chemokine receptor diverse data economic impact erythrocyte receptor experience infection risk innovation low and middle-income countries mortality novel novel vaccines open-access repositories parasite invasion polyclonal antibody protein expression receptor receptor binding research clinical testing response screening technological innovation transcriptome sequencing transmission process vaccine candidate vaccine development vaccinology

项目摘要

Summary Despite recent progress in reducing severe disease in sub-Saharan Africa, malaria remains one of the largest global public health burdens and a leading cause of mortality in children in low and middle income countries. There is an urgent need for an effective malaria vaccine because resistance has emerged to every antimalarial drug that has been publicly released to date. Vaccines against Plasmodium falciparum, the major cause of malaria in Africa, have received extensive support and are showing encouraging signs, but vaccine research for Plasmodium vivax, the major cause of malaria outside of Africa, has to date been extremely limited. This proposal will use the lessons from P. falciparum vaccine development, which for too long focussed on a limited number of candidates and did not make use of the full depth of available genomic sequence information. The central objective is to carry out the first comprehensive reverse vaccinology assessment of P. vivax blood stage antigens, combining advanced genomic and cellular techniques with ex vivo phenotyping assays. An established eukaryotic protein expression system will be used to express a library of >200 P. vivax blood stage vaccine candidates, which will be selected based on gene expression, biophysical characteristics and genomic diversity criteria. All expression constructs will be made freely available to the research community to aid global P. vivax vaccine and biology research efforts. The expressed proteins will be screened for antibody binding to confirm correct folding, and used in erythrocyte and receptor binding assays to prioritise targets for further study. Polyclonal antibodies will be raised against 100 targets and used in ex vivo P. vivax invasion phenotyping assays, to identify antibodies that block parasite invasion or growth. P. vivax parasites from both South America and Southeast Asia will be used at this stage of screening, introducing antigenic diversity at the earliest stage of target prioritization, another important lesson from P. falciparum vaccine development where strain-specific inhibitory responses derailed several promising candidates. Antibodies that provide cross- strain inhibition will be tested in combination to identify >4 highly effective and synergistic candidates for future development and potential clinical testing. The proposal will radically change the scale and pace of P. vivax vaccine development, and will produce resources of broad utility to the malaria research community.

概括尽管最近在减少撒哈拉以南非洲严重疾病方面取得了进展，但疟疾仍然存在全球最大的公共卫生负担之一，也是儿童死亡的主要原因低收入和中等收入国家。迫切需要有效的疟疾疫苗因为每种公开发布的抗疟药都出现了耐药性迄今为止。恶性疟原虫疫苗是非洲疟疾的主要原因获得了广泛的支持并显示出令人鼓舞的迹象，但疫苗研究间日疟原虫是非洲以外地区疟疾的主要原因，迄今为止，该病已被严重有限的。该提案将借鉴恶性疟原虫疫苗开发的经验教训，太长时间专注于有限数量的候选人，没有充分利用深度可用的基因组序列信息。中心目标是落实第一间日疟原虫血期抗原的全面反向疫苗学评估，将先进的基因组和细胞技术与离体表型分析相结合。一个建立的真核蛋白表达系统将用于表达>200 P的文库。间日血液阶段候选疫苗将根据基因表达进行选择，生物物理特征和基因组多样性标准。所有表达式结构将是免费提供给研究界，以帮助全球间日疟原虫疫苗和生物学研究工作。将筛选表达的蛋白质的抗体结合以确认正确折叠，并用于红细胞和受体结合测定，以确定目标的优先顺序进一步研究。将针对 100 个靶标产生多克隆抗体并用于体外 P. 间日疟原虫入侵表型分析，以确定阻止寄生虫入侵的抗体或生长。来自南美洲和东南亚的间日疟原虫将用于此筛选阶段，在目标优先排序的最早阶段引入抗原多样性，恶性疟原虫疫苗开发的另一个重要教训是，菌株特异性抑制反应使一些有前途的候选人脱轨。提供交叉的抗体将组合测试菌株抑制，以确定 >4 种高效且具有协同作用的药物未来开发和潜在临床测试的候选者。该提案将从根本上改变间日疟原虫疫苗开发的规模和步伐，并将产生对疟疾研究界有广泛的用途。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Analysis of Plasmodium vivax schizont transcriptomes from field isolates reveals heterogeneity of expression of genes involved in host-parasite interactions.

DOI：
10.1038/s41598-020-73562-7
发表时间：
2020-10-07
期刊：
Scientific reports
影响因子：
4.6
作者：
Siegel SV;Chappell L;Hostetler JB;Amaratunga C;Suon S;Böhme U;Berriman M;Fairhurst RM;Rayner JC
通讯作者：
Rayner JC

Using Plasmodium knowlesi as a model for screening Plasmodium vivax blood-stage malaria vaccine targets reveals new candidates.

DOI：
10.1371/journal.ppat.1008864
发表时间：
2021-07
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Ndegwa DN;Kundu P;Hostetler JB;Marin-Menendez A;Sanderson T;Mwikali K;Verzier LH;Coyle R;Adjalley S;Rayner JC
通讯作者：
Rayner JC

The structure of a Plasmodium vivax Tryptophan Rich Antigen domain suggests a lipid binding function for a pan-Plasmodium multi-gene family.

DOI：
10.1038/s41467-023-40885-8
发表时间：
2023-09-14
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Kundu, Prasun;Naskar, Deboki;Mckie, Shannon J.;Dass, Sheena;Kanjee, Usheer;Introini, Viola;Ferreira, Marcelo U.;Cicuta, Pietro;Duraisingh, Manoj;Deane, Janet E.;Rayner, Julian C.
通讯作者：
Rayner, Julian C.