Novel Engineering of a P. falciparum Merozoite Surface Protein 1 Malaria Vaccine
恶性疟原虫裂殖子表面蛋白 1 疟疾疫苗的新型工程
基本信息
- 批准号:7687892
- 负责人:
- 金额:$ 19.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-17 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAdverse effectsAntibodiesAntibody FormationAntibody SpecificityBloodC-terminalCleaved cellClinical ResearchDeveloped CountriesDeveloping CountriesDevelopmentDiseaseEngineeringEnhancing AntibodiesEpitopesEquilibriumGeneral PopulationGenerationsGenetic VariationGrowthHumanImmune responseImmunityImmunizationImmunization ScheduleInjection of therapeutic agentLeadLogisticsMalariaMalaria VaccinesMediatingMerozoite Surface Protein 1ModelingMonkeysN-terminalParasitesPlasmodium falciparumPopulationProcessRelianceSafetyStagingT-Lymphocyte EpitopesTechnologyTranscendTreatment ProtocolsVaccine DesignVaccinesValidationVariantaluminum sulfatebaseimprovednovelnovel vaccinespublic health relevanceresponsesuccessvaccination strategyvaccine developmentvaccine-induced immunity
项目摘要
DESCRIPTION (provided by applicant): The 42 kDa processed fragment of the Plasmodium falciparum Merozoite Surface Protein 1, MSP1-42, is a leading protective human malaria vaccine currently undergoing clinical studies. Protective immunity is antibody-mediated, and directed to the C-terminal, immunodominant 19 kDa region of MSP1-42, or MSP1-19. Available evidence indicates that the vaccine-induced immunity to MSP1-42 or MSP-19 relies on the use of very powerful adjuvants (i.e. CFA) and on repeated hyper-immunizations to elicit high levels of protective antibodies. These are formidable obstacles in the way of field deployment of the malaria vaccine. Recently, we have shown that by refocusing the antibody responses to the N-terminal immuno-silent region of MSP1-42, MSP1-33, biologically active antibodies can be produced when combined with low concentrations of anti-MSP1-42 antibodies. This creates an opportunity to devise new vaccine constructs and/or immunization regimens to efficiently induce protective antibodies under the more favorable logistics of a reduced immunization schedule and the use of readily acceptable adjuvants. Accordingly, Specific Aim 1 will explore strategies to develop bivalent MSP1 vaccines as well as prime/boost immunization regimens, based on MSP1-33 and MSP1-42, in order to achieve a balanced induction of protective antibody responses. The focus will be on the use of less powerful adjuvants and a reduced immunization schedule. Specific Aim 2 will define experimental conditions in which combinations of anti-MSP1-33 and anti-MSP1-42 antibodies will inhibit parasites carrying different allelic and variant forms of MSP-42. This information, together with the down-selected vaccination strategies from Specific Aim 1, will be used to formulate MSP1-33/MSP1-42 vaccines to elicit strain-transcending, parasite inhibitory antibody responses. Significance: This exploratory project provides the critical proof-of- principle on which further development and validation of the dual MSP1-33/MSP1-42 vaccine strategy can be based. The strategy will rapidly lead to a new generation of MSP1-based malaria vaccines deployable with significantly improved efficacy and logistical feasibility, while utilizing the already existing technologies/platforms of demonstrated safety.
PUBLIC HEALTH RELEVANCE - PROJECT NARRATIVE: Malaria is a major killer in developing countries and the development of effective vaccines is critical in controlling this deadly disease. This exploratory application seeks to improve the efficacy and the logistical feasibility of deployment of a leading candidate human malaria vaccine, Merozoite Surface Protein 1, MSP1. This is based on new and significant discovery of the immune responses to the MSP1 vaccine, which allows for novel re-design of the vaccine. Success in this project will move this vaccine forward in terms of significantly improving its potential to be effective in large populations in the field.
描述(由申请人提供):恶性疟原虫裂殖子表面蛋白1(MSP 1 -42)的42 kDa加工片段是目前正在进行临床研究的主要保护性人疟疾疫苗。保护性免疫是抗体介导的,并且针对MSP 1 -42或MSP 1 -19的C-末端、免疫显性19 kDa区域。现有证据表明,疫苗诱导的对MSP 1 -42或MSP-19的免疫依赖于使用非常强大的佐剂(即CFA)和重复的超免疫以引发高水平的保护性抗体。这些都是实地部署疟疾疫苗的巨大障碍。最近,我们已经表明,通过重新聚焦对MSP 1 -42、MSP 1 -33的N-末端免疫沉默区的抗体应答,当与低浓度的抗MSP 1 -42抗体组合时可以产生生物活性抗体。这创造了设计新的疫苗构建体和/或免疫方案的机会,以在减少的免疫方案和使用容易接受的佐剂的更有利的逻辑下有效地诱导保护性抗体。因此,具体目标1将探索基于MSP 1 -33和MSP 1 -42开发二价MSP 1疫苗以及初免/加强免疫方案的策略,以实现保护性抗体应答的平衡诱导。重点将放在使用效力较低的佐剂和减少免疫接种时间表上。具体目标2将定义实验条件,其中抗MSP 1 -33和抗MSP 1 -42抗体的组合将抑制携带MSP-42的不同等位基因和变体形式的寄生虫。该信息与特定目标1中的下选疫苗接种策略一起将用于配制MSP 1 -33/MSP 1 -42疫苗,以引发菌株超越性寄生虫抑制性抗体应答。 重要性:该探索性项目提供了关键的原理验证,可作为进一步开发和验证双重MSP 1 -33/MSP 1 -42疫苗策略的基础。该战略将迅速导致新一代基于MSP 1的疟疾疫苗的部署,其有效性和后勤可行性将大大提高,同时利用已经证明安全的现有技术/平台。
公共卫生相关性-项目叙述:疟疾是发展中国家的主要杀手,有效疫苗的开发对于控制这一致命疾病至关重要。这种探索性应用旨在提高一种主要候选人疟疾疫苗裂殖子表面蛋白1(MSP 1)的有效性和部署的后勤可行性。这是基于对MSP 1疫苗的免疫应答的新的和重要的发现,这允许对疫苗进行新的重新设计。该项目的成功将推动该疫苗在显著提高其在该领域大量人群中有效的潜力方面向前发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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George S Hui其他文献
George S Hui的其他文献
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{{ truncateString('George S Hui', 18)}}的其他基金
Novel Engineering of a P. falciparum Merozoite Surface Protein 1 Malaria Vaccine
恶性疟原虫裂殖子表面蛋白 1 疟疾疫苗的新型工程
- 批准号:
8054133 - 财政年份:2010
- 资助金额:
$ 19.19万 - 项目类别:
High School Students STEP-UP To Biomedical Research
高中生加强生物医学研究
- 批准号:
8054118 - 财政年份:2010
- 资助金额:
$ 19.19万 - 项目类别:
High School Students STEP-UP To Biomedical Research
高中生加强生物医学研究
- 批准号:
7845990 - 财政年份:2009
- 资助金额:
$ 19.19万 - 项目类别:
Novel Engineering of a P. falciparum Merozoite Surface Protein 1 Malaria Vaccine
恶性疟原虫裂殖子表面蛋白 1 疟疾疫苗的新型工程
- 批准号:
7367295 - 财政年份:2008
- 资助金额:
$ 19.19万 - 项目类别:
High School Students STEP-UP To Biomedical Research
高中生加强生物医学研究
- 批准号:
7269078 - 财政年份:2007
- 资助金额:
$ 19.19万 - 项目类别:
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