Novel Engineering of a P. falciparum Merozoite Surface Protein 1 Malaria Vaccine

描述(申请人提供)：恶性疟原虫裂殖子表面蛋白1的42 kDa加工片段，MSP1-42，是一种领先的保护性人类疟疾疫苗，目前正在进行临床研究。保护性免疫是由抗体介导的，针对MSP1-42或MSP1-19的C末端免疫优势19 kDa区域。现有证据表明，疫苗诱导的对MSP1-42或MSP-19的免疫依赖于使用非常强大的佐剂(即CFA)和重复的超免疫来诱导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，我们已经证明，通过将抗体反应重新聚焦到MSP1-42、MSP1-33的N端免疫沉默区域，当与低浓度的抗MSP1-42抗体结合时，可以产生生物活性抗体。这为设计新的疫苗结构和/或免疫方案创造了机会，以便在减少免疫计划和使用容易接受的佐剂的更有利的后勤条件下有效地诱导保护性抗体。因此，具体目标1将探索以MSP1-33和MSP1-42为基础开发双价MSP1疫苗以及加强免疫方案的战略，以实现保护性抗体反应的平衡诱导。重点将放在使用效力较弱的佐剂和减少免疫计划上。具体目标2将确定实验条件，在这些条件下，抗MSP1-33和抗MSP1-42抗体的组合将抑制携带不同等位基因和变异形式的MSP-42的寄生虫。这些信息与从特定目标1中选择的向下选择的疫苗接种策略将被用于研制MSP1-33/MSP1-42疫苗，以激发跨越菌株的寄生虫抑制性抗体反应。意义：这一探索性项目为进一步开发和验证MSP1-33/MSP1-42双重疫苗策略提供了关键的原则证明。该战略将迅速导致可部署的新一代基于MSP1的疟疾疫苗，在利用已证明安全的现有技术/平台的同时，大大提高效力和后勤可行性。 公共卫生相关性-项目叙述：疟疾是发展中国家的主要杀手，开发有效的疫苗对控制这一致命疾病至关重要。这一探索性应用旨在提高领先候选人类疟疾疫苗--裂殖子表面蛋白1，MSP1的效力和后勤可行性。这是基于对MSP1疫苗免疫反应的新的重大发现，这使得疫苗可以进行新的重新设计。该项目的成功将极大地提高疫苗在现场大量人群中有效的潜力，从而推动疫苗向前发展。

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.