Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910.
Division of Veterinary Medicine, Walter Reed Army Institute of Research, Silver Spring, MD 20910.
Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):3114-3122. doi: 10.1073/pnas.1911792117. Epub 2020 Jan 27.
vaccine RTS,S/AS01 is based on the major NPNA repeat and the C-terminal region of the circumsporozoite protein (CSP). RTS,S-induced NPNA-specific antibody titer and avidity have been associated with high-level protection in naïve subjects, but efficacy and longevity in target populations is relatively low. In an effort to improve upon RTS,S, a minimal repeat-only, epitope-focused, protective, malaria vaccine was designed. Repeat antigen copy number and flexibility was optimized using the tobacco mosaic virus (TMV) display platform. Comparing antigenicity of TMV displaying 3 to 20 copies of NPNA revealed that low copy number can reduce the abundance of low-affinity monoclonal antibody (mAb) epitopes while retaining high-affinity mAb epitopes. TMV presentation improved titer and avidity of repeat-specific Abs compared to a nearly full-length protein vaccine (FL-CSP). NPNAx5 antigen displayed as a loop on the TMV particle was found to be most optimal and its efficacy could be further augmented by combination with a human-use adjuvant ALFQ that contains immune-stimulators. These data were confirmed in rhesus macaques where a low dose of TMV-NPNAx5 elicited Abs that persisted at functional levels for up to 11 mo. We show here a complex association between NPNA copy number, flexibility, antigenicity, immunogenicity, and efficacy of CSP-based vaccines. We hypothesize that designing minimal epitope CSP vaccines could confer better and more durable protection against malaria. Preclinical data presented here supports the evaluation of TMV-NPNAx5/ALFQ in human trials.
疫苗 RTS,S/AS01 基于主要的 NPNA 重复序列和环子孢子蛋白(CSP)的 C 末端区域。在未经免疫的受试者中,RTS,S 诱导的 NPNA 特异性抗体滴度和亲和力与高水平保护相关,但在目标人群中的疗效和持久性相对较低。为了改进 RTS,S,设计了一种最小的重复仅、表位聚焦、保护性、疟疾疫苗。使用烟草花叶病毒(TMV)展示平台优化了重复抗原拷贝数和灵活性。比较显示 3 到 20 个 NPNA 拷贝的 TMV 展示的抗原性表明,低拷贝数可以减少低亲和力单克隆抗体(mAb)表位的丰度,同时保留高亲和力 mAb 表位。与几乎全长蛋白疫苗(FL-CSP)相比,TMV 展示提高了重复特异性 Abs 的滴度和亲和力。发现作为 TMV 粒子上的环展示的 NPNAx5 抗原是最理想的,其功效可以通过与包含免疫刺激剂的人类使用佐剂 ALFQ 联合进一步增强。这些数据在恒河猴中得到了证实,其中 TMV-NPNAx5 的低剂量可诱导 Abs 持续存在长达 11 个月的功能水平。我们在这里展示了 NPNA 拷贝数、灵活性、抗原性、免疫原性和基于 CSP 的疫苗功效之间的复杂关联。我们假设设计最小表位 CSP 疫苗可以提供更好和更持久的疟疾保护。本文提供的临床前数据支持在人类试验中评估 TMV-NPNAx5/ALFQ。
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