Reed R C, Louis-Wileman V, Wells R L, Verheul A F, Hunter R L, Lal A A
Department of Pathology and Laboratory Medicine, Emory University, Atlanta GA 30322, USA.
Vaccine. 1996 Jun;14(8):828-36. doi: 10.1016/0264-410x(95)00175-z.
Although the circumsporozoite protein (CSP) of the malaria parasite is the most immunologically characterized protein, the goal of using this protein in an effective vaccine has not yet been realized. Monoclonal antibody against the repetitive immunodominant B-epitope of the CSP can protect mice from malaria, but vaccines that induce antibody against this epitope do not consistently induce protection. Toward developing a rationale for a CSP-based effective vaccine, we have re-investigated the ability of anti-CSP repeat antibodies, as induced by different CSP vaccine formulations with several adjuvants, to confer sterile immunity against sporozoite challenge. Using Plasmodium berghei rodent malaria model and several CSP subunit vaccine constructs, we found that a formulation consisting of the P. berghei CSP repetitive epitope, (DPPPPNPN)2 (CS), conjugated to BSA by carbodiimide, formulated in a block copolymer and detoxified lipopolysaccharide (RaLPS) adjuvant, was particularly promising. Mice were immunized and boosted with vaccines that contain varying malarial peptide-carrier ratios of 6:1 (CS6-BSA), 55:1 (CS55-BSA) and 170:1 (CS170-BSA). Following immunization, the animals were challenged with live sporozoites. Two types of effects were observed in vaccinated mice. First, sterile immunity was induced in 100%, 50% and 29% of mice that were immunized with the CS170-BSA, CS55-BSA, and CS6-BSA vaccine conjugates, respectively. The second effect of immunization was observed with the CS170-BSA conjugate vaccine primed mice; a boost in IFA titers followed sporozoite challenge. In addition, we observed that IgG1 isotype titer against the surface of the sporozoite, as measured by IFA, and antibody avidity parallel sterile immunity. These findings reiterate the potential of the CSP as a malaria vaccine candidate antigen, and suggest that the induction of sterile immune responses depends on inducing antibody of the appropriate isotype, avidity and specificity.
尽管疟原虫的环子孢子蛋白（CSP）是免疫特征最明确的蛋白，但将该蛋白用于有效疫苗的目标尚未实现。针对CSP重复性免疫显性B表位的单克隆抗体可保护小鼠免受疟疾侵害，但诱导针对该表位抗体的疫苗并不能始终诱导出保护作用。为了开发基于CSP的有效疫苗的理论依据，我们重新研究了由不同CSP疫苗配方与几种佐剂诱导产生的抗CSP重复抗体赋予针对子孢子攻击的无菌免疫力的能力。使用伯氏疟原虫啮齿动物疟疾模型和几种CSP亚单位疫苗构建体，我们发现一种由伯氏疟原虫CSP重复表位（DPPPPNPN）2（CS）通过碳二亚胺与牛血清白蛋白（BSA）偶联、配制在嵌段共聚物和解毒脂多糖（RaLPS）佐剂中的配方特别有前景。用含有不同疟疾肽-载体比例6:1（CS6-BSA）、55:1（CS55-BSA）和170:1（CS170-BSA）的疫苗对小鼠进行免疫和加强免疫。免疫后，用活子孢子对动物进行攻击。在接种疫苗的小鼠中观察到两种类型的效应。首先，分别用CS170-BSA、CS55-BSA和CS6-BSA疫苗偶联物免疫的小鼠中，100%、50%和29%诱导出无菌免疫力。免疫的第二种效应在CS170-BSA偶联疫苗初免的小鼠中观察到；子孢子攻击后间接荧光抗体（IFA）效价升高。此外，我们观察到，通过IFA测量，针对子孢子表面的IgG1同种型效价以及抗体亲和力与无菌免疫力平行。这些发现重申了CSP作为疟疾疫苗候选抗原的潜力，并表明诱导无菌免疫反应取决于诱导具有适当同种型、亲和力和特异性的抗体。
