Multivalent Pneumococcal Protein Vaccines Comprising Pneumolysoid with Epitopes/Fragments of CbpA and/or PspA Elicit Strong and Broad Protection
Multivalent Pneumococcal Protein Vaccines Comprising Pneumolysoid with Epitopes/Fragments of CbpA and/or PspA Elicit Strong and Broad Protection
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DOI：
10.1128/cvi.00293-15
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发表时间：
2015-10-01
影响因子：
--
通讯作者：
Paton, James C.
中科院分区：
文献类型：
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作者：
Chen, Austen;Mann, Beth;Paton, James C.
用肺炎球菌蛋白肺炎球菌溶血素（Ply）、胆碱结合蛋白A（CbpA）或肺炎球菌表面蛋白A（PspA）免疫在动物模型中激发针对侵袭性肺炎球菌疾病的保护性应答。在这项研究中，我们使用不同的小鼠模型来测试多种基于多价蛋白质的疫苗的功效，所述疫苗包含免疫原Ply、CbpA或PspA：Ply类毒素的全长或肽区与L460 D取代的各种组合（本文称为L460 D）; L460 D与来自CbpA的保护性肽表位融合（YPT-L460 D-NEEK [YLN]）; L460 D与含有PspA的脯氨酸富集区（PRR）的CD 2肽融合在一些实施方案中，所述组合包括：CD 2-L460 D; L460 D和H70的组合（L460 D + H70），一种含有PRR和SM 1区的稍大的PspA衍生肽; H70 + YLN;以及其他组合。将每只小鼠腹膜内（i. p.）或皮下（s.c.）用明矾佐剂中的各种抗原组合的三个剂量（以2周间隔）接种，然后在以多种肺炎链球菌菌株的不同感染途径为特征的小鼠模型中攻击。在腹膜内感染脓毒症模型中，H70 + YLN始终提供针对三种不同攻击菌株（血清型1、2和6A）的显著保护; CD 2 + YLN和H70 + L460 D组合也引起显著保护。预防静脉注射（i. v.）脓毒症（3型和6A攻击菌株）在很大程度上依赖于PspA衍生的抗原组分，并且最大的保护作用是由具有或不具有L460 D或YLN的H70引起的。在4型肠内（i.t.）在导致进展为脑膜炎的攻击模型中，含有YLN的抗原组合引起最强的保护。因此，H70 + YLN的三价抗原组合在不同的肺炎球菌攻击模型中产生了最强和最广泛的保护作用。
Immunization with the pneumococcal proteins pneumolysin (Ply), choline binding protein A (CbpA), or pneumococcal surface protein A (PspA) elicits protective responses against invasive pneumococcal disease in animal models. In this study, we used different mouse models to test the efficacy of a variety of multivalent protein-based vaccines that comprised various combinations of full-length or peptide regions of the immunogens Ply, CbpA, or PspA: Ply toxoid with the L460D substitution (referred to herein as L460D); L460D fused with protective peptide epitopes from CbpA (YPT-L460D-NEEK [YLN]); L460D fused with the CD2 peptide containing the proline-rich region (PRR) of PspA (CD2-L460D); a combination of L460D and H70 (L460D + H70), a slightly larger PspA-derived peptide containing the PRR and the SM1 region; H70 + YLN; and other combinations. Each mouse was immunized either intraperitoneally (i.p.) or subcutaneously (s.c.) with three doses (at 2-week intervals) of the various antigen combinations in alum adjuvant and then challenged in mouse models featuring different infection routes with multiple Streptococcus pneumoniae strains. In the i.p. infection sepsis model, H70 + YLN consistently provided significant protection against three different challenge strains (serotypes 1, 2, and 6A); the CD2 + YLN and H70 + L460D combinations also elicited significant protection. Protection against intravenous (i.v.) sepsis (type 3 and 6A challenge strains) was largely dependent on PspA-derived antigen components, and the most protection was elicited by H70 with or without L460D or YLN. In a type 4 intratracheal (i.t.) challenge model that results in progression to meningitis, antigen combinations that contained YLN elicited the strongest protection. Thus, the trivalent antigen combination of H70 + YLN elicited the strongest and broadest protection in diverse pneumococcal challenge models.