Centro de Biotecnologia, Instituto Butantan, São Paulo, São Paulo, Brazil.
PLoS One. 2010 May 27;5(5):e10863. doi: 10.1371/journal.pone.0010863.
Streptococcus pneumoniae is the leading cause of respiratory acute infections around the world. In Latin America, approximately 20,000 children under 5 years of age die of pneumococcal diseases annually. Pneumococcal surface protein A (PspA) is among the best-characterized pneumococcal antigens that confer protection in animal models of pneumococcal infections and, as such, is a good alternative for the currently available conjugated vaccines. Efficient immune responses directed to PspA in animal models have already been described. Nevertheless, few low cost adjuvants for a subunit pneumococcal vaccine have been proposed to date. Here, we have tested the adjuvant properties of the whole cell Bordetella pertussis vaccine (wP) that is currently part of the DTP (diphtheria-tetanus-pertussis) vaccine administrated to children in several countries, as an adjuvant to PspA. Nasal immunization of BALB/c mice with a combination of PspA5 and wP or wP(low)--a new generation vaccine that contains low levels of B. pertussis LPS--conferred protection against a respiratory lethal challenge with S. pneumoniae. Both PspA5-wP and PspA5-wP(low) vaccines induced high levels of systemic and mucosal antibodies against PspA5, with similar profile, indicating no essential requirement for B. pertussis LPS in the adjuvant properties of wP. Accordingly, nasal immunization of C3H/HeJ mice with PspA5-wP conferred protection against the pneumococcal challenge, thus ruling out a role for TLR4 responses in the adjuvant activity and the protection mechanisms triggered by the vaccines. The high levels of anti-PspA5 antibodies correlated with increased cross-reactivity against PspAs from different clades and also reflected in cross-protection. In addition, passive immunization experiments indicated that antibodies played an important role in protection in this model. Finally, subcutaneous immunization with a combination of PspA5 with DTP(low) protected mice against challenge with two different pneumococcal strains, opening the possibility for the development of a combined infant vaccine composed of DTP and PspA.
肺炎链球菌是全球呼吸道急性感染的主要原因。在拉丁美洲，每年约有 20,000 名 5 岁以下儿童死于肺炎球菌疾病。肺炎球菌表面蛋白 A (PspA) 是研究最为透彻的肺炎球菌抗原之一，在肺炎球菌感染的动物模型中具有保护作用，因此是目前可用的结合疫苗的良好替代品。已经描述了针对 PspA 的动物模型中有效的免疫反应。然而，迄今为止，只有少数低成本的肺炎球菌亚单位疫苗佐剂被提出。在这里，我们测试了全细胞百日咳博德特氏菌疫苗 (wP) 的佐剂特性，wP 目前是在多个国家向儿童接种的 DTP（白喉-破伤风-百日咳）疫苗的一部分，作为 PspA 的佐剂。用 PspA5 和 wP 或 wP(low)（一种含有低水平 B. pertussis LPS 的新一代疫苗）的组合对 BALB/c 小鼠进行鼻腔免疫接种，可针对 S. pneumoniae 引起的呼吸道致死性攻击提供保护。PspA5-wP 和 PspA5-wP(low) 疫苗均诱导针对 PspA5 的高水平系统和粘膜抗体，具有相似的特征，表明 B. pertussis LPS 对 wP 的佐剂特性没有必要。因此，用 PspA5-wP 对 C3H/HeJ 小鼠进行鼻腔免疫接种可提供针对肺炎球菌攻击的保护，从而排除 TLR4 反应在疫苗引发的佐剂活性和保护机制中的作用。高水平的抗 PspA5 抗体与针对不同进化枝的 PspAs 的交叉反应性增加相关，也反映在交叉保护中。此外，被动免疫实验表明，抗体在该模型中发挥了重要的保护作用。最后，用 PspA5 与 DTP(low) 的组合进行皮下免疫接种可保护小鼠免受两种不同肺炎球菌菌株的攻击，为开发由 DTP 和 PspA 组成的联合婴儿疫苗开辟了可能性。
