Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark.
Infect Immun. 2012 May;80(5):1744-52. doi: 10.1128/IAI.00079-12. Epub 2012 Feb 27.
Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs, CpG ODN, are Toll-like receptor 9 agonists (TLR9a), which have been used as adjuvants in pneumococcal vaccines to improve antibody responses in immunodeficient patients. Here, we examined whether the coadministration of TLR9a with pneumococcal CRM(197)-conjugate vaccine enhances protection against pneumococcal colonization, the levels of antipolysaccharide antibodies, and the CD4(+) T-cell responses. Wild-type BALB/c mice and B-cell-deficient BALB/c Igh-J(tm1Dhu) mice were immunized twice with the following: (i) PCV alone; (ii) simultaneous PCV and TLR9a; (iii) PCV and then TLR9a, after a 48-h delay; (iv) TLR9a alone; and (v) phosphate-buffered saline. Nasopharyngeal protection, serum antibodies, CD4(+) T-cell responses, and clearance of bacteremia after intraperitoneal challenge with Streptococcus pneumoniae 6B were evaluated. We found decreased nasopharyngeal protection against S. pneumoniae 6B colonization after simultaneous immunization with PCV and TLR9a compared to immunization with PCV alone in wild-type BALB/c mice (P = 0.037). A similar trend was observed in B-cell-deficient BALB/c Igh-J(tm1Dhu) mice. Simultaneous administration did not enhance antibody levels and lowered the CRM(197)-specific cytokine release of gamma interferon, interleukin-2 (IL-2), IL-5 and IL-13. Immunization with PCV and then TLR9a, after a 48-h delay, significantly improved nasopharyngeal protection compared to simultaneous administration (P = 0.011). Furthermore, delaying TLR9a delivery increased antibody titers compared to both simultaneous administration (P = 0.001) and PCV immunization alone (P = 0.026). In conclusion, the immunological and clinical impact of adjuvanting a pneumococcal conjugate vaccine (Prevnar; Pfizer) with a TLR9a is highly depended on timing of the adjuvant administration. Thus, careful timing of adjuvant administration may improve novel vaccine formulations.
合成的寡脱氧核苷酸（ODN）含有未甲基化的 CpG 基序，CpG ODN 是 Toll 样受体 9 激动剂（TLR9a），已被用作肺炎球菌疫苗的佐剂，以改善免疫功能低下患者的抗体反应。在这里，我们研究了 TLR9a 与肺炎球菌 CRM（197）-缀合疫苗联合使用是否能增强对肺炎球菌定植的保护作用，提高抗多聚糖抗体水平以及 CD4+T 细胞反应。野生型 BALB/c 小鼠和 B 细胞缺陷型 BALB/c Igh-J（tm1Dhu）小鼠接受以下两种方案的两次免疫：（i）单独使用 PCV；（ii）同时使用 PCV 和 TLR9a；（iii）PCV 后 48 小时延迟再给予 TLR9a；（iv）单独使用 TLR9a；（v）磷酸盐缓冲盐水。评估了鼻内保护、血清抗体、CD4+T 细胞反应以及经腹腔内肺炎链球菌 6B 攻击后的菌血症清除情况。我们发现，与单独使用 PCV 相比，在野生型 BALB/c 小鼠中，同时免疫接种 PCV 和 TLR9a 会降低对肺炎球菌 6B 定植的鼻内保护作用（P = 0.037）。在 B 细胞缺陷型 BALB/c Igh-J（tm1Dhu）小鼠中也观察到了类似的趋势。同时给药并未增强抗体水平，并降低了 CRM（197）特异性细胞因子释放的γ干扰素、白细胞介素-2（IL-2）、IL-5 和 IL-13。与同时给药相比，PCV 后 48 小时延迟给予 TLR9a 可显著改善鼻内保护作用（P = 0.011）。此外，与同时给药（P = 0.001）和单独使用 PCV 免疫（P = 0.026）相比，延迟 TLR9a 给药可提高抗体滴度。总之，肺炎球菌结合疫苗（沛儿；辉瑞）佐剂 TLR9a 的免疫和临床影响高度依赖于佐剂给药的时间。因此，仔细调整佐剂给药时间可能会改善新型疫苗制剂。
