Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909).
Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909).
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DOI：
10.1016/j.vaccine.2014.01.096
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发表时间：
2014-11-28
期刊：
影响因子：
5.5
通讯作者：
Bernton, Edward W.
中科院分区：
文献类型：
--
作者：
Minang, Jacob T.;Inglefield, Jon R.;Harris, Andrea M.;Lathey, Janet L.;Alleva, David G.;Sweeney, Diane L.;Hopkins, Robert J.;Lacy, Michael J.;Bernton, Edward W.
NuThrax™（吸附CPG 7909佐剂的炭疽疫苗）（AV 7909）正在开发中。对Ib期临床试验中获得的样本进行检测，以确认先天免疫的生物标志物，并评价CPG 7909（PF-03512676）对获得性免疫的影响。受试者接受两次肌内给药的市售BioThrax®（吸附炭疽疫苗，AVA），或两次肌内给药的四种AV 7909制剂之一。IP-10、IL-6和C-反应蛋白（CRP）水平在AV 7909制剂给药后24 - 48小时升高，到第7天恢复至基线水平。AVA（无CPG 7909）导致IL-6和CRP升高，但不导致IP-10升高。CpG的另一个标志物，瞬时绝对淋巴细胞计数（ALC）下降，与瞬时增加的IP-10相关。通过在免疫前和第二次免疫后7天（研究第21天）对从受试者获得的冷冻保存的PBMC进行IFN-γ ELISpot测定来评估对炭疽保护性抗原（PA）或PA肽的细胞回忆应答。接受AV 7909和低剂量（0.25 mg/剂）CPG 7909的受试者中有一半对PA具有阳性第21天T细胞应答。相比之下，AVA治疗受试者的阳性T细胞应答发生率平均为11%（1/9）。由于CPG 7909剂量水平引起的细胞应答差异与体液抗PA IgG应答差异无关，与AVA接受者相比，AV 7909接受者的体液抗PA IgG应答升高。24或48小时的血清标志物（即% ALC降低或IL-6、IP-10或CRP升高）与1个月后的体液（抗体）应答相关，但与细胞ELISpot应答无关。总之，证实了对CPG 7909的早期应答的生物标志物，并且向施用两次的疫苗中添加CpG佐剂导致相对于单独的疫苗增加的T细胞效应。早期生物标志物的变化与随后的适应性体液免疫相关，但与细胞免疫无关。
NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a Phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax® (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24 to 48 hours after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALC), correlated with transiently increased IP-10. Cellular recall responses to anthrax Protective Antigen (PA) or PA peptides were assessed by IFN-gamma ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25 mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48 hours (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity.
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