Lin Yinling, Kwon Taewoo, Polo John, Zhu Yi-Fei, Coates Stephen, Crawford Kevin, Dong Christine, Wininger Mark, Hall John, Selby Mark, Coit Doris, Medina-Selby Angelica, McCoin Colin, Ng Philip, Drane Debbie, Chien David, Han Jang, Vajdy Michael, Houghton Michael
Novartis Vaccine and Diagnostic, Inc., Emeryville, California 94608, USA.
J Virol. 2008 Aug;82(15):7492-503. doi: 10.1128/JVI.02743-07. Epub 2008 May 28.
Broad, multispecific CD4(+) and CD8(+) T-cell responses to the hepatitis C virus (HCV), as well as virus-cross-neutralizing antibodies, are associated with recovery from acute infection and may also be associated in chronic HCV patients with a favorable response to antiviral treatment. In order to recapitulate all of these responses in an ideal vaccine regimen, we have explored the use of recombinant HCV polypeptides combined with various Th1-type adjuvants and replication-defective alphaviral particles encoding HCV proteins in various prime/boost modalities in BALB/c mice. Defective chimeric alphaviral particles derived from the Sindbis and Venezuelan equine encephalitis viruses encoding either the HCV envelope glycoprotein gpE1/gpE2 heterodimer (E1E2) or nonstructural proteins 3, 4, and 5 (NS345) elicited strong CD8(+) T-cell responses but low CD4(+) T helper responses to these HCV gene products. In contrast, recombinant E1E2 glycoproteins adjuvanted with MF59 containing a CpG oligonucleotide elicited strong CD4(+) T helper responses but no CD8(+) T-cell responses. A recombinant NS345 polyprotein also stimulated strong CD4(+) T helper responses but no CD8(+) T-cell responses when adjuvanted with Iscomatrix containing CpG. Optimal elicitation of broad CD4(+) and CD8(+) T-cell responses to E1E2 and NS345 was obtained by first priming with Th1-adjuvanted proteins and then boosting with chimeric, defective alphaviruses expressing these HCV genes. In addition, this prime/boost regimen resulted in the induction of anti-E1E2 antibodies capable of cross-neutralizing heterologous HCV isolates in vitro. This vaccine formulation and regimen may therefore be optimal in humans for protection against this highly heterogeneous global pathogen.
对丙型肝炎病毒（HCV）产生广泛的多特异性CD4(+)和CD8(+) T细胞反应以及病毒交叉中和抗体，与急性感染的恢复相关，在慢性HCV患者中也可能与对抗病毒治疗的良好反应相关。为了在理想的疫苗方案中重现所有这些反应，我们在BALB/c小鼠中探索了使用重组HCV多肽与各种Th1型佐剂以及编码HCV蛋白的复制缺陷型甲病毒颗粒，采用各种初免/加强免疫方式。源自辛德比斯病毒和委内瑞拉马脑炎病毒的缺陷嵌合甲病毒颗粒，编码HCV包膜糖蛋白gpE1/gpE2异二聚体（E1E2）或非结构蛋白3、4和5（NS345），引发了强烈的CD8(+) T细胞反应，但对这些HCV基因产物的CD4(+) T辅助细胞反应较低。相比之下，用含有CpG寡核苷酸的MF59佐剂的重组E1E2糖蛋白引发了强烈的CD4(+) T辅助细胞反应，但没有CD8(+) T细胞反应。当用含有CpG的Iscomatrix佐剂时，重组NS345多蛋白也刺激了强烈的CD4(+) T辅助细胞反应，但没有CD8(+) T细胞反应。通过先用Th1佐剂蛋白进行初免，然后用表达这些HCV基因的嵌合、缺陷型甲病毒进行加强免疫，可获得对E1E2和NS345的广泛CD4(+)和CD8(+) T细胞反应的最佳激发。此外，这种初免/加强免疫方案导致诱导出能够在体外交叉中和异源HCV分离株的抗E1E2抗体。因此，这种疫苗配方和方案在人类中可能是预防这种高度异质性全球病原体的最佳选择。
