Billeskov Rolf, Christensen Jan P, Aagaard Claus, Andersen Peter, Dietrich Jes
Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.
PLoS One. 2013 Aug 19;8(8):e72185. doi: 10.1371/journal.pone.0072185. eCollection 2013.
Here we report for the first time on the immunogenicity and protective efficacy of a vaccine strategy involving the adjuvanted fusion protein "H28" (consisting of Ag85B-TB10.4-Rv2660c) and Modified Vaccinia Virus Ankara expressing H28. We show that a heterologous prime-boost regimen involving priming with H28 in a Th1 adjuvant followed by boosting with H28 expressed by MVA (H28/MVA28) induced the highest percentage of IFN-γ expressing T cells, the highest production of IFN-γ per single cell and the highest induction of CD8 T cells compared to either of the vaccines given alone. In contrast, in mice vaccinated with adjuvanted recombinant H28 alone (H28/H28) we observed the highest production of IL-2 per single cell and the highest frequency of antigen specific TNF-α/IL-2 expressing CD4 T cells pre and post infection. Interestingly, TNF-α/IL-2 expressing central memory-like CD4 T cells showed a significant positive correlation with protection at week 6 post infection, whereas the opposite was observed for post infection CD4 T cells producing only IFN-γ. Moreover, as a BCG booster vaccine in a clinically relevant non-human primate TB model, the H28/H28 vaccine strategy induced a slightly more prominent reduction of clinical disease and pathology for up to one year post infection compared to H28/MVA28. Taken together, our data showed that the adjuvanted subunit and MVA strategies led to different T cell subset combinations pre and post infection and that TNF-α/IL-2 double producing but not IFN-γ single producing CD4 T cell subsets correlated with protection in the mouse TB model. Moreover, our data demonstrated that the H28 vaccine antigen was able to induce strong protection in both a mouse and a non-human primate TB model.
在此，我们首次报告了一种疫苗策略的免疫原性和保护效力，该策略涉及佐剂化融合蛋白“H28”（由Ag85B-TB10.4-Rv2660c组成）和表达H28的安卡拉痘苗病毒。我们发现，与单独使用任何一种疫苗相比，一种异源初免-加强方案（先用Th1佐剂中的H28进行初免，然后用MVA表达的H28进行加强免疫（H28/MVA28））诱导产生表达IFN-γ的T细胞的百分比最高，单个细胞产生IFN-γ的量最高，并且诱导CD8 T细胞的能力最强。相比之下，在单独接种佐剂化重组H28（H28/H28）的小鼠中，我们观察到单个细胞产生IL-2的量最高，并且在感染前后抗原特异性表达TNF-α/IL-2的CD4 T细胞频率最高。有趣的是，表达TNF-α/IL-2的中央记忆样CD4 T细胞在感染后第6周与保护作用呈显著正相关，而对于仅产生IFN-γ的感染后CD4 T细胞则观察到相反的情况。此外，作为临床相关非人灵长类动物结核病模型中的卡介苗加强疫苗，与H28/MVA28相比，H28/H28疫苗策略在感染后长达一年的时间里诱导临床疾病和病理的减轻更为显著。综上所述，我们的数据表明，佐剂化亚单位和MVA策略在感染前后导致不同的T细胞亚群组合，并且在小鼠结核病模型中，产生TNF-α/IL-2双阳性而非仅产生IFN-γ的CD4 T细胞亚群与保护作用相关。此外，我们的数据表明，H28疫苗抗原能够在小鼠和非人灵长类动物结核病模型中诱导强大的保护作用。
