Sundling Christopher, Schön Karin, Mörner Andreas, Forsell Mattias N E, Wyatt Richard T, Thorstensson Rigmor, Hedestam Gunilla B Karlsson, Lycke Nils Y
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden.
J Gen Virol. 2008 Dec;89(Pt 12):2954-2964. doi: 10.1099/vir.0.2008/005470-0.
Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in non-human primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env.
在全身和黏膜部位诱导针对人类免疫缺陷病毒1型（HIV-1）包膜糖蛋白（Env）的强效且广泛的抗体反应的策略是HIV-1疫苗开发的核心目标。在此，我们表明无毒的CTA1-DD佐剂在用三聚体或单体形式的HIV-1 Env对小鼠和非人类灵长类动物进行鼻内（i.n.）免疫后，促进了黏膜和全身的体液及细胞介导的免疫反应。免疫小鼠血清中的Env特异性IgG亚类反映了Th1/Th2型的平衡反应。引人注目的是，用Env和CTA1-DD佐剂进行鼻内免疫在支气管肺泡灌洗中诱导了大量的黏膜抗Env IgA，在阴道分泌物中也可检测到。相比之下，用Ribi配制的Env进行肠胃外免疫并未刺激黏膜IgA反应，而这两种佐剂在血清中诱导了相似的Env特异性IgG亚类分布。用Ribi佐剂中的Env对先前经鼻内用Env和CTA1-DD免疫的小鼠进行单次肠胃外加强免疫，使血清抗Env IgG水平提高到与用Ribi中的Env进行三次腹腔免疫后观察到的水平相似。CTA1-DD的增强效力与LTK63或CpG寡脱氧核苷酸（ODN）相似。然而，与CpG ODN不同，CTA1-DD和LTK63的作用似乎与MyD88和Toll样受体信号传导无关。这是首次证明CTA1-DD在非人类灵长类动物中也能增强特异性免疫反应，表明这种佐剂可作为针对HIV-1 Env的体液和细胞介导免疫的临床安全黏膜疫苗佐剂进行进一步探索。
