T Cell Responses Induced by Adenoviral Vectored Vaccines Can Be Adjuvanted by Fusion of Antigen to the Oligomerization Domain of C4b-Binding Protein

Viral vectored vaccines have been shown to induce both T cell and antibody responses in animals and humans. However, the induction of even higher level T cell responses may be crucial in achieving vaccine efficacy against difficult disease targets, especially in humans. Here we investigate the oligomerization domain of the α-chain of C4b-binding protein (C4 bp) as a candidate T cell “molecular adjuvant” when fused to malaria antigens expressed by human adenovirus serotype 5 (AdHu5) vectored vaccines in BALB/c mice. We demonstrate that i) C-terminal fusion of an oligomerization domain can enhance the quantity of antigen-specific CD4+ and CD8+ T cell responses induced in mice after only a single immunization of recombinant AdHu5, and that the T cells maintain similar functional cytokine profiles; ii) an adjuvant effect is observed for AdHu5 vectors expressing either the 42 kDa C-terminal domain of Plasmodium yoelii merozoite surface protein 1 (PyMSP142) or the 83 kDa ectodomain of P. falciparum strain 3D7 apical membrane antigen 1 (PfAMA1), but not a candidate 128kDa P. falciparum MSP1 biallelic fusion antigen; iii) following two homologous immunizations of AdHu5 vaccines, antigen-specific T cell responses are further enhanced, however, in both BALB/c mice and New Zealand White rabbits no enhancement of functional antibody responses is observed; and iv) that the T cell adjuvant activity of C4 bp is not dependent on a functional Fc-receptor γ-chain in the host, but is associated with the oligomerization of small (已有研究证实，病毒载体疫苗（viral vectored vaccines）可在动物与人体中诱导T细胞与抗体应答。不过，诱导更高水平的T细胞应答，或许是实现针对难治性疾病靶点的疫苗效力的关键，在人体中尤为突出。本研究以BALB/c小鼠为实验对象，探究了C4b结合蛋白（C4b-binding protein）α链的寡聚化结构域，当其融合至人类腺病毒血清型5（human adenovirus serotype 5, AdHu5）载体疫苗所表达的疟疾抗原时，作为T细胞"分子佐剂"的应用潜力。 本研究获得以下结果： i) 仅单次免疫重组AdHu5疫苗后，寡聚化结构域的羧基端融合即可提升小鼠体内诱导的抗原特异性CD4⁺与CD8⁺ T细胞应答的数量，且此类T细胞的功能性细胞因子谱保持一致； ii) 对于表达约氏疟原虫裂殖子表面蛋白1的42kDa羧基端结构域（PyMSP1₄₂）或恶性疟原虫3D7株顶端膜抗原1的83kDa胞外域（PfAMA1）的AdHu5载体，均可观察到佐剂效应，但针对候选的128kDa恶性疟原虫MSP1双等位融合抗原则未观察到该效应； iii) 对AdHu5疫苗进行两次同源免疫接种后，抗原特异性T细胞应答可进一步增强，但无论是在BALB/c小鼠还是新西兰白兔（New Zealand White rabbits）体内，均未检测到功能性抗体应答的提升； iv) C4b结合蛋白的T细胞佐剂活性不依赖宿主的功能性Fc受体γ链（Fc-receptor γ-chain），但与小分子（原文未完整提供后续内容）的寡聚化相关。