Azmi Fazren, Ahmad Fuaad Abdullah Al Hadi, Giddam Ashwini Kumar, Batzloff Michael R, Good Michael F, Skwarczynski Mariusz, Toth Istvan
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, St Lucia, Queensland 4072, Australia; Faculty of Pharmacy, National University of Malaysia, Kuala Lumpur, Malaysia.
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, St Lucia, Queensland 4072, Australia.
Bioorg Med Chem. 2014 Nov 15;22(22):6401-8. doi: 10.1016/j.bmc.2014.09.042. Epub 2014 Sep 26.
Peptides are of great interest to be used as vaccine antigens due to their safety, ease of manufacturing and specificity in generating immune response. There have been massive discoveries of peptide antigens over the past decade. However, peptides alone are poorly immunogenic, which demand co-administration with strong adjuvant to enhance their immunogenicity. Recently, fibril-forming peptides such as Q11 and lipoamino acid-based carrier have been identified to induce substantial immune responses when covalently linked to peptide epitope. In this study, we have incorporated either Q11 or lipoamino acids to a peptide epitope (J14) derived from M protein of group A streptococcus to develop self-adjuvanting vaccines. J14, Q11 and lipoamino acids were also conjugated together in a single vaccine construct in an attempt to evaluate the synergy effect of combining multiple adjuvants. Physicochemical characterization demonstrated that the vaccine constructs folded differently and self-assembled into nanoparticles. Significantly, only vaccine constructs containing double copies of lipoamino acids (regardless in conjugation with Q11 or not) were capable to induce significant dendritic cells uptake and subsequent J14-specific antibody responses in non-sizes dependent manners. Q11 had minimal impact in enhancing the immunogenicity of J14 even when it was used in combination with lipoamino acids. These findings highlight the impact of lipoamino acids moiety as a promising immunostimulant carrier and its number of attachment to peptide epitope was found to have a profound effect on the vaccine immunogenicity.
由于其安全性、易于制造以及在产生免疫反应方面的特异性,肽作为疫苗抗原备受关注。在过去十年中,已发现大量肽抗原。然而,单独的肽免疫原性较差,这需要与强佐剂共同给药以增强其免疫原性。最近,已确定诸如Q11之类的形成纤维的肽和基于脂氨基酸的载体在与肽表位共价连接时可诱导显著的免疫反应。在本研究中,我们将Q11或脂氨基酸掺入源自A组链球菌M蛋白的肽表位(J14)中,以开发自佐剂疫苗。J14、Q11和脂氨基酸也在单一疫苗构建体中共轭在一起,试图评估组合多种佐剂的协同效应。物理化学表征表明,疫苗构建体折叠方式不同并自组装成纳米颗粒。值得注意的是,只有含有双拷贝脂氨基酸的疫苗构建体(无论是否与Q11共轭)能够以非大小依赖的方式诱导显著的树突状细胞摄取以及随后的J14特异性抗体反应。即使与脂氨基酸联合使用,Q11对增强J14的免疫原性影响也很小。这些发现突出了脂氨基酸部分作为一种有前景的免疫刺激载体的影响,并且发现其与肽表位的连接数量对疫苗免疫原性有深远影响。