Department of Infectious Diseases, Imperial College London, St Mary's Campus, London, UK.
Bristol Veterinary School, University of Bristol, Bristol, UK.
Immunology. 2022 Mar;165(3):301-311. doi: 10.1111/imm.13429. Epub 2021 Dec 12.
Optimal immunogenicity from nucleic acid vaccines requires a balance of antigen expression that effectively engages the host immune system without generating a cellular response that rapidly destroys cells producing the antigen and thereby limiting vaccine antigen expression. We investigated the role of the cellular response on the expression and antigenicity of DNA vaccines using a plasmid DNA construct expressing luciferase. Repeated intramuscular administration led to diminished luciferase expression, suggesting a role for immune-mediated clearance of expression. To investigate the role of cell trafficking, we used the sphingosine 1-phosphate receptor (S1PR) modulator, FTY720 (Fingolimod), which traps lymphocytes within the lymphoid tissues. When lymphocyte trafficking was blocked with FTY720, DNA transgene expression was maintained at a constant level for a significantly extended time period. Both continuous and staggered administration of FTY720 prolonged transgene expression. However, blocking lymphocyte egress during primary transgene administration did not result in an increase of transgene expression during secondary administration. Interestingly, there was a disconnect between transgene expression and immunogenicity, as increasing expression by this approach did not enhance the overall immune response. Furthermore, when FTY720 was administered alongside a DNA vaccine expressing the HIV gp140 envelope antigen, there was a significant reduction in both antigen-specific antibody and T-cell responses. This indicates that the developing antigen-specific cellular response clears DNA vaccine expression but requires access to the site of expression in order to develop an effective immune response.
核酸疫苗需要达到最佳的免疫原性，就需要抗原表达达到平衡，既要有效地激发宿主免疫系统，又不能引起迅速破坏产生抗原的细胞的细胞应答，从而限制疫苗抗原的表达。我们使用表达荧光素酶的质粒 DNA 构建体，研究了细胞应答对 DNA 疫苗表达和抗原性的作用。重复肌肉内给药导致荧光素酶表达减少，表明免疫介导的清除表达具有作用。为了研究细胞迁移的作用，我们使用了鞘氨醇 1-磷酸受体（S1PR）调节剂，FTY720（fingolimod），它将淋巴细胞困在淋巴组织中。当用 FTY720 阻断淋巴细胞迁移时，DNA 转基因的表达在显著延长的时间内保持在恒定水平。FTY720 的连续和交错给药均可延长转基因的表达。然而，在初次转基因给药期间阻止淋巴细胞迁出并没有导致在二次给药期间转基因表达增加。有趣的是，转基因表达和免疫原性之间存在脱节，因为这种方法增加表达并没有增强整体免疫反应。此外，当 FTY720 与表达 HIV gp140 包膜抗原的 DNA 疫苗一起给药时，抗原特异性抗体和 T 细胞反应均显著降低。这表明正在发展的抗原特异性细胞应答清除 DNA 疫苗表达，但需要访问表达部位才能产生有效的免疫应答。
