Mucosal Application of gp140 Encoding DNA Polyplexes to Different Tissues Results in Altered Immunological Outcomes in Mice

Increasing evidence suggests that mucosally targeted vaccines will enhance local humoral and cellular responses whilst still eliciting systemic immunity. We therefore investigated the capacity of nasal, sublingual or vaginal delivery of DNA-PEI polyplexes to prime immune responses prior to mucosal protein boost vaccination. Using a plasmid expressing the model antigen HIV CN54gp140 we show that each of these mucosal surfaces were permissive for DNA priming and production of antigen-specific antibody responses. The elicitation of systemic immune responses using nasally delivered polyplexed DNA followed by recombinant protein boost vaccination was equivalent to a systemic prime-boost regimen, but the mucosally applied modality had the advantage in that significant levels of antigen-specific IgA were detected in vaginal mucosal secretions. Moreover, mucosal vaccination elicited both local and systemic antigen-specific IgG+ and IgA+ antibody secreting cells. Finally, using an Influenza challenge model we found that a nasal or sublingual, but not vaginal, DNA prime/protein boost regimen protected against infectious challenge. These data demonstrate that mucosally applied plasmid DNA complexed to PEI followed by a mucosal protein boost generates sufficient antigen-specific humoral antibody production to protect from mucosal viral challenge.

越来越多的研究证据表明，黏膜靶向疫苗可在诱导全身免疫的同时，强化局部体液与细胞免疫应答。为此，本研究探究了经鼻腔、舌下或阴道递送DNA-聚乙烯亚胺（PEI）多聚复合物，在黏膜蛋白加强免疫前启动免疫应答的能力。本研究使用表达模式抗原HIV CN54gp140的质粒开展实验，结果显示上述三类黏膜表面均支持DNA初免，并可产生抗原特异性抗体应答。经鼻腔递送PEI复合DNA，随后联合重组蛋白加强免疫所诱导的全身免疫应答，与传统全身初免-加强免疫方案相当；但黏膜递送方案具有独特优势：可在阴道黏膜分泌物中检测到高水平的抗原特异性免疫球蛋白A（IgA）。此外，黏膜免疫可同时诱导局部与全身的抗原特异性IgG阳性、IgA阳性抗体分泌细胞。最后，借助流感病毒攻毒模型，本研究发现经鼻腔或舌下实施的DNA初免-蛋白加强方案可抵御感染性攻毒，而经阴道递送的方案则无此保护效果。上述实验结果证实，经黏膜递送与PEI复合的质粒DNA，随后联合黏膜蛋白加强免疫，可产生足量的抗原特异性体液抗体，从而抵御黏膜病毒攻毒。