Dendrimer-conjugated peptide vaccine enhances clearance of Chlamydia trachomatis genital infection.
Dendrimer-conjugated peptide vaccine enhances clearance of Chlamydia trachomatis genital infection.
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DOI：
10.1016/j.ijpharm.2017.05.045
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发表时间：
2017-07-15
影响因子：
5.8
通讯作者：
Whittum-Hudson JA
中科院分区：
文献类型：
--
作者：
Ganda IS;Zhong Q;Hali M;Albuquerque RLC;Padilha FF;da Rocha SRP;Whittum-Hudson JA
近年来，基于肽的疫苗已经成为预防传染病的有希望的候选者。然而，在维持体内肽稳定性和增强肽免疫原性以产生增强感染清除的保护性免疫方面存在许多挑战。在这里，提出了一种基于树枝状聚合物的载体系统用于基于肽的疫苗递送，并显示了其在沙眼衣原体小鼠模型中的抗微生物可行性。衣原体是全世界最普遍的性传播细菌，也是沙眼的病原体，沙眼是可预防的传染性失明的主要原因。尽管这种传染性病原体很流行，以前也进行了许多疫苗相关的研究，但目前还没有市售疫苗。提出的载体系统由第4代羟基封端的聚酰胺胺（PAMAM）树枝状聚合物（G4OH）组成，衣原体糖脂抗原肽4（Pep4，AFPQFRSATLLL）的肽模拟物通过酯键与其缀合。预期G4OH和Pep4之间的酯键主要在细胞内环境中分解以用于抗原呈递。Pep4与树枝状聚合物缀合在皮下免疫后诱导衣原体特异性血清抗体。此外，这种新的疫苗制剂显着保护免疫动物免受感染性沙眼衣原体的阴道攻击，并减少感染负荷和组织（生殖道）损伤。与Pep4和佐剂（即明矾）相比，与G4OH缀合或仅与肽混合的Pep4提供增强的保护，表明PAMAM树枝状聚合物的潜在佐剂作用。结合，这些结果表明，羟基封端的PAMAM树枝状聚合物是一种有前途的聚合物纳米载体平台，用于肽疫苗的递送，这种方法有可能扩展到其他感染性细胞内细菌和病毒的公共卫生意义。
Peptide-based vaccines have emerged in recent years as promising candidates in the prevention of infectious diseases. However, there are many challenges to maintaining in vivo peptide stability and enhancement of peptide immunogenicity to generate protective immunity which enhances clearance of infections. Here, a dendrimer-based carrier system is proposed for peptide-based vaccine delivery, and shows its anti-microbial feasibility in a mouse model of Chlamydia trachomatis. Chlamydiae are the most prevalent sexually transmitted bacteria worldwide, and also the causal agent of trachoma, the leading cause of preventable infectious blindness. In spite of the prevalence of this infectious agent and the many previous vaccine-related studies, there is no vaccine commercially available. The carrier system proposed consists of generation 4, hydroxyl-terminated, polyamidoamine (PAMAM) dendrimers (G4OH), to which a peptide mimic of a chlamydial glycolipid antigen—Peptide 4 (Pep4, AFPQFRSATLLL) was conjugated through an ester bond. The ester bond between G4OH and Pep4 is expected to break down mainly in the intracellular environment for antigen presentation. Pep4 conjugated to dendrimer induced Chlamydia-specific serum antibodies after subcutaneous immunizations. Further, this new vaccine formulation significantly protected immunized animals from vaginal challenge with infectious Chlamydia trachomatis, and it reduced infectious loads and tissue (genital tract) damage. Pep4 conjugated to G4OH or only mixed with peptide provided enhanced protection compared to Pep4 and adjuvant (i.e. alum), suggesting a potential adjuvant effect of the PAMAM dendrimer. Combined, these results demonstrate that hydroxyl-terminated PAMAM dendrimer is a promising polymeric nanocarrier platform for the delivery of peptide vaccines and this approach has potential to be expanded to other infectious intracellular bacteria and viruses of public health significance.
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