A Novel Human Papillomavirus 16 L1 Pentamer-Loaded Hybrid Particles Vaccine System: Influence of Size on Immune Responses
A Novel Human Papillomavirus 16 L1 Pentamer-Loaded Hybrid Particles Vaccine System: Influence of Size on Immune Responses
复制标题
新型人乳头瘤病毒 16 L1 五聚体混合颗粒疫苗系统：大小对免疫反应的影响
DOI：
10.1021/acsami.8b11556
复制
发表时间：
2018-10-24
影响因子：
9.5
通讯作者：
Wang, Lianyan
中科院分区：
文献类型：
--
作者：
Jia, Chengcheng;Yang, Tingyuan;Wang, Lianyan
子宫颈癌仍然是世界上第二大流行的女性恶性肿瘤，导致绝大多数癌症相关死亡，主要发生在发展中国家。迫切需要开发一种有效和低成本的预防人乳头瘤病毒（HPV）感染的疫苗，特别是在医疗资金不足的地区。与市场上基于HPV L1病毒样颗粒（VLP）的疫苗相比，在大肠杆菌中表达的重组HPV L1五聚体代表了预防HPV感染的有希望且潜在成本有效的疫苗。与常规铝盐佐剂相比，包含聚合物核和脂质壳的杂合颗粒显示出巨大的潜力，并且迫切需要用于HPV L1五聚体疫苗。据报道，颗粒大小在调节免疫反应中至关重要。尽管如此，关于颗粒大小与由此产生的免疫应答之间关系的报道一直存在冲突，并且对于颗粒大小如何调节基于HPV L1五聚体的候选疫苗的特异性免疫应答没有答案。在这里，我们制造了HPV 16 L1五聚体加载聚（D，L-丙交酯-共-乙交酯）（PLGA）/卵磷脂混合颗粒具有均匀的大小（0.3，1，和3 μ m），并研究了抗原释放，淋巴细胞的激活，树突状细胞（DC）的激活和成熟，滤泡辅助CD 4（+）T（TFH）细胞分化，释放促炎细胞因子和趋化因子的颗粒大小的影响。与其他粒径相比，1 μ m颗粒诱导更强大的抗体保护，并产生更持久的抗体反应，以及更高的回忆反应后，重复接种。这种上级免疫应答可能归因于持续的抗原释放和强大的抗原摄取和转运，然后进一步促进一系列级联反应，包括增强DC成熟，增加淋巴细胞活化，以及增强引流淋巴结（DLN）中TFH细胞的分化。在这里，一个强大的和经济的平台，HPV疫苗和全面了解粒径对免疫反应的HPV L1五聚体为基础的候选疫苗。
Cervical cancer remains the second-most prevalent female malignancy around the world, leading to a great majority of cancer-related mortality that occurs mainly in developing countries. Developing an effective and low-cost vaccine against human papillomavirus (HPV) infection, especially in medically underfunded areas, is urgent. Compared with vaccines based on HPV L1 viruslike particles (VLPs) in the market, recombinant HPV L1 pentamer expressed in Escherichia coli represents a promising and potentially cost-effective vaccine for preventing HPV infection. Hybrid particles comprising a polymer core and lipid shell have shown great potential compared to conventional aluminum salts adjuvant and is urgently needed for HPV L1 pentamer vaccines. It is well-reported that particle sizes are crucial in regulating immune responses. Nevertheless, reports on the relationship between the particulate size and the resultant immune response have been in conflict, and there is no answer to how the size of particles regulates specific immune response for HPV L1 pentamer-based candidate vaccines. Here, we fabricated HPV 16 L1 pentamer-loaded poly(D,L-lactide-co-glycolide) (PLGA)/lecithin hybrid particles with uniform sizes (0.3, 1, and 3 mu m) and investigated the particle size effects on antigen release, activation of lymphocytes, dendritic cells (DCs) activation and maturation, follicular helper CD4(+) T (TFH) cells differentiation, and release of pro-inflammatory cytokines and chemokines. Compared with the other particle sizes, 1 mu m particles induced more powerful antibody protection and yielded more persistent antibody responses, as well as more heightened anamnestic responses upon repeat vaccination. The superior immune responses might be attributed to sustainable antigen release and robust antigen uptake and transport and then further promoted a series of cascade reactions, including enhanced DCs maturation, increased lymphocytes activation, and augmented TFH cells differentiation in draining lymph nodes (DLNs). Here, a powerful and economical platform for HPV vaccine and a comprehensive understanding of particle size effect on immune responses for HPV L1 pentamer-based candidate vaccines are provided.