Protein Nanoparticle-Mediated Delivery of Recombinant Influenza Hemagglutinin Enhances Immunogenicity and Breadth of the Antibody Response.
Protein Nanoparticle-Mediated Delivery of Recombinant Influenza Hemagglutinin Enhances Immunogenicity and Breadth of the Antibody Response.
复制标题
DOI：
10.1021/acsinfecdis.2c00362
复制
发表时间：
2023-02-10
影响因子：
5.3
通讯作者：
Wang, Szu-Wen
中科院分区：
文献类型：
--
作者：
Badten, Alexander J.;Ramirez, Aaron;Hernandez-Davies, Jenny E.;Albin, Tyler J.;Jain, Aarti;Nakajima, Rie;Felgner, Jiin;Davies, D. Huw;Wang, Szu-Wen
关键词：
每年接种的绝大多数季节性流感疫苗都是从鸡蛋中传播的病毒衍生出来的，使用的技术自20世纪30年代以来几乎没有变化。免疫原性、持久性和反应的广度可能会从基于重组纳米颗粒的方法中受益。虽然E2蛋白纳米颗粒(NP)平台已被证明能促进细胞对多肽表位的有效反应，但尚未有报道它能传递完整的蛋白质抗原。在这项研究中，我们合成了一种新型的马来酰亚胺三氮三乙酸(NTA)连接物，将H1N1流感病毒的血凝素(HA)偶联到E2 NP上，并用蛋白质芯片评估了HA特异性的抗体应答。我们发现，仅重组H1蛋白在小鼠中具有免疫原性，但需要两次加强免疫才能检测到IgG，并且是强烈的IgG1(Th2)极化。当与E2NPs结合时，会产生IgG2c，从而导致更平衡的Th1/Th2反应。Toll样受体4激动剂单磷酰脂A(Mpla)的加入显著增强了H1-E2 NPs的免疫原性，同时保持了Th1/Th2平衡。有趣的是，与使用或不使用Mpla的非结合H1相比，与Mpla结合的H1-E2也观察到了更广泛的同型和异型交叉反应。这些结果突出了基于NP的HA递送在调节基于HA的重组疫苗产生的免疫原性、广度和Th1/Th2平衡方面的潜力。此外，这种蛋白质-蛋白质结合策略的模块化可能对未来针对其他人类病原体的疫苗开发有用。
The vast majority of seasonal influenza vaccines administered each year are derived from virus propagated in eggs using technology that has changed little since the 1930s. The immunogenicity, durability, and breadth of response would likely benefit from a recombinant nanoparticle-based approach. Although the E2 protein nanoparticle (NP) platform has been previously shown to promote effective cell-mediated responses to peptide epitopes, it has not yet been reported to deliver whole protein antigens. In this study, we synthesized a novel maleimido tris-nitrilotriacetic acid (NTA) linker to couple protein hemagglutinin (HA) from H1N1 influenza virus to the E2 NP, and we evaluated the HA-specific antibody responses using protein microarrays. We found that recombinant H1 protein alone is immunogenic in mice but requires two boosts for IgG to be detected and is strongly IgG1 (Th2) polarized. When conjugated to E2 NPs, IgG2c is produced leading to a more balanced Th1/Th2 response. Inclusion of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) significantly enhances the immunogenicity of H1–E2 NPs while retaining the Th1/Th2 balance. Interestingly, broader homo- and heterosubtypic cross-reactivity is also observed for conjugated H1–E2 with MPLA, compared to unconjugated H1 with or without MPLA. These results highlight the potential of an NP-based delivery of HA for tuning the immunogenicity, breadth, and Th1/Th2 balance generated by recombinant HA-based vaccination. Furthermore, the modularity of this protein–protein conjugation strategy may have utility for future vaccine development against other human pathogens.
登录
查看更多内容
影响因子：
9.2
作者：
Nguyen B;Tolia NH
通讯作者：
Tolia NH
影响因子：
1.7
作者：
Gu, Xiu;Li, Peng;Sakuma, Tsutomu
通讯作者：
Sakuma, Tsutomu
DOI：
10.1016/s0021-9673(00)93969-4
发表时间：
1987-12-18
期刊：
JOURNAL OF CHROMATOGRAPHY
影响因子：
--
作者：
HOCHULI, E;DOBELI, H;SCHACHER, A
通讯作者：
SCHACHER, A
DOI：
10.1002/wnan.1681
发表时间：
2021-05
期刊：
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology
影响因子：
--
作者：
Butkovich N;Li E;Ramirez A;Burkhardt AM;Wang SW
通讯作者：
Wang SW
影响因子：
5.9
作者：
Chiba S;Frey SJ;Halfmann PJ;Kuroda M;Maemura T;Yang JE;Wright ER;Kawaoka Y;Kane RS
通讯作者：
Kane RS