Liaw Kevin, Konrath Kylie M, Trachtman Abigail R, Tursi Nicholas J, Gary Ebony N, Livingston Cory, Flowers Kaitlyn, Chu Jacqueline D, Hojecki Casey E, Laenger Niklas, McCanna Madison E, Agostino Colby J, Chokkalingam Neethu, Bayruns Kelly, Kriete Sinja, Kim Amber, Park Joyce, Monastra Cara, Pardo Lucas A, Jenison Sarah, Huang Jinwei, Mulka Kathleen, Patel Ami, Kulp Daniel W, Weiner David B
Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA 19104, USA.
Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Vaccine. 2025 Jun 20;59:127231. doi: 10.1016/j.vaccine.2025.127231. Epub 2025 May 20.
Current influenza vaccines induce mostly strain-specific immunity necessitating annual reformulation and dosing. Here, we developed an improved seasonal influenza vaccine based on A/H1N1/Wisconsin/588/2019. We designed a DNA-launched self-assembling nanoparticle that displayed seven Wisconsin/588/2019 hemagglutinin (HA) head domains (WI19-7mer). WI19-7mer nanovaccine improved heterologous HAI titers and CD8+ cellular responses in mice than DNA encoded HA trimer (WI19 HA). In human antibody repertoire mice, WI19-7mer induced superior breadth to a diverse panel of H1 HAs compared to WI19 HA immunized animals. Cross-reactive HAI titers were maintained better in mice immunized with WI19-7mer than WI19 HA. The WI19-7mer induced improved antibody binding breadth and provided superior protection in a heterologous challenge compared to challenge-matched HA trimer. Addition of the cytokine adjuvant (CTACK) to WI19-7mer significantly improved breadth, HAI, peripheral responses, and protection in heterologous challenge. These data demonstrate that combining nucleic acid delivery, immune focusing, low valency nanoparticle, and mucosal adjuvant for enhanced vaccine effectiveness has broader applications for other viruses.
目前的流感疫苗大多诱导的是毒株特异性免疫，因此需要每年重新配方和接种。在此，我们基于A/H1N1/威斯康星/588/2019研发了一种改良的季节性流感疫苗。我们设计了一种由DNA启动的自组装纳米颗粒，其展示了七个威斯康星/588/2019血凝素（HA）头部结构域（WI19 - 7聚体）。与DNA编码的HA三聚体（WI19 HA）相比，WI19 - 7聚体纳米疫苗提高了小鼠体内的异源血凝抑制（HAI）滴度和CD8 + 细胞反应。在人抗体库小鼠中，与WI19 HA免疫的动物相比，WI19 - 7聚体对多种H1 HA诱导出更高的广度。与WI19 HA相比，用WI19 - 7聚体免疫的小鼠中交叉反应性HAI滴度保持得更好。与攻击匹配的HA三聚体相比，WI19 - 7聚体诱导出更好的抗体结合广度，并在异源攻击中提供了更好的保护。向WI19 - 7聚体中添加细胞因子佐剂（CTACK）显著提高了广度、HAI、外周反应以及在异源攻击中的保护作用。这些数据表明，将核酸递送、免疫聚焦、低价纳米颗粒和黏膜佐剂相结合以提高疫苗效力，对其他病毒具有更广泛的应用。
