Hill-Batorski Lindsay, Hatta Yasuko, Moser Michael J, Sarawar Sally, Neumann Gabriele, Kawaoka Yoshihiro, Bilsel Pamuk
FluGen Inc., Madison, WI 53711, USA.
The Biomedical Research Institute of Southern California, Oceanside, CA 92056, USA.
Vaccines (Basel). 2023 Apr 4;11(4):798. doi: 10.3390/vaccines11040798.
Current influenza vaccines demonstrate low vaccine efficacy, especially when the predominantly circulating strain and vaccine are mismatched. The novel influenza vaccine platform M2- or BM2-deficient single replication (M2SR and BM2SR) has been shown to safely induce strong systemic and mucosal antibody responses and provide protection against significantly drifted influenza strains. In this study, we demonstrate that both monovalent and quadrivalent (Quad) formulations of M2SR are non-pathogenic in mouse and ferret models, eliciting robust neutralizing and non-neutralizing serum antibody responses to all strains within the formulation. Following challenge with wildtype influenza strains, vaccinated mice and ferrets demonstrated reduced weight loss, decreased viral replication in the upper and lower airways, and enhanced survival as compared to mock control groups. Mice vaccinated with H1N1 M2SR were completely protected from heterosubtypic H3N2 challenge, and BM2SR vaccines provided sterilizing immunity to mice challenged with a cross-lineage influenza B virus. Heterosubtypic cross-protection was also seen in the ferret model, with M2SR vaccinated animals exhibiting decreased viral titers in nasal washes and lungs following the challenge. BM2SR-vaccinated ferrets elicited robust neutralizing antibodies toward significantly drifted past and future influenza B strains. Mice and ferrets that received quadrivalent M2SR were able to mount immune responses equivalent to those seen with each of the four monovalent vaccines, demonstrating the absence of strain interference in the commercially relevant quadrivalent formulation.
目前的流感疫苗显示出较低的疫苗效力，尤其是当主要流行毒株与疫苗不匹配时。新型流感疫苗平台M2或BM2缺陷型单复制（M2SR和BM2SR）已被证明能安全诱导强烈的全身和黏膜抗体反应，并提供针对显著变异流感毒株的保护。在本研究中，我们证明M2SR的单价和四价（Quad）制剂在小鼠和雪貂模型中均无致病性，能引发针对制剂内所有毒株的强大中和及非中和血清抗体反应。在用野生型流感毒株攻击后，与假对照组相比，接种疫苗的小鼠和雪貂体重减轻减少，上、下呼吸道病毒复制减少，存活率提高。接种H1N1 M2SR的小鼠完全免受异源亚型H3N2攻击的影响，BM2SR疫苗为感染跨谱系乙型流感病毒的小鼠提供了无菌免疫。在雪貂模型中也观察到了异源亚型交叉保护，接种M2SR的动物在攻击后鼻腔冲洗液和肺中的病毒滴度降低。接种BM2SR的雪貂对过去和未来显著变异的乙型流感毒株产生了强大的中和抗体。接种四价M2SR的小鼠和雪貂能够产生与四种单价疫苗各自产生的免疫反应相当的免疫反应，这表明在商业相关的四价制剂中不存在毒株干扰。
