Zhang Anna J X, Li Can, To Kelvin K W, Zhu Hou-Shun, Lee Andrew C Y, Li Chuan-Gen, Chan Jasper F W, Hung Ivan F N, Yuen Kwok-Yung
State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.
Clin Vaccine Immunol. 2014 Apr;21(4):570-9. doi: 10.1128/CVI.00816-13. Epub 2014 Feb 12.
Toll-like receptors (TLRs) of the innate immune system are known targets for enhancing vaccine efficacy. We investigated whether imiquimod, a synthetic TLR7 agonist, can expedite the immune response against influenza virus infection when combined with influenza vaccine. BALB/c mice were immunized intraperitoneally with monovalent A(H1N1)pdm09 vaccine combined with imiquimod (VCI) prior to intranasal inoculation with a lethal dose of mouse-adapted A(H1N1)pdm09 virus. For mice immunized 3 days before infection, the survival rates were significantly higher in the VCI group (60%, mean survival time[MST], 11 days) than in the vaccine-alone (30%; MST, 8.8 days), imiquimod-alone (5%; MST, 8.4 days), and phosphate-buffered saline (PBS) (0%; MST, 6.2 days) groups (P < 0.01). In the VCI group, 45 and 35% of the mice survived even when they were infected 2 days or 1 day after immunization. Virus-specific serum IgM, IgG, and neutralizing antibodies appeared earlier with higher geometric mean titers in the VCI group than in the control groups. The pulmonary viral load was significantly lower at all time points postinfection in the VCI, vaccine-alone, and imiquimod-alone groups than in the PBS control group (P < 0.05). The protection induced by VCI was specific for A(H1N1)pdm09 virus but not for A(H5N1) virus. Since imiquimod combined with RNase-treated vaccine is as protective as imiquimod combined with untreated vaccine, mechanisms other than TLR7 may operate in expediting and augmenting immune protection. Moreover, increased gamma interferon mRNA expression and IgG isotype switching, which are markers of the Th1 response induced by imiquimod, were not apparent in our mouse model. The mechanisms of imiquimod-induced immune protection deserve further study.
天然免疫系统的Toll样受体(TLRs)是增强疫苗效力的已知靶点。我们研究了咪喹莫特(一种合成的TLR7激动剂)与流感疫苗联合使用时,是否能加速针对流感病毒感染的免疫反应。在经鼻接种致死剂量的小鼠适应株A(H1N1)pdm09病毒之前,用单价A(H1N1)pdm09疫苗联合咪喹莫特(VCI)对BALB/c小鼠进行腹腔免疫。对于在感染前3天免疫的小鼠,VCI组的存活率(60%,平均存活时间[MST]为11天)显著高于单独疫苗组(30%;MST,8.8天)、单独咪喹莫特组(5%;MST,8.4天)和磷酸盐缓冲盐水(PBS)组(0%;MST,6.2天)(P<0.01)。在VCI组中,即使在免疫后2天或1天感染,仍有45%和35%的小鼠存活。与对照组相比,VCI组中病毒特异性血清IgM、IgG和中和抗体出现得更早,几何平均滴度更高。在感染后的所有时间点,VCI组、单独疫苗组和单独咪喹莫特组的肺病毒载量均显著低于PBS对照组(P<0.05)。VCI诱导的保护作用对A(H1N1)pdm09病毒具有特异性,对A(H5N1)病毒则无特异性。由于咪喹莫特与经核糖核酸酶处理的疫苗联合使用时的保护作用与咪喹莫特与未处理疫苗联合使用时相同,因此除TLR7外的其他机制可能在加速和增强免疫保护中发挥作用。此外,在我们的小鼠模型中,咪喹莫特诱导的Th1反应标志物γ干扰素mRNA表达增加和IgG同种型转换并不明显。咪喹莫特诱导免疫保护的机制值得进一步研究。