Carol Yu Centre for Infection and Division of Infectious Diseases, University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, China.
Carol Yu Centre for Infection and Division of Infectious Diseases, University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China.
Lancet Infect Dis. 2016 Feb;16(2):209-18. doi: 10.1016/S1473-3099(15)00354-0. Epub 2015 Nov 9.
Pretreatment with topical imiquimod, a synthetic agonist of toll-like receptor 7, significantly improved the immunogenicity of influenza vaccination in elderly people. We aimed to clarify its effect in a younger age group.
In this double-blind, randomised controlled trial, we enrolled healthy volunteers aged 18-30 years in early 2014 to receive the 2013-14 northern-hemisphere winter trivalent influenza vaccine at the Queen Mary Hospital, (Hong Kong, China). Eligible participants were randomly assigned (1:1:1:1) to one of the four vaccination groups: the study group, topical imiquimod-cream followed by intradermal trivalent influenza vaccine (INF-Q-ID), or one of three control groups, topical aqueous-cream control followed by intradermal trivalent influenza vaccine (INF-C-ID), topical aqueous-cream control followed by intramuscular trivalent influenza vaccine (INF-C-IM), and topical imiquimod-cream followed by intradermal normal-saline injection (SAL-Q-ID). Randomisation was by computer-generated lists in blocks of four. The type of topical treatment was masked from volunteers and investigators, although not from the study nurse. Serum haemagglutination-inhibition and microneutralisation-antibody titres were assayed. The primary outcome was seroconversion at day 7 after treatment for three vaccine strains of influenza (A/California/07/2009 H1N1-like virus [A/California/H1N1], A/Victoria/361/2011 H3N2-like virus [A/Victoria/H3N2], and B/Massachusetts/2/2012-like virus [B/Yamagata lineage]) and four non-vaccine strains (A/HK/485197/14 [H3N2 Switzerland-like lineage], prototype A/WSN/1933 [H1N1], A/HK/408027/09 [prepandemic seasonal H1N1], and B/HK/418078/11 [Victoria lineage]). Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02103023.
We enrolled 160 healthy volunteers between March 1 and May 31, 2014, and 40 participants were randomly assigned to each study group. For the A/California/H1N1 strain, seroconversion at day 7 occurred in 39 participants (98%) in the INF-Q-ID group, 25 (63%) in the INF-C-ID group, 18 (45%) in the INF-C-IM group, and none in the SAL-Q-ID group; for the A/Victoria/H3N2, this was 30 (75%) in the INF-Q-ID group, four (10%) in the INF-C-ID group, four (10%) in the INF-C-IM group, and none in the SAL-Q-ID group; and for the B/Massachusetts (Yamagata lineage) strain, this was 36 (90%) in the INF-Q-ID group, 27 (68%) in the INF-C-ID group, 17 (43%) in the INF-C-IM group, and one (3%) in the SAL-Q-ID group (p<0·0001 for all three vaccine strains). Adverse reactions were infrequent and self-limited and did not differ between the four groups. Furthermore, the seroconversion rate against the four non-vaccine strains was better in the INF-Q-ID group than in the control groups on days 7 and 21 (p<0·0001). The most common adverse events were grade 1 redness (five participants in the INF-Q-ID group, three in INF-C-ID, one in INF-C-IM, and one in SAL-Q-ID) and grade 1 swelling (seven participants in INF-Q-ID group, five in INF-C-ID, three in INF-C-IM, and two in SAL-Q-ID.
Topical application of imiquimod before intradermal trivalent influenza vaccine significantly improved immunogenicity against the vaccine influenza strains in young healthy individuals and increased immunogenicity against the non-vaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-14 recommended vaccine. Further studies should be done to establish the efficacy and safety of this approach for other injectable vaccines to augment the onset and range of protection.
The Shaw Foundation Hong Kong, Health and Medical Research Fund (Hong Kong, China), The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Disease for the HKSAR (Department of Health, Hong Kong, China), The Providence Foundation, Respiratory Viral Research Foundation.
在老年人中，预先使用局部咪喹莫特（一种 Toll 样受体 7 的合成激动剂）可显著提高流感疫苗的免疫原性。我们旨在阐明其在年轻人群中的作用。
在这项 2014 年初进行的双盲、随机对照试验中，我们招募了年龄在 18-30 岁之间的健康志愿者，在香港玛丽医院接种 2013-14 年北半球冬季三价流感疫苗。符合条件的参与者被随机分配（1:1:1:1）至四个疫苗接种组之一：研究组，局部咪喹莫特乳膏联合皮内三价流感疫苗（INF-Q-ID），或三个对照组之一，局部水性乳膏对照联合皮内三价流感疫苗（INF-C-ID），局部水性乳膏对照联合肌肉内三价流感疫苗（INF-C-IM），以及局部咪喹莫特乳膏联合皮内生理盐水注射（SAL-Q-ID）。随机分组按 4 个单位的块进行。志愿者和研究者不知道局部治疗的类型，但研究护士知道。检测血清血凝抑制和微量中和抗体滴度。主要结局是接种三种流感病毒株（A/California/07/2009 类似 H1N1 病毒[A/California/H1N1]、A/Victoria/361/2011 类似 H3N2 病毒[A/Victoria/H3N2]和 B/Massachusetts/2/2012 类似病毒[B/Yamagata 谱系]）和四种非疫苗株（A/HK/485197/14[类似 H3N2 瑞士谱系]、原型 A/WSN/1933[H1N1]、A/HK/408027/09[流行季节 H1N1]和 B/HK/418078/11[类似 Victoria 谱系]）的血清转化率，接种后第 7 天。分析基于意向治疗。该试验在 ClinicalTrials.gov 上注册，编号为 NCT02103023。
我们于 2014 年 3 月 1 日至 5 月 31 日招募了 160 名健康志愿者，40 名参与者被随机分配至每个研究组。对于 A/California/H1N1 株，接种后第 7 天血清转化率为 39 名参与者（98%）在 INF-Q-ID 组，25 名（63%）在 INF-C-ID 组，18 名（45%）在 INF-C-IM 组，和 SAL-Q-ID 组均未发生；对于 A/Victoria/H3N2，该转化率为 30 名（75%）在 INF-Q-ID 组，4 名（10%）在 INF-C-ID 组，4 名（10%）在 INF-C-IM 组，和 SAL-Q-ID 组均未发生；对于 B/Massachusetts（Yamagata 谱系）株，该转化率为 36 名（90%）在 INF-Q-ID 组，27 名（68%）在 INF-C-ID 组，17 名（43%）在 INF-C-IM 组，和 1 名（3%）在 SAL-Q-ID 组（所有三种疫苗株的 p<0·0001）。不良反应少见且自限，且四组之间无差异。此外，与对照组相比，接种后第 7 天和第 21 天，INF-Q-ID 组对四种非疫苗株的血清转化率更高（p<0·0001）。最常见的不良事件为 1 级红斑（INF-Q-ID 组 5 名参与者，INF-C-ID 组 3 名参与者，INF-C-IM 组 1 名参与者，SAL-Q-ID 组 1 名参与者）和 1 级肿胀（INF-Q-ID 组 7 名参与者，INF-C-ID 组 5 名参与者，INF-C-IM 组 3 名参与者，SAL-Q-ID 组 2 名参与者）。
皮内三价流感疫苗前局部应用咪喹莫特可显著提高年轻健康个体对疫苗流感株的免疫原性，并增加对非疫苗株的免疫原性，特别是对 2015 年未包括在推荐疫苗中的抗原漂移 H3N2 株。应进一步研究这种方法对其他可注射疫苗的疗效和安全性，以增强起始和保护范围。
香港邵氏基金会，卫生和医学研究基金（中国香港），香港特别行政区增强新兴传染病实验室监测咨询服务（香港特别行政区卫生署），普罗维登斯基金会，呼吸道病毒研究基金会。
