Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: a single-centre, double-blind, randomised, controlled phase 2b/3 trial

• Published in: The Lancet infectious diseases 2016-02, Vol.16 (2), p.209-218
• Main Authors: Hung, Ivan Fan-Ngai, MD, Zhang, Anna Jinxia, PhD, To, Kelvin Kai-Wang, MD, Chan, Jasper Fuk-Woo, MBBS, Li, Patrick, MSc, Wong, Tin-Lun, BSc, Zhang, Ricky, MSc, Chan, Tuen-Ching, MD, Chan, Brian Chun-Yuan, BSc, Wai, Harrison Ho, Chan, Lok-Wun, Fong, Hugo Pak-Yiu, Hui, Raymond Kar-Ching, Kong, Ka-Lun, Leung, Arthur Chun-Fung, MBiochem, Ngan, Abe Ho-Ting, Tsang, Louise Wing-Ki, Yeung, Alex Pat-Chung, Yiu, Geo Chi-Ngo, Yung, Wing, Lau, Johnson Y-N, MD, Chen, Honglin, PhD, Chan, Kwok-Hung, PhD, Yuen, Kwok-Yung, Prof
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - administration & dosage; Administration, Topical; Adolescent; Adult; Aminoquinolines - administration & dosage; Chronic illnesses; Colleges & universities; Double-Blind Method; Epidemics; Female; Hong Kong; Humans; Immunogenicity; Infectious Disease; Infectious diseases; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H1N1 Subtype - immunology; Influenza A Virus, H3N2 Subtype - drug effects; Influenza A Virus, H3N2 Subtype - immunology; Influenza Vaccines - administration & dosage; Influenza, Human - immunology; Influenza, Human - prevention & control; Injections, Intradermal; Male; Medical research; Pain; Public health; Skin; Swine flu; Vaccines; Viruses; Young Adult
• ISSN: 1473-3099; 1474-4457
• DOI: 10.1016/S1473-3099(15)00354-0

Summary Background 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. Methods 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. Findings 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, 1