Intradermal trivalent influenza vaccine with topical imiquimod for cross-protection against non-vaccine and antigenically drifted virus: a double-blind, randomised controlled trial

Abstract

BackgroundPretreatment with topical imiquimod, a synthetic Toll-like receptor 7 agonist, significantly expedited, augmented, and prolonged the immunogenicity of influenza vaccination in elderly patients. The effect of imiquimod pretreatment in young, healthy people is unknown. MethodsIn this double-blind, randomised controlled trial, we enrolled healthy volunteers of both sexes (age 18–30 years) early 2014 from the University of Hong Kong, to receive the 2013–14 northern-hemisphere winter trivalent influenza vaccine (TIV) at the Queen Mary Hospital, University of Hong Kong Medical School. Eligible participants had not received the influenza vaccine in preceeding 3 months, had no history of allergy to the components of the vaccine, agreed to comply with study procedures, and gave written informed consent. Participants were randomly assigned (1:1:1:1) to four treatment groups by simple randomisation with no stratification: topical 5% 250 mg imiquimod ointment followed by intradermal TIV (Intanza 15, Sanofi-Pasteur, France; IQ group); topical aqueous cream followed by intradermal TIV (ID group); topical aqueous cream followed by intramuscular TIV (Vaxigrip, Sanofi-Pasteur, France; IM group); or topical imiquimod ointment followed by intradermal normal saline injection (NS group). In the IQ and NS groups, the content of one sachet of imiquimod ointment was applied to the deltoid region of one arm 5 min before vaccination. In the ID and IM groups, aqueous cream with no effect was applied. Participants in the IQ and ID groups received 0·1 mL intradermal TIV (15 μg of hemagglutinin [HA] per strain). In the IM group, participants received 0·5 mL intramuscular influenza vaccine (15 μg of HA per strain). In the NS group, participants received 0·1 mL of intradermal normal saline as sham vaccine. Imiquimod ointment or aqueous cream was removed 6 h after vaccination. Volunteers and investigators were blinded to group allocation. We measured hemagglutination inhibition (HI) and microneutralisation antibody (MN) titers. Primary outcome was seroconversion rate at day 7. This trial is registered at ClinicalTrials.gov, number NCT02103023. The study was approved by the institutional review board of the University of Hong Kong and the Hospital Authority. FindingsBetween March 1, 2014, and May 31, 2014, we enrolled 40 participants per group. The median age was 20 years (IQR 19–21), and 80 (50%) participants were men. Age (p=0·875) and sex (p=0·5) distribution did not differ between groups. Day 7 seroconversion rate for the IQ group was 39 (98%), 30 (75%), and 36 (90%) for the A/California/H1N1, A/Victoria/H3N2 and B/Massachusetts strains, respectively. The seroconversion rate in all three vaccine strains were significantly better on day 7 in the IQ group than in the three control groups by haemagglutination inhibition assay (p<0·0001). Cross-protective immunity against the four non-vaccine influenza strains, including the antigenically drifted A/HK/4851970/14 (H3N2 Switzerland lineage), A/HK/408027/09 (seasonal H1N1), A/WSN/33 (H1N1), and B/HK/418078/11 (Victoria lineage), was seen in the IQ group, with significantly better seroconversion on day 7 (p<0·0001) than in the three controls by assays of haemagglutination inhibition and neutralisation antibody titre. Adverse events were infrequent and self-limited, with no difference between the four groups. InterpretationPretreatment with topical imiquimod before intradermal TIV in young, healthy participants significantly expedited and augmented the immunogenicity against the vaccine strains. Imiquimod also increased the breadth of immunogenicity against the non-vaccine strains, including the antigenically drifted H3N2 strain, which was not included in the 2013-14 recommended vaccine. FundingHealth and Medical Research Fund, Hong Kong SAR. The Shaw Foundation Hong Kong Limited; Providence Foundation Limited in memory of the late Dr. Lui Hac Minh, a donation from Larry Chi-Kin Yung; Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Disease for the Hong Kong SAR Department of Health.