10 Nov 2015

Researchers from Li Ka Shing Faculty of Medicine, The University of Hong Kong (HKU) have completed an important double-blind, randomised, controlled trial, demonstrating that the topical application of imiquimod just before intradermal trivalent influenza vaccine in young healthy volunteers, significantly improved the immunogenicity against the vaccine strains. More importantly, imiquimod also increased the breadth of immunogenicity against the heterologous non-vaccine strains, including the antigenically drifted H3N2 strain, which was not included in the 2013-14 recommended vaccine. This important clinical finding is electronically published in the top infectious disease journal The Lancet Infectious Diseases (1).

Leader of the study, Professor Yuen Kwok-yung, Henry Fok Professor in Infectious Diseases, Chair Professor of Infectious Diseases from the Department of Microbiology, Li Ka Shing Faculty of Medicine, and Director of State Key Laboratory for Emerging Infectious Diseases, HKU says, “Every year, influenza infection causes a huge disease burden with significantly increased mortality (2,3), especially in years of antigenic drift such as in the winter of 2014/2015 (4,5). This is the first randomised controlled trial to use this approach with trivalent seasonal influenza vaccine in healthy individuals and show the early onset of significantly improved serological evidence of protection against vaccine and non-vaccine influenza virus strains when compared with the three control groups. Notably, our study demonstrated good heterologous antibody protection against non-vaccine virus strains including the antigenicially drifted influenza A H3N2 virus which caused 600 deaths in Hong Kong earlier this year.”

Dr Ivan Hung Fan-ngai, Clinical Associate Professor of the Department of Medicine, Li Ka Shing Faculty of Medicine, HKU and also another leader of the team further explains, “Our results suggest that topical imiquimod pretreatment before intradermal influenza vaccination is extremely safe. It improves the time to onset, extent and breadth of protective serological response against both vaccine influenza strains and heterologous non-vaccine-strains. This finding has important global health implications, especially at times of vaccine mismatch and during major outbreak.’

Impact of the study

a. Rapid onset of effective antibody response
b. Highly active against vaccine influenza virus strains
c. Highly active against non-vaccine related influenza virus strains
d. Likely to confer protection even when WHO wrongly predicts the epidemic strains
e. Should be tested for vaccines other than influenza

Research methodology

In this single-centre, double-blind, randomised controlled trial, we enrolled 160 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. Eligible participants were randomly assigned (1:1:1:1) to one of the four vaccination groups: topical imiquimod followed by intradermal vaccine, topical aqueous-cream control followed by intradermal vaccine, topical aqueous cream followed by intramuscular vaccine and topical imiquimod-cream followed by intradermal normal saline injection. Serum haemagglutination-inhibition and microneutralisation-antibody titres were assayed. The primary outcome was seroconversion at day 7 after treatment for the three vaccine strains: A/California/H1N1, A/Victoria/H3N2 and B/Yamagata lineage; and four non-vaccine strains: H3N2 Switzerland-like lineage, prototype A/WSN/1933 (H1N1), prepandemic seasonal H1N1 and B/Victoria lineage.

Background of the study

Influenza poses a heavy burden to the global and also local health services under the Hospital Authority of Hong Kong (2,3). The WHO estimates that seasonal influenza causes 250,000 – 500,000 deaths worldwide annually (6). Most recently, the antigenically drifted A/Switzerland/9715293/2013 virus caused major outbreaks in Europe and North America (4,5). Moreover avian influenza virus such as the A(H5N1) and A(H7N9) are associated with even higher mortality (7,8). Therefore any strategy, which may improve and expand the antigenic breadth of the protective immune response from influenza vaccination, would be especially important in the outbreak setting.

Research teams, including our own, have demonstrated that imiquimod, a synthetic TLR7 agonist indicated for the treatment of DNA virus infection, could improve vaccine immunogenicity against influenza virus in animal models (9-12). We were able to demonstrate that treatment with topical imiquimod before intradermal trivalent influenza vaccine (TIV) in the elderly subjects with chronic illness significantly expedited, augmented and prolonged the immunogenicity against the influenza vaccine strains (13). The objective of the current novel double-blind randomized controlled trial was to evaluate the effect and safety of topical treatment with imiquimod immediately before intradermal influenza vaccination in young healthy subjects against both vaccine and non-vaccine virus strains.

About the research team

The research team is headed by Professor Yuen Kwok-yung, Henry Fok Professor in Infectious Diseases, Chair Professor of Infectious Diseases, Department of Microbiology of Li Ka Shing Faculty of Medicine, and Director of State Key Laboratory for Emerging Infectious Diseases of HKU, and Dr Ivan Hung Fan-ngai, Clinical Associate Professor of the Department of Medicine, Li Ka Shing Faculty of Medicine, HKU.

Important donations from:
• D.H. Chen Foundation (Nan Fung Group)
• Madam Yat-Wah Fong & Shaw Foundation
• Mr. Pony Ma
• The University of Hong Kong
• The Hong Kong Polytechnic University
• Macau Henry Fok Foundation
• Stanley Ho Medical Foundation
• Moonchu Foundation

References

1. Hung IF, Zhang AJ, To KK, Chan JF, Li P, Wong TL, Zhang R, Chan TC, Chan BC, Wai HH, Chan LW, Fong HP, Hui RK, Kong KL, Leung AC, Ngan AH, Tsang LW, Yeung AP, Yiu GC, Yung W, Lau JY, Cheng H, Chan KH, Yuen KY. 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. Lancet Infectious Diseases 2015; doi.org/10.1016/s1473-3099 (Epub ahead of print)
2. Fleming DM, Elliot AJ. The impact of influenza on the health and health care utilisation of elderly people. Vaccine. 2005;23: S1-9.
3. Cheng VC, To KK, Tse H, Hung IF, Yuen KY. Two years after pandemic influenza A/2009/H1N1: what have we learned. Clin Microbiol Rev. 2012;25: 223-63.
4. Centres for Disease Control and Prevention HAN 00374 - Emergency Preparedness and Response. Health Advisory regarding the potential for circulation of drifted influenza A (H3N2) viruses. December 3, 2014.
5. Skowronski DM, Drews SJ, Fonseca K, Charest H, Chambers C, Sabaiduc S, et al. Interim estimates of 2014/5 vaccine effectiveness against influenza A (H3N2) from Canada’s sentinel physician surveillance network. Euro Surveill 2015;20. Pi: 21022.
6. World Health Organization Media Centre. Influenza (Seasonal) Fact Sheet N° 211. March, 2014 (http://www.who.int/mediacentre/factsheets/fs211/en/ )
7. Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, et al. Avian influenza A (H5N1) infection in humans. N Engl J Med. 2005;353: 1374-85.
8. Chen Y, Liang W, Yang S, Wu N, Gao H, Sheng J, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterization of viral genome. Lancet. 2013;381: 1916-25.
9. Thomsen LL, Topley P, Daly MG, Brett SJ, Tite JP. Imiquimod and resiquimod in a mouse model: adjuvants for DNA vaccination by particle-mediated immunotherapeutic delivery. Vaccine. 2004;22:1799-809.
10. Zuber AK, Bråve A, Engström G, Zuber B, Ljungberg K, Fredriksson M, et al. Topical delivery of imiquimod to a mouse model as a novel adjuvant for human immunodeficiency virus (HIV) DNA. Vaccine. 2004;22:1791-8.
11. Weldon WC, Zarnitsyn VG, Esser ES, Taherbhai MT, Koutsonanos DG, Vassilieva EV, et al. Effect of adjuvants on responses to skin immunization by microneedles coated with influenza subunit vaccine. PLoS One. 2012;7:e41501.
12. Zhang AJ, Li C, To KK, Zhu HS, Lee AC, Li CG, et al. Toll-like receptor 7 agonist imiquimod in combination with influenza vaccine expedites and augments humoral immune responses against influenza A(H1N1)pdm09 virus infection in BALB/c mice. Clin Vaccine Immunol. 2014;21:570-9.
13. Hung IF, Zhang AJ, To KK, Chan JF, Li C, Zhu HS, et al. Immunogenicity of intradermal trivalent influenza vaccine with topical imiquimod: a double blind randomized controlled trial. Clin Infect Dis 2014;59:1246-55.