MAJOR ARTICLE
Immunogenicity of Intradermal Trivalent Influenza Vaccine With Topical Imiquimod: A Double Blind Randomized Controlled Trial Ivan F. N. Hung,1,2 Anna J. Zhang,1 Kelvin K. W. To,1 Jasper F. W. Chan,1 Can Li,1 Hou-Shun Zhu,2 Patrick Li,1 Clara Li,1 Tuen-Ching Chan,2 Vincent C. C. Cheng,1 Kwok-Hung Chan,1 and Kwok-Yung Yuen1 State Key Laboratory for Emerging Infectious Diseases, Carol Yu’s Centre for Infection and Division of Infectious Diseases, and 2Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China
Background. Imiquimod, a synthetic Toll-like receptor 7 agonist enhanced immunogenicity of influenza vaccine in a mouse model. We hypothesized that topical imiquimod before intradermal influenza vaccination (TIV) would produce similar effect in human. Methods. We performed a prospective 1-year follow-up, double-blind, randomized, controlled trial with adults with comorbidities. Participants were randomized to 1 of the following 3 vaccinations: topical 5% 250 mg imiquimod ointment followed by intradermal TIV, topical aqueous-cream followed by intradermal TIV, or topical aqueouscream followed by intramuscular TIV. Patients and investigators were blinded to the type of topical treatment applied. Hemagglutination inhibition (HI) and microneutralization antibody titers were measured. The primary outcome was the day 7 seroconversion rate. Results. Ninety-one recruited participants completed the study. The median age was 73 years. On day 7, 27/30 (90%) patients who received imiquimod and intradermal TIV achieved seroconversion against the H1N1 strain by HI, compared with 4/30 (13.3%) who received aqueous-cream and intramuscular TIV (P < .001), and 12/31 (38.7%) who received aqueous-cream and intradermal TIV (P < .001). The seroconversion, seroprotection, and geometric mean titer–fold increase were met in all 3 strains in the imiquimod and intradermal TIV group 2 weeks earlier, and the better seroconversion rate was sustained from day 7 to year 1 (P ≤ .001). The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (P < .05). All adverse reactions were self-limited. Conclusions. Pretreatment with topical imiquimod significantly expedited, augmented, and prolonged the immunogenicity of influenza vaccination. This strategy for influenza immunization should be considered for the elderly population. Keywords. immunogenicity; imiquimod; intradermal; influenza; vaccine.
Influenza poses a heavy burden to our healthcare systems [1, 2]. Seasonal, zoonotic, and pandemic influenza are constant global threats. The World Health Organization (WHO) estimates that seasonal influenza causes
Received 26 March 2014; accepted 9 July 2014; electronically published 21 July 2014. Correspondence: Kwok-Yung Yuen, MD, Carol Yu Centre for Infection and Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong Special Administrative Region, China ([email protected]). Clinical Infectious Diseases® 2014;59(9):1246–55 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/cid/ciu582
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250 000–500 000 deaths worldwide annually, with an even higher mortality during the pandemic periods [3]. Moreover, zoonotic influenza such as the avianorigin H5N1 and the H7N9 influenza are associated with a much higher mortality than seasonal influenza [4, 5]. Elderly persons with comorbidities are at the highest risk of hospitalization for influenza infection and its complications. Vaccine immunogenicity among these at-risk individuals is suboptimal due to immunosenescence [6]. Various strategies including intradermal vaccination and new vaccine adjuvants have been shown to improve immunogenicity [7, 8]. Experience with the A(H1N1)pdm09 vaccine showed that mass production of an antigen-matched effective
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on November 12, 2014
1
METHODS Study Participants
Between January 2012 and March 2012, adults aged ≥21 years attending the medical specialist outpatient clinics (SOPCs) in the Hong Kong West Cluster hospitals who satisfied the WHO recommendations and indications for influenza
vaccination were screened for eligibility. The majority were elderly persons aged ≥65 years with comorbidities. Participants were included if they had not received the influenza vaccine in the prior 3 months and gave written informed consent. Participants with clinically significant immune-related diseases on long-term immunosuppressants and with a history of allergy to the vaccines’ components were excluded. The eligibility criteria are listed in the Supplementary Appendix. The study was approved by the institutional review board of the University of Hong Kong and Hospital Authority and is registered with ClinicalTrials.gov (NCT01508884). Study Design and Interventions
At the time of inclusion, the participants’ demographic and clinical characteristics were recorded. Simple randomization with no stratification was performed. Participants were randomly assigned to the experimental group (imiquimod ointment + intradermal vaccine [IQ]) or 1 of the 2 control groups (aqueous cream + intradermal vaccine [INT] or aqueous cream + intramuscular vaccine [IM]). Participants in the IQ and INT groups received a single dose of intradermal trivalent influenza vaccine (TIV; 15 µg of hemagglutinin [HA] per strain). Those in the IM group received a similar dose of intramuscular TIV. The study nurse marked a 16-cm2 square on the
Figure 1. Recruitment flow-chart of the 91 participants. Abbreviations: IM, aqueous cream + intramuscular vaccine; INT, aqueous cream + intradermal vaccine; IQ, imiquimod ointment + intradermal vaccine; SOPC, specialist outpatient clinic.
Intradermal TIV With Topical Imiquimod
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monovalent vaccine took at least 6 months from manufacture to delivery [9] and another 3 weeks to mount a seroprotective response after vaccination. Therefore, any strategy for expediting or augmenting the protective immune response from influenza vaccine would be especially important in the outbreak setting. Recently, imiquimod, a synthetic Toll-like receptor 7 (TLR7) agonist used for the treatment of DNA virus infection, was shown to improve vaccine immunogenicity against influenza virus in a mouse model [10, 11] and for other infections including human immunodeficiency virus (HIV) [12], human papillomavirus (HPV) [13], and malaria [14]. The objective of this prospective, double-blind, randomized, controlled trial was to evaluate the effectiveness and safety of topical treatment with imiquimod immediately before intradermal influenza vaccination. Our a priori hypothesis was that imiquimod pretreatment would expedite and augment the immunogenicity of influenza vaccination.
virus, influenza A/Perth/16/2009 (H3N2)–like virus, and influenza B/Brisbane/60/2008–like virus. The intradermal injection device, the Becton Dickinson (BD) Soluvia microinjection system, consists of a prefilled TIV, with a single 1.5-mm needle that penetrates perpendicularly into the skin [7]. The BD Soluvia is currently the only prefilled intradermal device licensed for influenza vaccine. Safety was evaluated by asking the participants to remain on the clinic premise for 30 minutes for observation post-immunization. An immediate adverse event checklist was completed before discharge. Participants were given a diary to document symptoms of local and systemic adverse events that occurred within the first 7 days post-vaccination. Systemic symptoms included fever (body temperature ≥37.5°C), headache, malaise, myalgia, arthralgia, and severe adverse events. Local symptoms included redness, swelling, induration, ecchymosis, and pain. Redness, swelling, induration, and ecchymosis were graded based on size as follows: grade 1
Immunogenicity of Intradermal Trivalent Influenza Vaccine With Topical Imiquimod: A Double Blind Randomized Controlled Trial Ivan F. N. Hung,1,2 Anna J. Zhang,1 Kelvin K. W. To,1 Jasper F. W. Chan,1 Can Li,1 Hou-Shun Zhu,2 Patrick Li,1 Clara Li,1 Tuen-Ching Chan,2 Vincent C. C. Cheng,1 Kwok-Hung Chan,1 and Kwok-Yung Yuen1 State Key Laboratory for Emerging Infectious Diseases, Carol Yu’s Centre for Infection and Division of Infectious Diseases, and 2Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China
Background. Imiquimod, a synthetic Toll-like receptor 7 agonist enhanced immunogenicity of influenza vaccine in a mouse model. We hypothesized that topical imiquimod before intradermal influenza vaccination (TIV) would produce similar effect in human. Methods. We performed a prospective 1-year follow-up, double-blind, randomized, controlled trial with adults with comorbidities. Participants were randomized to 1 of the following 3 vaccinations: topical 5% 250 mg imiquimod ointment followed by intradermal TIV, topical aqueous-cream followed by intradermal TIV, or topical aqueouscream followed by intramuscular TIV. Patients and investigators were blinded to the type of topical treatment applied. Hemagglutination inhibition (HI) and microneutralization antibody titers were measured. The primary outcome was the day 7 seroconversion rate. Results. Ninety-one recruited participants completed the study. The median age was 73 years. On day 7, 27/30 (90%) patients who received imiquimod and intradermal TIV achieved seroconversion against the H1N1 strain by HI, compared with 4/30 (13.3%) who received aqueous-cream and intramuscular TIV (P < .001), and 12/31 (38.7%) who received aqueous-cream and intradermal TIV (P < .001). The seroconversion, seroprotection, and geometric mean titer–fold increase were met in all 3 strains in the imiquimod and intradermal TIV group 2 weeks earlier, and the better seroconversion rate was sustained from day 7 to year 1 (P ≤ .001). The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (P < .05). All adverse reactions were self-limited. Conclusions. Pretreatment with topical imiquimod significantly expedited, augmented, and prolonged the immunogenicity of influenza vaccination. This strategy for influenza immunization should be considered for the elderly population. Keywords. immunogenicity; imiquimod; intradermal; influenza; vaccine.
Influenza poses a heavy burden to our healthcare systems [1, 2]. Seasonal, zoonotic, and pandemic influenza are constant global threats. The World Health Organization (WHO) estimates that seasonal influenza causes
Received 26 March 2014; accepted 9 July 2014; electronically published 21 July 2014. Correspondence: Kwok-Yung Yuen, MD, Carol Yu Centre for Infection and Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong Special Administrative Region, China ([email protected]). Clinical Infectious Diseases® 2014;59(9):1246–55 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/cid/ciu582
1246
•
CID 2014:59 (1 November)
•
Hung et al
250 000–500 000 deaths worldwide annually, with an even higher mortality during the pandemic periods [3]. Moreover, zoonotic influenza such as the avianorigin H5N1 and the H7N9 influenza are associated with a much higher mortality than seasonal influenza [4, 5]. Elderly persons with comorbidities are at the highest risk of hospitalization for influenza infection and its complications. Vaccine immunogenicity among these at-risk individuals is suboptimal due to immunosenescence [6]. Various strategies including intradermal vaccination and new vaccine adjuvants have been shown to improve immunogenicity [7, 8]. Experience with the A(H1N1)pdm09 vaccine showed that mass production of an antigen-matched effective
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on November 12, 2014
1
METHODS Study Participants
Between January 2012 and March 2012, adults aged ≥21 years attending the medical specialist outpatient clinics (SOPCs) in the Hong Kong West Cluster hospitals who satisfied the WHO recommendations and indications for influenza
vaccination were screened for eligibility. The majority were elderly persons aged ≥65 years with comorbidities. Participants were included if they had not received the influenza vaccine in the prior 3 months and gave written informed consent. Participants with clinically significant immune-related diseases on long-term immunosuppressants and with a history of allergy to the vaccines’ components were excluded. The eligibility criteria are listed in the Supplementary Appendix. The study was approved by the institutional review board of the University of Hong Kong and Hospital Authority and is registered with ClinicalTrials.gov (NCT01508884). Study Design and Interventions
At the time of inclusion, the participants’ demographic and clinical characteristics were recorded. Simple randomization with no stratification was performed. Participants were randomly assigned to the experimental group (imiquimod ointment + intradermal vaccine [IQ]) or 1 of the 2 control groups (aqueous cream + intradermal vaccine [INT] or aqueous cream + intramuscular vaccine [IM]). Participants in the IQ and INT groups received a single dose of intradermal trivalent influenza vaccine (TIV; 15 µg of hemagglutinin [HA] per strain). Those in the IM group received a similar dose of intramuscular TIV. The study nurse marked a 16-cm2 square on the
Figure 1. Recruitment flow-chart of the 91 participants. Abbreviations: IM, aqueous cream + intramuscular vaccine; INT, aqueous cream + intradermal vaccine; IQ, imiquimod ointment + intradermal vaccine; SOPC, specialist outpatient clinic.
Intradermal TIV With Topical Imiquimod
•
CID 2014:59 (1 November)
•
1247
Downloaded from http://cid.oxfordjournals.org/ at Northeastern University Libraries on November 12, 2014
monovalent vaccine took at least 6 months from manufacture to delivery [9] and another 3 weeks to mount a seroprotective response after vaccination. Therefore, any strategy for expediting or augmenting the protective immune response from influenza vaccine would be especially important in the outbreak setting. Recently, imiquimod, a synthetic Toll-like receptor 7 (TLR7) agonist used for the treatment of DNA virus infection, was shown to improve vaccine immunogenicity against influenza virus in a mouse model [10, 11] and for other infections including human immunodeficiency virus (HIV) [12], human papillomavirus (HPV) [13], and malaria [14]. The objective of this prospective, double-blind, randomized, controlled trial was to evaluate the effectiveness and safety of topical treatment with imiquimod immediately before intradermal influenza vaccination. Our a priori hypothesis was that imiquimod pretreatment would expedite and augment the immunogenicity of influenza vaccination.
virus, influenza A/Perth/16/2009 (H3N2)–like virus, and influenza B/Brisbane/60/2008–like virus. The intradermal injection device, the Becton Dickinson (BD) Soluvia microinjection system, consists of a prefilled TIV, with a single 1.5-mm needle that penetrates perpendicularly into the skin [7]. The BD Soluvia is currently the only prefilled intradermal device licensed for influenza vaccine. Safety was evaluated by asking the participants to remain on the clinic premise for 30 minutes for observation post-immunization. An immediate adverse event checklist was completed before discharge. Participants were given a diary to document symptoms of local and systemic adverse events that occurred within the first 7 days post-vaccination. Systemic symptoms included fever (body temperature ≥37.5°C), headache, malaise, myalgia, arthralgia, and severe adverse events. Local symptoms included redness, swelling, induration, ecchymosis, and pain. Redness, swelling, induration, and ecchymosis were graded based on size as follows: grade 1
