Intradermal Trivalent Influenza Vaccine With Imiquimod
Intradermal Trivalent Influenza Vaccine With Imiquimod
Despite the WHO International Health Regulations Emergency Committee declared an end to the
 2009 H1N1 pandemic globally, the emergence of the novel 2009 H1N1 virus in March 2009 has
 affected more than 214 countries with at least 18000 deaths [1]. Patients with chronic
 underlying illness and extreme of ages are at risk of developing severe disease and
 complications [2-3]. Resistance to oseltamivir has also been reported [4]. Therefore,
 vaccination with the 2010/2011 trivalent influenza vaccine (TIV) with the 2009 H1N1-like
 virus incorporated will be the best protection against the influenza infection, especially
 among the at risk population. Recent study on dose sparing seasonal influenza vaccine
 delivered via a novel intradermal microneedle has demonstrated good immunogenic responses
 similar to full-dose intramuscular vaccination [6]. Poor immunogenicity of the H1N1 2009
 component of the trivalent influenza has been reported [7].

 Study has also suggested the combined intradermal vaccination with local stimulation of
 dermal antigen presenting cells by applying imiquimod cream (Aldara) to the injection site,
 which activate antigen presenting cells (APC) through the toll-like receptor 7 (TLR7) may
 produce better immunogenicity [8].

 Imiquimod cream is currently registered for the treatment of warts and basal cell carcinoma.
 Scientific evidence has demonstrated that after treatment with imiquimod, the antigen is
 processed and presented to cells of the adaptive immune system leading to clearance of the
 virus and subsequent clearance of the lesions [9]. In addition to functional maturation,
 imiquimod induces migration of dendritic cells from the dermis to draining lymph nodes
 [10,11]. Subcutaneous administration of imiquimod as vaccine adjuvant simultaneously with the
 antigen of interest, has shown to induce enhanced responses towards the administered antigen
 [12].

 We therefore performed a prospective, double blind, randomized controlled study to compare
 the safety and immunogenicity between intradermal 2011/2012 TIV immunization with
 pretreatment of imiquimod cream and conventional full dose intramuscular 2011/2012 TIV
 immunization with pretreatment of aqueous cream as control.
References

 1. World Health Organization. Influenza A (H1N1) - update 95 [cited 2010 April 10].
 Available from http://www.who.int/csr/don/2009_12_30/en/index.html

 2. Echevarria-Zuno S, Mejia-Arangure JM, Mar-Obeso AJ, et al. Infection and death from
 influenza A H1N1 virus in Mexico: a retrospective analysis. Lancet 2009; 374: 2072-9.

 3. Louie JK, Acosta M, Winter K, et al. Factors associated with death or hospitalization
 due to pandemic 2009 influenza A(H1N1) infection in California. JAMA 2009; 302:
 1896-902.

 4. Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in
 the United States, April-June 2009. N Engl J Med 2009; 361:1935-44.

 5. Chen H, Cheung CL, Tai H, et al. Oseltamivir-resistant influenza A pandemic (H1N1) 2009
 virus, Hong Kong, China. Emerg Infect Dis 2009;15:1970-2.

 6. Van Damme P, Oosterhuis-Kafeja F, Van der Wielen M, et al. Safety and efficacy of a
 novel microneedle device for dose sparing intradermal influenza vaccination in healthy
 adults. Vaccine 2009;27:454-9

 7. Myers CA, Faix DJ, Blair PJ. Possible reduced effectiveness of the 2009 H1N1 component
 of live, attenuated influenza vaccine. Clin Infect Dis. 2011;15;53:207-8.9.

 8. Roukens R, Vossen AC, Boland GJ, et al. Intradermal hepatitis B vaccination in
 non-responders after topical application of imiquimod (Aldara). Vaccine 2010;4288-4293.

 9. Tyring S, Conant M, Marini M, Van Der Meijden W, Washenik K. Imiquimod, an international
 update on therapeutic uses in dermatology. Int J Dermatol 2002;41(11):810-6.

 10. Burns Jr RP, Ferbel B, Tomai M, Miller R, Gaspari AA. The imidazoquinolines, imiquimod
 and R-848, induce functional, but not phenotypic, maturation of human epidermal
 Langerhans' cells. Clin Immunol 2000;94(1):13-23.

 11. Suzuki H, Wang B, Shivji GM, Toto P, Amerio P, Tomai MA, et al. Imiquimod, a topical
 immune response modifier, induces migration of Langerhans cells. J Invest Dermatol
 2000;114(1):135-41.

 12. 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(13-14):1799-809.
Inclusion Criteria:

 -  All adult patients at the age of 21 or above with chronic illness and given written
 informed consent

 -  Subjects must be available to complete the study and comply with study procedures.
 Willingness to allow for serum samples to be stored beyond the study period, for
 potential additional future testing to better characterize immune response.

 Exclusion Criteria:

 -  Clinically significant immune-related diseases or significant recent co-morbidities

 -  Inability to comprehend and to follow all required study procedures

 -  History or any illness that might interfere with the results of the study or pose
 additional risk to the subjects due to participation in the study

 -  Have received 2011/2012 TIV

 -  Have a recent history (documented, confirmed or suspected) of a flu-like disease
 within a week of vaccination.

 -  Have a known allergy to eggs or other components of the Study Vaccines (including
 gelatin, formaldehyde, octoxinol, thimerosal, and chicken protein), or history of any
 anaphylaxis, serious vaccine reactions, to any excipients.

 -  Have a positive urine or serum pregnancy test within 24 hours prior to vaccination, or
 women who are breastfeeding.

 -  Female of childbearing potential, not using any acceptable contraceptive methods for
 at least 2 months prior to study entry or that do not plan to use acceptable birth
 control measures during the first 3 weeks after vaccination.

 -  Have immunosuppression as a result of an underlying illness or treatment, or use of
 anticancer chemotherapy or radiation therapy (cytotoxic) within the preceding 36
 months.

 -  Have an active neoplastic disease or a history of any hematologic malignancy.

 -  Have long-term use of glucocorticoids including oral, parenteral or high-dose inhaled
 steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the
 preceding 6 months. (Nasal and topical steroids are allowed).

 -  Have a history of receiving immunoglobulin or other blood product within the 3 months
 prior to vaccination in this study.

 -  Have known active human immunodeficiency virus (HIV) infection, acute hepatitis B or C
 infection, autoimmune hepatitis and related cirrhosis

 -  Received an experimental agent (vaccine, drug, biologic, device, blood product, or
 medication) within 1 month prior to vaccination in this study or expect to receive an
 experimental agent during this study. Unwilling to refuse participation in another
 clinical study through the end of this study.

 -  History of progressive or severe neurological disorders

 -  Have received any licensed vaccines within 4 weeks or inactivated licensed vaccines
 within 2 weeks prior to vaccination in this study or plan receipt of such vaccines
 within 21 days following the second vaccination (only exception being unadjuvanted
 seasonal influenza vaccines which are allowed until 1 week prior to and after 1 week
 study vaccinations).

 -  Axillary temperature ≥ 38°C or oral temperature ≥ 38.5°C within 3 days of intended
 study vaccination

 -  Surgery planned during the study period that in the Investigator's opinion would
 interfere with the study visits schedule

 -  Have a history of alcohol or drug abuse in the last 5 years.

 -  Have a history of Guillain-Barré Syndrome.

 -  Have any condition that the investigator believes may interfere with successful
 completion of the study.