Intradermal influenza vaccination of healthy adults using a new microinjection system: a 3-year randomised controlled safety and immunogenicity trial

Abstract

Background: Intradermal vaccination provides direct and potentially more efficient access to the immune system via specialised dendritic cells and draining lymphatic vessels. We investigated the immunogenicity and safety during 3 successive years of different dosages of a trivalent, inactivated, split-virion vaccine against seasonal influenza given intradermally using a microinjection system compared with an intramuscular control vaccine.

Methods: In a randomised, partially blinded, controlled study, healthy volunteers (1150 aged 18 to 57 years at enrollment) received three annual vaccinations of intradermal or intramuscular vaccine. In Year 1, subjects were randomised to one of three groups: 3 microg or 6 microg haemagglutinin/strain/dose of inactivated influenza vaccine intradermally, or a licensed inactivated influenza vaccine intramuscularly containing 15 microg/strain/dose. In Year 2 subjects were randomised again to one of two groups: 9 microg/strain/dose intradermally or 15 microg intramuscularly. In Year 3 subjects were randomised a third time to one of two groups: 9 microg intradermally or 15 microg intramuscularly. Randomisation lists in Year 1 were stratified for site. Randomisation lists in Years 2 and 3 were stratified for site and by vaccine received in previous years to ensure the inclusion of a comparable number of subjects in a vaccine group at each centre each year. Immunogenicity was assessed 21 days after each vaccination. Safety was assessed throughout the study.

Results: In Years 2 and 3, 9 microg intradermal was comparably immunogenic to 15 microg intramuscular for all strains, and both vaccines met European requirements for annual licensing of influenza vaccines. The 3 microg and 6 microg intradermal formulations were less immunogenic than intramuscular 15 microg. Safety of the intradermal and intramuscular vaccinations was comparable in each year of the study. Injection site erythema and swelling was more common with the intradermal route.

Conclusion: An influenza vaccine with 9 microg of haemagglutinin/strain given using an intradermal microinjection system showed comparable immunogenic and safety profiles to a licensed intramuscular vaccine, and presents a promising alternative to intramuscular vaccination for influenza for adults younger than 60 years.

Trial registration: (Clinicaltrials.gov) NCT00703651.

Figure 1

Randomisation strategy. Study subjects were randomised before each of the three vaccinations (represented by arrows): included subjects were randomised into three equally sized vaccine groups for the Year 1 vaccination, then in two equally sized vaccine groups in each of the subsequent years. Randomisation for vaccination in Years 2 and 3 was stratified for the vaccine received in previous years to ensure that a comparable number of subjects were included in each vaccine group. An additional Year 3 immunogenicity randomisation list was generated to select randomly a subset of approximately 30 subjects per vaccine stratum for blood sampling. Randomisation was also stratified for centre (not illustrated here). N = number of subjects randomised to each group (discontinuations are not represented).

Figure 2

Study flow chart. ID, intradermal; IM, intramuscular; N, number of subjects. *As one of the study centres (the Czech centre) did not participate in the third part of the study, a large number of subjects were discontinued from the study between the second and third vaccinations.