Recurrent episodes of shortage of sufficient influenza vaccine in the recent past and the recent experience with the novel 2009 H1N1 pandemic, have raised interest in ways to expand vaccination to more individuals while using available standard vaccine doses. Previous studies have demonstrated that smaller doses of influenza vaccine (ranging from 3 μg to 9 μg of influenza antigen) delivered by either the intramuscular or intradermal route induce immune responses comparable to the standard 15 μg dose of each antigen delivered intramuscularly [7
]. Intradermal injection delivers the antigen into the upper layers of the dermis, an area rich in antigen-presenting cells (APCs) [12
]. Thus, the ID route of vaccination may enhance the immune response to vaccines. While previous studies of ID administration of influenza vaccine have suggested utility of this route of vaccine delivery, the generalizability of these studies has been limited by sample size of subjects receiving a reduced dose, the route of the decreased dose, differing antigen doses and/or the age of the study subjects. The current study, comparing intradermal to intramuscular administration of trivalent influenza vaccine, utilized a novel system for ID administration and was designed to have sufficient power to determine if dosage, route of administration and/or age were associated with immune responses that were inferior to those when the vaccine in standard dosage is administered intramuscularly.
We demonstrated in the entire study population combined (adults 18-64 years of age), that both the 6 μg and 9 μg doses delivered by the ID route by BD Soluvia™ were non-inferior to a 15 μg dose by the IM route as measured by GMT or seroprotection rates. Neither intradermal dose, however, demonstrated superiority over the IM dose. The 3 μg dose given by Mantoux technique performed less well than either the 6 μg or 9 μg dose, showing non-inferiority to the 15 μg dose only for the A/H3N2 component of the vaccine, to which the majority of subjects already had elevated pre-immunization titers. A limitation of previous dose sparing studies of influenza vaccine has been that study subjects were primarily young adults who may respond to lower doses of vaccine regardless of the route of administration. In an open-label study, Belshe et al [8
] compared 119 subjects who received a reduced dose (6 μg) of TIV administered by Mantoux technique to an equal number of subjects vaccinated with standard TIV 15 μg IM. He observed that post-vaccination GMTs were higher among subjects 18-60 years (mean age 40±11) than those of subjects 60 years or older (mean age 70±6), whether intradermal or intramuscular immunization was used. Non-inferiority of GMTs induced by ID administration was reported compared to standard IM administration for the younger age group, but a trend toward a better response in the IM route compared to the ID route was observed for the older age group. These findings are consistent with results from the current study in which TIV was administered intradermally using the BD Soluvia™. GMTs were higher among subjects 18-49 years of age (33.3 ± 8.9 years) than those of the 50-64 year age group (56.2 ± 4.2) regardless of the route (ID or IM). When post-vaccination GMTs were further analyzed according to age stratification, non-inferiority of the 6 μg and the 9 μg ID doses of TIV compared to the 15 μg IM dose was established for all 3 strains of influenza in the 18-49 year age group. However, for the 50-64 year age group, the GMT responses to 6 μg ID formulation were found to be inferior to standard IM dose for 2 of the 3 influenza strains (A/H1N1 and B). Our conclusion is in line with findings of a recent study by Beran et al,(16) who evaluated doses of influenza vaccine ranging from 3 μg to 9 μg administered intradermally (with an earlier version of the microinjection system) compared to a 15 μg intramuscular dose [15
]. In the first year of the study, 1150 subjects, 18-57 years of age, were administered either 3 μg or 6 μg intradermal doses or a 15 μg intramuscular dose of TIV. In the following year, subjects in the intradermal groups all received a 9 μg dose because the 3 μg and 6 μg groups in the first year had immune responses statistically lower than the IM group. Subjects receiving the 9 μg ID dose had responses similar to the 15 μg IM dose
The current study also confirmed a finding from Treanor et al that subjects without a self-reported history of previous receipt of an influenza vaccine within the past 3 years had post-vaccination titers that were higher than the post-vaccination GMTs of subjects who had received a previous influenza vaccine [11
]. Due to the large sample size and the multiple doses studied, along with the stratification of dosing by age, we were able to evaluate the post-vaccination GMTs of all these groups according to report of previous receipt of influenza vaccine. While both groups had post-vaccination GMTs as well as seroprotection rates that were high, the difference between those who had received previous influenza vaccines and those that did not was present in every comparison. Why a previous receipt of an influenza vaccine results in lower post-vaccination GMTs is unclear and likely biologically insignificant, but it may be a factor to consider in the design of future influenza vaccine trials.
Reliability of administering a vaccine into the dermis was another issue addressed in the current study. Subjects in the 6 μg and 9 μg ID group were vaccinated using a new injection system specifically designed to reproducibly administer vaccine into the dermis [5
]. Study personnel quickly learned to use the intradermal injection system and no issues were noted regarding ability to deliver the vaccine into the dermis. This is in contrast to vaccination via the Mantoux method which requires skilled personnel to reliably deliver a product into the dermis. Another important point regarding intradermal vaccine administration is the acceptability by recipients. More than 97% of subjects given TIV by the BD Soluvia system stated they would be willing to receive another vaccine using the system and 50% stated they thought that vaccination using the BD Soluvia system was less painful than IM flu shots they had received in the past.
An interesting finding was that subjects vaccinated with the BD Soluvia system reported statistically higher average scores by the Visual Analog Scale (VAS) immediately after vaccination (17.19 and 17.31 for the 9 μg and 6 μg, respectively) compared to the group who received an IM injection (10.52) However, subjects immunized with the BD Soluvia system reported less pain at the injection site during the 7 day monitoring period (42.7% and 45.6%, respectively) compared to subjects in the IM group (54.0%).
Both the intradermal and intramuscular routes of administration for influenza immunization were well tolerated by subjects. Adverse events were typically mild and short lived. The principal adverse events were related to local reactogenicity, particularly injection site erythema and swelling. These two findings occurred significantly more commonly in the subjects who received intradermal vaccination, with either the BD Soluvia or by Mantoux, as compared to intramuscular injection. It is speculated that delivery of vaccine antigens into the dermis may result in injection site reactions appearing more visible than those associated with IM injection. However, it is important to emphasize that these injection site reactions were transient and resolved spontaneously, with none of them requiring medical intervention. Systemic adverse events were uncommon, mostly judged to be unrelated and occurred with similar frequencies and distribution between the vaccine groups.
A significant limitation of the current study was the lack of a 6 μg or 9 μg intramuscular dose group to allow direct comparison to the same dose administered by the intradermal route. A study by Treanor et al suggested half-dose influenza vaccine administered intramuscularly was less immunogenic than the full 15 μg IM dose [11
]. Additionally, a previous study of intradermal administration of influenza vaccine demonstrated lower dosages of vaccine produced post-vaccination GMTs comparable to subjects receiving vaccine intramuscularly [8
]. Thus the current study was designed as a larger scale study to only test decreased doses by the ID route as compared to IM administration. Subsequent to the conduct of this study, Belshe conducted a single site study comparing the same dosage administered intradermally and intramuscularly in subjects 18 to 49 years of age [16
]. He found that lower doses (3 μg, 6 μg or 9 μg) of vaccine given either intradermally or intramuscularly elicited post-vaccination GMTs nearly equivalent to the 15 μg IM dose and that the dose response curves over the range of 3 μg to 15 μg (IM group) or 3 μg to 9 μg (ID group) were nearly flat. They thus concluded that in healthy younger adults, the intradermal vaccination was not superior to intramuscular administration of influenza vaccine. Likely due to the historical decreased immune response in older people, Arnou et al (19, 20) and De Decker et al (21) recently reported use of a 15 μg dose of influenza vaccine administered ID using the BD Soluvia as compared to a 15 μg IM dose of vaccine in subjects over 60 years of age and demonstrated a superior immune response in the intradermal group. Thus, while our study was unable to demonstrate superiority of ID vaccination, the results of Arnou et al are intriguing and merit further study to determine if the superiority of the intradermal vaccine can be demonstrated.
In conclusion, reduced doses (6 μg and 9 μg) of TIV delivered ID using a microinjection system provided comparable HAI responses to standard TIV given IM while immune responses to the 3 μg dose administered ID by the Mantoux method were inferior. Whether the ease and reliability of administration using the BD Soluvia outweighs the likely cost increase as compared to using the Mantoux method was not addressed in this study but will need to be considered.