The primary aim of this study was to identify the HA dose that, when administered intradermally using a microinjection system, would elicit an immune response that is statistically non-inferior to that elicited by a standard IM vaccination of 15 μg of HA/strain. In line with previous observations [19
], ID vaccination with either 3 μg or 6 μg of HA was immunogenic and, in the case of the 6 μg vaccine, sufficiently immunogenic to comply with the EMEA immunogenicity recommendations [23
]. However, antibody responses to 6 μg were lower than with the standard IM vaccine and non-inferiority was not demonstrated. These results are consistent with those of a large study in healthy adults (20 to 50 years), in which a reduced-dose ID influenza vaccination led to inferior antibody responses compared with a standard IM vaccine, despite meeting the EMEA requirements [26
]. Two smaller studies have shown comparable immunogenicity of reduced-dose ID influenza to full-dose IM vaccines in adults aged between 18 and either 40 or 60 years [19
]. In our study, as non-inferiority was not demonstrated with either 3 μg or 6 μg of HA, we amended the protocol to continue vaccination in Years 2 and 3 with an escalated ID dose of 9 μg of HA/strain. This allowed the immunogenicity of this higher dose to be evaluated descriptively in preparation for a follow-up study that would be needed to repeat the formal non-inferiority analysis for such an escalated dose.
Despite the lower antigen content, the ID 9 μg vaccine was comparably immunogenic to the reference IM vaccine, satisfying EMEA criteria for all three virus strains. Although this study did not compare the same dosage given by ID and IM routes, these results are consistent with previous studies with rabies, hepatitis B and influenza vaccines that support the higher immunogenicity of the ID vaccination route [13
]. In a recently reported study of an investigational ID influenza for elderly adults, an ID vaccination with 15 μg of HA per strain was shown to elicit significantly higher immune responses than the IM vaccination, also with 15 μg HA per strain [27
]. The ID vaccine evaluated in elderly adults by Holland et al. [27
] was manufactured by Sanofi Pasteur (the manufacturers of the vaccines tested in our study), was administered using the same microinjection system, and was studied in comparison with the same control vaccine (Vaxigrip®
) as in our study.
Reactogenicity of the ID vaccine was comparable to that of the IM vaccine in terms of both EMEA reactions and solicited systemic reactions. It should be noted that the reactions listed in the EMEA Note for Guidance were specifically designed to determine the reactogenicity of IM vaccines and, as such, may not be fully appropriate for assessing reactogenicity after ID vaccination [23
]. As would be expected with a vaccine injected into the skin in comparison with an injection deep into the muscle, recipients of the ID vaccine more frequently reported local reactions at the injection site within 7 days of vaccination, particularly erythema. Importantly, these reactions were not associated with an increased incidence of injection site pain. Other studies have also shown increased local inflammation (mainly erythema and induration) to ID influenza vaccination compared with IM vaccination, but with a similar or lower incidence of injection site pain [19
]. This increase in local reactions is linked to the underlying inflammatory or immunological response in the skin, which is more visible with ID than IM vaccination.
It has been proposed that delivery of antigen via the ID route and associated activation of dermal dendritic cells favours the induction of a Th1-type cellular immune response, which can lead to delayed-type hypersensitivity [28
]. Repeated ID vaccination may, therefore, increase the risk of delayed-type hypersensitivity local reactions. In a study of a hepatitis B vaccine, secondary systemic or local reactions were more frequent with a mixed vaccine schedule (IM followed by ID or vice versa) than either an IM/IM or an ID/ID schedule [30
]. In our study, the safety profile after three ID vaccinations appeared similar to that after a single ID vaccination, suggesting that influenza ID vaccination can be repeated annually without increasing reactogenicity. Furthermore, interchanging the IM and ID vaccines from one year to the next did not adversely affect the safety profile.
Despite the documented health and economic burden of influenza disease in adults younger than 60 years [31
], surveys show that vaccine uptake is lower than the target coverage rates of between 50% to 90% set by national and international health organisations [35
]. Coverage rates of as low as 10% have been reported among Western European adults aged 20 to 40 years, with slightly higher rates, 15% to 20%, in adults aged 40 to 60 years [38
]. These rates are comparable with those reported in the USA, as well as in countries in Asia, Latin America and Eastern Europe [39
]. Several studies have investigated why vaccine uptake remains low. In two recent reports from Europe and the USA, 14% to 16% of individuals questioned cited a dislike of needles and injections as one of the reasons (although not the primary reason) for not getting vaccinated [38
]. This finding suggests that alternative vaccination methods that do not use a classic syringe and needle have the potential to contribute to increase vaccination coverage among such populations. The ID vaccine investigated in our study may represent such an alternative method. This vaccine used a newly developed microinjection system designed as an easy-to-use system with a very narrow, 1.5 mm long needle that is inserted perpendicularly into the skin to accurately inject antigen into the dermis [22
]. This ID influenza vaccine thus provides an alternative to IM vaccine for adults younger than 60 years that is convenient for the healthcare provider and may contribute to increase vaccine uptake in this population.
As the primary outcome was not met in the first year of the study, our findings are limited by the fact that the immunogenicity of the 9 μg ID vaccine was descriptively compared with the IM vaccine after the second and third vaccinations. A formal statistical comparison of the 9 μg ID vaccine dose to the IM vaccine was not possible, as the population was not representative of an ID vaccination-naïve population. This formal comparison was done in a second trial that has been reported separately [42
]. These trials formed part of a marketing authorisation application, which has been approved by the European Commission and will be marketed in the European Union under the trade names Intanza®