Abstract
BackgroundCurrent conventional vaccination approaches do not induce potent CD8 T-cell responses for fighting mostly variable viral diseases such as influenza, avian influenza viruses or HIV. Following our recent study on vaccine penetration by targeting of vaccine to human hair follicular ducts surrounded by Langerhans cells, we tested in the first randomized Phase-Ia trial based on hair follicle penetration (namely transcutaneous route) the induction of virus-specific CD8 T cell responses.Methods and FindingsWe chose the inactivated influenza vaccine – a conventional licensed tetanus/influenza (TETAGRIP®) vaccine – to compare the safety and immunogenicity of transcutaneous (TC) versus IM immunization in two randomized controlled, multi-center Phase I trials including 24 healthy-volunteers and 12 HIV-infected patients. Vaccination was performed by application of inactivated influenza vaccine according to a standard protocol allowing the opening of the hair duct for the TC route or needle-injection for the IM route. We demonstrated that the safety of the two routes was similar. We showed the superiority of TC application, but not the IM route, to induce a significant increase in influenza-specific CD8 cytokine-producing cells in healthy-volunteers and in HIV-infected patients. However, these routes did not differ significantly for the induction of influenza-specific CD4 responses, and neutralizing antibodies were induced only by the IM route. The CD8 cell response is thus the major immune response observed after TC vaccination.ConclusionsThis Phase Ia clinical trial (Manon05) testing an anti-influenza vaccine demonstrated that vaccines designed for antibody induction by the IM route, generate vaccine-specific CD8 T cells when administered transcutaneously. These results underline the necessity of adapting vaccination strategies to control complex infectious diseases when CD8 cellular responses are crucial. Our work opens up a key area for the development of preventive and therapeutic vaccines for diseases in which CD8 cells play a crucial role.Trial RegistrationClinicaltrials.gov NCT00261001
Highlights
Inducing CD8 T cell-mediated protective responses would be beneficial in eliminating infected cells and limiting virus or cancer dissemination
This Phase Ia clinical trial (Manon05) testing an anti-influenza vaccine demonstrated that vaccines designed for antibody induction by the IM route, generate vaccine-specific CD8 T cells when administered transcutaneously
We previously demonstrated that penetration of topically applied nanoparticles increased after application of cyanoacrylate skin surface stripping (CSSS) to human skin explants: the particles entered epidermal Langerhans cells (LCs), possibly via hair follicles [36]
Summary
Inducing CD8 T cell-mediated protective responses would be beneficial in eliminating infected cells and limiting virus or cancer dissemination. Benchmarks were determined for primary CD8+ T cell responses in humans induced by two of the most effective vaccines ever developed, those against yellow fever and smallpox [11] The importance of these responses has been shown in many viral diseases and cancers, in both mouse and human models [12,13,14,15], and their persistence has been observed in the absence of circulating antigens [16,17,18,19]. The generation of such immune cells is of crucial interest in studying long-term immune responses to pathogens and in vaccine development. Following our recent study on vaccine penetration by targeting of vaccine to human hair follicular ducts surrounded by Langerhans cells, we tested in the first randomized PhaseIa trial based on hair follicle penetration (namely transcutaneous route) the induction of virus-specific CD8 T cell responses
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