title: Efficient antigen delivery to the draining lymph nodes is a key component in the immunogenic pathway of the intradermal vaccine.
abstract: BACKGROUND
  It has been clinically demonstrated that intradermal (ID) vaccines have a potential to confer a superior immunogenic profile compared to intramuscular (IM) or subcutaneous (SC) vaccines. In terms of distribution of a vaccine antigen depending on the administration routes, at least two independent immunogenic pathways of the vaccines have been proposed: (1) the antigen recognition by the immune cells present at the vaccine-administered site and (2) the antigen recognition by the lymph node (LN)-resident immune cells through the lymphatic flow from the vaccine-administered site after the antigen is directly delivered into the draining LNs.
  
  
  OBJECTIVE
  In order to clarify the key components for the immunogenic pathway of the ID vaccine, the correlation between the kinetics of the antigen distribution to the draining LNs and antibody responses to the antigen were evaluated.
  
  
  METHODS
  We compared the antibody responses in the groups with by surgical removal of the administration site immediately after the ID administration, and by surgical removal of the draining LNs before the ID administration.
  
  
  RESULTS
  The results suggested that the efficient and direct antigen delivery to the draining LNs plays an important role in the antibody responses to the ID vaccine. Indeed, it was confirmed that the direct administration into the draining LNs with the antigen elicited comparable levels of the antibody responses with the ID vaccine. At the cellular level, it was shown that the LN-resident immune cells such as B cells, dendritic cells, and macrophages including medullary macrophages and subcapsular sinus macrophages interacting with the antigens following the ID administration. Finally, we demonstrated by immunofluorescence analysis that the lymphatic vessels are more diffusely distributed in the dermis as compared with the subcutaneous area and muscle.
  
  
  CONCLUSIONS
  The results of the present study suggested that the skin is an optimal tissue to facilitate the vaccine antigen access to the draining LNs, which is an important immunogenic pathway of the ID vaccine. Further elucidation of regulatory mechanisms underlying such an immunogenic pathway of the ID vaccine would provide us with elements for the development of novel adjuvants and devices to enhance the immunogenicity of the ID vaccines.
authors.affiliation: Kitasato Daiichi Sankyo Vaccine Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tozuka
authors.affiliation: Kitasato Daiichi Sankyo Vaccine Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Oka
authors.affiliation: Kitasato Daiichi Sankyo Vaccine Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Jounai
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Syogoin-Kawaramachi, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Gyohei
authors.initials: G
authors.lastname: Egawa
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki City, Osaka 567-0085, Japan.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Syogoin-Kawaramachi, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.affiliation: Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo 103-8426, Japan. Electronic address: takeshita.fumihiko.aw@daiichisankyo.co.jp.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeshita
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000008:administration & dosage* / Q000276:immunology; D000071497:Immunogenicity, Vaccine; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology; D007271:Injections, Intradermal; D007279:Injections, Subcutaneous; D007700:Kinetics; D008198:Lymph Nodes / Q000276:immunology* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D012867:Skin / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination
chemical_list: D000914:Antibodies, Viral; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines
keywords: Antigen delivery; Intradermal vaccine; Lymph nodes; Lymphatic vessels