Shinji Saito1, Akira Ainai2, Tadaki Suzuki3, Norihiro Harada4, Yasushi Ami5, Yoshikazu Yuki6, Haruko Takeyama7, Hiroshi Kiyono6, Hideo Tsukada4, Hideki Hasegawa8. 1. Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan; Department of Life Science and Medical Bioscience, Waseda University, Shinjuku-ku, Tokyo, Japan. 2. Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan; Influenza Virus Research Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan. 3. Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan. 4. PET Center, Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, Japan. 5. Division of Experimental Animal Research, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan. 6. Division of Mucosal Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan. 7. Department of Life Science and Medical Bioscience, Waseda University, Shinjuku-ku, Tokyo, Japan. 8. Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan. Electronic address: hasegawa@nih.go.jp.
Abstract
INTRODUCTION: Recently, we reported that intranasal vaccination of humans with whole inactivated influenza vaccine in the absence of mucosal adjuvant induced neutralizing antibody responses in the serum and nasal mucus. The mucoadhesive excipient carboxy-vinyl polymer (CVP) increases the viscosity and therefore mucoadhesiveness of intranasal medicaments and is an authorized excipient in Japan. In the present study, we analyzed the effect of adding CVP on intranasal whole inactivated influenza vaccine antigen dynamics and antibody responses. METHODS: Mice and nonhuman primates (NHPs) were intranasally administered the [(18)F]-radiolabeled vaccine and subjected to positron emission tomography analysis for 6h. Dendritic cells were stimulated in vitro with the vaccine mixed with or without a mucosal adjuvant (Ampligen) and/or CVP, after which the tumor necrosis factor (TNF)-α and interferon (IFN)-β levels in the supernatants were measured. Cynomolgus monkeys were immunized intranasally with the vaccine mixed with Ampligen and/or CVP and their vaccine-specific serum IgG and IgA titers were measured on days 0 and 33. RESULTS: The vaccine was retained significantly longer in the nasal cavity of both mice and NHPs when it was delivered with CVP rather than PBS. Accumulation of the radiolabeled vaccine in the central nervous system was not detected in either model regardless of whether CVP was used. CVP only very weakly increased the TNF-α production of vaccine-stimulated dendritic cells. IFN-β production was not observed regardless of the presence or absence of CVP. CVP increased the vaccine-specific IgA antibody responses of the intranasally vaccinated cynomolgus macaques. CONCLUSION: CVP increased intranasal retention of whole inactivated influenza vaccine, did not promote antigen redirection to the central nervous system, and improved mucosal antibody responses. The mechanism probably relates to its mucoadhesive properties rather than its ability to directly stimulate the immune system. Intranasal vaccines with CVP may be a promising candidate vaccine formulation for humans.
INTRODUCTION: Recently, we reported that intranasal vaccination of humans with whole inactivated influenza vaccine in the absence of mucosal adjuvant induced neutralizing antibody responses in the serum and nasal mucus. The mucoadhesive excipient carboxy-vinyl polymer (CVP) increases the viscosity and therefore mucoadhesiveness of intranasal medicaments and is an authorized excipient in Japan. In the present study, we analyzed the effect of adding CVP on intranasal whole inactivated influenza vaccine antigen dynamics and antibody responses. METHODS:Mice and nonhuman primates (NHPs) were intranasally administered the [(18)F]-radiolabeled vaccine and subjected to positron emission tomography analysis for 6h. Dendritic cells were stimulated in vitro with the vaccine mixed with or without a mucosal adjuvant (Ampligen) and/or CVP, after which the tumor necrosis factor (TNF)-α and interferon (IFN)-β levels in the supernatants were measured. Cynomolgus monkeys were immunized intranasally with the vaccine mixed with Ampligen and/or CVP and their vaccine-specific serum IgG and IgA titers were measured on days 0 and 33. RESULTS: The vaccine was retained significantly longer in the nasal cavity of both mice and NHPs when it was delivered with CVP rather than PBS. Accumulation of the radiolabeled vaccine in the central nervous system was not detected in either model regardless of whether CVP was used. CVP only very weakly increased the TNF-α production of vaccine-stimulated dendritic cells. IFN-β production was not observed regardless of the presence or absence of CVP. CVP increased the vaccine-specific IgA antibody responses of the intranasally vaccinated cynomolgus macaques. CONCLUSION:CVP increased intranasal retention of whole inactivated influenza vaccine, did not promote antigen redirection to the central nervous system, and improved mucosal antibody responses. The mechanism probably relates to its mucoadhesive properties rather than its ability to directly stimulate the immune system. Intranasal vaccines with CVP may be a promising candidate vaccine formulation for humans.
Authors: Dorothy I Jones; Justin J Pollara; Brandi T Johnson-Weaver; Celia C LaBranche; David C Montefiori; David J Pickup; Sallie R Permar; Soman N Abraham; Massimo Maddaloni; David W Pascual; Herman F Staats Journal: J Virol Date: 2019-06-28 Impact factor: 5.103
Authors: Mayuresh M Abhyankar; Mark T Orr; Robert Kinsey; Sandra Sivananthan; Andrew J Nafziger; David N Oakland; Mary K Young; Laura Farr; Md Jashim Uddin; Jhansi L Leslie; Stacey L Burgess; Hong Liang; Ines De Lima; Elise Larson; Jeffrey A Guderian; Susan Lin; Aaron Kahn; Prakash Ghosh; Sierra Reed; Mark A Tomai; Karl Pedersen; William A Petri; Christopher B Fox Journal: Front Immunol Date: 2021-06-25 Impact factor: 7.561