The effect of mucoadhesive excipient on the nasal retention time of and the antibody responses induced by an intranasal influenza vaccine

Shinji Saito, Akira Ainai, Tadaki Suzuki, Norihiro Harada, Yasushi Ami, Yoshikazu Yuki, Haruko Takeyama, Hiroshi Kiyono, Hideo Tsukada, Hideki Hasegawa

    Research output: Contribution to journalArticle

    6 Citations (Scopus)

    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 [18F]-radiolabeled vaccine and subjected to positron emission tomography analysis for 6 h. 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.

    Original languageEnglish
    Pages (from-to)1201-1207
    Number of pages7
    JournalVaccine
    Volume34
    Issue number9
    DOIs
    Publication statusPublished - 2016 Feb 24

    Fingerprint

    Influenza Vaccines
    Excipients
    Nose
    influenza
    Antibody Formation
    Polymers
    Vaccines
    polymers
    vaccines
    antibodies
    Inactivated Vaccines
    tumor necrosis factors
    Macaca fascicularis
    Dendritic Cells
    Immunoglobulin A
    Interferons
    Primates
    interferons
    dendritic cells
    Central Nervous System

    Keywords

    • Influenza virus
    • Intranasal vaccine
    • Mucoadhesive excipient
    • Nonhuman primate
    • Real-time imaging
    • Vaccine dynamics

    ASJC Scopus subject areas

    • Immunology and Microbiology(all)
    • Infectious Diseases
    • Public Health, Environmental and Occupational Health
    • veterinary(all)
    • Molecular Medicine

    Cite this

    The effect of mucoadhesive excipient on the nasal retention time of and the antibody responses induced by an intranasal influenza vaccine. / Saito, Shinji; Ainai, Akira; Suzuki, Tadaki; Harada, Norihiro; Ami, Yasushi; Yuki, Yoshikazu; Takeyama, Haruko; Kiyono, Hiroshi; Tsukada, Hideo; Hasegawa, Hideki.

    In: Vaccine, Vol. 34, No. 9, 24.02.2016, p. 1201-1207.

    Research output: Contribution to journalArticle

    Saito, S, Ainai, A, Suzuki, T, Harada, N, Ami, Y, Yuki, Y, Takeyama, H, Kiyono, H, Tsukada, H & Hasegawa, H 2016, 'The effect of mucoadhesive excipient on the nasal retention time of and the antibody responses induced by an intranasal influenza vaccine', Vaccine, vol. 34, no. 9, pp. 1201-1207. https://doi.org/10.1016/j.vaccine.2016.01.020
    Saito, Shinji ; Ainai, Akira ; Suzuki, Tadaki ; Harada, Norihiro ; Ami, Yasushi ; Yuki, Yoshikazu ; Takeyama, Haruko ; Kiyono, Hiroshi ; Tsukada, Hideo ; Hasegawa, Hideki. / The effect of mucoadhesive excipient on the nasal retention time of and the antibody responses induced by an intranasal influenza vaccine. In: Vaccine. 2016 ; Vol. 34, No. 9. pp. 1201-1207.
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    author = "Shinji Saito and Akira Ainai and Tadaki Suzuki and Norihiro Harada and Yasushi Ami and Yoshikazu Yuki and Haruko Takeyama and Hiroshi Kiyono and Hideo Tsukada and Hideki Hasegawa",
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    AU - Saito, Shinji

    AU - Ainai, Akira

    AU - Suzuki, Tadaki

    AU - Harada, Norihiro

    AU - Ami, Yasushi

    AU - Yuki, Yoshikazu

    AU - Takeyama, Haruko

    AU - Kiyono, Hiroshi

    AU - Tsukada, Hideo

    AU - Hasegawa, Hideki

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    N2 - 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 [18F]-radiolabeled vaccine and subjected to positron emission tomography analysis for 6 h. 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.

    AB - 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 [18F]-radiolabeled vaccine and subjected to positron emission tomography analysis for 6 h. 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.

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    KW - Intranasal vaccine

    KW - Mucoadhesive excipient

    KW - Nonhuman primate

    KW - Real-time imaging

    KW - Vaccine dynamics

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