Saito Shinji, Ainai Akira, Suzuki Tadaki, Harada Norihiro, Ami Yasushi, Yuki Yoshikazu, Takeyama Haruko, Kiyono Hiroshi, Tsukada Hideo, Hasegawa Hideki
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.
Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan; Influenza Virus Research Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan.
Vaccine. 2016 Feb 24;34(9):1201-7. doi: 10.1016/j.vaccine.2016.01.020. Epub 2016 Jan 20.
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.
引言：最近，我们报道了在无黏膜佐剂的情况下，用全灭活流感疫苗对人类进行鼻内接种可诱导血清和鼻黏液中的中和抗体反应。黏附性辅料羧基乙烯基聚合物（CVP）可增加鼻内药物的黏度，从而提高其黏附性，且在日本是一种获批的辅料。在本研究中，我们分析了添加CVP对鼻内全灭活流感疫苗抗原动态和抗体反应的影响。 方法：给小鼠和非人灵长类动物（NHP）鼻内接种[¹⁸F]放射性标记的疫苗，并进行6小时的正电子发射断层扫描分析。用与或不与黏膜佐剂（Ampligen）和/或CVP混合的疫苗在体外刺激树突状细胞，然后测量上清液中肿瘤坏死因子（TNF）-α和干扰素（IFN）-β的水平。食蟹猴用与Ampligen和/或CVP混合的疫苗进行鼻内免疫，并在第0天和第33天测量其疫苗特异性血清IgG和IgA滴度。 结果：当疫苗与CVP而非PBS一起给药时，在小鼠和NHP的鼻腔中保留的时间明显更长。在两种模型中，无论是否使用CVP，均未检测到放射性标记疫苗在中枢神经系统中的蓄积。CVP仅非常微弱地增加了疫苗刺激的树突状细胞产生的TNF-α。无论是否存在CVP，均未观察到IFN-β的产生。CVP增加了经鼻内接种的食蟹猴的疫苗特异性IgA抗体反应。 结论：CVP增加了全灭活流感疫苗在鼻内的保留时间，未促进抗原向中枢神经系统的重定向，并改善了黏膜抗体反应。其机制可能与其黏附特性有关，而非直接刺激免疫系统的能力。含CVP的鼻内疫苗可能是一种有前景的人类候选疫苗制剂。
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