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

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• 作者：Shinji Saito^a ; ^e ; ¹ ; Akira Ainai^a ; ^b ; ¹ ; Tadaki Suzuki^a ; Norihiro Harada^c ; Yasushi Ami^d ; Yoshikazu Yuki^f ; Haruko Takeyama^e ; Hiroshi Kiyono^f ; Hideo Tsukada^c ; Hideki Hasegawa^a ; ^{hasegawa@nih.go.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BM-DC ; bone marrow-derived dendritic cell ; CVP ; carboxy-vinyl polymer ; CNS ; central nervous system ; LPS ; lipopolysaccharide ; MRI ; magnetic resonance imaging ; NHP ; nonhuman primate ; PET ; positron emission tomography ; SUV ; standardized uptake value
• 刊名：Vaccine
• 出版年：2016
• 出版时间：24 February 2016
• 年：2016
• 卷：34
• 期：9
• 页码：1201-1207
• 全文大小：1248 K

文摘

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.