| Human respiratory syncytial virus (RSV) is the major viral agent of severe lower respiratory tract infection in infants and young children, worldwide, and causes deadly illness in the elderly and adults with underlying risk factors such as immunodeficiency. RSV is an enveloped, negative stranded RNA virus belonging to the subfamily Pneumovirinae of the family Paramyxoviridae with a genome that encodes 11 proteins. Two transmembrane surface glycoproteins of fusion protein (F) and attachment protein (G) are the neutralization antigens. Additionally, F is also a major target antigen of CD8+ cytotoxic T lymphocyte (CTL) in humans and mice, and sufficiently conserved between two RSV antigenic subgroups, A and B, being capable of evoking cross-protective antibodies against both subgroups.Since the failure of formalin-inactivated RSV vaccine, there have been various RSV vaccines developed. But none of these has been approved for use in humans. The World Health Organization has affirmed RSV vaccine as one of the highest priority vaccine to be developed.The replication-deficient first generation adenoviral vector (FGAd) is readily grown and purified in large scale, and able to express high level transgene in dividing and non-dividing cells, therefore, it is considered to be an attractive vaccine vector. Recent report showed that FGAd encoding genetically engineered G protein could successfully elicit a long-term protective immunity against RSV infection in mice. Whereas, there has been no FGAd encoding F protein (FGAd-F) vaccine reported. In contrast to FGAd, helper-dependent adenoviral vector (HDAd) is the vector with its all coding regions deleted, displaying much more reduced adenovirus (Ad) specific cellular immunity, possesing potent and long-term capacity of transgene expression in vivo. Additionally, HDAd is also a potent stimulator of dendritic cell (DC) maturation. Till now, neither is known about the potentiality for HDAd as a vaccine vector administered intranasally, nor the efficacy of RSV F vaccine based on HDAd vector.In this study, FGAd-F was constructed and evaluated for its protective role as an candidate RSV vaccine in a murine model. Intranasal (i.n.) immunization with FGAd-F generated serum IgG, mucosal secretory IgA , and RSV-specific CD8+ T-cell responses in BALB/c mice, with characteristic balanced or mixed Th1/Th2 CD4+ T-cell responses. Serum IgG was significantly elevated after boosting with i.n. immunization with FGAd-F. Upon challenge, i.n. immunization with FGAd-F displayed an effectivly protective role against RSV infection.To evaluate the potentiality of HDAd vaccine vector via mucosal route, mice were immunized intranasally with HDAd or FGAd encoding EGFP (HDAd-EGFP or FGAd-EGFP), and monitored for the induction of anti-EGFP and anti-Ad immunity. Although similar anti-Ad antibody responses were obtained in mice i.n. with FGAd, HDAd-EGFP induced some more transgene-specific serum IgG, mucosal IgA and cellular responses, as well as a longer-term serum IgG comparing to the same amount of FGAd, with the characteristic of balanced or mixed Th1/Th2 CD4+ T-cell responses. In addition, the homologous booster immunization with HDAd-EGFP can also enhance EGFP-specific humoral and cellular responses.HDAd encoding F protein (HDAd-F) was constructed and evaluated for its efficacy as RSV vaccine in a murine model. BALB/c mice were immunized intranasally with HDAd-F or FGAd-F, and monitored for the induction of RSV F-specific immune responses. HDAd vaccine could induce superior transgene-specific humoral and longer-term serum IgG compared to the same amount of FGAd.In summary, FGAd-F is able to effectivly induce protective immunity and is apromising candidate vaccine against RSV infection. By our view ,HDAd is even abetter mucosal vaccine vector in comparing with FGAd, employing EGFP as a modelantigen , examining in a murine model. The efficacy of HDAd-F vaccine may beelevated significantly by improving the expression level of transgene and reducing thedosage. |
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