Mucosal and systemic immune responses induced by immunisation of cotton rats with recombinant adenoviruses
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Replication-defective and replication-competent recombinant human adenovirus type 5 vectors efficiently expressed the glycoprotein D (gD) or the transmembrane anchor truncated gD (tgD) of bovine herpesvirus type 1 (BHV-1) in vitro. To facilitate the evaluation of the efficacy of immunisation with these recombinant adenoviruses in conferring protection against BHV-1 infection, a cotton rat (Sigmodon hispidus) model for intranasal BHV-1 challenge was developed. I used this model to assess the ability of different routes of immunisation with the recombinant adenoviruses to elicit gD-specific systemic and mucosal immunity and confer protection against BHV-1 challenge. Immunisation with gD-expressing vectors induced better immunity and protection than immunisation with tgD-expressing viruses. Mucosal immunisation with the replication-competent virus was more efficient than that with the replication-defective vector in inducing gD-specific antibody in the serum and the respiratory tract. In contrast, systemic immunisation with the two vectors stimulated similar gD-specific antibody levels. These results indicate that the route of immunisation was crucial when assessing the efficacy of recombinant adenoviruses as vaccine vectors. The importance of the route of administration was further demonstrated by the finding that intranasal immunisation with the replication-competent vector stimulated higher antigen-specific IgA levels and antibody-secreting cell numbers in the respiratory tract than intradermal, intraperitoneal or enteric immunisation. Protection correlated with gD-specific antibody levels such that intranasal immunisation, even 3 months following vaccination, conferred complete, while intradermal or enteric immunisation conferred partial protection of the lungs of cotton rats against intranasal BHV-1 challenge. Pre-existing active adenovirus-specific immunity significantly inhibited the development of gD-specific antibody responses and protection against BHV-1 challenge following immunisation with recombinant adenovirus, while only a slight inhibition was observed by passive transfer of adenovirus-specific antibody. Overall, the results demonstrated that mucosal and systemic immunisation with adenovirus vectors could induce antigen-specific immunity and protection against BHV-1 challenge. The level of gD-specific immune responses and protection from challenge were, however, dependent on the cellular localisation of the foreign gene expressed by the vectors, the replication-capability of the viruses, the route of immunisation and the presence or absence of pre-existing adenovirus-specific immunity in the cotton rat.