A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity

BACKGROUND. To understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray. METHODS. Viral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays. RESULTS. Ad4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60 % of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4(+) and CD8(+) T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine. CONCLUSION. Replicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.

Automated summary

A replicating vaccine delivered to the upper respiratory tract induced potent and durable immune responses, leading to high levels of H5-specific antibodies in serum and mucosal secretions. The duration of viral shedding post-vaccination correlated with the magnitude of neutralizing antibody response at week 26.