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

Matsuda, Kenta; Migueles, Stephen A; Huang, Jinghe; Bolkhovitinov, Lyuba; Stuccio, Sarah; Griesman, Trevor; Pullano, Alyssa A; Kang, Byong H; Ishida, Elise; Zimmerman, Matthew; Kashyap, Neena; Martins, Kelly M; Stadlbauer, Daniel; Pederson, Jessica; Patamawenu, Andy; Wright, Nathaniel E; Shofner, Tulley; Evans, Sean; Liang, C Jason; Candia, Julián; Biancotto, Angelique; Fantoni, Giovanna; Poole, April; Smith, Jonathan; Alexander, Jeff; Gurwith, Marc; Krammer, Florian; Connors, Mark

BACKGROUND Immunization with replication-competent recombinant vectors provides exposure to transgene-encoded antigens in the context of inflammation that may drive more potent and durable immunity compared to non-replicating vaccines. To understand the features of a replicating vaccine that drive such responses we tested a replication-competent adenovirus type 4 encoding influenza virus H5 hemagglutinin (Ad4-H5-Vtn) administered by an oral capsule or via a tonsillar swab or nasal spray. METHODS Viral shedding from the nose, mouth, and rectum was measured by PCR and culture. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition assay (PVEI), microneutralization (MN), and hemagglutinin inhibition (HAI). RESULTS Ad4-H5-Vtn DNA was shed from most upper respiratory tract (URT)-immunized volunteers for 2-4 weeks, but cultured from only 60% of participants with a median duration of one day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood and IgG and IgA in nasal, cervical and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAb) to H5 which remained stable at week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AE) were mild, and peak NAb titer was associated with overall AE frequency or duration. Serum neutralizing antibody titers could be boosted to very high levels 2-5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine. CONCLUSION Replicating Ad4 delivered to the URT causes prolonged exposure to antigen, drives durable systemic and mucosal immunity, and is a promising platform for the induction of immunity against viral surface glycoprotein targets. TRIAL REGISTRATION ClinicalTrials.gov NCT01443936, NCT01806909. FUNDING Intramural and Extramural Research Programs of the NIAID, NIH; and the Centers of Influenza Virus Research and SurveillanceFunding. Intramural and Extramural Research Programs of the NIAID, NIH; and the Centers of Influenza Virus Research and Surveillance.