A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity
Kenta Matsuda, … , Florian Krammer, Mark Connors
Kenta Matsuda, … , Florian Krammer, Mark Connors
Published February 2, 2021
Citation Information: J Clin Invest. 2021;131(5):e140794. https://doi.org/10.1172/JCI140794.
View: Text | PDF
Clinical Research and Public Health Immunology

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

Abstract

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.TRIAL REGISTRATION ClinicalTrials.gov NCT01443936 and NCT01806909.FUNDING Intramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).

Authors

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

×

Figure 2

Induction of H5-specific cellular and humoral responses following immunization with Ad4-H5-Vtn.

Options: View larger image (or click on image) Download as PowerPoint
Induction of H5-specific cellular and humoral responses following immuni...
(A) H5-specific CD4+ and CD8+ T cell responses measured after a 6-hour stimulation with an A/Vietnam/1203/2004 (H5N1) influenza virus peptide array are shown for samples taken at baseline (week 0 [W0]) and 4 weeks (W4) after immunization with the Ad4-H5-Vtn vaccine, which had been administered as an oral capsule (n = 9), by direct tonsillar application (n = 20), or by intranasal spray (n = 25). In addition, responses for individuals who were Ad4 seropositive prior to vaccination are shown as separate exploratory arm (XA) subgroups (Tonsillar XA, n = 4; Intranasal XA, n = 5). Background responses to media controls have been subtracted. Paired and unpaired 2-sample t tests were used for group comparisons. Only significant P values are shown. (B) Ad4 (oral, n = 9; tonsillar, n = 22; intranasal, n = 24) and H5 (oral, n = 7; tonsillar, n = 16; intranasal, n = 20; individuals with less than a 4-fold increase in Ad4 and H5 neutralization [neut.] titer after immunization were excluded) HA-specific neutralizing antibody titers, shown as ID50, were measured by a PVEI assay. The XA subgroups were excluded. Red horizontal bars indicate the median values. Generalized estimating equations with an autoregressive correlation structure were used to calculate P values (week 0 measurements were not included), and only significant P values are shown. (C) Correlation of H5-specific CD4 and CD8 responses with peak neutralization antibody titers (oral in black, n = 10; tonsillar in blue, n = 20; intranasal in red, n = 24) were assessed by the Spearman’s rank method. The XA subgroups were excluded. Only significant P values are shown. In multiple-comparison calculations including all P values, the FDR was estimated to be 6% using the Benjamini-Hochberg procedure, and a fixed P value significance threshold was set at 0.05.