There are several benefits of oral immunization including the ability to elicit mucosal immune responses that may protect against pathogens that invade through a mucosal surface. Our understanding of human immune biology is hampered by the difficulty in isolating mucosal cells from humans, and the fact that animal models may or may not completely mirror human intestinal immunobiology. In this human pharmacodynamic study, a novel adenovirus vector-based platform expressing influenza hemagglutinin was explored. We used radio-controlled capsules to deliver the vaccine to either the jejunum or the ileum. The resulting immune responses induced by immunization at each of the intestinal sites were investigated. Both intestinal sites were capable of inducing mucosal and systemic immune responses to influenza hemagglutinin, but ileum delivery induced higher numbers of antibody secreting cells of IgG and IgA isotypes, increased mucosal homing B cells, and higher number of vaccine responders. Overall, these data provided substantial insights into human mucosal inductive sites, and aided in the design and selection of indications that could be used with this oral vaccine platform.

BackgroundOral vaccines delivered as tablets offer several advantages over traditional injection-based vaccines including ease of distribution and administration as well as temperature-stable formulation options. Oral vaccination is also advantageous because it directly induces a strong mucosal response, which is thought to be critical for preventing future infections. Here we present results from a phase II clinical challenge study comparing efficacy of an oral recombinant adenovirus-based vaccine expressing hemagluttinin (HA) from A/California 04/09 to that of a commercial injectable quadrivalent (QIV) influenza vaccine.MethodsIn this 2016–2017 clinical trial (NCT02918006), subjects were immunized with either oral vaccine, QIV, or placebo and then challenged 90 days post-immunization with wildtype influenza A H1 virus to measure vaccine efficacy and durability. Protection was assessed by measuring changes in HAI titres, microneutralization, and IgA/IgG ASC assays. Additionally, exploratory flow cytometry evaluated quantitative and qualitative aspects of immunogenicity including markers of activation and mucosal homing on B cells. Analysis was performed on days 0 and 7 post-immunization and 0 and 6 days post-viral challenge. Plasmablasts sorted from PBMCs were then isolated for genomic DNA and sequenced for heavy chain receptor sequencing using NGS analysis.ResultsOf the subjects immunized with Vaxart’s oral tablet vaccine, 48% were protected. QIV, by comparison, protected 38% of immunized individuals. Only 37% of Vaxart subjects developed influenza infection compared with 44% of QIV subjects and 71% of placebo subjects. While both vaccines induced a humoral immune response, FACS analysis and NGS revealed that Vaxart subjects had more activated plasmablasts expressing surface mucosal homing markers and a more diverse B cell population than QIV subjects.ConclusionVaxart’s oral influenza tablet vaccine protected against influenza infection as well or better than injectable QIV. However, the mechanism of protection appears to be unique to the route of immunization; oral immunization allows for specific homing of influenza specific B cells to sites of infection and produces a more diverse antibody repertoire.Disclosures N. Kolhatkar, Vaxart, Inc.: Employee, Salary. K. Gottlieb, Vaxart, Inc.: Employee, Salary. K. Kasparek, Vaxart, Inc.: Employee, Salary. K. Hodgson, Vaxart, Inc.: Employee, Salary. S. Tucker, Vaxart, Inc: Employee, Salary. D. Liebowitz, Vaxart, Inc.: Employee and Investigator, Salary.