Oral Modeling of an Adenovirus-Based Quadrivalent Influenza Vaccine in Ferrets and Mice
Scallan CD, Lindbloom JD, Tucker SN. Infectious Diseases and Therapy. 2016 Apr 12. [Epub ahead of print] doi: 10.1007/s40121-016-0108-z
Introduction: Oral vaccines delivered as tablets offer a number of advantages over traditional parenteral-based vaccines including the ease of delivery, lack of needles, no need for trained medical personnel, and the ability to formulate into temperature-stable tablets. We have been evaluating an oral vaccine platform based on recombinant adenoviral vectors for the purpose of creating a prophylactic vaccine to prevent influenza, and have demonstrated vaccine efficacy in animal models and substantial immunogenicity in humans. These studies have evaluated monovalent vaccines to date. To protect against the major circulating A and B influenza strains, a multivalent influenza vaccine will be required.
Methods: In this study, the immunogenicity of orally delivered monovalent, bivalent, trivalent, and quadrivalent vaccines was tested in ferrets and mice. The various vaccine combinations were tested by blending monovalent recombinant adenovirus vaccines, each expressing hemagglutinin from a single strain. Human tablet delivery was modeled in animals by oral gavage in mice and by endoscopic delivery in ferrets.
Results: We demonstrated minimal interference between the various vaccine vectors when used in combination and that the oral quadrivalent vaccine compared favorably to an approved trivalent inactivated vaccine.
Conclusion: The quadrivalent vaccine presented here produced immune responses that we predict should be capable of providing protection against multiple influenza strains, and the platform should have applications to other multivalent vaccines.
Funding: Vaxart Inc.
High titre neutralising antibodies to influenza after oral tablet immunisation: a phase 1, randomised, placebo-controlled trial
Liebowitz D, Lindbloom JD, Brandl JR, Garg SJ, Tucker SN. Lancet Infectious Disease. 2015 Sep;15(9):1041-8. doi: 10.1016/S1473-3099(15)00266-2.
Background: Most influenza vaccines are manufactured in eggs, and the inactivated virus is purified for injection. For a seasonal influenza product, manufacturing, distribution, and perhaps even vaccine coverage, would be greatly improved with an oral tablet alternative made in cell culture. We aimed to assess the safety and immunogenicity of an oral tablet vaccine against influenza A H1N1 in healthy adults.
Methods: At a single site, we did a randomised, double-blind, placebo-controlled trial of a monovalent influenza A H1N1 vaccine to establish the safety and immunogenicity of a recombinant, non-replicating, adenovirus vector expressing haemagglutinin and double-stranded RNA adjuvant delivered orally by tablets. Participants had to have an initial haemagglutination inhibition titre of at most 1/20, be aged between 18 and 49 years, and be in good health. We randomly assigned (1:1) participants to receive either a single oral dose of vaccine or placebo. Randomisation was done by computer-generated assignment, and study drug was distributed with concealed identity to the masked staff by an unmasked pharmacist. Investigative site staff, people directly involved with immunological assays or the assessment of clinical safety, and participants were masked to treatment assignments. Solicited symptoms of reactogenicity were assessed, and all safety assessments were reported through the active phase of the study (day 28). Immunogenicity was assessed by haemagglutination inhibition titres, the percentage of participants that seroconverted, microneutralisation titres, and the number of antibody secreting cells. Descriptive statistics were used for continuous variables and t-tests or Fisher's exact tests were used to compare treatment groups. The study is registered at ClinicalTrials.gov, number NCT01688297.
Findings: 24 participants were enrolled in the study at WCCT Global between Dec 2, 2013, and April 15, 2014. Adverse events were mild in nature, and occurred with similar frequency in vaccine (four events) and placebo recipients (four events). After immunisation, 11 (92%) of 12 vaccine-treated participants had a four-fold increase in haemagglutination inhibition titres (group geometric mean fold rise of 7·7) and microneutralisation titres (group geometric mean fold rise of 29). No participants in the placebo group had a four-fold increase in haemagglutination inhibition titres (group geometric mean fold rise of 1·1) or microneutralisation titres (group geometric mean fold rise of 1·0). Neutralising antibody responses to influenza were not hindered by pre-existing immunity to the vector.
Interpretation: An oral recombinant adenovirus vaccine to influenza was well tolerated and can elicit neutralising antibody responses to influenza virus in human beings. These data are a step forward in making oral influenza vaccination possible.
Funding: Vaxart Inc.
Oral administration of an adenovirus vector encoding both an avian influenza A hemagglutinin and a TLR3 ligand induces antigen specific granzyme B and IFN-γ T cell responses in humans
Peters W, Brandl JR, Lindbloom JD, Martinez CJ, Scallan CD, Trager GR, Tingley DW, Kabongo ML, Tucker SN. Vaccine. 2013 Mar 25;31(13):1752-8. doi: 10.1016/j.vaccine.2013.01.023. Epub 2013 Jan 25.
Purpose: To test the safety and immunogenicity of an orally delivered avian influenza vaccine. The vaccine has a non-replicating adenovirus type 5 vector backbone which expresses hemagglutinin from avian influenza and a TLR3 ligand as an adjuvant.
Methods: Forty-two subjects were randomized into 3 groups dosed with either 1×10(10), 1×10(9), or 1×10(8) IU of the vaccine administered in capsules. Twelve subjects were vaccinated with identical capsules containing placebo. A portion of the 1×10(9) dose group were immunized a second time 4 weeks after the first immunization. The safety of the vaccine was assessed by measuring the frequency and severity of adverse events in placebo versus vaccine treated subjects. IFN-γ and granzyme B ELISpot assays were used to assess immunogenicity.
Results: The vaccine had a positive safety profile with no treatment emergent adverse events reported above grade 1, and with an adverse event frequency in the treated groups no greater than placebo. Antigen specific cytotoxic and IFN-γ responses were induced in a dose dependent manner and cytotoxic responses were boosted after a second vaccination.
Conclusion: This first in man clinical trial demonstrates that an orally delivered adenovirus vectored vaccine can induce immune responses to antigen with a favorable safety profile. Clinical Trial Registration number: NCT01335347.
An Adenovirus-Based Vaccine with a Double-Stranded RNA Adjuvant Protects Mice and Ferrets against H5N1 Avian Influenza in Oral Delivery Models
Ciaran D. Scallan, Debora W. Tingley, Jonathan D. Lindbloom, James S. Toomey, and Sean N. Tucker, Clin. Vaccine Immunol. Published ahead of print 14 November 2012, doi:10.1128/CVI.00552-12
An oral gene-based avian influenza vaccine would allow rapid development and simplified distribution, but efficacy has previously been difficult to achieve by the oral route. This study assessed protection against avian influenza virus challenge using a chimeric adenovirus vector expressing hemagglutinin and a double-stranded RNA adjuvant. Immunized ferrets and mice were protected upon lethal challenge. Further, ferrets immunized by the peroral route induced cross-clade neutralizing antibodies, and the antibodies were selective against hemagglutinin, not the vector. Similarly, experiments in mice demonstrated selective immune responses against HA with peroral delivery and the ability to circumvent preexisting vector immunity.
Oral adenoviral-based vaccines: historical perspective and future opportunity
Sean N. Tucker, Debora W. Tingley and Ciaran D. Scallan, Expert Review of Vaccines 7(1), 25–31 (2008).
Adenoviral vaccines delivered orally have been used for decades to prevent respiratory illness, but are now being seriously explored again as a platform technology to make vaccines against a variety of pathogens. Years of use in military populations as a preventative measure for adenoviral infection have demonstrated the safety of oral administration of adenovirus. The advantages of using this approach as a platform technology for vaccines include rapid development and distribution, as well as ease of administration. Recent discoveries may allow this platform approach to reach the clinic within a few years.