title: Nasal delivery of an adenovirus-based vaccine bypasses pre-existing immunity to the vaccine carrier and improves the immune response in mice.
abstract: Pre-existing immunity to human adenovirus serotype 5 (Ad5) is common in the general population. Bypassing pre-existing immunity could maximize Ad5 vaccine efficacy. Vaccination by the intramuscular (I.M.), nasal (I.N.) or oral (P.O.) route with Ad5 expressing Ebola Zaire glycoprotein (Ad5-ZGP) fully protected naïve mice against lethal challenge with Ebola. In the presence of pre-existing immunity, only mice vaccinated I.N. survived. The frequency of IFN-gamma+ CD8+ T cells was reduced by 80% and by 15% in animals vaccinated by the I.M. and P.O. routes respectively. Neutralizing antibodies could not be detected in serum from either treatment group. Pre-existing immunity did not compromise the frequency of IFN-gamma+ CD8+ T cells (3.9+/-1% naïve vs. 3.6+/-1% pre-existing immunity, PEI) nor anti-Ebola neutralizing antibody (NAB, 40+/-10 reciprocal dilution, both groups). The number of INF-gamma+ CD8+ cells detected in bronchioalveolar lavage fluid (BAL) after I.N. immunization was not compromised by pre-existing immunity to Ad5 (146+/-14, naïve vs. 120+/-16 SFC/million MNCs, PEI). However, pre-existing immunity reduced NAB levels in BAL by approximately 25% in this group. To improve the immune response after oral vaccination, the Ad5-based vaccine was PEGylated. Mice given the modified vaccine did not survive challenge and had reduced levels of IFN-gamma+ CD8+ T cells 10 days after administration (0.3+/-0.3% PEG vs. 1.7+/-0.5% unmodified). PEGylation did increase NAB levels 2-fold. These results provide some insight about the degree of T and B cell mediated immunity necessary for protection against Ebola virus and suggest that modification of the virus capsid can influence the type of immune response elicited by an Ad5-based vaccine.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Croyle
authors.forename: Ami
authors.initials: A
authors.lastname: Patel
authors.forename: Kaylie N
authors.initials: KN
authors.lastname: Tran
authors.forename: Michael
authors.initials: M
authors.lastname: Gray
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: James E
authors.initials: JE
authors.lastname: Strong
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
authors.forename: Gary P
authors.initials: GP
authors.lastname: Kobinger
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D000281:Administration, Intranasal; D000818:Animals; D000917:Antibody Formation / Q000502:physiology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D016503:Drug Delivery Systems / Q000379:methods*; D046129:Ebola Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D029043:Ebolavirus / Q000276:immunology; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology / Q000473:pathology / Q000662:veterinary; D018928:Immunity, Mucosal / Q000187:drug effects / Q000502:physiology*; D016233:Immunotherapy, Active / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D016019:Survival Analysis; D022701:Virosomes / Q000276:immunology
chemical_list: D046129:Ebola Vaccines; D022701:Virosomes; D011092:Polyethylene Glycols