Circumvention of vector-specific neutralizing antibody response by alternating use of human and non-human adenoviruses: implications in gene therapy.
To determine whether non-human adenovirus-specific antibodies are cross-neutralizing, rabbit and mouse anti-human adenovirus type 5 (HAd5), anti-bovine adenovirus type 3 (BAd3), and anti-porcine adenovirus type 3 (PAd3) sera were used in cross-virus neutralization assays. Adenovirus neutralizing antibodies were found to be virus-specific, suggesting that virus neutralizing epitope differs significantly in HAd5, BAd3, and PAd3. To further investigate whether immunity to an HAd5-derived vector could be circumvented by the use of non-human adenoviruses in vivo, mice were first immunized either intranasally or intraperitoneally with HAd5, BAd3, PAd3, or BAd3 + PAd3, and after development of adenovirus-specific antibodies, animals were inoculated with the HAd5 recombinant (AdCA36lacZ) containing the bacterial beta-galactosidase gene under the control of murine cytomegalovirus immediate-early promoter. Virus-inoculated animals developed virus-specific IgG and IgA antibodies. LacZ expression in animals initially primed with HAd5 was significantly reduced (P < 0.05), suggesting that the immune response against the vector could prevent the transgene expression following subsequent inoculation of the same vector, whereas LacZ expression in mice initially primed with BAd3, PAd3, or BAd3 + PAd3 was significantly higher (P > 0.05) than that obtained in HAd5-primed animals. Our results suggest that HAd5-, BAd3-, or PAd3-based vectors may be used sequentially for human gene therapy or vaccine production as a means to avoid immunity to the vector.
Moffatt
S
S
Department of Veterinary Pathobiology, School of Veterinary Medicine, West Lafayette, Indiana 47907, USA.
Hays
J
J
HogenEsch
H
H
Mittal
S K
SK
D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D002417:Cattle; D002460:Cell Line; D003429:Cross Reactions / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D017921:Mastadenovirus / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D011817:Rabbits; D013552:Swine / Q000821:virology; D019076:Transgenes / Q000235:genetics
D000914:Antibodies, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G