Humoral immune response to the capsid components of recombinant adenoviruses: Routes of immunization modulate virus‐induced Ig subclass shifts

Abstract

This study examines in detail the capsid-specific humoral immune response of BALB/c mice after one single injection of a replication-defective adenovirus. Two routes of immunization, intravenous (i.v.) and intraperitoneal (i.p.), were compared for the response induced against the adenovirus particle and the three major components of the viral capsid, hexon, penton base, and fiber. A single immunization with the replication-defective adenovirus induces a long and persistent humoral response specific for the virus. However, the molecular components of the viral capsid are differentially recognized depending on the route of immunization. The sera from mice immunized i.p. recognized only the hexon protein and a preferential switch to the IgG2a subclass was obtained which remained stable 100 days post-immunization. The sera obtained from mice immunized i.v. gave a more complex response. At the beginning of the response, an isotype bias toward the IgG2a subclass was observed, but the isotype distribution changed during the whole period of the response. Neutralizing activity was maximum 45 days after immunization by both routes, and no activity was detectable after 3 months. However, the i.v. serum displayed a higher neutralizing activity than the i.p. serum. The IgM antiviral antibodies appeared to be an important component of the neutralizing activity, and the two routes of immunization do not induce the same IgG isotypes to neutralize viral infectivity. Extension of these findings to human gene therapy using recombinant adenoviruses may help to characterize the precise viral protein targets of neutralizing antibodies.

Effective repeat administration with adenovirus vectors to the muscle

“…32,33 To determine the minimal dose of vector that results in the production of neutralizing antibodies when delivered by the i.m. route, mice were immunized with escalating doses of an adenovirus vector that expressed luciferase from the RSV promoter.…”

Adenovirus complexed with polyethylene glycol and cationic lipid is shielded from neutralizing antibodies in vitro

“…With the different administration routes, the neutralizing activity may vary; after delivery to the lungs it may be due primarily to IgA 16,34 and after intravenous administration it may be due primarily to IgG and IgM. 35 To avoid an immune response to the reporter, the transgene expressed by the immunizing virus was different from that used to assay expression. We analyzed transgene expression soon after administration, to minimize the effect of any cell-mediated immune response.…”

Transient blocking of both B7.1 (CD80) and B7.2 (CD86) in addition to CD40–CD40L interaction fully abrogates the immune response following systemic injection of adenovirus vector

“…repeated systemic administrations do not achieve efficient re-transduction of the target tissues due to the production of circulating neutralizing antibodies (NAbs). 1,[6][7][8][9] In mouse models, transient depletion or blocking of the CD4 + T cell population decreases the production of anti-Ad antibodies (Abs) and permits vector readministration. 10,11 However, these strategies induce profound immunosuppression, potentially detrimental to patients with genetic diseases.…”