Long‐term persistence of hepatitis B surface antigenand antibody induced by DNA‐mediated immunization results in liver and kidney lesions in mice

Abstract

DNA-mediated immunization has been recognized as a new approach for prevention and treatment of hepatitis B virus (HBV) infection. However, the side effects of this approach have not been well described. Here we report that DNA-mediated immunization by intramuscular injection of plasmid DNA encoding HBV surface antigen (HBsAg) induced long-term persistence of HBsAg and HBsAg-specific antibody (anti-HBs) in the sera of the immunized BALB/c mice and resulted in liver and kidney lesions. The lesions persisted for 6 months after injection. Lesions were also found in normal mice injected with the sera from immunized mice, and in HBV-transgenic mice injected with anti-HBs antibody, or sera from immunized mice. Furthermore, lesions were accompanied by deposition of circulating immune complex (CIC) of HBsAg and anti-HBs antibody in the damaged organs. These results indicate that long-term persistence of HBsAg and anti-HBs in the immunized mice can result in deposited CIC in liver and kidney, and in development of lesions. The use of DNA containing mammalian replication origins, such as the plasmids used in this study, is not appropriate for human vaccines due to safety concerns relating to persistence of DNA; nevertheless, the safety of DNA-mediated immunization protocols still needs to be carefully evaluated before practical application.

Technologies for enhanced efficacy of DNA vaccines

“…Data from animal studies showed that DNA vaccines could increase the production of anti-DNA autoantibodies but did not increase disease severity in lupus-prone animals nor induce autoimmunity in healthy animals [18,19]. Injection of mice with a plasmid encoding hepatitis B surface antigen (HBsAg) induced liver and kidney damage that was explained by the prolonged expression of HBsAg resulting in the formation of immune complexes [20]. Parker et al failed to find evidence of pathological changes after repeated injections of DNA in mice or rabbits [21].…”

“…Over the last 15 years, DNA vaccines have proved effective in animal models including against HIV, malaria and influenza [1]. DNA vaccines have been extensively evaluated in humans with a recent review identifying 72 Phase I, 20 Phase II and two Phase III human trials [2]. DNA vaccines have a good safety record, with the most common adverse reactions being mild-moderate inflammation with associated pain, redness and swelling at the injection site [1].…”

The Adoptive Transfer of HBsAG-specific Splenocytes from Balb/c Congenic Donors into HBsAg Transgenic Mice is not associated to Histographological Damage

“…It was reported in experiments with transgenic mice that WKH GHSRVLWLRQ RI LPPXQH FRPSOH[ DQWLJHQDQWLERG\ VSHFL¿F against HBsAg could cause damage at liver and kidney levels. 9 Based on all the above evidences, the present work explore with more details safety aspects related with the nasal/parenteral administration of the therapeutic vaccine candidate NASVAC. With that purpose we simulated the environment of a chronic patient that develops a potent immune response against the surface and nucleocapsid antigens of HBV after the administration of said vaccine + T lymphocytes.…”

WITHDRAWN: Enhancing efficacy and mucosa-tropic distribution of an oral HIV-PsV DNA vaccine in animal models

“…or intramuscular injection (i.m.) administration (Nishikawa et al, 1998;Zi et al, 2006). Our results with naked plasmid DNA vaccination, via both i.v.…”