© 1993 Oxford University Press
RESEARCH-ARTICLE |
DNA-based immunization induces continuous secretion of hepatitis B surface antigen and high levels of circulating antibody
1Physiotherapy Program and Department of Physiology, University of Ottawa 451 Smyth Road, Ottawa K1H 8M5, Canada 2Unité de Recombinaison et Expression Génétique INSERM U163 3Département de Biologie Moléculaire, Institut Pasteur 25, rue du Docteur Roux, 75724 Paris cedex 15, France
*To whom correspondence should be addressed at: Physiotherapy Program, University of Ottawa, 451 Smyth Road, Ottawa K1H 8M5, Canada
Received July 19, 1993; Revised August 26, 1993; Accepted August 26, 1993
The possibility of inducing an immune response to a protein expressed directly from an introduced gene represents an alternative to classic vaccination. We evaluated the ability of plasmid-based eukaryotlc expression vectors to produce the Hepatitis B surface antigen (HBsAg) after injection of pure DNA Into mouse tibialls anterior muscles. DNA was injected into either normal mature muscle, or regenerating muscle following cardiotoxin-induced degeneration. The sera obtained from these animals contained significant levels of HBsAg as early as 10 days after gene transfer, at which time low levels of antibodies to HBsAg (anti-HBsAg) were already present. Between 15–60 d after DNA transfer, serum levels of anti-HBsAg steadily increased whereas those for HBsAg fell, most likely due to the neutralizing effect of the antibodies. Analysis of proportions of HBs-seropositive mice showed that within 2 wk of injection of 100 µg pCMV-HBs in regenerating muscle, 91% of the mice were seropositive [defined as having more than 1 milli-international Unit/ml (mlU/ml) of anti-HBsAg]. Even at that early time, 68% had titers of anti-HBsAg greater than 10 mlU/ml, a level that is recognized as being sufficient in humans to confer protection against natural Hepatitis B virus infection. The proportion of seropositive animals rose to 95% by 4 wk, and 1007percnt; by 8 wk, at which time all mice had greater than 100 mlU antl-HBsAg in their sera. We have thus demonstrated that direct intramuscular injection of a plasmid vector encoding the HBsAg will give rise to secretion of the viral surface protein into the circulation which leads to an appropriate antibody response. Obtaining secretion of foreign proteins could have several therapeutic uses, particularly in situations where production at low levels is required over long periods of time.
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