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Vol. 46, No. 5, 2003
Issue release date: September–October 2003
Intervirology 2003;46:270–276
(DOI:10.1159/000073206)

Safety Evaluation of GX-12, a New HIV Therapeutic Vaccine: Investigation of Integration into the Host Genome and Expression in the Reproductive Organs

Kang K.K. · Choi S.M. · Choi J.H. · Lee D.S. · Kim C.Y. · Ahn B.O. · Kim B.M. · Kim W.B.
Research Laboratories, Dong-A Pharmaceutical Co. Ltd., Yongin-shi, Kyunggi-do, Korea
email Corresponding Author

Abstract

AIDS is one of the greatest infectious disease threats to human health despite the extensive efforts made since the discovery of HIV in 1983. The use of plasmid DNA vaccination to elicit humoral and cell-mediated immune responses against HIV infection has produced promising results in animal and in human trials. However, there are several safety concerns about the use of a DNA vaccine, which include the possibility of integration into the host genome, adverse immunopathology, and anti-DNA autoantibody induction. In this study, we examined the potential integration and distribution of GX-12, a new therapeutic vaccine for HIV infection, at various times in muscles and reproductive organs of rats. Animals of both sexes were injected with GX-12 at the dose of 400 µg/animal i.m. once a week for 4 weeks, and host genome integration and tissue distribution were examined on day 1, 5, 15, 30 and 45 days after the final injection. A PCR-based assay revealed that GX-12 was not integrated into the host genome, nor expressed in reproductive organs at any time. These findings suggest that the risk of mutation or germline transmission due to GX-12 injection is negligible.


 goto top of outline Key Words

  • DNA vaccine
  • GX-12
  • Genomic integration
  • Reproductive organs
  • Tissue distribution

 goto top of outline Abstract

AIDS is one of the greatest infectious disease threats to human health despite the extensive efforts made since the discovery of HIV in 1983. The use of plasmid DNA vaccination to elicit humoral and cell-mediated immune responses against HIV infection has produced promising results in animal and in human trials. However, there are several safety concerns about the use of a DNA vaccine, which include the possibility of integration into the host genome, adverse immunopathology, and anti-DNA autoantibody induction. In this study, we examined the potential integration and distribution of GX-12, a new therapeutic vaccine for HIV infection, at various times in muscles and reproductive organs of rats. Animals of both sexes were injected with GX-12 at the dose of 400 μg/animal i.m. once a week for 4 weeks, and host genome integration and tissue distribution were examined on day 1, 5, 15, 30 and 45 days after the final injection. A PCR-based assay revealed that GX-12 was not integrated into the host genome, nor expressed in reproductive organs at any time. These findings suggest that the risk of mutation or germline transmission due to GX-12 injection is negligible.

Copyright © 2003 S. Karger AG, Basel


 goto top of outline References
  1. Lee DJ, Corr M, Carson DA: Control of immune responses by gene immunization. Ann Med 1998;30:460–468.
  2. Casares S, Inaba K, Brumeanu TD, Steinman RM, Bona CA: Antigen presentation by dendritic cells after immunization with DNA encoding a major histocompatibility complex class II-restricted viral epitope. J Exp Med 1997;186:1481–1486.
  3. Mor G: Plasmid DNA: A new era in vaccinology. Biochem Pharmacol 1998;55:1151–1153.
  4. Sharma AK, Khuller GK: DNA vaccines: Future strategies and relevance to intracellular pathogens. Immunol Cell Biol 2001;79:537–546.
  5. Dolin R, Graham BS, Greenberg SB, Tacket CO, Belshe RB, Midthun K, Clements ML, Gorse GJ, Horgan BW, Atmar RL: The safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant gp160 candidate vaccine in humans. NIAID AIDS Vaccine Clinical Trials Network. Ann Intern Med 1991;114:119–127.
  6. Edgeworth RL, San JH, Rosenzweig JA, Nguyen NL, Boyer JD, Ugen KE: Vaccine development against HIV-1: Current perspectives and future directions. Immunol Res 2002;25:53–74.
  7. Billich A: AIDSVAX. VaxGen. Curr Opin Investig Drugs 2001;2:1203–1208.
  8. Robertson JS, Griffiths E: Assuring the quality, safety, and efficacy of DNA vaccines. Mol Biotechnol 2001;17:143–149.
  9. Nichols WW, Ledwith BJ, Manam SV, Troilo PJ: Potential DNA vaccine integration into host cell genome. Ann NY Acad Sci 1995;772:30–39.
  10. Manam S, Ledwith BJ, Barnum AB, Troilo PJ, Pauley CJ, Harper LB, Griffiths TG 2nd, Niu Z, Denisova L, Follmer TT, Pacchione SJ, Wang Z, Beare CM, Bagdon WJ, Nichols WW: Plasmid DNA vaccines: Tissue distribution and effects of DNA sequence, adjuvants and delivery method on integration into host DNA. Intervirology 2000;43:273–281.
  11. Ledwith BJ, Manam S, Troilo PJ, Barnum AB, Pauley CJ, Griffiths TG 2nd, Harper LB, Beare CM, Bagdon WJ, Niochols WW: Plasmid DNA vaccines: Investigation of integration into host cellular DNA following intramuscular injection in mice. Intervirology 2000;43:258–272.
  12. Sambrook J, Frisch EF, Maniatis T: Molecular Cloning. A Laboratory Manual, ed 2. New York, Cold Spring Harbor Laboratory Press, 1989.
  13. Cichutek K: DNA vaccines: Development, standardization and regulation. Intervirology 2000;43:331–338.
  14. World Health Organization: Acceptability of cell substrates for production of biologicals. Technical Report Series World Health Organization, No 747, 1987.
  15. Points to consider on plasmid DNA vaccines for preventive infectious disease indications. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Vaccine Research and Review, Docket No 96-N-0400, 1996.

 goto top of outline Author Contacts

Kyung Koo Kang
Research Laboratories
Dong-A Pharmaceutical Co. Ltd.
47-5, Sanggal-ri, Kiheung-up, Yongin-shi, Kyunggi-do 449-905 (Korea)
Tel. +82 31 280 1394, Fax +82 31 282 8564, E-Mail kangkk@donga.co.kr


 goto top of outline Article Information

Received: February 17, 2003
Accepted: March 24, 2003
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 3, Number of References : 15


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)
Founded 1973 by J.L. Melnick; continued by F. Rapp (1986–1990); M.J. Buchmeier and C.R. Howard (1991–1993)

Vol. 46, No. 5, Year 2003 (Cover Date: September-October 2003)

Journal Editor: Rüdiger W. Braun, Stuttgart
ISSN: 0300–5526 (print), 1423–0100 (Online)

For additional information: http://www.karger.com/journals/int


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

AIDS is one of the greatest infectious disease threats to human health despite the extensive efforts made since the discovery of HIV in 1983. The use of plasmid DNA vaccination to elicit humoral and cell-mediated immune responses against HIV infection has produced promising results in animal and in human trials. However, there are several safety concerns about the use of a DNA vaccine, which include the possibility of integration into the host genome, adverse immunopathology, and anti-DNA autoantibody induction. In this study, we examined the potential integration and distribution of GX-12, a new therapeutic vaccine for HIV infection, at various times in muscles and reproductive organs of rats. Animals of both sexes were injected with GX-12 at the dose of 400 µg/animal i.m. once a week for 4 weeks, and host genome integration and tissue distribution were examined on day 1, 5, 15, 30 and 45 days after the final injection. A PCR-based assay revealed that GX-12 was not integrated into the host genome, nor expressed in reproductive organs at any time. These findings suggest that the risk of mutation or germline transmission due to GX-12 injection is negligible.



 goto top of outline Author Contacts

Kyung Koo Kang
Research Laboratories
Dong-A Pharmaceutical Co. Ltd.
47-5, Sanggal-ri, Kiheung-up, Yongin-shi, Kyunggi-do 449-905 (Korea)
Tel. +82 31 280 1394, Fax +82 31 282 8564, E-Mail kangkk@donga.co.kr


 goto top of outline Article Information

Received: February 17, 2003
Accepted: March 24, 2003
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 3, Number of References : 15


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)
Founded 1973 by J.L. Melnick; continued by F. Rapp (1986–1990); M.J. Buchmeier and C.R. Howard (1991–1993)

Vol. 46, No. 5, Year 2003 (Cover Date: September-October 2003)

Journal Editor: Rüdiger W. Braun, Stuttgart
ISSN: 0300–5526 (print), 1423–0100 (Online)

For additional information: http://www.karger.com/journals/int


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Lee DJ, Corr M, Carson DA: Control of immune responses by gene immunization. Ann Med 1998;30:460–468.
  2. Casares S, Inaba K, Brumeanu TD, Steinman RM, Bona CA: Antigen presentation by dendritic cells after immunization with DNA encoding a major histocompatibility complex class II-restricted viral epitope. J Exp Med 1997;186:1481–1486.
  3. Mor G: Plasmid DNA: A new era in vaccinology. Biochem Pharmacol 1998;55:1151–1153.
  4. Sharma AK, Khuller GK: DNA vaccines: Future strategies and relevance to intracellular pathogens. Immunol Cell Biol 2001;79:537–546.
  5. Dolin R, Graham BS, Greenberg SB, Tacket CO, Belshe RB, Midthun K, Clements ML, Gorse GJ, Horgan BW, Atmar RL: The safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant gp160 candidate vaccine in humans. NIAID AIDS Vaccine Clinical Trials Network. Ann Intern Med 1991;114:119–127.
  6. Edgeworth RL, San JH, Rosenzweig JA, Nguyen NL, Boyer JD, Ugen KE: Vaccine development against HIV-1: Current perspectives and future directions. Immunol Res 2002;25:53–74.
  7. Billich A: AIDSVAX. VaxGen. Curr Opin Investig Drugs 2001;2:1203–1208.
  8. Robertson JS, Griffiths E: Assuring the quality, safety, and efficacy of DNA vaccines. Mol Biotechnol 2001;17:143–149.
  9. Nichols WW, Ledwith BJ, Manam SV, Troilo PJ: Potential DNA vaccine integration into host cell genome. Ann NY Acad Sci 1995;772:30–39.
  10. Manam S, Ledwith BJ, Barnum AB, Troilo PJ, Pauley CJ, Harper LB, Griffiths TG 2nd, Niu Z, Denisova L, Follmer TT, Pacchione SJ, Wang Z, Beare CM, Bagdon WJ, Nichols WW: Plasmid DNA vaccines: Tissue distribution and effects of DNA sequence, adjuvants and delivery method on integration into host DNA. Intervirology 2000;43:273–281.
  11. Ledwith BJ, Manam S, Troilo PJ, Barnum AB, Pauley CJ, Griffiths TG 2nd, Harper LB, Beare CM, Bagdon WJ, Niochols WW: Plasmid DNA vaccines: Investigation of integration into host cellular DNA following intramuscular injection in mice. Intervirology 2000;43:258–272.
  12. Sambrook J, Frisch EF, Maniatis T: Molecular Cloning. A Laboratory Manual, ed 2. New York, Cold Spring Harbor Laboratory Press, 1989.
  13. Cichutek K: DNA vaccines: Development, standardization and regulation. Intervirology 2000;43:331–338.
  14. World Health Organization: Acceptability of cell substrates for production of biologicals. Technical Report Series World Health Organization, No 747, 1987.
  15. Points to consider on plasmid DNA vaccines for preventive infectious disease indications. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Vaccine Research and Review, Docket No 96-N-0400, 1996.