First Human Trial of a DNA-Based Vaccine for Treatment of Human Immunodeficiency Virus Type 1 Infection: Safety and Host Response

MacGregor, Rob Roy; Boyer, Jean; Ugen, Kenneth E.; Lacy, K. E.; Gluckman, Stephen J.; Bagarazzi, Mark L.; Chattergoon, Michael A.; Baine, Yaela; Higgins, Terry J.; Ciccarelli, Richard B.; Coney, Leslie R.; Ginsberg, Richard S.; Weiner, David B.

doi:10.1086/515613

Cited by 576 publications

(312 citation statements)

References 44 publications

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“…Unfortunately, clinical trials have shown the limited efficacy of DNA vaccination in human volunteers, which necessitates the identification of technologies that can enhance DNA vaccines [20,21]. Among the strategies being evaluated to increase the efficiency of DNA vaccination is the use of non-viral vectors to deliver the DNA.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous scientific publications have reported the effectiveness of DNA vaccines in providing potent immune responses or protective immunity against viruses, bacteria and parasites in several species including human volunteers [19][20][21]. DNA vaccination has become an accepted method in the research community, and is now being tested on humans.…”

Section: Introductionmentioning

confidence: 99%

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Induction of gp120-specific protective immune responses by genetic vaccination with linear polyethylenimine–plasmid complex

Garzón

Berraondo

Crettaz

et al. 2005

Vaccine

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The induction of IFN-␥-secreting CD8+ T cells and neutralizing antibodies to HIV-1 are both key requirements for prevention of viral transmission and clearance of pathogenic HIV. Although DNA vaccination has been shown to induce both humoral and cellular immune responses against HIV antigens, the magnitude of the immune responses has always been disappointing. In this report, we analyze the ability of polyethylenimine (PEI)-DNA complex expressing an HIV-glycoprotein 120 (gp120) antigen (PEI-pgp120) to induce systemic CD8+ T cell and humoral responses to the gp120 antigen. The administration of PEI-plasmid complex resulted in rapid elevation of serum levels of IL-12 and IFN-␥. Furthermore, a single administration of PEI-pgp120 complex elicits a number of gp120-specific CD8+ T cells 20 times higher than that elicited by three intramuscular injections of naked DNA. Interestingly, we found that systemic vaccination with PEI-pgp120 induced protective immune responses against both systemic and mucosal challenges with a recombinant vaccinia virus expressing a gp120 antigen. The data also demonstrated that the depletion of macrophages with liposome-encapsulated clodronate completely abolished gp120-specific cellular response. Overall, our results showed that a single administration of PEI-pgp120 complexes, eliciting strong immune responses, is an effective vaccination approach to generate protection against systemic and mucosal viral infections.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of gp120-specific protective immune responses by genetic vaccination with linear polyethylenimine–plasmid complex

Garzón

Berraondo

Crettaz

et al. 2005

Vaccine

View full text Add to dashboard Cite

show abstract

“…In addition, we initiated the ®rst human trials for DNA vaccines. The preliminary results of these studies reveal immune enhancement and no clinical or laboratory adverse e ects measured in three dosage groups (30, 100, 300 mg) (RR MacGregor, 1998).…”

Section: Discussionmentioning

confidence: 81%

Molecular and immunological analysis of genetic prostate specific antigen (PSA) vaccine

et al. 1998

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Nucleic acid immunization has been investigated as immunotherapy for infectious diseases as well as for treating speci®c types of cancers. In this approach, nucleic acid expression cassettes are directly inoculated into the host, whose transfected cells become the production source of novel and possibly immunologically foreign protein. We have developed a DNA vaccine construct which encodes for PSA by cloning a cDNA for PSA into a mammalian expression vector under control of a CMV promoter. We investigated and characterized the immunogenicity of PSA DNA expression cassettes in mice. PSA-speci®c immune responses induced in vivo by immunization were characterized by enzyme-linked immunosorbent assay (ELISA), T helper proliferation cytotoxic T lymphocyte (CTL), and¯ow cytometry assays. We observed a strong and persistent antibody response against PSA for at least 180 days following immunization. In addition, a signi®cant T helper cell proliferation was observed against PSA protein. Using synthetic peptides spanning the PSA open frame, we identi®ed four dominant T helper epitopes of PSA. Furthermore, immunization with PSA plasmid induced MHC Class I CD8+ T cell-restricted cytotoxic T lymphocyte response against tumor cell targets expressing PSA. The prostate represents a very speci®c functional organ critical for reproduction but not for the health and survival of the individual. Understanding the immunogenicity of PSA DNA immunization cassettes o ers insight into the possible use of this tumorassociated antigen as a target for immunotherapy. These results demonstrate the ability of the genetic PSA to serve as a speci®c immune target capable of generating both humoral and cellular immune responses in vivo.

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“…Although DNA vaccines have thus far performed poorly in clinical trials, [23][24][25] their efficacy in preclinical small rodent models against infectious diseases or cancers has been impressive. 26,27,[4][5][6] DNA vaccines are easy to construct and they induce a full spectrum of immune responses including CD8 + T cells, 26 which have been implicated to play a major role in tumor cell eradication.…”

Section: Discussionmentioning

confidence: 99%

A DNA vaccine expressing tyrosinase-related protein-2 induces T-cell-mediated protection against mouse glioblastoma

et al. 2003

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A mouse glioblastoma cell line, termed GL261, was shown to express high levels of proteins involved in melanin biosynthesis such as the tyrosinase-related protein-2 (TRP-2), which is commonly overexpressed in melanoma cells. Mice injected with GL261 cells developed a CD8 + T-cell response to TRP-2 and a DNA vaccine expressing human (h)TRP-2 induced CD8 + T cells that recognized TRP-2 expressed by GL261 cells indicating that this melanoma-associated antigen may be suited for active immunotherapy of glioblastoma. Mice vaccinated with a DNA vaccine expressing TRP-2 were partially protected against subcutaneous, intravenous, or intracerebral challenge with the glioblastoma cells. Vaccine-induced protection against intracerebral challenge required both CD4 + and CD8 + T cells. Vaccine efficacy was enhanced upon addition of IL-12 as a genetic adjuvant. These results indicate that this well-defined melanoma-associated antigen can induce an adaptive immune response, which limits the intracerebral progression of a glioblastoma.

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First Human Trial of a DNA-Based Vaccine for Treatment of Human Immunodeficiency Virus Type 1 Infection: Safety and Host Response

Cited by 576 publications

References 44 publications

Induction of gp120-specific protective immune responses by genetic vaccination with linear polyethylenimine–plasmid complex

Induction of gp120-specific protective immune responses by genetic vaccination with linear polyethylenimine–plasmid complex

Molecular and immunological analysis of genetic prostate specific antigen (PSA) vaccine

A DNA vaccine expressing tyrosinase-related protein-2 induces T-cell-mediated protection against mouse glioblastoma

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