Safety and Immunogenicity of a Gag-Pol Candidate HIV-1 DNA Vaccine Administered by a Needle-Free Device in HIV-1-Seronegative Subjects

Tavel, Jorge A.; Martin, Jennifer; Kelly, Gerald D.; Enama, Mary E.; Shen, Jean; Gomez, Phillip L.; Andrews, Charla; Koup, Richard A.; Bailer, Robert T.; Stein, Judy; Roederer, Mario; Nabel, Gary J.; Graham, Barney S.

doi:10.1097/qai.0b013e3180417cb6

Cited by 53 publications

(44 citation statements)

References 15 publications

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“…Adverse events were mostly local site reactions, and there were no dose-limiting toxicities. These data are consistent with several other trials showing that DNAbased vaccination strategies are safe (9,11,12,20,21,30,33). One participant was found to have positive anti-DNA antibody, but this was not considered clinically significant.…”

Section: Discussionsupporting

confidence: 80%

Phase I Study of a Herpes Simplex Virus Type 2 (HSV-2) DNA Vaccine Administered to Healthy, HSV-2-Seronegative Adults by a Needle-Free Injection System

Cattamanchi

Posavad

Wald

et al. 2008

Clin Vaccine Immunol

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We conducted a double-blind, vehicle-controlled, dose escalation safety and immunogenicity trial of a candidate herpes simplex virus type 2 (HSV-2) surface glycoprotein D2 (gD2) DNA vaccine administered by use of a needle-free device. Sixty-two healthy adults were randomized using a 4:1 vaccine-to-placebo ratio. Half of the participants were HSV-1 seronegative, and all were HSV-2 seronegative. Vaccine doses included 100 g, 300 g, 1,000 g or 3,000 g of a plasmid expressing the gD2 protein. Subjects received vaccine at 0, 4, 8, and 24 weeks. Some subjects received an additional 1,000-g boost at 52 weeks. We found that the vaccine was safe and well tolerated, with most adverse events being local site reactions. No dose-limiting toxicities were observed. gD2-specific cytotoxic T-lymphocyte and lymphoproliferation responses were detected 2 weeks after the third vaccine injection in one of four HSV-1-seronegative, HSV-2-seronegative participants who received 3,000 g of vaccine. A DNA-based vaccination strategy against HSV-2 appears to be safe and may generate a vaccine-specific cellular immune response, but high vaccine doses are likely needed to elicit an immune response in most vaccinees.Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent sexually transmitted infections worldwide and is a major cause of genital ulcer disease in developed and developing countries (Ahmed et al. 2003, Chen et al. 2000, Mertz et al. 1998, Fleming et al. 1997, Xu et al. 2006. In addition, a growing body of literature suggests that HSV-2 increases the risk of human immunodeficiency virus type 1 (HIV-1) acquisition and transmission (5, 7). HSV-2 also causes neonatal herpes, which is a rare but serious condition that often results in permanent neurodevelopmental sequelae (14). Development of an HSV vaccine is a high priority.Two HSV-2 subunit vaccines have completed phase III trials and provided insight into the immunology of HSV infection. The first contained two major HSV-2 surface glycoproteins, glycoproteins D and B (gB and gD), with an adjuvant, MF59, previously shown to elicit a Th2-type response (31). No protection against HSV-2 acquisition or genital herpes disease was demonstrated, despite elicitation of high HSV-2-specific neutralizing antibody titers (6). The second vaccine contained a truncated form of gD with another adjuvant, aluminum hydroxide plus 3-O-deacylated monophosphoryl lipid A (alum-MPL), previously shown to elicit a Th1-type response (24, 31). This candidate vaccine elicited partial protection against genital herpes disease in women who were seronegative for HSV-1 and -2. The difference in efficacy between these subunit vaccines was attributed to the adjuvants (32). Animal models also suggest that cellular immunity is important in defending against HSV-2 infection (22,23). These data highlight the likelihood that a robust cellular immune response in addition to neutralizing antibodies is critical in protection against HSV-2 infection.DNA vaccination is an attractive approach toward HSV vaccin...

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Section: Discussionsupporting

confidence: 80%

Phase I Study of a Herpes Simplex Virus Type 2 (HSV-2) DNA Vaccine Administered to Healthy, HSV-2-Seronegative Adults by a Needle-Free Injection System

Cattamanchi

Posavad

Wald

et al. 2008

Clin Vaccine Immunol

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“…Preclinical testing of DP6-001 demonstrated no significant adverse reactions in either rabbits or non-human primates despite the induction of robust immunity [2,3]. Previously tested HIV DNA vaccines have demonstrated excellent human safety profiles [4][5][6][7][8][9]. Recombinant protein-based HIV vaccines formulated with QS21 adjuvant have reported local reactions, but have shown limited systemic adverse events in humans [10][11][12][13][14][15].…”

Section: Hiv; Vaccine; Adverse Event; Vasculitismentioning

confidence: 99%

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

Kennedy

Green

et al. 2008

Vaccine

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This report describes the safety observations following administration of a polyvalent DNA primeprotein boost HIV-1 vaccine formulated with adjuvant QS21. Local injection site reactionswere the most common (65% of subjects), and included type IV delayed-type hypersensitivity (DTH) reactions at prior DNA inoculation sites in 12 of 28 (43%) subjects following protein vaccination. Systemic reactions revealed two cases of vasculitis temporally related to inoculation with recombinant Env protein + QS21 adjuvant. Questions remain regarding the cause of the vasculitis, but the unique DTH observation may have contributed to the high level of immune responses previously reported for this vaccine. Keywords HIV; vaccine; adverse event; vasculitisOver the past two decades, various HIV vaccines have been tested for safety and several for efficacy in humans. However, the majority have not reproduced, in humans, the high immunogenicity seen in preclinical testing. Recently, we reported that a novel multi-gene, polyvalent DNA prime-recombinant protein boost HIV vaccine formulation, DP6-001, elicited strong and balanced humoral and cell-mediated immunity in healthy, HIV-1-negative adult subjects [1]. Preclinical testing of DP6-001 demonstrated no significant adverse reactions in either rabbits or non-human primates despite the induction of robust immunity [2,3]. Previously tested HIV DNA vaccines have demonstrated excellent human safety profiles [4][5][6][7][8][9]. Recombinant protein-based HIV vaccines formulated with QS21 adjuvant have reported local reactions, but have shown limited systemic adverse events in humans [10][11][12][13][14][15]. The current report summarizes the phase 1 clinical safety and tolerability data, highlighting local and *Address correspondence to: Jeff Kennedy, M.D., Division of Molecular Medicine, Wadsworth Center, Biggs Laboratory, ESP, C606, NYS Department of Health, P.O. Box 509, Albany, New York 12201-0509, P: 518-473-8421, F: 518-473-2900, E: jsk07@health.state.ny.us. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The clinical trial was an open-label, 3-arm design requiring each subject to receive two vaccine components; three sequential inoculations using a DNA plasmid vaccine administered either intradermally (ID) or intramuscularly (IM) followed by two sequential inoculations using a protein vaccine as shown in Table 1. Healthy HIV-negative adults (aged 18-50) were enrolled under informed consent as previously described [1]. This study involved 2 dose levels of DNA vaccines (1.2mg (Groups A and B); 7.2mg (Group C)) expressing five gp120 Env ant...

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“…Promising strategies not involving DNA include nonreplicating recombinant adenovirus rAd26/rAd5 (12), replicating recombinant adenovirus plus protein boost (13), or recombinant rhCMV (14). Despite improvements of DNA vaccines, human trials have indicated that the magnitude of immune responses after DNA vaccination remains low (1,(15)(16)(17)(18) compared to levels reported in macaques. The ability to increase the magnitude and quality of the immune responses and to achieve protection in a strict macaque SIV challenge model may provide critical information to improve DNA vaccination efficacy in humans.…”

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confidence: 99%

DNA vaccination in rhesus macaques induces potent immune responses and decreases acute and chronic viremia after SIVmac251 challenge

Rosati¹,

Bergamaschi²,

Valentı́n³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Optimized plasmid DNAs encoding the majority of SIVmac239 proteins and delivered by electroporation (EP) elicited strong immune responses in rhesus macaques. Vaccination decreased viremia in both the acute and chronic phases of infection after challenge with pathogenic SIVmac251. Two groups of macaques were vaccinated with DNA plasmids producing different antigen forms, ''native'' and ''modified,'' inducing distinct immune responses. Both groups showed significantly lower viremia during the acute phase of infection, whereas the group immunized with the native antigens showed better protection during the chronic phase (1.7 log decrease in virus load, P ‫؍‬ 0.009). Both groups developed strong cellular and humoral responses against the DNA vaccine antigens, which included Gag, Pol, Env, Nef, and Tat. Vaccination induced both central memory and effector memory T cells that were maintained at the day of challenge, suggesting the potential for rapid mobilization upon virus challenge. The group receiving the native antigens developed higher and more durable anti-Env antibodies, including neutralizing antibodies at the day of challenge. These results demonstrate that DNA vaccination in the absence of any heterologous boost can provide protection from high viremia comparable to any other vaccine modalities tested in this macaque model. AIDS ͉ DNA vaccine ͉ macaque animal model ͉ prophylactic vaccination

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Safety and Immunogenicity of a Gag-Pol Candidate HIV-1 DNA Vaccine Administered by a Needle-Free Device in HIV-1-Seronegative Subjects

Cited by 53 publications

References 15 publications

Phase I Study of a Herpes Simplex Virus Type 2 (HSV-2) DNA Vaccine Administered to Healthy, HSV-2-Seronegative Adults by a Needle-Free Injection System

Phase I Study of a Herpes Simplex Virus Type 2 (HSV-2) DNA Vaccine Administered to Healthy, HSV-2-Seronegative Adults by a Needle-Free Injection System

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

DNA vaccination in rhesus macaques induces potent immune responses and decreases acute and chronic viremia after SIVmac251 challenge

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