Phase 1 Safety and Immunogenicity Evaluation of a Multiclade HIV‐1 DNA Candidate Vaccine

Graham, Barney S.; Koup, Richard A.; Roederer, Mario; Bailer, Robert T.; Enama, Mary E.; Moodie, Zoe; Martin, Jennifer; McCluskey, Margaret; Chakrabarti, Bimal K.; Lamoreaux, Laurie; Andrews, Charla; Gomez, Phillip L.; Mascola, John R.

doi:10.1086/509259

Cited by 200 publications

(217 citation statements)

References 35 publications

Supporting

Mentioning

192

Contrasting

Unclassified

Order By: Relevance

“…In contrast, recent progress with gene-based vaccination approaches, which have used either DNA or viral vectors as delivery systems, have been effective in eliciting cell-mediated immune (CMI) responses in early phase human studies. However, these studies either did not put forth an effort to elicit protective antibody responses [12,13] or were not effective, when used alone, in eliciting neutralizing antibodies (NAbs) against even relatively sensitive viral isolates [14,15].…”

Section: Introductionmentioning

confidence: 99%

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Wang

Kennedy

West

et al. 2008

Vaccine

124

View full text Add to dashboard Cite

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report the induction of Human Immunodeficiency Virus Type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6−001 in a Phase I clinical trial conducted in healthy adult volunteers of both genders. Robust cross-subtype HIV-1-specific T cell responses were detected in IFNγ ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 Env antigens and also neutralized pseudotyped viruses that express the primary Env antigens from multiple HIV-1 subtypes. These findings demonstrate that the DNA prime-protein boost approach is an effective immunization method to elicit both humoral and cellmediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds.

show abstract

Section: Introductionmentioning

confidence: 99%

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Wang

Kennedy

West

et al. 2008

Vaccine

124

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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...

show abstract

“…The HIV vaccine was included in this study to evaluate its immunogenicity and to interrogate possible interference of the two types of CE DNA vaccine regimens, since we and others previously reported potent inhibition of Gag T cell responses by FL Env vaccines. 78–81 The 31 Indian rhesus macaques enrolled in this study are described in Table 1. Two groups of animals received the same CE DNA vaccine but differed in the delivery routes (Figure 1B), intramuscular (IM) followed by electroporation (EP) using CELLECTRA® 5P (CE IM group) versus intradermal (ID) followed by EP using CELLECTRA®3P (CE ID group).…”

Section: Resultsmentioning

confidence: 99%

“…To evaluate the potential interference between Env and Gag epitopes that has been reported previously in mice, macaques and humans, 78–81 , 87 macaques immunized with the SIV Gag CE and FL gag DNA also received the HIV Env CE and FL env DNA vaccine. Importantly, and in contrast to previous observations using only full-length immunogens, we did not find any interference or negative effects from the Env CE DNA immunogen on the cellular responses targeting Gag CE.…”

Section: Discussionmentioning

confidence: 99%

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

Valentı́n

et al. 2018

Human Vaccines & Immunotherapeutics

View full text Add to dashboard Cite

HIV sequence diversity and the propensity of eliciting immunodominant responses targeting inessential variable regions are hurdles in the development of an effective AIDS vaccine. We developed a DNA vaccine comprising conserved elements (CE) of SIV p27Gag and HIV-1 Env and found that priming vaccination with CE DNA is critical to efficiently overcome the dominance imposed by Gag and Env variable regions. Here, we show that DNA vaccinated macaques receiving the CE prime/CE+full-length DNA co-delivery booster vaccine regimens developed broad, potent and durable cytotoxic T cell responses targeting conserved protein segments of SIV Gag and HIV Env. Gag CE-specific T cells showed robust anamnestic responses upon infection with SIVmac239 which led to the identification of CE-specific cytotoxic lymphocytes able to recognize epitopes covering distinct CE on the surface of SIV infected cells in vivo. Though not controlling infection overall, we found an inverse correlation between Gag CE-specific CD8+ T cell responses and peak viremia. The T cell responses induced by the HIV Env CE immunogen were recalled in some animals upon SIV infection, leading to the identification of two cross-reactive epitopes between HIV and SIV Env based in sequence homology. These data demonstrate that a vaccine combining Gag and Env CE DNA subverted the normal immunodominance patterns, eliciting immune responses that included subdominant, highly conserved epitopes. These vaccine regimens augment cytotoxic T cell responses to highly conserved epitopes in the viral proteome and maximize response breadth. The vaccine-induced CE-specific T cells were expanded upon SIV infection, indicating that the predicted CE epitopes incorporated in the DNA vaccine are processed and exposed by infected cells in their natural context within the viral proteome.

show abstract

Phase 1 Safety and Immunogenicity Evaluation of a Multiclade HIV‐1 DNA Candidate Vaccine

Abstract: DNA vaccination induced antibody to and T cell responses against 3 major HIV-1 subtypes and will be further evaluated as a potential component of a preventive AIDS vaccine regimen.

Cited by 200 publications

References 35 publications

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

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

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

Contact Info

Product

Resources

About