A phase I trial in HIV negative healthy volunteers evaluating the effect of potent adjuvants on immunogenicity of a recombinant gp120W61D derived from dual tropic R5X4 HIV-1ACH320

McCormack, Sheena; Tilzey, AntheaJ.; Carmichael, Andrew; Gotch, Frances; Kepple, Jessica D.; Newberry, A; Jones, Gayle; Lister, Simon; Beddows, Simon; Cheingsong, Rachanee; Rees, A.; Babiker, Abdel; Banatvala, J. E.; Bruck, Claudine; Darbyshire, JH; Tyrrell, D. Lorne; Hoecke, C. Van; Weber, Jonathan

doi:10.1016/s0264-410x(99)00388-6

Cited by 54 publications

(19 citation statements)

References 35 publications

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“…It should be noted that the VAX003 and VAX004 gp120 efficacy trials required repeated boosting at 6-mo intervals to keep antibody titers in a range where they were predicted to be protective (11,12,73). The sawtooth behavior of the antibody decay curves in a study by Gilbert et al (11) are reminiscent of those antibody decay curves observed in the study by McCormack et al (72), where responses were only present during zones 1 and 2, strongly indicating a persistence problem. The best example of this problem is the RV144 efficacy trial, in which modest protection was observed (21).…”

Section: Strategies To Elicit Continuous Protection Against Hiv By Vasupporting

confidence: 64%

“…An example of poor persistence of human antibody responses elicited by gp120 in potent adjuvants is provided in a study by McCormack et al (72). In that study, healthy human volunteers were immunized with gp120 formulated in alum, QS21 plus 3-deacyl-monophosporyl-lipid A, or water in oil emulsion of QS21 plus 3-deacyl-monophosporyl-lipid A.…”

Section: Strategies To Elicit Continuous Protection Against Hiv By Vamentioning

confidence: 99%

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Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

Lewis

DeVico

Gallo

2014

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

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The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibodymediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4 + T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Envbased AIDS vaccines regardless of the mechanism of antibody-mediated protection.

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Section: Strategies To Elicit Continuous Protection Against Hiv By Vasupporting

confidence: 64%

Section: Strategies To Elicit Continuous Protection Against Hiv By Vamentioning

confidence: 99%

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

Lewis

DeVico

Gallo

2014

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

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“…The active ingredients of both adjuvants are 3-deacylated MPL (3D-MPL) (35)(36)(37)(38), a nontoxic derivative of LPS and QS21 (a triterpene glycoside purified from the bark of Quillaja saponaria, (39 -41), and both components have a good clinical safety record (31,32,42,43). The biological properties of MPL are attributed to its immunostimulatory effects on the innate immune system (via activation of the Toll-like receptor 4) and the direct activation of APCs resulting in enhanced phagocytosis and microbicidal activities as a consequence of the production of IL-12, TNF-␣, GM-CSF, and IFN-␥ (36,38,44,45).…”

Section: Discussionmentioning

confidence: 99%

Differential Immune Responses and Protective Efficacy Induced by Components of a Tuberculosis Polyprotein Vaccine, Mtb72F, Delivered as Naked DNA or Recombinant Protein

Skeiky

Alderson

Ovendale

et al. 2004

The Journal of Immunology

271

184

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Key Ags of Mycobacterium tuberculosis initially identified in the context of host responses in healthy purified protein derivative-positive donors and infected C57BL/6 mice were prioritized for the development of a subunit vaccine against tuberculosis. Our lead construct, Mtb72F, codes for a 72-kDa polyprotein genetically linked in tandem in the linear order Mtb32C-Mtb39-Mtb32N. Immunization of C57BL/6 mice with Mtb72F DNA resulted in the generation of IFN-γ responses directed against the first two components of the polyprotein and a strong CD8+ T cell response directed exclusively against Mtb32C. In contrast, immunization of mice with Mtb72F protein formulated in the adjuvant AS02A resulted in the elicitation of a moderate IFN-γ response and a weak CD8+ T cell response to Mtb32c. However, immunization with a formulation of Mtb72F protein in AS01B adjuvant generated a comprehensive and robust immune response, resulting in the elicitation of strong IFN-γ and Ab responses encompassing all three components of the polyprotein vaccine and a strong CD8+ response directed against the same Mtb32C epitope identified by DNA immunization. All three forms of Mtb72F immunization resulted in the protection of C57BL/6 mice against aerosol challenge with a virulent strain of M. tuberculosis. Most importantly, immunization of guinea pigs with Mtb72F, delivered either as DNA or as a rAg-based vaccine, resulted in prolonged survival (>1 year) after aerosol challenge with virulent M. tuberculosis comparable to bacillus Calmette-Guérin immunization. Mtb72F in AS02A formulation is currently in phase I clinical trial, making it the first recombinant tuberculosis vaccine to be tested in humans.

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“…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.…”

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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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A phase I trial in HIV negative healthy volunteers evaluating the effect of potent adjuvants on immunogenicity of a recombinant gp120W61D derived from dual tropic R5X4 HIV-1ACH320

Cited by 54 publications

References 35 publications

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

Differential Immune Responses and Protective Efficacy Induced by Components of a Tuberculosis Polyprotein Vaccine, Mtb72F, Delivered as Naked DNA or Recombinant Protein

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

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