Elsevier

Vaccine

Volume 26, Issue 8, 20 February 2008, Pages 1098-1110
Vaccine

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

https://doi.org/10.1016/j.vaccine.2007.12.024Get rights and content

Summary

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 on 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 cell-mediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds.

Introduction

Development of an effective HIV vaccine is critical to control the worldwide AIDS pandemic, which has caused 25 million deaths in the last 25 years and is the cause for more than 40 million people living with HIV/AIDS today [1]. Early efforts in HIV vaccine development focused on the induction of humoral responses by using recombinant Env glycoproteins [2], [3], [4], [5]. The immunogenicity of recombinant Env protein-based vaccines was poor in humans, as shown by overall low-level binding antibodies measured by solid phase assays [6] and by the narrow spectrum of neutralizing activities mainly against T cell line adapted (TCLA) viral isolates [7], [8], [9]. Ultimately, recombinant protein-based HIV-1 vaccines failed to show protection efficacy in Phase III clinical trials [10], [11]. 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].

Recently, we demonstrated that a DNA prime–protein boost immunization strategy was effective in eliciting humoral and CMI responses in both small animals and non-human primates, including sterilizing immunity in a non-pathogenic SHIV model [16], [17], [18]. Our preclinical study results also indicated that this combination vaccination approach, but not recombinant protein alone, was effective in eliciting NAbs against primary HIV isolates [19], a finding that has since been confirmed by other independent studies [20], [21], [22], [23], [24], [25], [26]. Furthermore, when polyvalent primary Env antigen formulations were used, the DNA prime–protein boost approach was more effective than the monovalent primary Env antigen in eliciting rabbit NAbs against a wide range of selected primary viral isolates across subtypes A–E [27]. In the current study, a multi-gene, polyvalent DNA prime–protein boost HIV-1 vaccine was formulated based on the above preclinical study findings, and its immunogenicity was tested in healthy adults in a Phase I clinical trial. These results demonstrate that this formulation was able to induce balanced cell-mediated and antibody immune responses against HIV-1 antigens, including low but positive neutralizing activities against selected primary HIV-1 isolates across different subtypes.

Section snippets

DNA vaccines

The DP6-001 vaccine contains equal amounts of six individual DNA plasmid components utilizing the same vector pSW3891 [17]: five plasmids each encoding a codon-optimized gp120 gene sequence from the following primary HIV-1 envelope proteins: subtypes A (92UG037.8), B (92US715.6 and Bal), C (96ZM651) and E (93TH976.17) and the sixth plasmid encoding a codon-optimized gag gene from subtype C (96ZM651) as previously described [28]. The cGMP plasmid DNA for this Phase I clinical trial was produced

Design of the Phase I clinical trial in healthy adult volunteers

The multi-gene, polyvalent primary Env DNA prime–protein boost HIV vaccine, DP6-001, included 6 DNA plasmids (one expressing a subtype C full length Gag antigen and the other five each expressing one of the five primary gp120 antigens from subtypes A, B, C or E) as the prime and five recombinant gp120 proteins matching the Env DNA prime as the boost (Table 1). The study was a 3-group trial that tested two dosing levels of DNA administered either intradermally (ID) or intramuscularly (IM) and

Discussion

Induction of anti-Env antibody responses in small animals was one of the first pieces of evidence that established DNA immunization as a novel approach for vaccination [35]. Although significant progress has been made using DNA immunization to elicit HIV-1-specific CMI in small animals, non-human primates and humans over the past 15 years [12], [13], [14], [15], [16], [18], [36], [37], [38], [39], there has been no report of using Env DNA immunization to elicit broadly cross-reactive antibodies

Acknowledgements

This work was supported in part by the HIV Vaccine Design and Development Teams contract N01AI05394, and grants R29AI40337, R21AI46294 and R01AI65250 from the National Institute of Allergy and Infectious Diseases to S.L. and AI46705 and AI30034 to D.C.M. The PhenoSense neutralization assay was conducted at the Mongram, Inc. and funded by the International AIDS Vaccine Initiative. The project also used core facility resources at the University of Massachusetts Medical School supported by NIH

References (48)

  • HIV/AIDS JUNPo. Report on the global AIDS epidemic 2006. 2006 [cited 2007 14 February]; Availablefrom:...
  • G.J. Gorse et al.

    HIV-1MN recombinant glycoprotein 160 vaccine-induced cellular and humoral immunity boosted by HIV-1MN recombinant glycoprotein 120 vaccine. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group

    AIDS Res Hum Retroviruses

    (1999)
  • J.H. Kim et al.

    Specific antibody responses to vaccination with bivalent CM235/SF2 gp120: detection of homologous and heterologous neutralizing antibody to subtype E (CRF01.AE) HIV type 1

    AIDS Res Hum Retroviruses

    (2003)
  • M.L. Ackers et al.

    Human immunodeficiency virus (HIV) seropositivity among uninfected HIV vaccine recipients

    J Infect Dis

    (2003)
  • S. Beddows et al.

    Comparison of the antibody repertoire generated in healthy volunteers following immunization with a monomeric recombinant gp120 construct derived from a CCR5/CXCR4-using human immunodeficiency virus type 1 isolate with sera from naturally infected individuals

    J Virol

    (1999)
  • J.R. Mascola et al.

    Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group

    J Infect Dis

    (1996)
  • R. Bures et al.

    Immunization with recombinant canarypox vectors expressing membrane-anchored glycoprotein 120 followed by glycoprotein 160 boosting fails to generate antibodies that neutralize R5 primary isolates of human immunodeficiency virus type 1

    AIDS Res Hum Retroviruses

    (2000)
  • P.B. Gilbert et al.

    Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial

    J Infect Dis

    (2005)
  • N.M. Flynn et al.

    Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection

    J Infect Dis

    (2005)
  • M. Mwau et al.

    A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans

    J Gen Virol

    (2004)
  • N. Goonetilleke et al.

    Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime–boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes

    J Virol

    (2006)
  • B.S. Graham et al.

    Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 DNA candidate vaccine

    J Infect Dis

    (2006)
  • A.T. Catanzaro et al.

    Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 candidate vaccine delivered by a replication-defective recombinant adenovirus vector

    J Infect Dis

    (2006)
  • R. Pal et al.

    Polyvalent DNA prime and envelope protein boost HIV-1 vaccine elicits humoral and cellular responses and controls plasma viremia in rhesus macaques following rectal challenge with an R5 SHIV isolate

    J Med Primatol

    (2005)
  • Cited by (0)

    1

    These authors contributed equally to this work.

    View full text