Elsevier

Vaccine

Volume 24, Issue 4, 23 January 2006, Pages 417-425
Vaccine

Phase I clinical trial safety of DNA- and modified virus Ankara-vectored human immunodeficiency virus type 1 (HIV-1) vaccines administered alone and in a prime-boost regime to healthy HIV-1-uninfected volunteers

https://doi.org/10.1016/j.vaccine.2005.08.041Get rights and content

Abstract

DNA- and modified virus Ankara (MVA)-vectored candidate vaccines expressing human immunodeficiency virus type 1 (HIV-1) clade A-derived p24/p17 gag fused to a string of HLA class I epitopes, called HIVA, were tested in phase I trials in healthy, HIV-1/2-uninfected adults in Oxford, United Kingdom. Eighteen volunteers were vaccinated with pTHr.HIVA DNA (IAVI-001) alone, 8 volunteers received MVA.HIVA (IAVI-003) alone and 9 volunteers from study IAVI-001 were boosted with MVA.HIVA 9–14 months after DNA priming (IAVI-005). Immunogenicity results observed in these trials was published previously [Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG-T, et al. An 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;85:911–9]. Here, we report on the safety of the two vaccines and the vaccine regimes. Overall, both candidate vaccines were safe and well tolerated. There were no reported vaccine-related adverse events over the 6-month period of the study and up to 2 years after the last vaccination. There were no moderate or severe local symptoms recorded after the pTHr.HIVA DNA intramuscular administration. Almost all participants experienced local reactogenicity events such as redness and induration after MVA.HIVA intradermal injection. Thus, the results from these initial small phase I trials administering the pTHr.HIVA DNA and MVA.HIVA vaccines either alone or in a prime-boost regime to healthy HIV-1/2-negative adults indicated that the vaccines were safe and warranted further testing of this approach in larger phase I/II studies.

Introduction

Despite the urgent need for the accelerated development of an effective prophylactic vaccine against human immunodeficiency virus type 1 (HIV-1), the safety of the novel experimental vaccines must remain the primary concern. In preclinical studies, we have found that a successive immunization with DNA- and modified virus Ankara (MVA)-based vaccines expressing a common immunogen is a potent way of inducing CD8+ cytotoxic T lymphocytes (CTL) in animal models [1], [2]. Particularly encouraged by the immunogenicity of this approach in non-human primates [3], [4], [5], [6], we designed and constructed DNA and MVA-vectored vaccine candidates for clinical trials in humans, which express immunogen HIVA consisting of consensus HIV-1 clade A gag p24/p17 sequences coupled to a string of CTL epitopes [7]. These vaccines do not contain the complete env gp120 gene and focus on induction of T cell mediated immunity. The vaccine immunogenicity results of these first DNA prime-MVA boost HIV-1 vaccines used in clinical trials were published separately [8]. Here and for the first time, we report their safety.

Section snippets

pTHr.HIVA DNA vaccine

The vaccine pTHr.HIVA [7] DNA was produced by Cobra Therapeutics (Keele, UK) and formulated as 1.0 mg plasmid DNA/ml in 0.1× TE buffer (1 mM Tris–HCL pH 7.6, 0.1 ml mM EDTA). It was presented in 3-ml sterile Type I glass vials and stored frozen at −20 °C. Following arrival of the vaccine vials at the local Pharmacy and in addition to all the QC tests carried out by the manufacturer, the vaccine's potency in a group of five mice and identity were confirmer in validated assays. Before use, the DNA was

Study participants

Total of 129 people responded to the advertising campaign, of whom 37 (28.7%) were willing to be screened and 26 (20.2%) were eligible and enrolled into the trials. Twenty volunteers were randomised for pTHr.HIVA DNA trial IAVI-001, of whom two withdrew their consent. Of the 18 volunteers completing the initial follow-up to day 189, 9 consented to participate in trial IAVI-005 and receive two doses of MVA.HIVA boost 9–14 months after priming. Eight volunteers were enrolled in the MVA.HIVA trial

Discussion

In the three clinical trials in healthy HIV-1/2-uninfected individuals reported here, the pTHr.HIVA DNA and MVA.HIVA candidate vaccines either alone or combined were in general safe and well tolerated. Vaccine safety was monitored by recording and assessing any signs and symptoms, adverse experiences and unusual or unanticipated events that were reported either by the volunteers or detected by the clinical team.

Clinical trials of HIV-1 prophylactic HIV-1 vaccines require the enrolment of

Acknowledgements

The authors are grateful to the volunteers who participated in this study in a true spirit of altruism. The authors also thank for their help in setting up this trial, its conduct and particularly for clinical and regulatory issues: Sarah Baily, Seth Berkley, Chip Carnathan, Anne-Marie Coriat, Sue Clarke, Adrian Hill, Peggy Johnston, Rob McMichael, Althea Thomas, Denise Brown, Vanessa Loach, Wayne Koff, Diane McLaren, Carey Lewis, Jack Melling, Andreas Neubert, Tim Peto, Rick Randall, Andrea

References (48)

  • T.M. Allen et al.

    Induction of AIDS virus-specific CTL activity in fresh, unstimulated peripheral blood lymphocytes from rhesus macaques vaccinated with a DNA prime/modified vaccinia virus Ankara boost regimen

    J Immunol

    (2000)
  • R.R. Amara et al.

    Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine

    Science

    (2001)
  • T.M. Allen et al.

    Effects of cytotoxic T lymphocytes (CTL) directed against a single simian immunodeficiency virus (SIV) Gag CTL epitope on the course of SIVmac239 infection

    J Virol

    (2002)
  • T. Hanke et al.

    Design and construction of an experimental HIV-1 vaccine for a year-2000 clinical trial in Kenya

    Nat Med

    (2000)
  • M. Mwau et al.

    An 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)
  • M.C. Keefer et al.

    Safety profile of phase I and II preventive HIV type 1 envelope vaccination: experience of the NIAID AIDS Vaccine Evaluation Group

    AIDS Res Hum Retroviruses

    (1997)
  • V.S. Moorthy et al.

    Safety of DNA and modified vaccinia virus Ankara vaccines against liver-stage P. falciparum malaria in non-immune volunteers

    Vaccine

    (2003)
  • K. Cichutek

    DNA vaccines: development, standardization and regulation

    Intervirology

    (2000)
  • T. Martin et al.

    Plasmid DNA malaria vaccine: the potential for genomic integration after intramuscular injection

    Hum GeneTher

    (1999)
  • J.S. Robertson et al.

    Assuring the quality, safety, and efficacy of DNA vaccines

    Mol Biotechnol

    (2001)
  • S. Manam et al.

    Plasmid DNA vaccines: tissue distribution and effects of DNA sequence, adjuvants and delivery method on integration into host DNA

    Intervirology

    (2000)
  • B.J. Ledwith et al.

    Plasmid DNA vaccines: investigation of integration into host cellular DNA following intramuscular injection in mice

    Intervirology

    (2000)
  • T. Hanke et al.

    Lack of toxicity and persistence in the mouse associated with administration of candidate DNA- and modified vaccinia virus Ankara (MVA)-based HIV vaccines for Kenya

    Vaccine

    (2002)
  • R.M. Conry et al.

    Safety and immunogenicity of a DNA vaccine encoding carcinoembryonic antigen and hepatitis B surface antigen in colorectal carcinoma patients

    Clin Cancer Res

    (2002)
  • Cited by (112)

    • Use of functional genomics to understand replication deficient poxvirus-host interactions

      2016, Virus Research
      Citation Excerpt :

      In particular, MVA, due to its avirulence and inability to replicate productively after in vivo inoculation, has a better safety profile than replication competent VACV, with similar levels of gene expression and better immunostimulatory properties (Antoine et al., 1998; Gomez et al., 2013; Meyer et al., 1991; Verheust et al., 2012). These characteristics have stimulated the development of MVA-based vaccines for a wide range of pathogens including malaria, leishmania (Moss, 1996; Schneider et al., 1998) and HIV, as well as for the treatment of cancer acting as a vector for delivery of effector molecules against tumors (Cebere et al., 2006; Corona Gutierrez et al., 2004; Gilbert et al., 2006; Harrop et al., 2006; Smith, 2013). MVA is also a potentially safe vaccine candidate for smallpox, in the hypothetical case of a recurrence of the virus as a bioterrorist weapon (Belyakov et al., 2003; Drexler et al., 2003; Earl et al., 2004; Wyatt et al., 2004).

    • Recombinant Newcastle disease viral vector expressing hemagglutinin or fusion of canine distemper virus is safe and immunogenic in minks

      2015, Vaccine
      Citation Excerpt :

      The restriction of lentogenic NDV replication in mammalian host cells is one of the most attractive properties of NDV in terms of its safety when used as a live vaccine vector in humans and other animals [20–24]. This is also the case for fowlpox virus [34] and the modified vaccinia virus Ankara [35,36]. This shows that recombinant NDV expressing CDV H is a safe strategy for the vaccination of mink and other exotic species and non-human primates.

    View all citing articles on Scopus
    1

    Present address: Richard Stevens Waed – Stroke Unit, William Harvey Hospital, Ashford, Kent, TN 24 0LZ, UK.

    View full text