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