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

Abstract

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...

Characterization and Immunogenicity of a Novel Mosaic M HIV-1 gp140 Trimer

“…These preclinical studies have highlighted potential benefits of Env cocktails. The feasibility and utility of multivalent Env vaccination have also been explored in clinical trials (45,46). The current study extends these prior studies and shows that a bivalent combination of the MosM and NatC trimers resulted in improved nAb responses compared with either trimer alone in guinea pigs.…”

Characterization of T-Cell Responses in Macaques Immunized with a Single Dose of HIV DNA Vaccine

“…However, we cannot totally exclude that DNA has persisted in the muscle injection site (2,44). In a recent DNA vaccine study of humans, the authors found a delayed-type hypersensitivity (DTH) response at the site of DNA injection following a protein boost (27). Taken together, persistent DNA and/or DTH may participate in the persistence and/or late reemergence of IR observed in the absence of any antigen boost in our study.…”

Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001

“…The plasma samples used for ADCP assays were collected at week 0 (prebleed) and week 30 (post-protein boosts). The PBMCs used for Env-specific MAb isolation were collected from subjects ABL-001, ABL-003, and ABL-034 after two protein boosts and from subject ABL-040 after one protein boost due to the early termination of group C after one protein boost (13).…”

“…Group C volunteers received the same formulation, except that they received (i) a higher-dose DNA prime immunization by the i.m. route (7.2 mg each time) and (ii) only a single gp120 protein boost immunization due to the early stop of the clinical trial in this group of volunteers (13). In the current pilot study, MAbs were generated from one group A volunteer, two group B volunteers, and one group C volunteer ( Fig.…”