Safety Profile of Phase I and II Preventive HIV Type 1 Envelope Vaccination: Experience of the NIAID AIDS Vaccine Evaluation Group

Abstract

The NIAID-sponsored AIDS Vaccine Evaluation Group was established in 1988 to perform phase I/II clinical trials with candidate preventive HIV-1 vaccines. This report includes safety data from 1398 HIV-negative, healthy volunteers who were enrolled into 25 phase I and 1 phase H multicentered, randomized, double-blind studies evaluating seven recombinant HIV-1 envelope vaccines, two V3 loop synthetic peptide vaccines, and two live poxvirus-vectored recombinant envelope vaccines. All studies but three were placebo controlled; the placebo was either the adjuvant alone or, in studies of recombinant poxvirus vaccines, it was the vector with no gene insert or a non-HIV gene insert. All candidate vaccines were generally well tolerated. The only adverse effects that were clearly related to vaccination were occasional acute local and systemic reactions that were associated with the adjuvants. Three adjuvants in particular were associated with moderate to severe local reactions: alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), and QS21 (Genentech, Inc.). MTP-PE was also associated with self-limited severe systemic reactions. There were no serious adverse laboratory toxicities and no evidence of significant immunosuppressive events after receipt of the candidate vaccines. A few volunteers experienced symptoms that might relate to an underlying immunopathologic mechanism (rash, hemolytic anemia, arthralgia), but their presentations were mild and their incidence was low. Eleven volunteers were diagnosed with malignancies during or after their participation, which was within the 95% confidence interval of the number of cases predicted by the National Cancer Institute SEER (Program for cancer surveillance, epidemiology, and end result reporting) database. In conclusion, the envelope-based recombinant or synthetic candidate HIV-1 vaccines appear to be safe and this work has prepared the way for the testing of increasingly complex candidate HIV-1 vaccines.

Stakeholder engagement to informHIVclinical trials: a systematic review of the evidence

“…Of the 108 studies, 48 studies (44.4%) conducted stakeholder engagement in high‐income countries 5, 23, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70. In contrast, fewer studies conducted stakeholder engagement in middle‐ (30 studies; 27.8%) 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,...…”

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

“…The temporal relationship to vaccination suggests mechanisms for the vasculitis in our study could include a strong cytokine production or enhanced reactions to Env antigen resulting from the adjuvant used, and/or another unknown immune activation mechanism resulting in an amplified reaction to the protein-adjuvant mix when the host is DNA primed. In support of a role for an adjuvant in the systemic events observed, reactogenic events associated with several well known adjuvants, including QS21 have been reported [15,21,22,[25][26][27][28][29].…”

“…One major difference between the current trial and previous QS21-adjuvanted recombinant Env protein-based HIV vaccine trials [10,15] vaccines [21-23]. These two cases of vasculitis are the first to be reported that were temporarily related to inoculation using HIV-1 Env in combination with the saponin adjuvant QS21 in humans.…”

“…The temporal relationship to vaccination suggests mechanisms for the vasculitis in our study could include a strong cytokine production or enhanced reactions to Env antigen resulting from the adjuvant used, and/or another unknown immune activation mechanism resulting in an amplified reaction to the protein-adjuvant mix when the host is DNA primed. In support of a role for an adjuvant in the systemic events observed, reactogenic events associated with several well known adjuvants, including QS21 have been reported [15,21,22,[25][26][27][28][29].The design of the phase I study does not allow firm conclusions to be drawn regarding the etiology of these unusual local and systemic reactions. Given their occurrence in association with the high antibody and cellular immune responses to HIV Env induced by this DNA primeprotein boost vaccine, along with the recognition that HIV infected individuals display a varied autoimmune antibody repertoire to self-antigens [30][31][32][33][34][35], a potential relationship to HIV Env warrants consideration in the design and analysis of this and other vaccine trials.…”

“…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.…”