Safety and Immunogenicity of a Candidate HIV-1 Vaccine in Healthy Adults: Recombinant Glycoprotein (rgp) 120: A Randomized, Double-Blind Trial

15 August 1996 | Volume 125 Issue 4 | Pages 270-279

Objective: To evaluate the safety and immunogenicity of recombinant glycoprotein (rgp) 120, a candidate vaccine for the human immunodeficiency virus (HIV), formulated with a novel adjuvant, MF59, with or without a biological response modifier, MTP-PE.

Design: Multicenter, double-blind, randomized trial.

Setting: University medical centers.

Participants: 49 healthy, HIV-seronegative volunteers 18 to 60 years of age who were at low risk for HIV type 1 (HIV-1) infection.

Interventions: In part A of the study, 32 participants were randomly assigned to receive either 15 µg of rgp120 in MF59, 15 µg of rgp120 in MF59 plus 50 µg of MTP-PE, 50 µg of rgp120 in MF59, or 50 µg of rgp120 in MF59 plus 50 µg of MTP-PE. Participants were vaccinated at 0, 1, 6, and 12 to 18 months. In part B, 17 participants were randomly assigned to receive five monthly injections of either 50 µg of rgp120 in MF59 or MF59 alone followed by a booster injection at 12 to 18 months.

Main Outcome Measures: Local and systemic reactions; laboratory measures of hepatic, renal, immunologic, and bone marrow toxicity; and HIV-specific serologic and cell-mediated immune responses.

Results: 13 patients in part A received 50-µg doses of rgp120; type-specific neutralizing antibody responses against the SF-2 strain of HIV-1 (HIV-1/SF-2) were induced in all 13. Nine of the 13 had cross-reactive neutralizing activity against the MN strain of HIV-1 (HIV-1/MN), and 2 had cross-reactive neutralizing activity against the IIIB strain of HIV-1 (HIV-1/IIIB). Twelve patients had type-specific fusion inhibition activity; only 1 had cross-reactive fusion inhibition activity against HIV-1/MN.

The monthly vaccination schedule used in part B resulted in decreased antibody titers, indicating that a rest period in the schedule is necessary for maximal immunogenicity.Lymphoproliferative responses against gp120 were induced in all vaccine recipients. The stimulation index to gp120 was persistently greater than 15 for 6 months after the last booster vaccination was given. CD8⁺ cytotoxic T-lymphocyte activity was detected in 1 of the 11 participants tested. Vaccine that contained MTP-PE caused a greater number of moderate or severe local and systemic reactions (of 16 participants, 4 had local reactions and 13 had systemic reactions) than did vaccine formulated with MF59 alone (of 16 participants, 7 had local reactions [P < 0.01] and 0 had systemic reactions [P < 0.001]).

Conclusions: The SF-2 rgp120 vaccine is safe and immunogenic. Three vaccinations with rgp120 in MF59 can induce type-specific and cross-reactive neutralizing antibody against B-subtype laboratory strains of HIV-1. Human immunodeficiency virus-specific lymphoproliferative responses were induced in all vaccinated participants, and CD8 (⁺) cytotoxic T-lymphocyte activity was shown in one participant. A trend toward the augmentation of lymphoproliferative and humoral responses by MTP-PE was seen in the participants receiving 15 µg of rgp120. However, MTP-PE caused a statistically significant increase in the incidence of local and systemic side effects, which was felt to outweigh the small increase in immunogenicity provided by this biological response modifier in an otherwise well-tolerated vaccine.

*For a listing of additional authors, see end of text.

Author and Article Information

From Vanderbilt University School of Medicine, Nashville, Tennessee; University of Rochester School of Medicine and Dentistry, Rochester, New York; University of Washington School of Medicine, Seattle, Washington; St. Louis University School of Medicine, St. Louis, Missouri; Johns Hopkins School of Hygiene and Public Health and Johns Hopkins School of Medicine, Baltimore, Maryland; Duke University, Medical Center, Durham, North Carolina; EMMES Corp., Potomac, Maryland; Biocine/Chiron Corp., Emeryville, California; and the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Acknowledgments: The authors thank Dr. Kathleen M. Neuzil for reviewing the manuscript and acknowledge the generosity and commitment of the study participants and the contributions made by the following persons: Dr. David T. Karzon, Dr. Mary Alice Harbison, Lois Wagner, Kyle Rybzyck, Mary Braeuner, Wanda Battle, Dr. Gwendolyn Rees, Frances Robinson, Linda Horton, Dr. Irina Kuli-Zade, Helen Jordan, Roberta Cornell, and Mentoria Jennings (Vanderbilt University School of Medicine, Nashville, Tennessee); Dr. Donald J. Kennedy, Dr. Sharon E. Frey, Heidi Israel, Carol Berry, Becca Reed, Teresa Spitz, Gira Patel, Mahendra Mandava, Laura McDurmont, and Kathy Feurer (St. Louis University School of Medicine, St. Louis, Missouri); Carol Hilton and Dr. Ann Funkhouser (Johns Hopkins University School of Medicine, Baltimore, Maryland); Dr. John S. Lambert, Dr. William Bonnez, Dr. Richard C. Reichman, Dr. Norbert J. Roberts, Jr., Dr. Lisa Demeter, Shirley Erb, Mary Ann Pugliese, Joan Nichols, and Elizabeth O'Leary (University of Rochester School of Medicine and Dentistry, Rochester, New York); David Berger, Helen Stacey, and Lyn Burke (University of Washington School of Medicine, Seattle, Washington); Sue L. Wescott, Dr. Mary Clare Walker, and Dr. Nzeera Ketter (National Institute of Allergy and Infectious Diseases, Bethesda, Maryland); Carol M. Smith, Donna M. Brown, Dr. Richard Sposto, Phyllis Barr, Natalie Lomax, and Tamara Voss (EMMES Corporation, Potomac, Maryland); Dr. Cornelia L. Dekker, Dr. Juerg Baenziger, Dr. Kathy Steimer, Diana Lee, and Kathey Hesterman (Chiron/Biocine Corporation, Emeryville, California); and Dr. David C. Montefiori, Charlene McDanal, Teresa Greenwell, Donna Davison, and Daniel Woodford (Duke University Medical Center, Durham, North Carolina).
Grant Support: In part by contracts NO1-AI-82500, NO1-AI-05061, NO1-AI-05062, NO1-AI-05063, NO1-AI-05064, NO1-AI-05065, and NO1-AI-15106 from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Requests for Reprints: Barney S. Graham, MD, PhD, A-3310 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232-2605.
Current Author Addresses: Dr. Graham: A-3310 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232-2605.