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Interpreting HIV Serodiagnostic Test Results in the 1990s: Social Risks of HIV Vaccine Studies in Uninfected Volunteers

Robert B. Belshe, MD; Mary Lou Clements, MD; Michael C. Keefer, MD; Barney S. Graham, MD, PhD; Lawrence Corey, MD; Richard Sposto, PhD; Sue Wescott, MA; Dale Lawrence, MD, NIAID AIDS Vaccine Clinical Trials Group.
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From St. Louis University School of Medicine, St. Louis, Missouri; Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland; University of Rochester School of Medicine and Dentistry, Rochester, New York; Vanderbilt University School of Medicine, Nashville, Tennessee; University of Washington at Seattle School of Medicine, Seattle, Washington; the EMMES Corporation, Potomac, Maryland; the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. For members of the NIAID AIDS Vaccine Clinical Trials Group, see the Appendix. Requests for Reprints: Robert B. Belshe, MD, Division of Infectious Diseases, St. Louis University Medical School, 3635 Vista Avenue, FDT-8N, St. Louis, MO 63110. Grant Support: By N01-AI-05064, N01-AI-05061, N01-AI-05063, N01-AI-05062, N01-AI-05065, and N01-AI-82500 from the National Institute of Allergy and Infectious Diseases.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1994;121(8):584-589. doi:10.7326/0003-4819-121-8-199410150-00005
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Objective: To evaluate the influence of a human immunodeficiency virus (HIV) vaccine given to uninfected volunteers on the interpretation of serodiagnostic HIV test results.

Design: Retrospective cohort study.

Setting: 5 AIDS Vaccine Evaluation Units funded by the National Institute of Allergy and Infectious Diseases.

Participants: The first 266 healthy adult volunteers (aged 18 to 60 years) who did not have HIV infection and whose history suggested that they were at low risk for acquiring HIV infection.

Measurements: HIV antibody was measured by enzyme-linked immunosorbent assay (ELISA) and Western blot test, the results of which were interpreted on the basis of four different published criteria.

Results: At some time during the first 12 months of the vaccine studies, 68% of volunteers were positive for HIV antibodies by ELISA. Depending on criteria used to interpret Western blot test results, 0% to 44% of volunteers had positive results that might have caused them to be incorrectly labeled as HIV infected.

Conclusions: Significant social risks to volunteers participating in HIV vaccine studies were identified. Persons interpreting HIV serodiagnostic test results must consider that an HIV vaccine can cause a positive result in persons who are not infected.

Figures

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Figure 1.
Examples of vaccine-induced antibodies detected by Western blots.

Reactive Western blots of serum samples from volunteers who received vaccines for HIV-1, including rgp160/IIIB produced in a baculovirus vector system (lane 1), rgp160/IIIB produced in Vero cells (lane 2), rgp120/SF2 produced in yeast cells (lane 3), rgp120/MN produced in Chinese hamster ovary cells (lane 4), and live vaccinia vector expressing rgp160/IIIB and boosted with rgp160 produced in a baculovirus vector system (lane 5). A control serum from a person with HIV infection is represented in lane 6.

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Figure 2.
Frequency of volunteers' serum samples fulfilling criteria for HIV seropositivity.

Development of test results interpreted as positive for HIV infection among uninfected, low-risk recipients of HIV vaccine according to four sets of criteria. The criteria of the Association of State and Territorial Public Health Laboratory Directors/Centers for Disease Control and Prevention (ASTPHLD/CDC) includes a positive ELISA result and any two of p24, gp41, or gp120/160 bands. The criteria of the Consortium for Retrovirus Serology Standardization (CRSS) includes a positive ELISA result and 2 or more bands of p24 or p31 plus gp41 or gp120/160. The criteria of the American Red Cross (ARC) includes a positive ELISA result and 3 or more bands, 1 each of gag, pol, and env. The criteria of the Food and Drug Administration (FDA)-approved package insert (Cambridge Biotech) includes a positive ELISA result and the presence of p24, p31, and either gp41 or gp120/160. * indicates that no volunteers were HIV positive according to the FDA criteria. A = rgp160/IIIB virus (produced by baculovirus); B = rgp160/IIIB virus (produced by Vero tissue culture cell); C = rgp120/SF-2 virus (produced by yeast cells); D = rgp120/IIIB virus (produced by Chinese hamster ovary [CHO] cells); E = rgp120/MN virus (produced by CHO cells); F = live recombinant vaccinia expressing rgp160 (HIVAC-1e) followed by rgp160/IIIB boosting.

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Figure 3.
Examples of indeterminate Western blots and subsequent reactivity after immunization.Left.Right.

Low-risk, uninfected volunteers before immunization with indeterminate Western blot bands at p17 (volunteer A); p24 (volunteers B and C); p24 and P55 (volunteer D); p24, p66, and p80 (volunteer E); and p55, p66, and p80 (volunteer F). Lanes 2 to 8 of serial Western blots from an uninfected person receiving a gp160 vaccine (arrows indicate vaccine days). The p24 band was preexisting and varied in intensity depending on the lot of Western blot test kit used to monitor the development of antibody after vaccination. The presence of p24 bands was common among low-risk, uninfected volunteers and complicated the interpretation of the Western blot test results.

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