Seattle Treatment Education Project (STEP) Perspective, Vol. 5, No. 2 - July 1993 * 127 Broadway E. Ste 200 Seattle, WA 98102
Joel Gibson M.S

Researchers from the Immune Response Corporation in La Jolla, California (the Salk Institute) reported on some of their earliest trials as well as their current study. The immunogen, i.e. the substance used to produce the immune response, used by this group is whole, killed HIV which has part of the viral envelope (gp120) removed. Similarly, the adjuvant, a substance used to enhance the immune response, they employ is a mixture of oil and water (aka Freund's incomplete). In their study 1A/1B, 35 gay men with progressive, generalized lymphadenopathy (PGL) for greater than three years prior to entry, were enrolled for an average follow up of 3.4 years. Eight of the 35 men had ARC, the rest being asymptomatic. The average CD4 count at entry was 321. There were mild side effects from the vaccine which lasted for 24-48 hours. The investigators regularly measured the p24 antibody (not antigen) for changes. The antibody levels increased at least four-fold in 38% of participants. The antibody levels were stable in 57% of the men, and decreased in only 5%. Additionally, 52% of individuals regained delayed-type hypersensitivity (DTH) to common recall antigens. This is the familiar "skin test", similar to that of the PPD employed in routine tuberculosis testing. The investigators go on to state that there is a positive correlation between (+) DTH and clinical course. In another trial (study 104), 12 asymptomatic subjects with greater than 600 CD4 cells were randomized to received vaccine/adjuvant combination or just the adjuvant, which acted as a placebo. They found that the immunogen stimulated both humoral (i.e. antibody production) and cell-mediated immunity. Further, they state that the 100 mcg dosage is the lowest dose which gives a statistically significant difference in the parameters measured. However, they did not mention which parameters they used here. In their current study, #103, 103 asymptomatic participants had a mean CD4 count of 656 (233-1211). The trial had a one year duration. The 100 mcg dose of the immunogen/adjuvant combination was given at entry, and again at three and six months later. Adjuvant given alone was the "placebo." DTH responses were statistically significant just after the six month boost. However, there was no difference between the two groups in p24 antigen levels, CD4 counts, or quantitative microculture assays. Nonetheless, a quantitative DNA PCR assay at six months, showed significant decreases in viral copy number in the treated group compared with placebo. Also, p24 antibody levels increased in the treated group vs. the placebo group (not statistically significant).

In a trial using a different approach, an effort was made to increase the antibody response to the part of the viral envelope which attaches to human CD4 cells, i.e. gp120. In preclinical studies, this area was found to have broad neutralizing activity. Conducted at the University of California at San Diego, 24 people with greater than 600 CD4 cells were enrolled in a phase I study into one of four treatment arms. The immunogen, 3C9, was given in a dose of 2.5 mg. Two adjuvants were used: SAF-m or AF. The four treatment arms were 3C9 by itself, SAF-m by itself, 3C9 & SAF-m, and 3C9 & AF. Participants were immunized on the following schedule: week one, three, five, seven, 15, and 23. Antibody levels to 3C9 were significantly higher in the two groups which received 3C9 plus one of the adjuvants than when 3C9 was given alone. There were no significant differences in CD4 counts in the four treatment groups at any time point or in changes of CD4 count over time within individuals. Quantitative microculture assays showed decreases in viral titers in the 3C9 treated groups compared with the untreated group. Only trends were seen in this regard. Adverse effects were primarily due to the use of adjuvants, with SAF-m causing more pronounced ones than AF.

An ex vivo study looked at cryopreservation (i.e. freezing) and expansion of CD8 cells from HIV infected individuals. PBMCs from asymptomatic individuals with greater than 300 CD4 cells and with a CD4/CD8 ratio of at least 0.3, were enrolled. CD8 cells were separated from other PBMCs and frozen in liquid nitrogen. After thawing, the cells were expanded to very large numbers. Many experiments were performed to determine the optimal method and recovery of CD8 cell expansion. Also the ability of the CD8 cells to function after freezing/expansion was determined. It was discovered that cryopreserved cells do not inhibit future proliferation or lead to a change in viral phenotype. When infected CD4 cells were placed in culture with the expanded CD8 cells, no significant decrease in p24 antigen production was seen.

In AIDS Vaccine Evaluation Group trial #101 (AVEG 101), rgp160 was given to 55 asymptomatic individuals, 30% of whom were women. The trial of this therapeutic vaccine began in June of 1992 at John Hopkins, St. Louis University, and Vanderbilt in Nashville. This vaccine is made by Immuno, headquartered in Vienna. Vaccinations occurred monthly. The trial lasted six months. The immunogen was based on the IIIB strain of HIV. The adjuvant used was a combination of alum and deoxycholate. Results show that the vaccine did not stimulate increased production of HIV. Although this group of individuals was considered mostly healthy, the participants showed no evidence of cellular immunity to HIV envelope proteins. However, repeated injections of the vaccine induced or restored at least one aspect of cellular immunity, the T-cell memory recognition of HIV envelope proteins. T-cell memory function is normally lost in people with HIV infection. Other immunologic assays are yet to be performed to determine if cytotoxic T lymphocytes (CTL) or new antibody responses were induced. Immuno announced the beginning of a new clinical trial with a new rgp160, based on the MN strain of HIV. The MN strain is genetically closer to the majority of isolates of HIV obtained from Europe and North America. This trial will enroll 20 asymptomatic individuals with CD4 counts greater than 500. The optimal dose of rgp160 which will elicit the best HIV-specific antibody response will be studied. Information gleaned from this study will be used in a future trial involving subjects with CD4 counts of 50- 500.

In a trial designed to offer treatment to late-stage AIDS patients, monthly infusions of plasma from healthy HIV positive individuals (hyperimmune plasma) and haplotype-matched PBMCs were given. The PBMCs came from HIV negative volunteers and were matched for the following human leukocyte antigen (HLA) loci: A, B, DR & DQ. Additionally, the cells were tested in vitro (cross matched) with the patient's plasma to predict unfavorable responses. The healthy HIV positive plasma donors must have had greater than 500 CD4 cells and have a titer of anti-p24 antibody of at least 1:625. Sixteen patients with an initial mean CD4 count of 25 were enrolled. The hyperimmune plasma was infused first, followed 24 hours later by the PBMC infusion. Side effects included lymphadenopathy and fever less than 101oF, three to five days following the cell infusion. The fever lasted two to three days. The mean length of study duration was 3.2 months. The procedure in general was well tolerated, although two individuals required transfusions after significant decreases in the hematocrit were seen.

The effect of low dose oral IFN-alpha (Kemron) in the management of symptomatic HIV infection was presented. This trial was conducted in Uganda in symptomatic individuals with less than 300 CD4 cells. One hundred and fifty IU/day of the drug was administered sublingually. The trial was placebo controlled. Initially, the study was to last 30 weeks, but was extended to 60 weeks in all individuals who completed the first 30 weeks of study. There was no difference between the treated and placebo groups in the following: survival, disease progression, CD4%, weight gain, or Karnofsky score. The investigators concluded that low dose oral IFN-alpha had no therapeutic benefit.

References

1. WS B28 (1,3,4,5,7). 1993. IX International Conference on aids. Berlin, Germany. June 1993.

2. Barr, Mike. 1993. HIV Therapeutic Vaccines: The Next Phase. Treatment Issues 7(5):1-5,7.
9307
STEP5205

Copyright © 1993 - Seattle Treatment Education Project (STEP) - All rights reserved. Noncommercial reproduction is encouraged. STEP is published four times a year by the Seattle Treatment Education Project, 127 Broadway East, 3rd Floor, Seattle, WA 98102.    Email: step100@aol.com  STEP web page