Clinical Trials of HIV/AIDS Vaccines IX International Conference on AIDS Highlights
The following summaries describe studies conducted by the AIDS Vaccine Clinical Trials Network (AVCTN), supported by the National Institute of Allergy and Infectious Diseases (NIAID). An additional tip focuses on study results from the AIDS Links to Intravenous Experience (ALIVE) study, funded by the National Institute of Drug Abuse and NIAID. This information is scheduled for presentation at the IX International Conference on AIDS in Berlin from June 7 to 11, 1993. All information contained in these summaries is embargoed until presentation time. To pursue these or related stories, call the NIAID Office of Communications at (301) 402-1663.
Since 1988, more than 1,100 people have participated in 19 multicenter Phase I and Phase II clinical trials of candidate HIV vaccines at the AVCTN's five AIDS Vaccine Evaluation Units (AVEUs), which are collectively known as the AIDS Vaccine Evaluation Group (AVEG). These trials have focused on 10 different products used alone or in combination. The AVEG's main focus is developing preventive HIV vaccines, and 15 trials include only volunteers not infected with HIV. The AVEUs are located at the University of Washington in Seattle, The Johns Hopkins University in Baltimore, Md., the University of Rochester, N.Y., St. Louis University, Mo., and Vanderbilt University in Nashville, Tenn.
NIAID, a component of the National Institutes of Health (NIH), supports research on AIDS, tuberculosis, allergies, immunology, transplantation and infectious diseases. NIH is an agency of the Public Health Service, part of the U.S. Department of Health and Human Services.
Genentech Vaccine Induces Neutralizing Antibodies Against Several HIV Strains Oral, Tuesday, June 8, 1 p.m. (7 a.m. EDT)
Three doses of Genentech's rgp120 MN candidate HIV vaccine given within six months can safely stimulate neutralizing antibodies to the HIV strain MN as well as to two other strains. "This cross-neutralization is a significant finding that we hope to capitalize on for vaccine development," says Robert Belshe, M.D., principal investigator of the study and of the St. Louis University AVEU. Neutralizing antibodies are lethal proteins custom-made by the immune system upon exposure to a virus or other invader.
The candidate rgp120 MN vaccine is a recombinant form of HIV MN envelope protein formulated with alum adjuvant and manufactured by the South San Francisco, Calif., company Genentech Inc. MN and SF-2 are most representative of the HIV strains found in North American and Europe. The Genentech vaccine is one of two being tested in the only Phase II preventive HIV vaccine trial under way worldwide, and is carried out through the AVEG.
In Berlin, Dr. Belshe plans to describe the latest results of AVEG trial 009, a double-blind, randomized Phase I controlled trial of the Genentech vaccine in noninfected people at low risk of HIV infection. The AVEU researchers randomly divided 48 volunteers into four equal-sized groups assigned to receive either 100 micrograms (æg), 300 æg or 600 æg of rgp120 MN, or 300 æg rgp120 MN plus 300 æg rgp120 IIIB. The investigators injected each participant three times -- at the beginning and one and six months later -- and measured immune responses before and two weeks after each injection.
Neutralizing antibodies to MN developed after the second injection in participants who received the 300 æg, 600 æg or combination vaccine. In the 300-æg and 600-æg groups, the third dose stimulated neutralizing antibodies to HIV SF-2 and IIIB strains as well. Experiments are planned to determine if neutralizing antibodies to other HIV strains also can be induced.
Dr. Belshe says analysis of the results reveals other interesting information as well. Two doses of the candidate vaccine can evoke antibodies to MN's V3 loop, the principal neutralizing domain found on gp120. By the third dose, however, V3 antibody levels decrease as MN neutralizing antibody levels increase and neutralizing antibody responses to other strains begin to appear. Dr. Belshe says this pattern suggests that parts of HIV gp120 other than the V3 loop also may be important sites for stimulating neutralizing antibodies.
"Safety and Immunogenicity of HIV-1 (MN) rgp120 Vaccine in Low Risk Volunteers." Robert Belshe, M.D., Michael Keefer, M.D., Barney Graham, M.D., Ph.D., Dani Bolognesi, Ph.D., Tom Twaddell, M.D., Pat Fast, M.D., Ph.D., and the NIAID AIDS Vaccine Clinical Trials Network. St. Louis University, Mo.
Neutralizing Antibodies Stimulated by Biocine Vaccine Poster, Tuesday, June 8, 11:30 a.m. (5:30 a.m. EDT)
Biocine's rgp120 SF-2 candidate vaccine is well-tolerated and stimulates high levels of neutralizing antibodies to two HIV strains, SF-2 and MN, according to AVEG trial results.
Men and women in AVEG 007, a randomized, double-blind trial, received a low (15 æg) or high dose (50 æg) of the vaccine and one of two forms of a novel adjuvant. The participants were given a primer vaccination and two boosters at one and six months.
A separate group of only women volunteers received either the high-dose vaccine with one form of the adjuvant or an inactive placebo vaccine once a month for five months.
Although both dosages of vaccine stimulated neutralizing antibodies, the higher one evoked a significantly better response. After the third injection, nearly all the participants in the first group (13/13 at the high dose and 11/15 at the low dose) developed neutralizing antibody against HIV SF-2. Of these 24 responders, two-thirds also developed neutralizing antibodies against HIV MN and five developed antibodies against HIV IIIB. Investigators detected a lower but significant level of neutralizing antibody activity in all women on the accelerated schedule after only their third vaccination.
Researchers formulate vaccines with adjuvants to boost the type, strength and durability of immune responses. The trial tested two forms of adjuvant with the Biocine vaccine: MTP-PE/MF59 and MF59 alone. The form incorporating the immunomodulator MTP-PE did not significantly enhance the immune response except at the lower dose and it caused a short-lived, flu-like syndrome in some individuals.
Unlike a live-virus vaccine, one dose of a genetically engineered vaccine cannot be expected to protect against HIV. Currently, the AVEG is evaluating how rapidly neutralizing antibodies against HIV can be generated by accelerating immunization schedules, such as in this trial. Such protocols also can serve as models for the shortened immunization schedules necessary for trials in HIV-infected pregnant women. Within the next few months, the Biocine vaccine is scheduled to join two other vaccines in tests being conducted in HIV-infected pregnant women.
The Biocine vaccine is based on a recombinant form of HIV SF-2 envelope protein. The rgp120 retains the shape of native HIV gp120 through production in mammalian cells. SF-2 and MN are similar and both representative of most HIV strains found in North America and Europe. The vaccine, manufactured by Biocine (a joint venture of Chiron and CIBA-GEIGY) is one of two candidate HIV vaccines being tested in the only Phase II preventive HIV vaccine trial ongoing worldwide, which the AVEG is conducting.
"Phase I Trial of Native HIV-1 SF-2 rgp120 candidate vaccine. Barney Graham, M.D., Ph.D., Michael Keefer, M.D., Julie McElrath, M.D., Ph.D., Thomas Matthews, Ph.D., David Schwartz, M.D., Ph.D., Geoffrey Gorse, M.D., Richard Sposto, Ph.D., David Chernoff, M.D., and the NIAID AIDS Vaccine Clinical Trials Network. Vanderbilt University, Nashville, Tenn.
Versatile Technique Detects Killer T-Cell Responses More Easily Poster, Tuesday, June 8, 11:30 a.m. (5:30 a.m. EDT)
University of Washington AVEU investigators have developed a method that should help researchers more accurately assess HIV vaccine trial results. The technique detects cellular immune responses thought to be important to protection from HIV.
One unusual property of HIV is that it can be transmitted by infected cells. Cytotoxic T-lymphocytes (CTLs), also known as killer T-cells, can destroy virus-infected cells. The main advantage of the new CTL assay is its unambiguous results: it discerns CTL responses directed against HIV but not against any other virus vectors used in the assay. In addition to being highly specific, the new technique is versatile and can be used to look for CTL responses against multiple HIV antigens in samples from both infected and uninfected trial volunteers.
Julie McElrath, M.D., Ph.D., Lawrence Corey, M.D., and their colleagues have used the assay to look at blood samples gathered earlier from participants in a prime-boost HIV vaccine trial. The noninfected volunteers received live vaccinia vector encoding HIV-1 gp160 (v-env, Bristol-Myers Squibb, Seattle, Wash.) either alone or with booster shots of a gp160 subunit vaccine (VaxSyn) made by MicroGeneSys, Inc., of Meriden, Conn.
So far, the Washington group has found evidence of HIV CTLs in two of four people who received the combination vaccine regimen. In one of these individuals, the CTL responses have persisted for more than a year. Formerly, CTLs directed to the live vaccinia virus from the v-env vaccine had made detection of HIV CTLs by other assays very difficult.
Dr. McElrath and her colleagues are continuing their evaluation of CTL responses in 20 people without prior smallpox vaccinations who received v-env alone, and in 12 volunteers who have been boosted with v-env following initial v-env priming and rgp160 boosting.
"Analysis of Cytotoxic T Lymphocyte Responses in HIV-1 Seronegative Recipients of Recombinant Vaccinia Vectors Encoding HIV-1 gp160 and Envelope Subunit Protein Vaccines." Julie McElrath, M.D., Ph.D., Philip Greenberg, M.D., Mark Hoffman, B.S., Sara Klucking, B.S., Myron Rabin, B.S., and Kent Weinhold, Ph.D., and the NIAID AIDS Vaccine Clinical Trials Network. University of Washington, Seattle, Wash.; Duke University, Durham, N. C.
Therapeutic Vaccine Candidate Proves Well-Tolerated in Women and Men Poster, Tuesday, June 8, 11:30 a.m. (5:30 a.m.)
An rgp160 candidate HIV vaccine has proved safe and well-tolerated in volunteers infected with HIV but without AIDS symptoms. Preliminary analysis of the data shows that the vaccine did not stimulate increased production of HIV, one of many questions being looked at in the relatively untested waters of therapeutic vaccine research. HIV production was determined by measuring cultured virus.
AVEG 101 began in June 1992 as the first trial within the Network to test the concept of using HIV vaccines therapeutically. Thirty percent of the 55 trial volunteers were women. This fact has significance because of the trial design: vaccinations occurred monthly, and the schedule was completed within six months, a timetable compatible with vaccinating HIV-infected pregnant women.
At entry, even the most healthy participants showed no evidence of cellular immunity to HIV envelope proteins, says David Schwartz, M.D., Ph.D., of The Johns Hopkins University and principal investigator of the study. Repeated injections of the vaccine, however, induced or restored at least one aspect of cellular immunity, T-memory cell recognition of HIV envelope proteins. Still to be analyzed are data that will show if the vaccine candidate induces cytotoxic T lymphocytes or stimulates new antibody responses.
The experimental vaccine, a recombinant gp160 protein shaped like native gp160 based on IIIB HIV and combined with alum and deoxycholate adjuvant, is made by IMMUNO-AG of Vienna, Austria.
"Interim Results of rgp160 Vaccine Trial in HIV+ Volunteers." David Schwartz, M.D., Ph.D., Mary Lou Clements, M.D., M.P.H., Robert Belshe, M.D., Geoffrey Gorse, M.D., Peter Wright, M.D., and Barney Graham, M.D., Ph.D. The Johns Hopkins University, Baltimore, Md.; St. Louis University, Mo.; Vanderbilt University, Nashville, Tenn.
Injection-Drug Users Strongly Interested in Participating in AIDS Vaccine Studies Poster, Tuesday, June 7, 11:30 a.m. (5:30 a.m. EDT)
Injection-drug users (IDUs) have substantial interest in participating in clinical trials of candidate AIDS vaccines, even knowing that subsequent tests will show they carry HIV antibodies, according to NIH-supported investigators. Because the rate of new infections is high among IDUs, such interest must be considered when planning vaccine trials.
The surveyed individuals are among the 2,921 IDUs participating in the AIDS Links to Intravenous Experience (ALIVE) study, funded by the National Institute of Drug Abuse and NIAID. The participants are at high risk for or already have HIV. When the study began in 1988 at The Johns Hopkins School of Public Health, 24 percent of the IDUs were HIV-infected. The current rate of new infections is 4 percent each year.
Investigators found from surveys of 215 ALIVE participants that 83 percent thought it likely that any IDU would volunteer for an AIDS vaccine trial. On a personal level, 81 percent of the IDUs said they would participate in a Phase II vaccine study, the stage at which safety, dose and immune system responses are evaluated. When considering a larger Phase III trial, which would test vaccine effectiveness, 83 percent said they would join.
Once told that they would test positive for initial screening tests because AIDS vaccine recipients usually develop certain antibodies to HIV even though not infected, the number of participants willing to volunteer for trials declined to 49 percent.
In addition, 36 percent said any IDU would be likely to engage in high risk activity after immunization, but 94 percent reported they personally would continue to practice safer behaviors after receiving a vaccine.
The discrepancy between percents of what ALIVE participants think any IDU would do versus what they themselves would do probably reflects socially desirable responses, the investigators explain.
"Interest in HIV Vaccines Among Seronegative Injection Drug Users." David Vlahov, Ph.D., Liza Solomon, Dr.P.H., Lisa Basarab, M.A., Jacquie Astemborski, M.S., Don C. Des Jarlais, Ph.D., Kenrad E. Nelson, M.D. The Johns Hopkins University, Baltimore, Md., and Beth Israel Medical Center, New York, N.Y.
Clinical Research Overview -- NIAID AIDS Vaccine Clinical Trials Network (Note: This is not based on a particular Berlin presentation.)
This last year, the number and variety of experimental HIV vaccines entering into human clinical trials increased significantly. AVEG investigators began the first trial of a peptide vaccine and the second of a live-vector vaccine, based on canarypox virus.
Of the four therapeutic vaccine trials, two that recently opened are enrolling pregnant women who are infected with HIV but have no AIDS symptoms. These unprecedented trials will determine if therapeutic vaccination can safely boost the immunity of the women. The trial also is the first step toward larger trials that will examine if this strategy can prevent transmission of HIV to their babies.
In December 1992, the AVCTN launched the world's first Phase II preventive HIV vaccine trial. Two gp120 candidate vaccines, one made by Genentech Inc. of South San Francisco, Calif., and the other by Biocine (a joint venture of Chiron and CIBA-GEIGY) of Emeryville, Calif., are being tested in people without HIV, although some have a history of high-risk behavior. All participants are counseled regularly, however, to avoid any activities that might put them at risk for becoming infected.
In June 1993, AVEG begins two Phase I HIV vaccine comparative adjuvant trials. Investigators will compare various adjuvants paired with the two candidate vaccines being tested in the Phase II preventive trial to determine the best vaccine formulations to pursue.
The AVEG trials continue to show the experimental vaccines to be well-tolerated and capable of stimulating antibodies. An important insight from this last year is evidence that neutralizing antibody can be achieved in almost everyone by vaccinating with gp120 vaccines made in mammalian cells, which allows them to maintain the viral protein's native shape. The trials also have demonstrated that cytotoxic T lymphocytes (CTLs) can be induced by boosting with vaccinia-gp160 after priming with vaccinia-gp160 and boosting with gp160. Experience with an accelerated immunization schedule in two trials indicates that giving three immunizations one month apart can generate low-level immunity but that an interim "rest period" of a few months is needed to generate the best immune responses.
Vaccine researchers say one of the biggest challenges for the coming year will be defining how broad the neutralization and CTL responses are to determine if they will react with the various virus strains found in recently infected people.
The principal investigators of the AVEUs are Lawrence Corey, M.D., at the University of Washington in Seattle., Mary Lou Clements, M.D. M.P.H., at The Johns Hopkins University in Baltimore, Md., Raphael Dolin, M.D., at the University of Rochester, N.Y., Barney Graham, M.D., Ph.D., at the St. Louis University, Mo., and Robert Belshe, M.D. at Vanderbilt University, Nashville, Tenn.
A Central Immunology Laboratory affiliated with the AVEUs and located at Duke University in Durham, N.C., performs a standard set of sophisticated immunologic evaluations for each trial, looking for evidence of both humoral and cellular immunity, which complements testing performed at each AVEU. The Network also encompasses a Clinical Specimen Repository to store and maintain the clinical samples and make them available to researchers as needed, and a Statistical Coordinating Center that coordinates communication between the components of the Network and collects, manages and provides analysis of the trial data.
The Vaccine Research and Development Branch (VRDB) of NIAID's Division of AIDS, headed by Alan Schultz, Ph.D., facilitates the activities of the Network. Patricia Fast, M.D., Ph.D., chief of the Clinical Development Section, and the VRDB staff work closely with the AVEU investigators to coordinate and expedite these studies.