The National Institute of Allergy and Infectious Diseases (NIAID) sponsors clinical trials of experimental vaccines made to prevent or to treat HIV disease. 1993 has been a productive year: NIAID has launched many new clinical investigations, a record number of people have entered into trials and important results have begun to emerge. This document highlights significant clinical trials initiated since the spring of 1993, as well as key research findings.
The AIDS Vaccine Evaluation Group (AVEG), which conducts Phase I and II clinical trials of experimental vaccines to prevent HIV infection, is the backbone of NIAID's HIV vaccine clinical trials effort. AVEG comprises five university-based clinical trial sites, support laboratories and a statistics and data analysis center. Between Feb. 2, 1988, and Sept. 1, 1993, AVEG initiated 19 trials and enrolled 1,312 volunteers. One-third of these volunteers, about 60 per month, enrolled in 1993.
Although AVEG primarily focuses on vaccines to prevent HIV disease, the group has initiated a few investigations in HIV-infected individuals. Some of these studies are conducted jointly with NIAID's AIDS Clinical Trials Group (ACTG), a nationwide clinical research network for testing AIDS therapies. ACTG carries out most NIAID-funded trials examining the therapeutic potential of candidate HIV vaccines. The Institute's Terry Beirn Community Programs for Clinical Research on AIDS also has recruited 137 of the several hundred people in a Phase II collaborative study with the Walter Reed Army Institute of Research investigating whether or not an experimental HIV vaccine benefits people infected with the virus.
NIAID announced several significant HIV/AIDS vaccine trials in the last year:
* the first Phase II preventive HIV vaccine trial worldwide (Dec. 1, 1992; AVEG 201);
* the first Phase I preventive trial in the United States of an experimental vaccine made from a chemically synthesized protein fragment, or peptide, of HIV (Feb. 12, 1993, AVEG 011);
* the first trials of candidate HIV vaccines in asymptomatic HIV-infected children between 1 month and 12 years old (Mar. 30, 1993, ACTG 218);
* the first trials of candidate AIDS vaccine in pregnant HIV-infected women who have few or no symptoms (May 5, 1993; AVEG 102/ACTG 234 and AVEG 104/ACTG 235).
Separate updates describing these studies are available from NIAID's Office of Communications.
NIAID Opens First Comparative Vaccine Adjuvant Trials
NIAID has begun the first clinical trials comparing the ability of several novel adjuvants to enhance the potency of candidate AIDS vaccines. Adjuvants are substances added to vaccines in an attempt to increase the type, strength or duration of immune responses they elicit.
Since 1926, the only adjuvants incorporated into human vaccines licensed in the United States have been aluminum salts, generically known as alum. Alum can increase the magnitude of antibody responses provoked by a vaccine but generally does not induce cytotoxic T cell responses. The latter are thought to be important to HIV immunity because they help kill HIV-infected cells.
A pair of separate Phase I trials, begun in June 1993 and expected to last 18 months, will identify the adjuvants that induce the most robust immune responses from two promising experimental AIDS vaccines. The trials also will provide the first information about how well humans tolerate these novel vaccine/adjuvant formulations.
The vaccine being tested in each trial contains a recombinant form of one part of HIV-l, the gp120 surface protein, thought to be important for stimulating immunity. Monkey studies of similar subunit vaccines--tailor-made using new tools of molecular biology and genetic engineering--have shown that such vaccine constructs are potentially safer but that they perform more poorly than expected compared with conventional vaccines for other diseases made from weakened or inactivated whole viruses such as measles or polio.
The gp120 vaccines are undergoing evaluation in NIAID's only Phase II trial of preventive HIV vaccines. Earlier studies of these same vaccines indicate that both are safe and that they stimulate similar immune responses, including neutralizing antibodies that laboratory tests show inactivate HIV and neutralize laboratory strains of the virus somewhat different from the strains used to make the respective vaccines. Furthermore, antibodies to the vaccines appear to persist in the circulation for months. Although these findings are encouraging, novel adjuvants may optimize protective immune responses and, by generating stronger, potentially more effective immune responses, allow smaller doses of the vaccines to be used.
The adjuvant trial AVEG 015 compares seven different immunogen/adjuvant formulations against alum alone given as a placebo control. Each formulation contains 50 ug of the immunogen, recombinant gp120 (rgp 120) based on HIV's SF-2 strain, made by Biocine (Emeryville, Calif., a joint venture of Chiron and CIBA-GEIGY). These adjuvants are:
* Aluminum hydroxide (alum) * Monophosphoryl lipid A (MPL; Ribi ImmunoChem Research, Inc., Hamilton, Mont.) * Liposome-encapsulated MPL with alum (liposomes made by Washington, D.C. researchers at the Walter Reed Army Research Institute) * MF59 (Biocine) * MF59 plus MTP-PE (Biocine) * SAF/2 (Biocine) * SAF/2 plus MDP (Syntex Corp., Palo Alto, Calif.)
The trial participants, 110 healthy noninfected men and women at low risk for HIV infection, are randomly assigned to the different study arms. Neither the researchers nor the participants know what rgp120-adjuvant combination each volunteer receives. A primary immunization is followed by boosters at two and six months.
The second study, AVEG 016, is comparing different dosages of rgp120 MN strain (Genentech, Inc., South San Francisco) formulated with varied amounts of the adjuvant QS-21, a detergent-like substance made by Cambridge Biotech (Worcester, Mass.) from the bark of the South American soap bark tree.
Each of the 80 participants in the double-blind trial, healthy noninfected men and women at low risk of HIV infection, receives a primary vaccination and boosters at one and six months or one and 10 months. Three different doses of rgp 120, each combined with 50 or 100 ug of QS-21, are being tested in 68 volunteers. Some formulations also include alum. These participants will be compared with those twelve who receive just the QS-21 with or without alum.
Trial Tests Safety of HIV Vaccines in Neonates at Risk for HIV Infection
The ACTG is evaluating the safety and immune-stimulating ability of two experimental HIV vaccines in babies born to HIV-infected mothers. The babies, younger than 3 days old, are at risk for HIV infection, but their HIV status is unknown.
The Phase I trial, known as ACTG 230, is enrolling 120 infants at selected ACTG sites. The first babies enrolled in the trial are receiving low doses of Genentech's gp120 MN vaccine with alum or Biocine's gp120 SF-2 vaccine with the experimental adjuvant MF59. If three-fourths of the newborns in these low-dose groups show no signs of serious toxicity, the investigators will proceed to test a bigger dose in other infants. Similar criteria must be met before a third group of infants receives an even higher dosage of vaccine.
The study, which opened in mid-July, is expected to take two years to complete. The infants will be randomly assigned to either of two schedules of four shots given over a period of five months.
Vaccine Uses Bird Virus as Shuttle for HIV Gene
In May, AVEG investigators began a Phase I trial of ALVAC-gp160, a live recombinant vaccine made by inserting the gene for HIV's gp160 MN coat protein into a canarypox virus. The vaccine, made by Virogenetics of Albany, N.Y., a subsidiary of Pasteur Merieux-Connaught Laboratories in Swiftwater, Pa, is being tested in uninfected adults at low risk for HIV infection. The trial is expected to be completed in late 1994.
AVEG and other scientists have been evaluating live recombinant vaccines based on a vaccinia virus (the vaccine used against smallpox) that has been modified to make copies of the HIV gp160 surface protein. Results from these trials indicate that antibody- and cell-mediated immune responses can be stimulated by priming with the vaccinia construct and boosting with a recombinant subunit vaccine containing gp160. Although no serious adverse reactions to vaccinia virus recombinants have been observed in these trials, concerns have been raised about the potential for an inadequately weakened vaccinia to cause infection.
Unlike vaccinia virus, canarypox virus does not replicate in mammalian cells. However, like vaccinia, the canarypox virus can accommodate large amounts of foreign DNA in its genome and can infect mammalian cells and use them to produce foreign proteins. This virus also does not need refrigeration and is relatively inexpensive to produce. Live viruses such as vaccinia and canarypox generally elicit strong immune responses, and their use may increase the response to the HIV proteins made by the vaccines.
The new Phase I study, AVEG 012, was designed to complement trials of the vaccine already under way in France. One vaccination schedule in the AVEG trial calls for a second priming immunization at two months rather than one month. Also, half of the volunteers will receive two booster shots of ALVAC-gp160 rather than two booster doses of a vaccine containing gp160 antigen alone.
The trial has two parts. Initially, 10 volunteers who have received smallpox vaccinations and 10 who have not are being given ALVAC-gp160 to determine if immunity conferred by smallpox vaccination interferes with the immune response to the canarypox vaccine. The eight other volunteers, five of whom will be vaccinia-immune, are receiving a control vaccine. The control is ALVAC-RG, a recombinant canarypox virus vaccine for rabies that has caused no serious side effects in animals or in humans.
If the initial dosage of ALVAC-gp160 is well tolerated, 40 additional vaccinia-immune volunteers will be enrolled in a test of a higher dose of ALVAC-gp160. They will be similarly divided at random to the different schedules of primary immunizations and the different type of booster shots. An additional 10 people will receive the control ALVAC-RG vaccine.
Therapeutic Vaccine Trial Enrolls People with More Advanced Disease
Most studies of therapeutic HIV vaccines enroll HIV-infected individuals with relatively intact immune systems as indicated by CD4+ T-cell counts above 500/mm3 of blood. In one of the first HIV vaccine trials in people with more advanced HIV disease, NIAID-supported researchers are investigating how immune competence and antiviral treatment affect the response to therapeutic HIV vaccines.
ACTG 209 is a Phase I/II trial testing the safety and therapeutic potential of Genentech's rgp120 MN vaccine in people with CD4+ T cell levels between 50 and 500/mm3. The trial began in March 1993 and has enrolled or screened the 168 HIV-infected individuals needed for the study. The individuals are stratified by CD4 count into four groups.
Participants with 350 to 500 CD4+ T cells/mm3 have been split into two groups. The first group--those with no prior ddi or ddC treatment who tolerated two to 12 months of 500 to 600 mg zidovudine (AZT) daily immediately prior to study entry--are receiving either 600 ug/month of vaccine or placebo control, alum adjuvant, in addition to a daily dose of 600 mg of AZT. The second group--those with 350 to 500 CD4+ T cells/mm3 and no history of antiretroviral therapy, or less than one month of therapy three or more months ago--is receiving 600 ug of the vaccine per month.
Volunteers with 200 to 349 CD4+ T cells/mm3 and the same history of retroviral drug treatment as those in the first group are receiving the same treatment as that group. Individuals in the fourth group, those with 50 to 199 CD4+ T cells/mm3 and a minimum of two months previous therapy with AZT, ddI or ddC, are receiving either 600 ug/month of vaccine or alum control plus their current daily dose of antiretroviral therapy.
All participants receive two 300-ug immunizations into the muscle each month for six months. Periodically, the investigators look for any changes in measurable virus, CD4+ T-cell count, specific immune responses and disease progression. Follow-up will last six months after the last immunization.
Vaccine Trials In Search of Recruits
Individuals interested in volunteering for an HIV vaccine trial can find for which ones they may be eligible by calling 1-800-TRIALS-A, the AIDS Clinical Trials Information Service hotline, weekdays between 9:00 am. and 7:00 p.m. Eastern time.
Spanish-speaking personnel can assist callers.
The following NIAID-sponsored trials currently need more volunteers.
HIV-infected pregnant women with few or minor disease symptoms:
AVEU 102/ACTG 234 - A Phase I trial of the MicroGeneSys rgp160 vaccine and alum in pregnant women infected with HIV. Potential volunteers must have few or no symptoms and CD4+ T cell counts of 400/mm3 or more. Volunteers should enroll early after conception to receive the first immunization between the fourth and sixth month of pregnancy. Although coordinated through the AVEU, this trial is being conducted only at Yale University in New Haven, Conn.
AVEU 104/ACTG 235 - A Phase I trial of Genentech's rgp120 MN vaccine with alum adjuvant. Same criteria as for AVEU 102. Trial being conducted at all AVEU sites and the University of California at San Francisco pediatric AIDS Clinical Trials Unit.
ACTG 233 - This new Phase I trial is testing Biocine's yeast-derived rgp120 SF-2 vaccine in the same population as AVEU 102. Volunteers are being recruited through five ACTG sites in Philadelphia, Miami, New York City, New Orleans and Worcester.
Noninfected healthy men and women at higher risk for HIV infection: AVEU 201 - A Phase II study of Genentech and Biocine rgp120 vaccines. Enrollment near complete, but heterosexuals between 16 to 28 years old who have multiple sex partners or are otherwise practicing high risk sexual behavior are still needed. Also recruiting heterosexuals between 18 and 60 whose partners are HIV-infected and who do or do not practice safer sex.
HIV-infected children: ACTG 218 - A Phase I clinical trial to evaluate the safety and immunogenicity of recombinant envelope proteins (MicroGeneSys gp160 IIIb, Genentech rgp120 MN and Biocine rgp120 SF-2) in children 1 month or older with asymptomatic HIV infection.
Neonates born to HIV-infected mothers: ACTG 230 - A Phase I trial to evaluate the safety and immunogenicity of two recombinant subunit vaccines (Genentech rgp120 MN and Biocine rgp120 SF-2) in newborns up to 3 days old who are born to HIV-infected mothers but whose HIV status is unknown.