Three new trials of experimental vaccines to prevent HIV infection or AIDS recently began enrolling 144 total needed volunteers, the National Institute of Allergy and Infectious Diseases (NIAID) announced.
Volunteers are being recruited through NIAID's AIDS Vaccine Evaluation Group (AVEG), which consists of six clinical units located in St. Louis, Nashville, Seattle, Birmingham, Baltimore and Rochester (N.Y.).
These new trials are among the 23 trials of 16 preventive AIDS vaccines NIAID has sponsored since 1988. "NIAID is committed to advancing the best candidate HIV vaccines into the testing pipeline," says Anthony S. Fauci, M.D., the Institute director, "and we appreciate the contribution of the nearly 1,700 non-HIV-infected healthy men and women who have volunteered for these trials so far."
According to Patricia Fast, M.D., Ph.D., chief of the Clinical Development Branch for NIAID's Division of AIDS Vaccine and Prevention Research Program, "In these trials, we are tackling several challenges facing HIV vaccine developers. These challenges include trying to induce antibodies at the surfaces where HIV enters the body after sexual exposure, and stimulating killer T cells that might attack a range of HIV strains by destroying the cells they infect."
The new Phase I trials, called AVEG 019, 022 and 023, will look for any adverse side effects and evaluate vaccine-induced immune responses. Because none of the vaccines in these trials contain live or killed HIV, they pose no risk of transmitting HIV infection or AIDS. NIAID, part of the National Institutes of Health, supports biomedical research to prevent, diagnose and treat illnesses such as AIDS, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services. Additional information about each trial follows.
AVEG 019 is testing a novel HIV vaccine called p17/p24:Ty- VLP made by British Biotech Pharmaceuticals Limited of Oxford, United Kingdom. Copies of pieces of two internal HIV proteins, p17 and p24, are incorporated with a yeast protein (Ty) that helps them assemble into virus-like particles (VLPs). In ongoing small studies in humans, the vaccine so far appears to be safe.
The trial has two main goals: first, to determine if the vaccine induces cellular immunity--specifically, killer T cells--in addition to anti-HIV antibodies. Although the components of protective immunity against HIV remain unknown, most investigators think that an effective HIV vaccine will need to induce cellular immunity to destroy HIV-infected cells that have evaded antibody protection. Second, the investigators will look for evidence that administering oral or rectal booster doses stimulates antibodies at the mucosal surfaces lining the body's entryways, where the virus is sexually transmitted.
The vaccine has the potential to react with a broad range of HIV strains because the p17 and p24 proteins on which it is modeled come from HIV's interior. Across multiple HIV strains, these core proteins do not change as much as the gp120 and gp160 HIV surface proteins used in many first-generation HIV vaccines.
AVEG 019 will enroll 36 people at low risk of HIV infection. In the first part of the trial, volunteers will be randomly chosen to receive intramuscular injections at three time points--the beginning of the study, two months and six months later--with active vaccine (20 volunteers) or an inactive placebo (16 volunteers). In some cases, the active vaccine will be formulated with alum, which improves the vaccine's performance and also serves as the placebo.
In the second part, all volunteers will receive two more doses of vaccine or placebo, 10 and 11 months after their initial injection. These booster doses will be the same product given either by mouth or by rectal enema. The assignments to the vaccine or placebo groups will not be known by the volunteers or the investigators until the trial ends.
Four AVEG sites--Vanderbilt University in Nashville, the University of Rochester Medical Center in New York state, the University of Washington in Seattle and the University of Alabama at Birmingham--are participating in the study, chaired by Paul Spearman, M.D., of Vanderbilt University.
AVEG 022 takes a new twist on vector vaccines, which use a non-disease-causing virus or bacterium to transport HIV or other foreign genes into the body. The vaccine being evaluated, a live recombinant vector vaccine called ALVAC-HIV (vCP205), is made by Pasteur-Merieux/Connaught of Swiftwater, Pa., from a weakened canarypox virus used as a vaccine for birds.
First-generation vector vaccines based on vaccinia, a cowpox virus used in the human smallpox vaccine, have already been tested in the AVEG. Like vaccinia virus, canarypox virus can fit large pieces of foreign DNA in its genome, infect human cells and cause them to produce foreign proteins. Unlike vaccinia, however, canarypox virus does not grow in human cells, which is an important safety feature.
In addition, although vaccinia-based HIV vaccines and an earlier version of the ALVAC vaccine contain copies of only one HIV surface protein gene, ALVAC-HIV (vCP205) contains copies of genes for three pieces of HIV--the surface protein, the core protein and one enzyme--more than any other experimental preventive HIV vaccine tested so far. When the ALVAC vaccine infects human cells, the cells make proteins from the genes and package the proteins into HIV-like particles called pseudovirions. Although not infectious, these pseudovirions fool the immune system and trigger an immune response.
The trial will enroll 76 adults at low risk of HIV infection, half of whom must not have received a smallpox vaccination, to test if smallpox vaccine changes the immune responses. Each volunteer will receive between three and five intramuscular injections of ALVAC-HIV (vCP205) or a placebo over the two-year course of the study. The placebo is an experimental rabies vaccine (ALVAC-RG) made by a similar process that in other trials appears quite safe. The researchers and volunteers will not know which product each volunteer received until the study ends.
Two different immunization schedules will be compared: a primary immunization and boosters at one and six months, or one, three and six months. Another booster at 12 months may be added.
The study chair for AVEG 022 is Lawrence Corey, M.D., of the University of Washington in Seattle. All five other AVEG sites--Johns Hopkins University, the University of Rochester Medical Center, St. Louis University School of Medicine, Vanderbilt University and the University of Alabama at Birmingham--also are participating in this study.
AVEG 023, focused primarily on mucosal immunity, is evaluating the sequential administration of an injectable and an oral peptide vaccine (peptides are the building blocks of proteins) made by United Biomedical, Inc. (UBI) of Hauppauge, N.Y.
The main goal is to determine if priming the immune system with an intramuscular injection before giving oral booster doses stimulates better mucosal immunity than an oral-intramuscular or an oral-oral regimen. The latter two strategies are already being tested in AVEG 018, which began in June 1994.
Prior animal experiments suggest that this strategy may work. Five of six rhesus monkeys that received a systemic (intramuscular) killed simian immunodeficiency virus (SIV) vaccine before a series of mucosal (oral) booster doses were protected against vaginal challenge with SIV, the virus that causes an AIDS-like disease in certain species of monkeys.
The injectable vaccine consists of eight identical peptides arranged like branches on an inert backbone. The peptides are synthetic copies of a part of the virus envelope known to stimulate anti-HIV neutralizing antibodies. The vaccine is formulated in alum, a compound that improves the vaccine's effects and also serves as a study placebo for the intramuscular injection. AVEG began the first human trials of this vaccine in February of 1993.
For the oral version, UBI scientists encased the same branched peptide in microparticles made from materials that have proved safe in humans when used as biodegradable sutures and controlled-release drug-delivery systems. The microparticles allow the manufacturer to modify the vaccine into a controlled-release formula. Thus, a single dose could be used instead of booster shots. Moreover, tests in small animals show that delivering HIV peptides in microparticles increases antibody production. The microparticles alone will be used as a control in the boosting phase of the protocol.
No serious safety problems have been reported with the injectable or oral UBI vaccine in other AVEG trials in which these vaccines are being tested separately.
AVEG 023 will enroll 32 men and women at low or intermediate risk for HIV-1 infection. By random assignment, half will receive their first immunization in the upper arm and the other half in the front of the thigh to see if the latter location induces better genital antibody responses after oral boosting. Each group will enroll at least five women. Twelve in each group of 16 will receive active vaccine and four an inactive look-alike or placebo. All 32 volunteers will be boosted with the oral UBI vaccine or placebo one, two and eight months later. Neither the investigators nor the patients will know who is getting vaccine or placebo.
The 14-month trial also will determine if a faster immunization schedule (zero, one and two months) stimulates optimal immune responses, or if a rest period followed by a fourth immunization (month eight) is needed. The results of AVEG 023 will be compared with those of a similar ongoing UBI-sponsored trial that requires booster shots at one and six months only.
The study is being conducted at three AVEG sites: the University of Alabama at Birmingham (UAB), the University of Rochester Medical Center and the University of Washington. Mark Mulligan, M.D., of UAB chairs the study.