WASHINGTON _ Federally sponsored AIDS vaccine research is stillat least two years away from finding a viable product candidate forlarge-scale testing.

The obstacles to vaccine development are considerable: lack of knowncorrelates of protective immunity, genetic diversity of the HIV proteinand need to prevent further transmission of the virus.

Two strategies are being pursued by researchers to deal with theseobstacles. Some are targeting the immune response to specific HIV-1and B cell and T cell epitopes. Others are focusing on development ofvaccines that mimic attenuated and inactivated HIV-1 or that induce ananti-HIV immune response in the mucosa.

Although testing of these potential vaccines has not progressed farenough to make any of them candidates for larger Phase III trials,federal researchers are undaunted.

"Our vaccines have not failed," said Patricia Fast, clinical developmentchief for the AIDS vaccine and prevention research program of theNational Institute of Allergy and Infectious Disease (NIAID).

"So far none has produced the immune response in humans we arelooking for. But there are active discussions now about which vaccinemay be a candidate for large Phase III human trials," she told BioWorldToday. "Those clinical trials may take place in the U.S. or overseas incooperation with the World Health Organization in countries whereAIDS prevalence is higher, such as Uganda, Thailand or Brazil."

Fast added, "While the prevalence of AIDS infection is too high inhuman terms in the U.S., it is relatively low so that those who tend toget infected with AIDS are not easy to enroll in clinical trials. A PhaseIII trial would be a difficult and expensive trial to run."

Searching For The Right One

Fast also said, "NIAID is now sifting through a large number ofpotential vaccines which might produce an immunogenic response inprimates and humans. Vaccines developed so far have lost theirimmunogenicity as they are tested higher and higher up theevolutionary scale. We are interested in finding a vaccine that triggersthe appropriate immune response in humans."

The institute is conducting basic research to understand what helps thebody stave off HIV infection as well as understand "how we canmanipulate the immune response," Fast added.

NIAID's relationship with biotechnology drug firms is a truecollaboration. Federally funded researchers share facilities, knowledgeand money with scientists from biotechnology companies.

"If we have a vaccine that's ready for testing in animals or humans, wework with six clinical centers around the country to test the vaccine'ssafety and immune response, not efficacy," Fast said. "Or sometimes abiotechnology firm supplies the vaccine and the institute helps themenroll volunteers."

NIAID in mid-June announced three more AIDS vaccine clinical trials,bringing its total to 23 studies of 16 vaccines. The newly announcedtrials focus on "trying to induce antibodies at the surfaces where HIVenters the body after sexual exposure and stimulating killer T cells thatmight attack a range of HIV strains by destroying the cells they infect,"Fast said.

One trial is testing a novel biotechnology vaccine, called p17/p24:Ty-VLP, made by British Bio-Technology Group, of Oxford, England.Copies of pieces of two internal HIV proteins, p17 and p24, areincorporated with a yeast protein (Ty) that helps them assemble intovirus-like particles (VLP).

Investigators think the vaccine has the potential to react with a broadrange of HIV strains because the p17 and p24 proteins are copies ofinterior proteins. Among multiple HIV strains, these core proteins donot vary as much as the gp120 HIV surface proteins used in many first-generation HIV vaccines.

Animal studies have been completed. The current Phase I trial willenroll 36 people at low risk of HIV infection to test if the vaccineinduces cellular immunity, specifically T cells in addition to anti-HIVantibodies. Intramuscular injections will be administered at three timesin the study.

In the second part of the study, all participants will receive boosterdoses of the vaccine either by mouth or rectal enema.

Most investigators believe that an effective HIV vaccine will need toinduce cellular immunity to destroy HIV-infected cells that haveevaded antibody protection. Investigators are also looking for evidencethat administering oral or rectal booster doses of the vaccine stimulatesantibodies at the mucosal surfaces where the virus is sexuallytransmitted.

The second virus is a live recombinant vector vaccine, called ALVAC-HIV, made by Pasteur-Merieux/Connaught, of Swiftwater, Pa. It uses aweakened canarypox virus to fit large pieces of DNA into its genome,infects human cells and causes them to produce foreign proteins.However, canarypox does not grow in human cells.

Vector Vaccine Uses Canarypox

The ALVAC-HIV contains copies of genes for three pieces of HIV,more than any other experimental vaccine tested so far. When theALVAC vaccine infects human cells, the cells make proteins from thegenes and package the proteins into HIV-like particles called apseudovarus, which can fool the immune system and trigger an immuneresponse.

Each of the 76 persons enrolled in the trial will receive between threeto five intramuscular injections over a two-year period.

The goal of the Phase I trial involving a vaccine made by UnitedBiomedical Inc., of Hauppauge, N.Y., is to determine if priming theimmune system with an intramuscular injection before giving an oralbooster stimulates mucosal immunity better than a solely intramuscularor oral regimen.

The injectable vaccine is a peptide version made of the synthetic copiesof the virus envelop known to stimulate anti-HIV neutralizingantibodies. The oral version uses the same peptides encased inmicroparticles made for materials used in biodegradable sutures andcontrolled-release drug delivery systems.

The trial will enroll 32 men and women at intermediate risk of HIVinfection to determine if a faster immunization schedule stimulatesoptimal immune response. n

-- Michele L. Robinson Washington Editor

(c) 1997 American Health Consultants. All rights reserved.