Background

In his commencement address at Morgan State University on May 18, 1997, President Clinton asked the nation to commit to creating a vaccine against AIDS within 10 years. To accelerate this quest, he announced that a new Vaccine Research Center would be established at the National Institutes of Health (NIH).

Last year, AIDS vaccine advocates marked the anniversary of this announcement by designating May 18 as AIDS Vaccine Awareness Day. Communities nationwide organized teach-ins and other activities to educate people about AIDS vaccine research and to honor the several thousand U.S. volunteers who have already participated in clinical trials of experimental AIDS vaccines. The National Institute of Allergy and Infectious Diseases (NIAID) supported their efforts by coordinating national media contacts. Similar events are planned again this year to mark this anniversary.

This document summarizes progress in NIH-sponsored AIDS vaccine research in the two years since the President's commencement address at Morgan State University.

Vaccine Research Center at the NIH

• Since the announcement of the new Vaccine Research Center, and even before building began, a core group of NIH scientists with expertise in immunology, virology, and vaccine development has met regularly to help develop the concept of the "Center without walls."

• Construction of the $30 million, 50,000-square-foot Center building started in August 1998 and is expected to be completed in mid-2000. When fully operational, the state-of-the-art facility will house approximately 100 scientists and support staff. The scientists will be able to take a vaccine from concept through vaccine design and pilot-lot production.

• On April 11, 1999, Dr. Gary Nabel of the University of Michigan was named the Center's first director. Dr. Nabel has begun recruiting scientific staff and charting the Center's research course. He is a superb scientist who has excelled at the frontiers of virology, immunology, gene therapy, and molecular biology. His research career has focused on developing gene therapy for AIDS and novel vaccine strategies against cancer and the Ebola virus.

Budget and Leadership

• The Clinton/Gore Administration has doubled the NIH funding for AIDS vaccine research by 100 percent since FY 1995. In FY 1999, funding for AIDS vaccine research increased by 30 percent over the previous year to about $194 million. The President's NIH budget request for FY 2000 includes $204 million for AIDS vaccine research.

• In May 1998, NIH Director Dr. Harold Varmus named Dr. Neal Nathanson as the new director of the NIH Office of AIDS Research. Dr. Nathanson, a world-renowned virologist from the University of Pennsylvania Medical Center, has a broad background in virology, epidemiology, and public health and is a member of the NIH AIDS Vaccine Research Committee chaired by Dr. David Baltimore.

• In September 1998, Dr. Margaret (Peggy) I. Johnston rejoined NIH to assume two key posts in AIDS vaccine research at the National Institute of Allergy and Infectious Diseases (NIAID). She is Assistant Director for HIV/AIDS Vaccines at NIAID, a newly created position; and Associate Director of the Vaccine and Prevention Research Program in NIAID's Division of AIDS. Dr. Johnston returned to NIH after serving two years as the top scientific administrator at the International AIDS Vaccine Initiative, a renowned not-for-profit organization whose mission is to foster the development of safe, effective, and accessible preventive HIV vaccines for use throughout the world.

• With the appointments of Drs. Nathanson and Johnston, and the establishment of an entirely new Vaccine Research Center led by Dr. Nabel, the NIH AIDS vaccine program has developed a strong leadership base and infrastructure for AIDS vaccine development.

NIH AIDS Vaccine Research Committee

• The AIDS Vaccine Research Committee, chaired by Nobel Laureate Dr. David Baltimore, was formed in early 1997 to improve coordination of NIH-supported AIDS vaccine activities. It has provided guidance to the NIH in developing a comprehensive research program aimed at developing a safe and effective AIDS vaccine. It has also advised the NIH about scientific opportunities, gaps in knowledge, and future directions of AIDS vaccine research, most notably contributing to the genesis and science of the Innovation Grant Program. A workshop co-sponsored by NIAID and the AVRC on May 3-5, 1999, brought together more than 700 researchers to discuss new research findings in HIV vaccine development.

Clinical Trials Progress

• Since 1987, more than 3,200 non-HIV-infected volunteers have enrolled in 52 NIAID-supported preventive vaccine studies (50 Phase 1 safety studies; two Phase 2 safety and immunogenicity studies) involving 27 vaccines. These trials have been conducted primarily at six university-based AIDS Vaccine Evaluation Group (AVEG) sites nationwide. NIAID's HIV Prevention Trials Network (HIVNET), which includes international as well as U.S. sites, and NIAID investigators in Bethesda have also led or helped conduct some of these trials.

• Earlier this year, NIAID opened the first AIDS vaccine trial in Africa, an important step for global vaccine development. This small study in Uganda will help determine if it is necessary to tailor-make vaccines for different parts of the world. The vaccine being tested is based on subtype B, the HIV variant most often found in the United States and Europe. The researchers will determine if the immunized volunteers develop immune responses that in laboratory experiments cross-react to the two other HIV subtypes, A and D, the cause of most infections in Uganda.

• NIAID has initiated clinical trials of several novel vaccine approaches in the past two years. One trial is testing novel routes of immunization. The vaccine is applied topically to the moist tissues lining the vagina, rectum, and other mucosal surfaces where most HIV infections are acquired. A second study employs a non-disease- causing form of Salmonella bacteria to present an HIV protein to the immune system. This is the first vaccine that NIAID has funded all the way from the laboratory to clinical trials without industry sponsorship. A third study is combining a new adjuvant (GM-CSF) with an experimental vaccine to see if the adjuvant can enhance the immune responses stimulated by the vaccine.

• In June 1997, NIAID initiated its second intermediate-size AIDS vaccine trial and quickly completed enrollment of 420 volunteers. The Phase 2 trial is testing a combination of two different vaccines. This strategy offers the advantage of stimulating both components of the immune system. One vaccine, based on a harmless canarypox virus designed to carry genes coding for a few pieces of HIV, primarily stimulates cellular immune responses that kill HIV-infected cells. The other vaccine, a genetically engineered surface protein of HIV (gp120), primarily stimulates anti-HIV antibodies. Researchers are completing their analysis of the trial data. Trials that are ongoing and planned will assess modified versions of the canarypox-based vaccine to see if they stimulate better immune responses. The data from all these studies will form the basis for a future decision about proceeding to larger-scale efficacy trials that will determine if the vaccine protects against HIV infection.

• In June 1998, the first efficacy trial of an AIDS vaccine in the United States got underway. Although the trial is funded primarily by the vaccine manufacturer, VAXGEN, NIAID will collaborate with the company on ancillary studies of the samples they will collect. The trial, which is testing a bivalent subunit vaccine made from the gp120 surface protein of HIV, is expected to last three years and enroll 5,000 people in the United States, Canada, and the Netherlands.

NIAID's Restructured AIDS Vaccine Program

New initiatives have been launched by NIAID's Division of AIDS to enhance opportunities for vaccine discovery and to help move vaccine concepts from basic research through clinical trials. The overall objective is to increase the number of new, innovative and promising vaccine concepts flowing through the pipeline.

• Innovation Grant Program for Approaches in HIV Vaccine Research: In September 1997, NIAID announced the selection of the first 49 grantees for a new program to foster innovative research on AIDS vaccines. More grant awards have subsequently been made; the current total is 97. The Innovation Grant Program encourages early exploration of novel and innovative vaccine concepts and attempts to attract scientists currently working in other areas.

• HIV Vaccine Research and Design Program: This initiative supports traditional mid-stage, targeted research, including animal model studies, to help develop promising vaccine concepts.

• Integrated Preclinical/Clinical Program: This program funds the iterative processes of product development, optimization, and refinement, including clinical studies.

• Other programs that will be implemented in the near future include HIV Vaccine Design and Development Teams, which will advance vaccine concepts to the product stage, a program to encourage innovative research on improved technologies for evaluating immune responses, and resources to help advance products from preclinical to clinical research.

• NIAID has begun the process to restructure the AVEU and HIVNET networks. The reorganization will consolidate scientific responsibility and create two comprehensive networks for AIDS vaccine trials and non-vaccine HIV prevention research.

Recent Scientific Advances

• Knowing Surface Structures Could Help Block Virus: NIH-supported scientists have determined the 3-D crystal structures of two surface proteins of HIV, gp120 and gp41, which help the virus attach to cells. Studies of intermediate molecules formed during virus-cell fusion are helping explain the step-by-step process by which HIV enters the cell, which could lead to new vaccine approaches for inducing antibodies to block its entry.

• Removing Sugar Coating Improves Immunity: The outer surface protein of HIV is coated with sugar molecules that may prevent it from being recognized by the immune system. An NIAID grantee has shown that selectively deleting certain of these sugar molecules from SIV, the monkey equivalent of HIV, can bring the mutant virus under immune control much faster than the normal virus. Hence, using similarly modified HIV molecules as potential vaccines may improve the immune response.

• Testing New Vaccine Vectors: A non-disease causing Venezuelan equine encephalitis (VEE) virus suitable for humans was modified to carry selected HIV genes. When given to mice, the vaccine induced both antibodies to the virus and immune responses that killed HIV-infected cells. These experiments, and additional experiments in monkeys, demonstrate the potential for VEE-based vaccines to stimulate both arms of the immune system and to control the level of virus. Another novel vector, a weakened form of vaccinia virus called MVA, has been developed and has been shown to induce good immune responses in rodents and monkeys.

• Novel Form of HIV Induces Good Immunity: Scientists have developed a novel vaccine based on HIV fusion molecules exposed only by freezing the virus in the act of infecting a cell. This virus-cell fusion mixture, when injected into mice genetically engineered to ignore key human proteins on the cells, made antibodies against the virus-cell fusion mixture. In laboratory tests, these antibodies were able to neutralize 23 of 24 strains of HIV representing a variety of different genetic subtypes and all isolated from infected individuals.

• DNA Vaccine Protects Monkeys: Several investigators have been pursuing research on DNA vaccines. Most recently, a chimeric DNA vaccine made from harmless genes of HIV and SIV, its monkey equivalent, has shown promise in monkey studies.

  The vaccine, when combined with "booster shots" made from a specially engineered virus carrying the same genes, seemed to protect animals later given doses of a live hybrid virus made from HIV and SIV. The vaccine did not keep the animals from getting infected but seemed to keep the hybrid virus under control, making it undetectable in the blood.

• New Tests Developed to Measure Cellular Immunity: During the past year, several new assays to measure cell-mediated immunity have been developed. These assays allow researchers to better compare the effectiveness of vaccine candidates in stimulating critical immune responses.

Other Federal Agencies

• Within the federal government, several other agencies also have a role in AIDS vaccine research, including the Centers for Disease Control and Prevention (CDC); the Department of Defense (DoD); and the Food and Drug Administration (FDA). The roles of these different agencies in AIDS vaccine development are related and complementary and span the spectrum from basic research to licensure and program implementation. For example, CDC conducts epidemiologic studies and surveillance needed to define health priorities, and develops recommendations for vaccine use. The FDA establishes standards for the processes, facilities, and pre- and post-licensing studies needed to insure the safety and effectiveness of vaccines. And the NIH supports most of the basic and clinical research in fields such as immunology and microbiology that lead to vaccine development.