Anthony S. Fauci, M.D., NIAID

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Testimony
Before the Committee on Health, Education, Labor and Pensions
United States Senate

Responding to the Challenges of the 21^st Century: NIH's Role in Vaccine Research and Development

Statement of
Anthony S. Fauci, M.D.
Director National Institute of Allergy and Infectious Diseases,
National Institutes of Health
Department of Health and Human Services

For Release on Delivery
Expected at 10:00 am
on Tuesday, November 27, 2001

Mr. Chairman and Members of the Committee, thank you for calling this hearing and for giving me the opportunity to provide an update on the state of vaccine research at the National Institutes of Health (NIH). As you know, vaccine research has long been a cornerstone of the NIH, particularly for the National Institute of Allergy and Infectious Diseases (NIAID), which I oversee. I would like to take this opportunity to highlight our major accomplishments and goals in this area.

NIAID-supported research has led to the development of many new and improved vaccines that are now widely used, such as those against Haemophilus influenzae type b, pertussis, chickenpox, pneumococcal disease, and hepatitis A and B. In addition to the development of vaccines against classic infectious diseases, NIAID is working to develop vaccines against chronic diseases with infectious origins, potential agents of bioterrorism, and autoimmune diseases and other immune-mediated conditions.

The rapidly evolving science base in pathogen genomics, immunology and microbiology will facilitate further progress in developing new and improved vaccines. In particular, the availability of the genomic sequences of major microbial pathogens will lead to the identification of a wide array of new vaccines. In addition, vaccines that are easy to administer -- orally, nasally, or trans-dermally - will have great utility in resource-poor settings and for mass immunization programs.

Vaccination has been recognized as the greatest public health achievement of the 20th century. Without question, vaccines have been our most powerful tools for preventing disease, disability, and death and controlling health care costs.

Recognizing the extraordinary benefits of vaccines, U.S. government agencies charged with protecting and improving the public health have traditionally made vaccine research and development a top priority. Within the Federal government, more than 20 different agencies have a role in vaccine research. Among these, the NIH, the Centers for Disease Control and Prevention (CDC), the Department of Defense (DoD), the Food and Drug Administration (FDA), and the United States Agency for International Development (USAID) are the Federal agencies with the largest investment in vaccine research, development, and distribution.

The roles of these different agencies in vaccine development are related and complementary, and span from basic research to licensure and implementation. Moreover, NIH and other agencies actively pursue research that involves interaction with industry and academia and the transfer of technology to the private sector for commercialization. Historically, an important focus of these efforts has been to further explore concepts that may not be of immediate financial interest, including those for which the principal market might be less developed countries, but nonetheless that are of great public health importance. For example, NIAID's investment in the new vaccine against Streptococcus pneumoniae, one of the leading causes of morbidity and mortality in children worldwide, exemplifies our commitment to global health. Our pharmaceutical partner in this effort developed and licensed a highly efficacious pneumococcal vaccine for use in the United States and has continued to expand on the formulation of this vaccine to add pneumococcal types prevalent in less developed geographic areas.

The NIH has three broad goals in vaccine research:

Identifying new vaccine candidates to prevent diseases for which no vaccines currently exist;
Improving the safety and efficacy of existing vaccines; and
Designing novel vaccine approaches, such as new vectors and adjuvants.

To carry out these goals, NIH supports basic and applied research in fields such as immunology and microbiology that leads to vaccine development. The first step in developing new medical advances often occurs in laboratories such as those at NIH and universities around the world where NIH-supported scientists perform experiments to answer fundamental questions about infectious microbes and the human immune system. Scientific knowledge gained through this basic research provides the foundation for designing new or improved vaccines, treatments, or diagnostics.

NIH, particularly NIAID, has made a significant investment in the burgeoning field of microbial genomics, which will undoubtedly be a critical component of this century's strategy to develop new vaccines. We have funded projects to sequence the full genomes of over 50 medically important microbes, including the bacteria that cause tuberculosis, gonorrhea, chlamydia and cholera, as well as individual chromosomes of important organisms such as the parasite that causes malaria and the mosquito that transmits the disease. Many of these microbes have been completely sequenced and are now being annotated and analyzed. The availability of the genomic sequences of major microbial pathogens will facilitate the identification of a wide array of new antigens for vaccine targets.

NIAID maintains a strong clinical research infrastructure to carry out vaccine-related clinical studies in humans. For example, NIAID supports Vaccine and Treatment Evaluation Units, which conduct Phase I, II, and III clinical trials to test and evaluate vaccine candidates for infectious diseases. This network has served as a national resource for the independent evaluation of vaccines since 1962.

NIAID also has the primary responsibility for HIV vaccine research and development. In order to expedite the development and testing of HIV vaccines, the Institute has developed an integrated and comprehensive research program that supports the entire spectrum of research ranging from the earliest stages of HIV vaccine discovery, through product development and all phases of human clinical trials.

NIAID also plays a critical role in vaccine development by providing scientists with reagents that might not otherwise be shared because of proprietary interests. The importance of this role was clearly demonstrated during the 1997 Hong Kong outbreak of H5N1 avian influenza. Fortuitously, as part of NIH's long-standing research into respiratory viruses, the specific antiserum needed to identify the H5N1 avian influenza strain was available in sufficient quantities from the Institute to quickly develop test kits for detecting the avian influenza virus. CDC, WHO, the Hong Kong Department of Health and other collaborators used these kits in their extraordinarily successful public health response to the outbreak. NIAID also supported the emergency production of a pilot lot of vaccine against this influenza strain and conducted two trials in humans.

Most recently, NIAID has established the Dale and Betty Bumpers Vaccine Research Center within the NIH intramural research program, which provides a unique resource dedicated to vaccine science. The Vaccine Research Center (VRC) has 3 major goals: 1) scientific design and rational development of effective vaccine candidates; 2) evaluation and optimization of immune responses generated by candidate vaccines; and 3) advancement of promising vaccine candidates into human trials.

The VRC is dedicated to translating basic findings into clinically relevant vaccine products. This will require the ability to manufacture candidate vaccines and to evaluate them in Phase I and II clinical studies. The Center will establish the infrastructure to manage regulatory issues and to oversee the good manufacturing practice (GMP) required for vaccine production and human testing. In addition, the VRC houses a small production laboratory.

The VRC also has recently begun human testing of a new DNA-based HIV vaccine and has several potential candidates in the pipeline. Future plans include the evaluation of several novel HIV vaccine strategies, such as the targeting of HIV regulatory proteins, as well as new vaccine delivery mechanisms and adjuvants to boost immunogenicity.

Together, these efforts have created the strong foundation from which NIH carries out vaccine research and development activities. Indeed, our investment in this research has led to the development of many new vaccines against a wide variety of diseases. For example, NIH's research support led to the licensure of Haemophilus influenzae type b (Hib) vaccine just over ten years ago. In 1985, an estimated 20,000 cases of Hib invasive disease occurred each year in this country; Hib was the leading cause of childhood bacterial meningitis and postnatal mental retardation. Since licensure of conjugate vaccines for children in 1987 and infants in 1990, rates of Hib disease among children less than 5 years old have declined by approximately 99% in the United States.

In addition, NIH devotes substantial resources to developing improved vaccines that are more effective and have fewer side effects than currently licensed vaccines. The story of NIAID's role in the development of acellular pertussis vaccines for infants during the mid 1990s exemplifies the public health benefits of the Institute's investment in basic research and its international collaborations with partners in government, industry, and academia. The new acellular pertussis vaccines are safer and cause fewer side effects because they use only select parts of the disease-causing microbe that are important for immunity.

One of the important challenges for the 21st century is the development of safe and effective vaccines for the three greatest microbial killers worldwide: HIV/AIDS, malaria, and tuberculosis. These three diseases account for one-third to one-half of healthy years lost in less developed countries. In recent years, global infectious diseases have been viewed in the context of foreign policy. The White House, Congress, foreign governments, international organizations, industry and major philanthropies all have made major commitments to fighting these infectious diseases. NIAID has a robust portfolio of vaccine research and development for these and other diseases of global importance.

NIAID has also employed innovative strategies to deal with recent vaccine shortages. For example, last summer when NIAID learned that there would be a substantial delay in the distribution of the influenza vaccine and potentially fewer total doses of vaccine for distribution than the previous year, we rapidly implemented a clinical trial to compare the immune response of a half-dose of influenza vaccine to a whole dose of influenza vaccine in healthy adults aged 18-49. While the results of the study showed that the immune response generated by the half-dose was less than that of the full dose, the difference was less than expected and suggested that if a substantial shortage of vaccine had occurred in 2000, administration of half a dose of vaccine to healthy adults might have been a viable option.

Most recently, NIAID has developed a smallpox vaccine research agenda in response to a potential bioterrorism threat. This strategy for smallpox vaccine research is a three-part program that addresses immediate, intermediate, and long-term needs. In the near-term, a bioterrorist attack involving smallpox would require the utilization of the existing smallpox vaccine supply. Approximately 15 million doses of the FDA-licensed "Dryvax" vaccine have been stored since production stopped in 1983 and clearly would not be enough to respond to a national smallpox epidemic. In this regard, NIAID last year initiated a study to determine the feasibility of expanding the use of the existing stores of the Dryvax vaccine by dilution. In this study, investigators examined the skin and immune system responses of normal unimmunized adult volunteers who were given a 1:10 dilution (10 percent) or a 1:100 dilution (1 percent) of off-the-shelf Dryvax vaccine. They compared responses to those from other volunteers who had received the full-strength vaccine. The results showed that the full-strength vaccine had maintained its potency, and that 70 percent of people who received a single dose of the 10-percent diluted vaccine developed a sore followed by a scab at the injection site and antibodies in their blood, strongly suggesting protection. Even though the 10-percent vaccine was capable of stimulating an immune response in most people in the study, it is unlikely that it would protect enough people in a large population to sufficiently stop the spread of smallpox.

Based on these findings, a larger study was designed to determine if a diluted vaccine combined with an alternative vaccination schedule could protect a greater number of people than did the standard dose and regimen. This study, which will enroll up to 684 people, is evaluating three different doses of Dryvax. Researchers will study the ability of the various vaccine formulations to stimulate a scab, or "take," at the vaccination site and to produce antibodies in the blood. If participants have not developed a scab in seven to nine days after vaccination, they will be revaccinated with the same vaccine they received the first time. By that strategy, researchers hope to learn which vaccine dose given in a single injection elicits the desirable response among the largest number of people and whether "boosters" can increase the take rate on a population basis.

NIAID is designing protocols for clinical testing of Dryvax and the newer cell culture based smallpox vaccines for use in children and previously immunized adults. At the same time, we are looking into alternative vaccine strategies with the goal of designing safer and more effective vaccines.

NIAID has also been collaborating with DOD to support the development of the next generation of anthrax vaccines that may be more appropriate than the current anthrax vaccine for use in the civilian population. At present, we are currently planning Phase 1 safety and immunogenicity trials for the recombinant protective antigen (rPA), one of the leading anthrax vaccine candidates.

As we have done in the past, we make every effort to encourage private-sector involvement in our effort to attack several of the world's most deadly infectious diseases. For example, last fall, NIAID launched its Challenge Grants program, which provides matching funds to companies who will commit their own dollars and resources toward developing new drugs and vaccines against malaria, tuberculosis (TB), influenza, and dengue virus. Some of the exciting work being done through this program includes the development of an influenza vaccine that will be administered as a nasal mist instead of an injection, making it a promising option for widespread distribution and use. The biotechnology company Aviron is currently working to provide FDA with additional clinical and manufacturing data to support the licensure of this nasal mist product. This influenza research builds on NIAID/NIH's long-standing involvement in the development of a live-attenuated influenza vaccine; since 1976, NIAID has worked with industry partners on the development of live-attenuated influenza vaccines.

NIAID has outlined its future vaccine research plans in a number of public documents, including the NIAID Strategic Plan and the NIAID Global Health Plan for HIV/AIDS, Malaria and Tuberculosis. We remain steadfast in our commitment to supporting a broad-based infectious diseases research portfolio with the goal of creating new and improved vaccines while also recognizing that we must be prepared for future bioterrorist attacks. In that regard, we will incorporate bioterrorism preparedness as a priority area of interest in several of the new research initiatives we will unveil in the coming months.

The integration of expertise brought to the vaccine development process by various partners will continue to be critical to dealing with the challenges posed by infectious diseases. As we prepare for the public health challenges of endemic, emerging and re-emerging diseases, basic research and cross-sector collaboration must be maintained. Only with such collaborations can we successfully translate basic research findings and technological advances into improved health through immunization.

This concludes my testimony. I would be happy to answer any questions that you or Members of the Committee may have.