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molecular biological studies could enable investigators to determine sites, unique and essential to the parasite, which are potentially subject to inhibition. Such studies will lead to the rational design of new drugs which will selectively kill the parasite without harming the host.
Vaccine development. In terms of cost-benefit ratios the most successful method to prevent disease by infectious agents has been achieved by means of vaccination, as witnessed by smallpox eradication and polio control. Similar control of parasitic agents does not exist. Simply put there are no vaccines for any human parasitic infection. Much work needs to be done to increase our understanding of man's immune response to parasites. Further molecular biological research, combined with immunological knowledge, could lead to the identification of parasite constituents useful as vaccines. The ability of biotechnology to produce these candidate vaccines holds great promise for future control efforts.
Vector biology. Many of the tropical diseases are transmitted by vectors such as mosquitoes and snails. The initiation of molecular biological studies would lead to the identification of vectors responsible for disease transmission. Further, novel approaches to alter the genes of these vectors may lead to new methods of preventing infection in man.
Question. If you had additional resources to support activities in tropical medicine, could you describe what you believe to be the greatest unmet need with respect to training specialists either in the U.S. or in overseas locations?
Answer. The training of tropical medicine specialists would be greatly enhanced by providing additional institutional support to academic groups of tropical disease investigators and practitioners associated with schools of medicine and/or public health. The groups would provide training for specialists interested in clinical and public health as well as biomedical research aspects of tropical medicine. According to a recent Institute of Medicine report, "The U.S. Capacity to Address Tropical Infectious Disease Problems", such groups" are needed to sustain a core of U.S. expertise and leadership to deal with tropical disease problems." Such sustained support would provide the basis for the development of multidisciplinary approaches needed to control these diseases. The support would provide visibility and stability to the field and would thus be useful in recruiting new professionals.
Question. How is the NIAID responding to last year's report language requiring some of the new monies in the FY 1991 appropriation to be allocated to tropical medicine?
Answer. The NIAID has focused its efforts on enhancing the support for tropical disease research by funding unsolicited, investigator initiated research grants in the areas of drug and vaccine development, diagnosis and vector control, on the assumption that this will allow scientists the opportunity to follow up on leads as they arise. The NIAID will expand the number of Tropical Disease Research Units, our domestic centers for research on tropical diseases, from three to four in 1991. ́ In addition, the Institute is expanding research opportunities for individuals working in endemic areas through the support of Tropical Medicine Research Centers
(TMRC) and International Collaboration in Infectious Disease (ICIDR) programs. During FY 1991 the NIAID established three TMRCS in endemic areas. These centers provide both U.S. and foreign scientists an opportunity to investigate and collaborate on these problems which are of major public health importance.
Question. Dr. Fauci, I was contacted recently about the AIDS vaccine which has been developed by MicroGeneSys. I understand that the drug is ready to move into Phase II clinical trials to determine whether or not the drug is effective. Dr. Fauci, what is the status of clinical trials for the AIDS vaccine developed by MicroGeneSys?
Answer. The NIAID has conducted two trials, one at the NIH itself and at one of its vaccine evaluation units, to test this vaccine for safety and ability to induce an immune response. Enrollment in the second trial was completed this month, and it will be months before the data are complete. The MicroGeneSys vaccine has also been used as a booster in some individuals that had first been immunized with a different product, HIVAC-le, which is based on vaccinia, and this seems to be a very promising combination. The criteria for moving into trials of protection against HIV infection in man are still under discussion. However, some leading scientists believe that vaccine candidates should be shown to protect monkeys against simian immunodeficiency virus (SIV) or chimpanzees against human immunodeficiency virus (HIV), and the MicroGeneSys vaccine has not yet been proven to do this. We are now arranging for a trial in monkeys for the SIV equivalent of this vaccine. Our current trials will tell us more about how much of this vaccine should be given, and how often it must be given, to induce the long-lasting and vigorous response that any vaccine must produce before it can be tested for efficacy.
Question. Please tell the Committee the overall status of work to develop AIDS vaccines. How many are now being tested? When do you expect to have a safe and effective vaccine?
Answer. There are three areas that we are working especially diligently on to further our chances of developing an effective AIDS vaccine. The first is the issue of the genetic variation of the virus. Studies that explore the immunologic consequences of HIV genetic variation in terms of vaccine development are important because the production of a vaccine for AIDS is made much more difficult by the frequency with which HIV mutates. These mutations can result in subtle but significant changes in viral structure, which could render a vaccine ineffective. Investigation into the rate and extent of viral genetic mutation will provide scientists with critical knowledge needed for developing an effective AIDS vaccine.
The second is the area of adjuvant development. Several subunit vaccines which utilize proteins or peptides of the virus are likely to be candidates for clinical trials. Thus, an effective adjuvant, or a compound that enhances the immune response to a vaccine, may be critical to boosting the host response to the vaccine. Moreover, effective adjuvants may be necessary to induce long-term immunological memory, thereby decreasing the number of booster immunizations required to elicit protective immunity.
The third area includes basic immunological issues, such as identifying the components of the immune response needed for an effective vaccine. This issue is vital because HIV/SIV vaccines may require both antibody and cellular components of the immune system to be effective. Research into mechanism of protective immunity should provide insights into optimal strategies for vaccine design.
Currently, seven vaccines are in clinical trial in uninfected volunteers, and six vaccines are being evaluated in HIV-positive asymptomatic volunteers.
These preliminary studies are addressing safety and ability of the vaccine to induce immune responses. The goal of these first studies is to obtain comprehensive immunologic analyses on each candidate, and to compare these data to comparable animal model studies. In addition, there are currently several other candidate vaccines in preclinical development, and it is anticipated that a number of these will enter clinical studies in 1991.
QUESTIONS SUBMITTTED BY SENATOR ROBERT C. BYRD
Question. Dr. Fauci, there have been a number of newspaper reports that several AIDS vaccines have been found to be safe for use in humans. What vaccines hold out the most promise at this time?
Answer. It is true that several candidate vaccines have been shown to be safe in uninfected individuals, but it is impossible for us to judge which of the several vaccine candidates is most promising at this time. We are pressing ahead to determine what kinds of immune reactions each vaccine elicits, so that we can make such
Question. What plans are underway to expand human clinical trials of AIDS vaccines which have been found safe in humans to determine the effectiveness of those vaccines in both preventing and treating AIDS?
Answer. The NIAID is developing protocols to test several candidate AIDS vaccines in infected individuals. One such trial is currently underway and is sponsored by the AIDS Clinical Trial Group. This is a small trial to investigate the end points necessary to determine efficacy in this study population. Expansion of human clinical trials will take place as more and more safe AIDS vaccine candidates become available and as more is learned about the end
points necessary to judge effectiveness. The NIAID is in the process of putting in place the infrastructure necessary to carry out such trials.
Question. Given the mortality rates of those infected with HIV, what plans does the NIH have to begin efficacy tests on AIDS vaccines which have proven to be safe for use in humans?
Answer. No vaccine candidate will be tested in large scale efficacy tests until it is proven safe and capable of eliciting a vigorous immune response. We are searching diligently for clues as
to what kind of immune response protects individuals against HIV infection--if we find that, we will be able to speed up vaccine development enormously, because we will know how to tailor and how to select the vaccines. Until then, we have to rely on tests in monkeys and chimpanzees to help us decide which candidate vaccines are likely to protect humans against HIV infection.
Question. How much funding is included in the FY 1992 budget request for Phase II testing of vaccines and what funding levels would be required to implement Phase II testing on promising vaccines?
Answer. At present, the budget is not broken down into arbitrary divisions of Phase I and Phase II. However, it is estimated that the dollar figure will be in the millions for Phase II testing.
QUESTIONS SUBMITTTED BY SENATOR DANIEL K. INOUYE
Question. Dr. Fauci, I read in several newspapers in January of this year that an AIDS vaccine produced by a company named MicroGeneSys has been found to be safe for use in humans. The articles also indicated that the vaccine also produced some immunological response. Can you tell me what plans are underway to expand human clinical trials of any AIDS vaccines which have been found safe to Phase II testing to determine the vaccine's effectiveness in both preventing and treating AIDS?
Answer. The NIAID is developing protocols to test several AIDS vaccine candidates in infected individuals, and one such trial is currently underway, sponsored by the AIDS Clinical Trial Group. These are small trials. Designing large trials for efficacy in preventing AIDS is difficult; a very large number of individuals at high risk for acquiring the disease must be enrolled, they must be vigorously advised to change their behavior so that their risk will decrease, and they must be followed for a long time to determine whether they become infected. We are now considering the best way to implement such trials.
Question. It seems that the risk of delaying further investigation of a vaccine which might be the answer or might lead to the answer to AIDS is more significant than any risk of conducting those tests using a vaccine which has already proven to be safe in humans. Given the mortality and infection rates of AIDS, why shouldn't we begin efficacy tests on an AIDS vaccine which has proven to be safe for use in humans?
Answer. It is not a good use of our limited resources to test vaccines without enough data to evaluate which ones are most promising, which dose should be used, how and when the immunizations should be given, and so on. We simply do not have all of this information yet, although we are trying very hard to get it. One of the biggest limitations we have seen so far, in the current vaccines, is that the immune responses do not last very long, so even if the vaccine is capable of producing immunity it might last only a month
or two, and we do not know when people in the trial will be exposed to the virus.
Question. How much money would be required to conduct efficacy studies on AIDS vaccines which have completed Phase I safety tests, including the cost of purchasing the product used in the study?
Answer. The cost of efficacy studies on a product which has completed Phase I testing would be in the millions. The cost for vaccine used in these studies would have to be determined on a case by case basis as some vaccines are more costly to manufacture than others.
Question. I understand that some scientists believe that efficacy testing on an AIDS vaccine should be delayed until the vaccine achieves positive results in animals. I also understand almost all of the vaccines currently in use were not developed using animal models and that some vaccines which looked extremely promising in animals did not achieve significant results in humans. Do you believe that animal tests should come before human efficacy tests even when a vaccine has proved to be safe to administer to humans? If so, how do you reconcile the history of the role of animal models in vaccine development with your conclusion?
Answer. Actually, there are several examples in which animal experiments have been important in vaccine development, including the recently developed hepatitis B vaccine. The data we obtain from animal models has definite limitations, but it is regarded by many scientists as a strong argument in favor of human efficacy testing if protection has been shown in monkeys against SIV. Other information, such as the ability to produce a longlasting and strong immune response, such as antibodies that inactivate or neutralize the virus or white blood cells that destroy cells infected by the virus, would also be good evidence that a human test should be done, but so far we do not have all of this information about any of the vaccines. Phase I clinical trials show safety but do not determine efficacy. Promising new candidate AIDS vaccines are being developed and tested in Phase I for safety. Due to limited resources, it is important to have as much data as possible, both animal data and human safety data, in order to help evaluate whether a vaccine is a good candidate for efficacy testing.
QUESTIONS SUBMITTTED BY SENATOR DALE BUMPERS
Question. How much money did the NIAID request of the Assistant Secretary for Health for HIV programs, as compared to the final level
forwarded in the President's budget? If it was more, what program
areas were cut to meet the President's level?
Answer. The NIAID requested $581,471,000 of the Assistant Secretary for Health (ASH) for HIV programs in FY 1992. The amount included in the NIAID's FY 1992 President's Budget for HIV activities totaled $459,339,000. The programmatic areas that were reduced from the ASH request to meet the President's Budget level were as follows. Basic science research was reduced about $44 million, drug