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

AIDS VACCINES

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

us -

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

AIDS

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

development and clinical trial activities were reduced $29 million, vaccine development and clinical trial activities were reduced $28 million, and studies of the natural history, transmission and risk factors were reduced $21 million.

Question. There has been some interesting news reported regarding progress in the development of AIDS vaccines. To date, only Phase I trials have been undertaken. Has the NIAID made any estimates of what the cost would be of initiating Phase II or III trials of a candidate vaccine and have any plans been made for identifying these resources in a short period of time?

Answer. Presently, the budget is separately developed for Phase I, Phase II, and Phase III Trials. However, we estimate that the dollar figure will be in the millions for Phase II and Phase III testing. The cost for vaccines 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. 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.

Question. A recent report on a VA study of the value of early intervention with AZT suggests a possible differential impact for minorities with HIV infection. Can you comment on this study and explain what progress the NIAID has made in increasing the

demographic diversity of participation in the ACTG trials? How do these statistics compare to enrollment in the Community Program for Clinical Research on AIDS?

Answer. The Veterans Administration (VA) Cooperative Trial #298 looked at early versus late initiation of zidovudine in symptomatic HIV infected but non-AIDS patients. It, as well as the larger ACTG studies 016 and 019, showed a significant benefit of zidovudine in delaying progression to AIDS with early use compared to placebo. In a analysis done retrospectively, the VA investigators did not find an apparent benefit of early versus late therapy for Blacks and Hispanics as compared to Whites.

However, both larger NIAID AIDS Clinical Trial Group (ACTG) studies, each of which enrolled more minority patients than the VA study, showed significant benefit of early zidovudine as compared to placebo in delaying progression to AIDS for Blacks and Hispanics. It is probable that the apparent divergent results stem from differences between the two ACTG studies and the VA study in terms of degree of illness of patients, compliance rates, dropout rates from study, and other confounding factors.

Regarding demographics, in the past three years, the ACTG has made significant strides toward increasing the diversity of participants to reflect better the demographics of HIV-infection in the general population. Currently, Women represent 9.6 percent of the AIDS cases in this country and represent 6.2 percent of the patient caseload of the ACTG. With respect to Blacks and Hispanics, as a percent of AIDS cases, they represent 28.3 percent and 16 percent respectively. Within our ACTG, this same group represents

16.9 percent and 15.1 percent respectively. This is a substantial increase from 1987, when they made up only 7 percent and 11 percent of the patients in trials. We recognize that these figures are not optimum, but we are making every effort to close the gap and create parity between the percent of cases to percent of participation in the ACTG.

Within our Community Program for Clinical Research on AIDS the demographics are more reflective of the populations cited, with Women representing 18 percent of the cases, Blacks 38 percent and Hispanics 16 percent.

Question. There has been growing interest in research into treatments for opportunistic infections in addition to clinical trials of anti-viral treatments. Of the estimated 7,500 persons currently in clinical trials funded by the NIAID, how many are participating in anti-viral trials and how many are participating in opportunistic infections treatment trials?

Answer. Cumulatively, 8,685 patients have been enrolled in antiviral studies and 2,914 in opportunistic infections treatment trials in the AIDS Clinical Trials Group. As a result of a heightened emphasis in opportunistic infection (01) research by NIAID, 1,008 patients have been enrolled into OI trials during the past year.

Question. If additional funds were provided for AIDS research beyond the President's budget request, what areas would you identify as the top priority for expansion?

Answer. The area where funds are most needed would be vaccine research and development. These funds would be used to build the infrastructure necessary for phase II and III efficacy trials.

QUESTIONS SUBMITTTED BY SENATOR HARRY REID

CHRONIC FATIGUE SYNDROME

Question. How many full-time staff are working on chronic fatigue syndrome research activities at the NIAID? Will any staff be added for these activities soon?

Answer. We do not have any staff assigned full-time to the study of chronic fatigue syndrome (CFS), however, within our Intramural program, two physicians and two nurses devote substantial portions of their time to clinical studies of CFS. They are assisted by research fellows as they rotate through the infectious diseases program. Two doctorate-level researchers also are involved in laboratory studies in addition to two scientists who are conducting contracted laboratory research activities for the Institute. Three doctorate-level scientists are involved in the administration and stimulation of extramural research. We have no plans to hire additional personnel in the immediate future.

Question. What types of research is the NIAID pursuing on

chronic fatigue syndrome?

Answer. The NIAID's broadly-based intramural research includes studies of Human Herpesvirus-6 and -7, enteroviruses and retroviruses, immunologic competence, sleep disorder,

neuropsychiatric and neuroendocrine function, patient-care regimens, and therapies.

The extramural CFS program includes studies of prevalence, risk factors, natural history, role of viral reactivation, immunologic markers and psychoneurologic correlates. Relevant viral and immunological studies being conducted at present include:

A recently funded study of enterovirus-induced polymyositis in mice provides an animal model that could yield insights about the pathogenesis of CFS.

Ongoing studies of the effects of acute viral infection involving white blood cells on immunological function, activation and suppression are providing invaluable data with which to compare immunological parameters in CFS.

Studies of the molecular basis of reactivation of latent viruses continue to build the foundation for our understanding and ultimate control of this important process which may contribute to the morbidity in CFS.

The NIAID supports major research efforts on mechanisms of immunologic diseases and on the biology of the immune system. These studies should lead to a better understanding of the immune mechanisms and/or dysfunctions which may underlie the complex CFS syndrome.

Question. Which Institutes of the NIH are involved in chronic fatigue syndrome research? Which are cooperating in this research?

Answer. The NIAID is the only institute with a chronic fatigue syndrome research program, but NIAMS has a program of intramural and extramural research in fibromyalgia, a closely related illness. Investigators at the NIAID are collaborating with investigators at the NINDS and NCI at the NIH and also with colleagues at the NIMH. They also are providing advice to and collaborating with extramural scientists.

Question. What additional extramural research on chronic fatigue syndrome will be conducted by the NIAID in the future?

Answer. The NIAID recently solicited applications for a cooperative research center for multidisciplinary studies and expects to make at least one award in FY 1991. A program announcement of interest in receiving applications concerned with natural history and etiology also is planned.

Question. Dr. Fauci, you have reported to the Congress that chronic fatigue syndrome is triggered by an infectious agent. The CDC has reported that this illness sometimes appears in "clusters," such as we have had in the Lake Tahoe area. What research is the NIAID doing to help identify agents that might cause this type of "cluster?"