Range and cost of major chronic neurological and sensory disorders-Continued Legally blind. Partially seeing.. 411,000 3,500,000 Hearing disorders: $600, 000, 000- "New Vistas for the Blind," p. 7, HEW Indicators, October 1966. About half of total blind are not employed; an estimated 76.4 percent of legally blind population in the United States is 40 years and over. Over half of the 3,500,000 partially seeing are under age 65 (U.S. National Health Survey). Almost 1,000,000 of the 3,500,000 have severe visual_impairment (U.S. National Health Survey). Almost 12,000,000 (estimated) children in the United States require eye care (National Society for the Prevention of Blindness). In October 1964, 32,256 pupils were enrolled in American schools and classes for the deaf, according to American Annals of the Deaf (January 1965) at an average institutional cost of $4,000 per year. Of the estimated 80,000 totally deaf adults, half are assumed to be fully disabled and half partially disabled. Deafness incidence rises rapidly with age. Prevalence based on data collected during U.S. National Health Survey, 1959-61. Concerning activity limitation, the survey reports: "About 93 percent of persons with hearing impairments have no limitation of any kind in their usual activities because of this type of impairment." Data collected by U.S. National Health Survey (National Center for Health Statistics) in household interviews during 1959-61 indicates 1⁄2 of all reported speech defects were among children under age 15. Note. The 2 deficits, "hard of hearing" and "speech and hearing" frequently occur together, making it difficult, statistically, to separate these 2 categories of impairments. Average prevalence of cases is based on data collected by the National Center for Health Statistics. An estimated 15 to 20 percent of the school population is affected by other degrees of speech impairment. In fall of 1966 there were 43,055,000 children in grades kindergarten through 12th grade in U.S. public schools, and an estimated 6,700,000 more in private schools, Fizures indicate deaths from neurological ailments during 1964, as reported by U.S. National Vital Statistics Division, PHS. 1 Morbidity estimates, for most specific neurological diseases, not available from Division of Health Interview Statistics. Institute estimates obtained from the respective voluntary associations. 1 Figures on cost of neurological disorders are estimates only, calculated on the following assumptions: (a) Assume that the annual maintenance of the partially disabled individual costs approximately $500 per year for drugs, physicians' fees, and special management. (b) Assume that the annual maintenance of the totally disabled individual cared for at home costs approximately $1,000 per year. (c) Assume that the annual maintenance of the totally disabled individual cared for in public and private institutions costs approximately $2,000. 3110,039,00) per year according to conservative estimates for direct expenditures for services and supplies for diagnosis, treatment, and rehabilitation of stroke victims (Report to the President, a National Program To Conquer Heart Disease, Cancer and Stroke. vol. 1, December 1964). ALS fact sheet, "Amyotrophic Lateral Sclerosis," NINDB. "Spinal Birth Defects, Hope Through Research," 1966. Caveness, William F., and Walker, E. A., editors: "Head Injury Conference Proceedings," J. B. Lippincott Co., 1966. For 1953, Federal, State, and local financial aid to 97,800 blind persons totaled $97,000,000. ⚫5 percent of schoolchildren. #5 to 10 percent of all schoolchildren. NOTE. The commonly accepted estimate is that 10,000,000 to 20,000,000 Americans have 1 or more neurological handicaps; many have multiple handicaps. MENTAL ILLNESS Statistics on the total current number of mentally ill persons receiving psychiatric care by type of facility and estimated costs. I. Estimated number of patients under care More than 2.4 million Americans received care for mental illness during 1965 in a variety of hospitals, clinics, and other outpatient units. Not included in this total are persons treated by private psychiatrists or other mental health practitioners, or treated in nonpsychiatric mental health facilities, or patients in institutions for the mentally retarded. The 2.4 million persons represent the sum of all admissions (excluding transfers) during the year and resident patients at the beginning of the year; for outpatient psychiatric clinics the number on the rolls of the clinics plus admissions during the year. To the extent that psychiatric patients are discharged from such facilities as general hospitals to mental hospitals or to psychiatric clinics there is some duplication in the count of admissions in combining data. The 2.4 million persons were treated in the following types of facilities: To Federal, state, and local governments for care of patients, fiscal year 1966, $2,354,181,000. BIOLOGICS STANDARDS ONCOGENICITY IN RELATION TO VACCINES Studies of the relationship between certain viruses and the tumors they produce in experimental animals have constituted, as in prior years, a major portion of the DBS research program. Many mammalian and avian species harbor latent viruses, some of which have been found to have an oncogenic or tumor-producing potential. These findings are of particular consequence in biologics control since most virus vaccines are produced in mammalian or chick embryo tissue culture or in embryonated eggs. When the oncogenic virus is a contaminant of the vaccine it can be eliminated by changing production techniques; however, if the vaccine virus itself has an oncogenic potential, the problem is infinitely more complex, requiring broad studies of long duration involving large numbers of animals to demonstrate the effects. The demonstrated capacity of simian virus 40 (SV40) and of certain adenoviruses to produce malignant tumors when injected into newborn hamsters has evoked wide interest in the scientific community and has stimulated a variety of investigations of the mode of action of these agents. Contributions of the DBS staff to the development of this subject began with the first demonstration of the ability of SV40 to produce subcutaneous sarcomas in newborn hamsters in 1961. Although the relevance of tumors in newborn hamsters to the problems of human cancer has yet to be assessed, and the hamster tumor viruses at the present time pose only a hypothetical threat to the public health, there is no tendency to minimize the eventual significance of the research under way in this area, and the newborn hamster stands out clearly as the animal of choice for testing potentially oncogenic viruses of mammalian origin. The hamster test, in fact, has become a criterion to be invoked in appraising the safety of viral vaccines for human use. All of the animal tumor viruses thus far encountered have the property of remaining in their hosts for long periods of time without causing any apparent disease. In this state they are latent (lying in wait) until induced to spring forth and manifest their malignant effects. Simian virus 40 (SV40) and adenovirus 12 have been studied in detail by Dr. Bernice E. Eddy with respect to their propensity for remaining latent in human cell cultures, retaining throughout many passages the ability to produce fatal tumors when injected into newborn hamsters. Dr. Paul Gerber, investigating the relationship between SV40 and its cellular environment, has found that cell-free fluids from hamster tumors produced by SV40 usually fail to yield any infectious virus, but cells from the tumor, when seeded onto sensitive indicator cells, become foci of SV40 infection. These cells, said to be in a "virogenic state," can be induced to pass on the SV40 infection to adjacent sensitive cells with increased efficiency following exposure to ultraviolet irradiated, non-infectious Sendai virus. The mechanism responsible has not been elucidated, but the inductive effect of the non-viable Sendai virus upon the totally unrelated latent SV40 virus adds another dimension to the concept of latency of viral infection. When SV40 and adenovirus 12 were injected simultaneously into newborn hamsters by Dr. Ruth L. Kirschstein and her associates, 63 to 80 percent of the animals developed, within 12 weeks, tumors which were histologically identified as produced by adenovirus 12. Most of the remaining animals after 16 to 28 weeks developed tumors characteristic of SV40. No new types of tumors resulted from the double infection, and there was no evidence that either virus had been altered in its course by the presence of the other. Although independently tumorigenic, SV40 and the adenoviruses are known to be capable of combining forces in a sinister way to form a hybrid virus with mutual survival benefits for the two parent viruses. The hybrid of SV40 with adenovirus 7 has been found by Dr. Kirschstein, in collaboration with Drs. Alan S. Rabson and George T. O'Conor of the National Cancer Institute, to produce SV40-type brain tumors in newborn hamsters after intracerebral inoculation. This confirms that the hybrid virus contains that portion of the SV40 genome which carries the oncogenic message. The hybrid does not exhibit the infective behavior of SV40, however, and thus is believed to contain only a part of the SV40 genome. Adenovirus 3 is another of the adenovirus group which appears to be capable of hybridizing with SV40. Dr. J. Anthony Morris, working in collaboration with Dr. Eddy, and a group of investigators in NIAID, has found two strains of adenovirus 3 which, having come into contact with SV40, have acquired the ability to produce SV40 tumor antigen in cell cultures and SV40-type tumors in newborn hamsters. In a research contract supervised by Dr. Kirschstein and Dr. Amos E. Palmer, a wide variety of biological products are being tested for freedom from oncogenic properties in newborn hamsters. Involving many hundreds of animals, each intensively observed for its lifetime, this study, while intricate, difficult, expensive, and of minor academic interest, nevertheless is believed to be essential to maintain our confidence in the safety of the biological products licensed by DBS for human use. In a separate project, also under the research contracts program, some of the chemically-defined ingredients of biological products (such as preservatives, stabilizers, and other chemicals) will be investigated to verify their freedom from oncogenic effects. The tests will be conducted in several species of rodents and will include repeated injections of the substances at maximum tolerated dose. A number of other projects are being organized to assess the carcinogenic or toxic effects of mineral oil emulsifier preparations of vaccines, to develop techniques for the detection of latent viruses in tissue cultures and other substrates for vaccine production, and to explore the usefulness of chromosomal analysis for discerning early changes in cells as indices of oncogenic effects. Thus, the research contracts program, which permits the temporary expansion of facilities and personnel to attack problems of current importance, promises to become a vital part of the DBS armamentarium. It represents, so far as possible, an extension of the interests and concerns of DBS scientists for the safety of biological products. RUBELLA VACCINE Rubella (German measles) is one of the common viral communicable diseases of childhood. It is usually clinically benign. The major hazard of the rubella virus lies in the risk of its transmission to the fetus during early pregnancy, resulting in fetal abnormalities, known as teratogenesis. These rubella-induced defects include blindness, deafness, congenital heart disease, and brain involvement resulting in mental retardation. Since the disease is less communicable than rubeola (common measles) and chickenpox, about 1 in 5 persons can expect to reach adulthood without having had rubella. Thus, a sizable percentage of women in their child-bearing years possess no protective antibodies against rubella, and if exposed during pregnancy, may give birth to deformed children. Rubella was first linked with birth defects in 1941 by Dr. Norman Gregg, an Australian ophthalmologist, who traced an unprecedented number of cataracts in babies to an epidemic in 1940. Methods for laboratory study of the agent did not become available until 1962 when two groups of investigators, one at the Harvard School of Public Health and the other at Walter Reed Army Institute of Research, simultaneously reported the propagation of the virus in cell cultures. The discovery, a result of experiments completed in late 1961 and early 1962, was achieved independently and by different methods by Drs. Thomas H. Weller and Franklin A. Neva, of Harvard, and by Drs. Paul D. Parkman, Edward L. Buescher, and Malcolm S. Artenstein of the Walter Reed Army Institute of Research. Shortly thereafter, the impact of the nationwide epidemics (1964 and 1965). with an estimated 20,000 babies born with rubella-induced abnormalities, focused the public attention on the rubella problem and the need for a vaccine to prevent the disease. Since that time, investigators in this country and abroad have attempted to develop immunizing preparations with both killed and live rubella virus. Both preparations, however, posed problems of considerable complexity. There has been little progress in the development of a "killed" rubella virus vaccine. Although the rubella virus is readily inactivated, thus far no one has been able to prepare a completely inactivated virus preparation that retains sufficient antigenicity to evoke a protective antibody response in man. Initial work by several research groups with live virus preparations were equally discouraging. Several tissue culture propagated rubella virus materials when inoculated into volunteers produced a rash disease and the infection spread to involve uninoculated persons. As a result of the increasingly intensive study of rubella by a number of investigative groups, the Division, in 1964, established a comprehensive research program in order to facilitate the ultimate licensing and control testing of the hoped-for vaccine. Drs. Harry M. Meyer, Jr., and Paul D. Parkman, because of their arcknowledged expertise in viral immunology, were placed in charge of the program. In the course of two years of intensive study, they developed a rubella virus strain which meets the generally accepted requirements-that is, one that will produce a non-transmissible infection, yet confer long-term immunity. Since earlier workers in the rubella field had ben hamstrung by a lack of assay methods which could be used to signal that their manipulations had actually modified the virus, the DBS workers first concentrated on the development of laboratory methods that could be employed to detect changes in the virus induced by protracted cell culture passage. They subjected several rubella virus strains to repeated passage in primary African green monkey cell cultures. As the progressively higher virus passage levels were obtained, their biological characteristics were carefully studied. High-passage virus was found by in vitro techniques to be distinctly different from low-passage "virulent" virus. The high-passage material caused a rapid cytopathic effect and other distinctive changes in certain types of tissue cultures relatively unaffected by the "virulent" virus. Also, the high-passage virus induced the production of increased amounts of interferon when propagated in tissue cultures. Of primary importance, however, was the finding that the high-passage virus of the 77th passage level (HPV-77 strain) when inoculated into rhesus monkeys, resulted in the development of immunity without viremia or spread to uninoculated contacts. These laboratory observations clearly indicated that the HPV-77 rubella virus strain had been sufficiently modified by tissue culture passage to use in an experimental vaccine. The vaccine was prepared under the same rigorous standards and safety tests that apply to the production of the live attenuated vaccines for measles and poliomyelitis. The next step was a clinical trial of the vaccine. Clinical trials of adequately tested rubella virus preparations offer little risk if done in such a way as to insure that pregnant women are not exposed to vaccinees or to persons infected by contact with vaccinees. These precautions can best be carried out in institutions where the population is less mobile than in the community-at-large and the movement of personnel is subject to administrative control. The Arkansas Children's Colony, a State educational institution for mentally retarded children, met these requirements. The Colony is situated in a rural area near Conway, Arkansas, and the children live in cottages, thus making it possible to isolate small groups from outside contact for a number of weeks with no interruption in their training program. It was here that the Meyer-Parkman team conducted the pilot studies with their experimental vaccine, working with the full cooperation of the Department of Pediatrics, University of Arkansas School of Medicine, and personnel of the Arkansas Children's Colony. Sixteen girls, with the written consent of their partents, were selected for the study. All were rubella-susceptible. Eight were inoculated with the high passage virus preparation. The other eight served as controls. All lived in the same cottage in close contact with one another. None of the inoculated girls showed any sign of rash, or enlargement of the lymph nodes, or illness which could be attributed to the vaccine, yet all developed virus neutralizing antibodies indicative of immunity. None of the uninoculated became infected. These results indicated that the HPV-77 rubella virus strain was attenuated and produced non-communicable, immunizing infections in recipients. Drs. Meyer and Parkman immediately revealed their findings to senior scientists in several universities. In these consultations, all agreed that it was important to confirm these observations with the least possible delay by conducting a similar but more extensive trial. The second study involved three cottages and 48 rubella-susceptible children. Twenty-six children were inoculated; 22 served as controls. The results of this trial completely confirmed the findings of the original pilot study and were promptly reported to the scientific community. The DBS research team was honored in a special PHS awards ceremony for developing the first attenuated rubella virus strain, and for using this strain to produce an effective live rubella virus vaccine. Dr. Meyer was awarded the Meritorious Service Medal, one of the highest honors awarded by the Department to a member of the PHS Commissioned Corps, and Dr. Parkman the Service's comparable award for civil servants, the Superior Service Medal. The two pediatrician-virologists also received personal letters of congratulations from President Johnson. In the ensuing months, Drs. Meyer and Parkman have conducted further clinical studies with their experimental vaccine. Also, several university groups have used the vaccine to confirm the original findings of the DBS investigators. The HPV-77 strain has been made freely available to investigators, and a number of pharmaceutical manufacturers, both in the United States and abroad, are now engaged in further developmental research with this and other experimental rubella virus preparations. The NIAID Vaccine Development Branch is presently engaged in studies with the HPV-77 virus strain. The DBS research group is working in close cooperation with them, and every effort is being made to speed the development of a rubella vaccine that can be licensed for commercial use. The continuing efforts of the DBS research team and of the Vaccine Development Branch of NIAID will make it possible for the DBS rubella research breakthrough to be carried into the large-scale studies necessary to achieve the final goal-eradication of rubella. RUBELLA IMMUNITY TEST The remarkable progress since 1961 in the study of the rubella virus, the disease and, this year, the experimental vaccines, makes it possible to predict that rubella and its associated birth defects can be brought under control. However, |