OTHER DEVELOPMENTS As for the parainfluenza viruses, a trivalent vaccine, containing types 1, 2, and 3, has been developed and seems to be effective. It will soon be evaluated in children. A vaccine against the common cold is much further away chiefly because there are more than 70 rhinoviruses. But NIAID and Abbott Laboratories are collaborating on this problem. NIAID is also collaborating with Children's Hospital in Columbus, Ohio, to set up a rhinovirus reference typing center to lessen confusion in a very crowded field. The Columbus center will try to classify and maintain pure strains of known and newly discovered rhinoviruses. CONCLUSION Much more work will have to be done before the incidence of acute respiratory illness can be significantly reduced by the widespread use of effective vaccines. The early promising results of the Institute's vaccine development program are evidence, however, that the problem is not insoluble. In addition, these encouraging advances show that a well-planned and well-coordinated collaborative program-involving the resources of Government, the universities, and industry— works. SPECIAL REPORT ON RUBELLA VACCINE DEVELOPMENT The epidemic of rubella (German measles) during the spring of 1964 was one of the most severe in the history of the United States. It resulted in more than 1,800,000 illnesses and damaged an estimated 10,000 to 20,000 infants whose mothers contracted rubella during early pregnancy. The epidemic reached its peak in April in the eastern and southeastern parts of the country and in June in the north-central and north-western areas. The rest of the Nation was not spared: A 1965 epidemic struck the west coast, Hawaii, and Puerto Rico. SUFFERING AND ECONOMIC LOSS The epidemics left overwhelming personal tragedy in their wake. Hopes of parenthood were blighted by abortions, stillbirths, and congenital deformities. The mother-to-be and her family lived in dread that the rubella virus would strike in the first 3 months of pregnancy, when it can kill or cripple the unborn child. The suffering and economic loss to the Nation caused by the rubella epidemics cannot be fully calculated. It is estimated that as many as 20 percent of the babies whose mothers contracted the disease during the first 3 months of pregnancy were afflicted with one or more defects. In one study of a group of these women, 38 percent delivered defective infants. In two other studies, 16 percent had deformed babies. The toll has not been completely assessed. But enough evidence has been col. lected to indict rubella as a major medical and socioeconomic problem. CONGRESS TAKES ACTION Congress earmarked for 1966 an additional $1 million for a stepped-up program to develop a rubella vaccine. By protecting susceptible young married women against rubella infection before they became pregnant, the vaccine would solve this serious national problem. Responsibility for coordinating the difficult task of developing a rubella vaccine was centered in the National Institute of Allergy and Infectious Diseases. THE DISEASE Caused by a filtrable virus, rubella is a benign infection of children and young adults. It is spread by droplet spray from the nose and throat. The one severe but rare complication is encephalitis. Infection with the disease confers last. ing immunity. Usually accompanied by a pink rash that spreads over the entire body, rubella otherwise has no definite clinical manifestations. There may be cough, sore throat, and nasal catarrh. Headache, fever malaise, muscular pain, and swelling of the neck may precede the rash. Since these are also symptoms of other diseases, rubella is not an easy illness to diagnose. It is difficult at times to distinguished rubella from measles, from infectious mononucleosis, and from scarlet fever. Rubella is ordinarily a serious disease only when it occurs during the first 3 months of pregnancy. During this period, the fetus is particularly vulnerable to the virus. SOME RESEARCH ADVANCES An importance advance came in 1962 with the cultivation of the rubella virus in tissue culture. This finding raised high hopes that a rubella vaccine would eventually be developed. It also led to the development of techniques for isolating and identifying the virus and of serological tests for demonstrating previous infection and immunity. These techniques and tests opened the way for new light to be shed on the disease during the epidemics of 1964 and 1965. Further evidence was uncovered during these outbreaks about the serious effects the disease may have on the fetus and the newborn baby. The fetus under 12 weeks of age is particularly susceptible to rubella infection. If a spontaneous abortion or stillbirth does not result, the virus-which persists throughout pregnancy and is still present at birth-may cause one or more severe birth defects. Intensive studies on mothers and babies attacked by rubella during the epidemics brought new insights into these defects. It was learned that thrombocytopenic purpura (a frequently serious hematological, or blood, abnormality). transient bone lesions, hepatitis, and anemia are common defects in newborn infants with congenital rubella. These newly recognized conditions were added to a long list of other abnormalities that make up the congenital rubella syndrome; mental retardation, deafness, serious eye defects (such as glaucoma, cataracts, and abnormally small eyeballs), heart disease, enlargement of the liver and spleen, closure of the esophagus, and genitourinary defects. The rubella virus acquired during early pregnancy has been found to persist in infants for as long as 18 months after birth. These virus-shedding babies may pass the disease on to others, including women in early pregnancy. To add to the problem, these infants may not shown any signs of rubella infection. These findings highlighted the importance of isolating rubella-exposed babies from young married women not known to have been previously infected with the disease. A major contribution to the battle against rubella was the development in 1965 by scientists of the National Institute of Neurological Diseases and Blindness and the National Institute of Allergy and Infections Diseases of a simple and rapid blood test for rubella. The test is based on the principle of complement fixation, a sensitive indicator of recent infection. By detecting antibodies against rubella, it shows whether a woman has had the disease-and is therefore immune to it. The test will also aid the program to develop a vaccine, which requires thousands of tests on animals and people. VACCINE IS URGENTLY NEEDED Despite advances in our knowledge of rubella, many problems remain unsolved. No one knows, for example, how rubella causes birth defects or how infectious the virus is. The period of infectiousness is uncertain. Experts disagree on whether gamma globulin (antibody-containing human blood serum) inoculated in early pregnancy can forestall rubella infection and thus protect the unborn child. But a safe, effective method of prevention is still the biggest need in the battle against the disease. What is urgently required is a vaccine against rubella. The vaccine must be one that will not result in infection that can be spread to contacts. In other words, it must not endanger unprotected pregnant women in close contact with those who have been vaccinated. A COLLABORATIVE EFFORT UNDERTAKEN Several drug firms undertook to develop a rubella vaccine when the virus was first isolated in 1962. Success did not come easily. The main reason was that methods successfully used to develop inactivated poliomyelitis and measles vaccines failed to produce a satisfactory prototype rubella vaccine. It became apparent that the development of a rubella vaccine required a nationwide effort. Hence, the decision of Congress to place the support of the Federal Government behind the effort. In the early stages of planning, an advisory committee of virologists and pediatricians recommended that the development of a rubella vaccine be undertaken by a collaborative program directed by the Institute. Through such a program, which has worked well in the effort to develop respiratory virus vaccines, a partnership of industry, universities, and Government wages a concerted drive to produce a nationally needed product in the shortest possible time. The Institute will keep a continuing watch over the work on a rubella vaccine. It will keep in close touch with commercial concerns, the National Institute of Neurological Diseases and Blindness, and NIH's Division of Biologics Standards. Efforts will be made to quicken the pace of developing a safe and effective rubella vaccine by concentrating on those areas of research that appear to be lagging and by developing new knowledge of the natural history of rubella infection. PROGRAM MOVES AHEAD By the end of 1965, contracts had been awarded to eight of the Nation's leading pharmaceutical companies. These companies are all concentrating on removing a major obstacle to the development of an effective vaccine: the refusal of the rubella virus to multiply to high concentrations in primary tissue culture The obstacle involves the lack of an effective system for growing the rubella virus. The eight companies are exploring different systems in an effort to decide upon the most promising one. Efforts are being made to achieve conditions that will yield the highest possible concentrations of virus, using different virus isolates in monkey, bovine, and dog kidney cells and human diploid tissue cultures. Advanced techniques are being used-for example, zonal ultracentrifugation and column chromatography in attempts to concentrate and purify the virus, and cobalt irradiation-a unique method of inactivation-in efforts to find methods of inactivating the virus without losing antigenicity. The effort to produce a rubella vaccine involves a wide variety of activities by one or more of the companies engaged in the NIAID program: (1) Studying the susceptibility of the fetus to rubella infection, using the ferret, which is now the animal of choice in tests of susceptibility to rubella. (2) Developing ways to attenuate the virus, using various animal systems to indicate virulence, the ability to infect, and antibody production. (3) Preparing immune antisera to rubella isolates as needed for working reagents. (4) Developing techniques for filtering rubella virus in tissue culture fluids without significant loss. (5) Studying the physical properties of the rubella virus; for example, its reactions to freezing and drying. One important research effort is concerned with developing a live rubella vaccine taken orally in a coated capsule. It would work in much the same way as a live oral vaccine against adenovirus-4, the first promising product of the Institute's vaccine development program. The possible protective effectiveness of pooled antibodies of gamma globulin is not being ignored. One major research effort is concerned with the preparation of a gamma globulin that will have high levels of antibodies against rubella virus. Work on the development of a vaccine is expanding, and additional proposals for contract research are expected. These will contribute to the forward thrust of the work. Long-range goals are not being neglected; for example, plans are being made for facilities to field test the prototype vaccines as they emerge from the developmental stage. The National Institute of Neurological Diseases and Blindness and the National Institute of Allergy and Infectious Diseases have also increased their own basic research into the nature of the virus and the immunity produced by rubella infection. Scientists of these Institutes are also serving as project officers responsible for the coordination, administration, and technical direction of the rubella vaccine development program with the collaborative contractors. The work toward the development of a vaccine against rubella is being pursued vigorously and effectively with the advice and assistance of the Nation's leading experts. The additional funds appropriated by Congress have provided a good base for a full-scale program against a disease that has taken a tragic toll in death and disability of the Nation's infants. SPECIAL REPORT ON TISSUE TRANSPLANTATION IMMUNOLOGY THE PROBLEM OF GRAFT REJECTION One of the recurrent dreams of medicine has been to replace diseased tissues with healthy ones. So far the dream has not been fully realized. The major obstacle to successful tissue transplantation is no longer a lack of surgical techniques. The techniques for transplanting kidneys have for the most part been worked out and are continually being refined. Even lungs and livers have been transplanted in experimental animal studies. What still cannot be adequately controlled, however, is graft rejection, an immunological phenomenon which prevents transplants from remaining functional except for a relatively short time. Thus, the immunologist has replaced the surgeon as the leading character in the tissue transplantation drama. The body defends itself against attack by infectious microbes or invasion by other foreign substances by making counterattacking substances, called antibodies, and by mobilizing specialized defensive cells, such as white blood cells, or leucocytes. This defense mechanism is called the immune response and it is triggered by substances in the foreign material called antigens. Unfortunately, the body reacts to a lifesaving graft as if it were a life-threatening virus or bacterium. Following a series of complex events, the body floods the graft with immunologically active leucocytes which attack the graft and kill it. There is a major exception. When a graft is transplanted from one identical twin to another, there is no immune response. The recipient seems to “recognize" the graft and accepts it because the donor's and the recipient's cells are alike; that is, they are compatible. It was, in fact, the first successful transplantation of a kidney from one iden tical twin to another in 1954 that gave the science of tissue transplantation immunology a big boost. Five years later, there was another success, this time between nonidentical twins. And in 1962, doctors recorded a long-term graft between unrelated persons. Since 1955, about a thousand people throughout the world have received kidney grafts. A record of such grafts, the human kidney transplant register, is being kept at Peter Bent Brigham Hospital in Boston. It lists 719 cases (including 47 patients who have received 2 or more transplants) with an overall 1-year survival rate of 31 percent. AN INTENSIVE SEARCH FOR SOLUTIONS Congress authorized the NIAID in 1964 to set up a broad program of research in tissue transplantation immunology. This program has a short-term and a long-term goal. Both are related to the immunological problem of graft rejection. The short-term goal is to develop a battery of fast, simple tissue-typing tests for matching a recipient to an immunologically similar, or compatible, donor in much the way that blood donors and recipients are now matched. The long-term goal is to break down the biological barrier between donor and recipient by solving the basic riddle of graft rejection; namely, the immune response. Today NIAID, 10 contractors, and 97 grantee teams scattered throughout the world are working toward these goals. By the end of fiscal year 1966, almost $8 million will have been invested in the program, including an increase of $250,000 for fiscal year 1966. A POSSIBLE TISSUE TYPING TEST In typing for routine blood transfusion, only the various complexities of the red cells (erythrocytes) need ordinarily be considered. In typing for tissue transplantation, however, the more numerous complexities of the leucocytes and possibly other cells must be matched. Researchers know, for instance, that the mouse, which is often used as a model system in immunological studies, has 24 transplantation antigens. A possible tissue-typing test would work something like this. The physician would take a sample of the recipient's blood, separate the leucocytes, and mix them in test tubes with leucocytes from each of several prospective donors. Absence of reaction between the cells in a mixture would indicate compatibility. This is, of course, a greatly simplified version of a tissue-typing test. More over, it is not clear whether all transplantation antigens are located in the leuco cytes or whether some are in the cells of various organs. Answers to this ques tion may come from studies being conducted by several Institute grantees who are trying to find antigens in organ cells. Although work in such a new area as tissue typing takes time to yield results, the Institute's systematic and collaborative approach through contracts with universities, hospitals, and industrial research firms shows promise. Nine of the NIAID contractors (five in the United States and four in Europe) began collecting blood late in 1965. They are fractionating it and trying to iso late and identify transplantation antigens. Two of the contractors (one in the United States, the other in Europe) are also acting as serum banks for the others. The 10th contractor, a mathematician at the University of North Carolina, is developing data-processing methods for handling the results of the tissue-typing project. In 1966, some of the antigenic reagents now being produced will be sent to collaborative laboratories for cross-matching. The best typing antigensthose that cross-match most effectively among all laboratories-will become interim reference standards. They will then be deposited in the two banks for reshipping to participating research groups. RELATED RESEARCH Studies conducted by the Nobel laureate, Dr. Peter B. Medawar, have shown that the immune response can be minimized by inoculating recipients with antigenic substances before a transplant operation. Now donors are getting the same kind of treatment in studies being conducted by NIAID intramural scientists. They have found, for example, that if a donor is treated with antigenic material before a transplant operation, the graft takes more readily. This procedure has been done with such diverse materials as viral, bacterial, invertebrate, and mammalian antigens. The main focus here is not on matching donor and recipient but on modifying donor antigens so that they will not trigger the immune response in the recipient. Other research workers, their minds more on the recipient, are trying to find improved immunosuppressive chemicals which will selectively limit the immune response for a short time and in the area of the graft rather than throughout the body. Presently used agents, such as azathioprine, azaserine, and cortisone, prevent graft rejection but weaken the recipient's ability to fight infection. The Institute has invested most of its transplantation immunology funds in 97 grant-supported fundamental studies. Reports on these in 1965 included the following highlights: For the kidney graft recipient, the first 90 days are the most critical. If he retains the transplant that long, chances are quite good that he will retain it for a year. More efforts should be made to preserve and store cadaver kidneys, since they are more readily available. It seems more advisable to accept kidneys from live adult donors only in special circumstances. An experimental immunochemical method has been developed for determining the probability of kidney rejection. It is now being tested on patients. Kidney graft survival time has been lengthened in animals from 17 to 87 days through a kind of antigenic desensitization treatment of the recipient with fractions of donor spleen. Using standard experimental techniques, one group of workers has performed liver grafts on 80 dogs and observed the first long-term survivors. A HOPEFUL LOOK AHEAD NIAID experts and research workers have set up the ground rules for successful tissue transplantation, hopefully in the near future: Through tissue typing, choose a donor carefully and matched his immunologic characteristics as closely as possible to those of the recipient so that the immune response will be minimal. Through some procedure, modify as much as possible antigenic substances in the graft even before it is removed from the donor, to further minimize the immune response. Through adequate treatment of the recipient with immunosuppressive agents before and after surgery, selectively limit any remaining immune response without endangering the recipient. To be really useful, these three procedures must be refined. The Institute's broad program is aimed at doing just that, to the end that tissue transplantation will eventually become as routine and successful as blood transfusion. SPECIAL REPORT ON ROLE OF RESPIRATORY INFECTIONS IN EMPHYSEMA More than 10,000 Americans will die of emphysema this year. Reported deaths from this lung disorder have risen more than sevenfold in the last decade. The death toll from emphysema in the United States was 1,914 in 1952. It |