Physician researchers discovered that it was possible to attenuate, or weaken, the rubella virus and use it as an effective vaccine to prevent German measles.
Rubella, also known as German measles, lasts less than two weeks in children. Symptoms include swollen glands, a low fever, and a transient three-day rash. In pregnant women, however, the virus that causes German measles can infect the developing fetus, especially during the first three months of pregnancy, and can cause serious developmental abnormalities. Approximately 15 to 20 percent of pregnant women who acquire German measles during the first three months of gestation give birth to infants that have one or more of the following problems: heart abnormalities (50 percent), hearing impairment (50 percent), eye abnormalities and blindness (40 percent), mental abnormalities (40 percent), blood abnormalities such as anemia and bleeding (30 percent), bone lesions, enlarged liver, enlarged spleen, and hand abnormalities. About 10 percent of babies born with congenital rubella die, while severe infections of the fetus result in spontaneous abortion.
The most severe abnormalities occur when the infection occurs during the first two months of pregnancy. Studies show that 50 percent of pregnant women infected during the first month give birth to defective babies, but only about 10 percent of the babies had abnormalities when the mothers were infected during the third month. Less than 5 percent of pregnant women infected in the fourth month of gestation have defective babies. Infections after the fourth month cause less serious and cryptic abnormalities in the fetus.
The reported incidence of German measles in the United States during the early 1960’s usually ranged between forty thousand and forty-five thousand cases per year. In the spring of 1964, an especially severe epidemic of rubella occurred that resulted in approximately seven thousand fetal deaths and twenty thousand babies with congenital abnormalities. It is estimated that twenty-five hundred babies died. Serum from the babies with congenital abnormalities contained antibodies against the rubella virus and many had viruses in their throat secretions, urine, cerebrospinal fluid, and most tissues.
The rubella virus interferes with the development of many organs and continues to cause damage to many infants after they are born. Nearly 10 percent of the infants with congenital rubella still shed viruses ten to thirteen months after their birth. About 35 percent of these babies have extremely low platelet counts that result in spontaneous bleeding. Low numbers of red blood cells, inflammation of the liver, and bone disease afflict many of the bleeding babies, who often die in the first year after birth. The rubella virus has been shown to inhibit the division of human embryonic cells in cell cultures and cause chromosome breaks. This may explain why infants with congenital rubella generally have organs that are reduced in size.
Congenital rubella represented an important public health problem before the development of vaccines because affected newborns shed the virus for up to a year after their birth. This exposed pregnant women and personnel at doctors’ offices to the virus. Newborns with congenital rubella also were a problem in hospitals because secreted viruses would infect other newborns in pediatric wards. The development of a safe vaccine was an important first step in reducing the incidence of congenital rubella.
A 1962 paper by Paul D. Parkman describes how his research group isolated, propagated, and characterized the agent responsible for German measles. His associates collected throat washings from hospitalized patients who had signs and symptoms of German measles. Also collected from all patients were blood samples. The throat washings were mixed with African green monkey kidney cells, and the cells were then grown in culture. The agent collected from the patients produced no visible changes in the cells; however, the agent’s presence was detected by adding the echo virus. If the rubella virus was infecting the monkey cells, the cells would be resistant to the echo virus, but if they were not infected, the cells would lyse, or disintegrate.
Parkman’s group found that sixteen (80 percent) of twenty throat washings from patients diagnosed with rubella interfered with echo virus lysis of the cells. Fourteen (67 percent) of twenty-one patients with probable rubella had viruses in their throat washings. Only one (4 percent) of the twenty-five patients diagnosed with scarlet fever and four (30 percent) of thirteen patients with atypical skin rashes were found to have rubella virus in their throat washings. These data suggested that a common virus was found in the throat washings of persons with German measles.
It was found that patients with German measles all developed antibodies against the rubella viruses. The concentration of antibodies was shown to increase eight- to sixteen-fold in the two-week period following the rubella rash. The antibodies were specific, having no inhibitory effect on a number of other viral types. In addition, the cultured rubella virus was not neutralized by antisera against other viruses.
With the development of immunological methods for identifying the rubella virus, Parkman’s research group showed that the virus reproduces in the throat for about two weeks before symptoms appear. Viruses are found in the blood as much as a week before the rash. The two-week incubation period is followed by swelling of the lymph nodes behind the head and ears. A few days later, the rash develops as well as antibodies against the virus. Over the next two weeks, the viral infection diminishes but viruses can still be isolated from the throat in many cases. The shedding of viruses for as much as a week before symptoms appear, as well as after symptoms disappear, makes this disease difficult to control by isolating patients.
Parkman, Harry M. Meyer, Jr., and their associates found that some viral strains changed as they were transferred repeatedly to fresh monkey cells. One virus, transferred seventy times, became very aggressive toward rabbit kidney cells, lysing them after a week’s growth. Viruses from the first cell cultures did not lyse the rabbit cells. Also, it was found that the viruses from the later monkey cell cultures induced much higher levels of interferon than low-passage viruses (viruses transferred only a few times).
An important consideration in developing an attenuated, or weakened, vaccine was to find a virus that would not be shed. This would prevent vaccinated children from infecting pregnant women. An attenuated virus might still be dangerous to a fetus. Monkeys were used to determine whether high-passage viral strains (those transferred seventy or more times) were sufficiently attenuated, induced antibodies, or were shed. Parkman and his associates found that low-passage viral strains produced clinical signs of rubella in monkeys as well as neutralizing antibodies. In addition, these viruses were shed from the throat and rectum and transmitted to other monkeys. Viruses were found in the blood also. In contrast, high-passage viral strains were not shed from the throat or rectum and were not transferred to other monkeys. Also, these viruses were not found in the blood. Nevertheless, the high-passage viral strains induced neutralizing antibodies. Experiments using monkeys were fine, but it was not known if the virus would have the same characteristics in humans.
Meyer, Parkman, and Theodore C. Panos
By 1968, four different research groups had developed rubella vaccines with attenuated viruses. Parkman and Meyer had obtained theirs in monkey cells, another doctor grew his virus in rabbit cells, Stanley A. Plotkin obtained his virus in diploid human cells, while Maurice R. Hilleman had attenuated his virus in duck cells. The danger of preparing vaccines in mammalian (monkey, rabbit, human) cells was that they often harbored a variety of viruses or proviruses that might infect humans and cause cancer. To avoid this possibility, Hilleman grew attenuated viruses in duck cells. The cells were from birds that developed spontaneous tumors very infrequently.
A comparison of Hilleman’s vaccine with that developed by Parkman and Meyer showed that a number of Hilleman’s viral strains were effective and not passed on to contacts. Vaccination of 265 rubella-susceptible children with the Parkman-Meyer virus grown in duck cells resulted in 256 (97 percent) of the children developing antibodies. None of the children, however, had clinical signs of rubella. In addition, none of the 262 siblings or 34 parents who functioned as controls developed antibodies, indicating that the secreted viruses produced no apparent infections in contacts.
Hilleman and his associates tested the Parkman-Meyer virus on susceptible women of childbearing age. In this group, the attenuated viruses were more virulent than in the children tested. Thirty-five women were inoculated with rubella vaccine. Unlike the results obtained with children, the symptoms of mild clinical rubella developed in twenty women (fifteen showed no signs or symptoms). Fifteen suffered with pain in their joints (arthritis), eight developed a rash, six felt poorly, five had swollen nodes, and three had no appetite. Thirty-four (97 percent) of the thirty-five women developed antibodies against the rubella virus. These results indicated that the Parkman-Meyer vaccine was more virulent for adults than for children.
In 1969, a number of vaccines were licensed for general use. The Parkman-Meyer attenuated virus was grown in dog kidney cells by Parkman and Meyer but in duck embryo cells by Hilleman. These vaccines were designated DK-12 and DE-5, respectively. Another viral vaccine produced using rabbit kidney cells became known as RK, or the Cendehill strain. The Plotkin vaccine made from viruses grown in human diploid cells was designated as RA 27/3. From 1970 to 1975, more than 55 million children and women of childbearing age in the United States were vaccinated. The vaccination program had a dramatic effect on the epidemiology of German measles. The most obvious effect was that the incidence of German measles in the United States dropped from forty thousand to about twelve thousand cases. Before the vaccine, epidemics of German measles occurred every six to nine years.
The vaccine prevented the severe epidemics expected in the 1970’s and 1980’s. Nevertheless, there was a slight increase in the incidence of rubella from 1975 to 1977. From 1977 through 1989, the incidence of German measles decreased from about sixteen thousand to less than four hundred cases per year. In 1990, the incidence of German measles increased 2.5 times to more than one thousand cases. This increase may have reflected the fact that more and more children were not being vaccinated in the 1980’s before they entered school. Many states still do not have mandatory vaccination for rubella. Most of the children acquiring rubella come from economically disadvantaged homes, where the parents do not have the money for vaccinations and do not understand the public health importance of vaccination.
The safety of vaccines developed by each of the groups is being studied. The DK-12 vaccine developed by Parkman and Meyer was associated with many more cases of pain in the joints, arthritis, and nerve damage than other vaccines. Also, the DK-12 vaccine produced more severe symptoms. Therefore, it was removed from distribution in the early 1970’s. The other vaccines appeared to be equally effective and safe.
A number of studies have indicated that immunized children are not contagious. No examples of vaccinated children transmitting the attenuated virus to their susceptible mothers or other contacts have been documented. Thus, vaccination of young children is an effective measure for blocking wild-type infections that are frequently transmitted from young children to their pregnant mothers.
Data on fifty-six susceptible women who were inadvertently vaccinated shortly before or after conception suggest that there is a small risk of fetal infection by the attenuated viruses. Twenty-three (41 percent) of these women gave birth to normal babies with no evidence of rubella viruses. Twenty-eight (50 percent) had abortions because of the fear of giving birth to defective children. There was no information on the state of the aborted fetuses. Apparently, they were normal. Yet, the gestational tissues of five women (9 percent) contained viruses. Whether this would have led to some cases of congenital rubella is not known. These limited data indicated that the incidence of congenital rubella, when pregnant women are vaccinated within the first three months of their pregnancy, would be less than 2 percent.
A study of vaccinated children indicates that the antibodies against the rubella virus persist for as long as seven years. Reinfection of these children with wild-type rubella virus protects most of them from developing any signs or symptoms of German measles. No viruses are found in their blood. This suggests that pregnant women, previously vaccinated, have little chance of being reinfected by a wild-type virus. Even if they should be infected, the virus would not be able to migrate through the blood to the fetus.
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Cooper, Louis Z. “German Measles.” Scientific American, July, 1966, 30-37. This article explains how German measles was defined as a separate and distinct disease in the 1800’s and how in the 1940’s congenital rubella in newborns was associated with German measles in pregnant women. Most of the paper is concerned with the symptoms of congenital rubella. Drawings illustrating the abnormalities that may occur in the heart and eye are very informative. -
Gershon, Anne A., Peter J. Hotez, and Samuel L. Katz. Krugman’s Infectious Diseases of Children. 11th ed. Philadelphia: Mosby, 2004. A resource of more than one thousand pages on children and infectious diseases, including German measles, or rubella. -
Hilleman, Maurice R., Eugene Buynak, Robert E. Weibel, and Joseph Stokes. “Live, Attenuated Rubella-Virus Vaccine.” New England Journal of Medicine 279 (August 8, 1968): 300-302. This article considers four rubella vaccines that had been developed by 1968 and compares the Parkman and Meyer strain with a viral strain developed by Hilleman at the Merck Institute for Therapeutic Research at West Point, Pennsylvania. This paper clearly illustrates the concern scientists had that their vaccines might not be safe and the number of clinical trials performed before any vaccine could be licensed. -
Krugman, Saul, and Samuel L. Katz. “Rubella Immunization: A Five-Year Progress Report.” New England Journal of Medicine 290 (July 13, 1974): 1375-1376. This short article reported on the effectiveness and safety of the rubella vaccines licensed in 1969. One vaccine, which was developed by Parkman and Meyer in dog kidney cells (DK-12), was recalled because of the high incidence of joint pain, arthritis, and neurological problems associated with it. -
Link, Kurt. The Vaccine Controversy: The History, Use, and Safety of Vaccinations. Westport, Conn.: Praeger, 2005. In addition to a chapter on the rubella vaccine, this work includes chapters on “The Immune System and Surviving Infection,” “Vaccine History and Types,” and “Vaccines of the Future.” -
Meyer, Harry M., and Paul D. Parkman. “Attenuated Rubella Virus, II: Production of an Experimental Live-Virus Vaccine and Clinical Trial.” New England Journal of Medicine 275 (September 15, 1966): 575-580. This article describes the clinical results obtained with the Parkman and Meyer vaccine. It was found that the vaccine was safe in children. None of the children developed a rash or enlarged lymph nodes. Viruses could not be isolated from any blood samples. Nevertheless, a number of children shed the virus in their throats. Worthwhile reading because it shows how scientists go about testing a new vaccine and what results concern them. -
Parkman, P. D., E. L. Buescher, and M. S. Artenstein. “Recovery of Rubella Virus from Army Recruits.” Proceedings of the Society for Experimental Biology and Medicine 111 (1962): 225-230. Describes how Parkman and his research group at the Walter Reed Army Institute of Research in Washington, D.C., characterized the agent responsible for German measles and demonstrated that it was a virus. Also noteworthy was the discovery that the virus could be identified by antibodies developed in rabbits against a strain of the rubella virus grown and maintained in African green monkey cells. -
Parkman, Paul D., Harry M. Meyer, Ruth L. Kirschstein, and Hope E. Hopps. “Attenuated Rubella Virus, I: Development and Laboratory Characterization.” New England Journal of Medicine 275 (September 15, 1966): 569-574. Describes how Parkman and Meyer attenuated a rubella virus and discovered that it might be a good candidate for making a safe vaccine. Shows precisely how a group of scientists obtained an attenuated virus and how they tested it to determine whether it had the characteristics they thought were important in a rubella vaccine. -
Weibel, Robert E., Joseph Stokes, Eugene B. Buynak, and Maurice R. Hilleman. “Rubella Vaccination in Adult Females.” New England Journal of Medicine 280 (March 27, 1969): 682-685. Illustrates how an attenuated rubella virus may produce more severe infections in one group of humans than in another. The Parkman and Meyer viral strain grown in duck cells by Hilleman produced no signs and symptoms in hundreds of children tested but produced signs and symptoms of German measles in 57 percent of the women of childbearing age.
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