History of Rubella Vaccines and the Recent History of Cell Culture

Stanley A. Plotkin

The name of a disease is always a matter of some importance. It should be short for the sake of convenience in writing, and euphonious for ease in pronunciation... Rotheln is harsh and foreign to our ears... I therefore venture to propose Rubella as a substitute for Rotheln, or, as a name for the disease which it has been my object in this paper to describe.

Henry Veale

Rubella is not one of those diseases whose origins are lost in antiquity. Unknown until the end of the eighteenth century, it remained an unimportant rash disease for almost 200 years, when it was discovered to be a fetal teratogen. Twenty years later, the viral agent of rubella was isolated, and vaccines were developed and

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commercialized within 10 years. By 5 years postlicensure, an impact on rubella incidence was evident, but another 5 years were required, together with changes in public health policy towards more universal vaccination, before congenital rubella syndrome (CRS) became rare.

Rubella was first discussed in the medical literature under the name "rotheln," which reflects its original description by German physicians at the end of the eighteenth century [1]. Maton [2], in 1815, is credited with the first English language description of the disease, and it was Veale [3], a military physician writing from India, who conferred on it the eponym "rubella" - "little red" in Latin. Subsequent writers were mostly concerned with rubella as a problem in differential diagnosis of rash disease, particularly in relation to measles and scarlet fever, until a consensus was reached in 1881 that rubella was indeed a specific illness [1]. This clinical inference was confirmed in 1938, when two Japanese scientists, Hiro and Tasaka [4], transmitted the disease from human to human using throat washings.

Today, rubella is understood as a viral upper respiratory infection in which replication takes place initially in the nasopharynx and then in adjacent lymph nodes, from which a viremia is generated. After an incubation period of 14-21 days, there is a short febrile prodromal illness, followed by a fine maculopapular rash beginning on the face and extending over the entire body surface. Resolution of rash occurs rapidly, but there are three principal complications of acquired disease: arthritis, encephalitis, and thrombocytopenia. Arthritis occurs in 70% of adults, encephalitis in 1 of 6,000 infections (but occasionally at a much higher rate), and thrombocytopenia in 1 of 3,000 patients [5, 6].

However, the fourth and most important clinical complication was discovered by a remarkable Australian ophthalmologist, Norman McAlister Gregg (1891-1966). In 1939, Australia became involved in the Second World War, with resultant recruitment and mixing of large numbers of young men, creating the right conditions for rubella epidemics. These epidemics inevitably spread to the soldiers' young female consorts. In 1940, Gregg began to see an unusual number of infants with congenital cataracts. By taking accurate histories from the new mothers, Gregg found that many had had rubella early in pregnancy. From this, Gregg drew the correct inference that rubella had affected the ocular development of the fetus [7].

Space does not permit a full description of the CRS and its interesting pathogen-esis. Table 1 summarizes the important clinical aspects of the disease. CRS is a disseminated viral infection of the fetus secondary to maternal viremia, which results in a myriad of anatomic and functional abnormalities.

Gregg's identification of rubella as the cause of congenital disease went through the usual period of criticism and doubt, but by the end of the 1940s, ample confirmation had been obtained throughout the world. Volunteer experiments confirmed that rubella is caused by a virus, but no success was reported in cultivating the agent by animal inoculation or by growth in cell culture.

Table 1 Prominent clinical findings in congenital rubella syndrome

Encephalitis Microcephaly Mental retardation Autism

Patent ductus arteriosus Peripheral pulmonic artery stenosis Cochlear deafness Central auditory imperception

Intrauterine growth retardation

Metaphyseal rarefactions

Hepatosplenomegaly Thrombocytopenic purpura Interstitial pneumonitis Diabetes Hypothyroidism

Retinitis Cataracts Microphthalmia Glaucoma

Modified from Alford CA, Griffiths PD. Rubella. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. Philadelphia: WB Saunders, 1983.

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