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SUPPLEMENT ARTICLE

The History of Rubella and Rubella Vaccination


Leading to Elimination
Stanley A. Plotkin
Department of Pediatrics, University of Pennsylvania, Philadelphia, and Sanofi Pasteur, Doylestown, Pennsylvania

Congenital rubella syndrome (CRS) was discovered in the 1940s, rubella virus was isolated in the early 1960s,
and rubella vaccines became available by the end of the same decade. Systematic vaccination against rubella,
usually in combination with measles, has eliminated both the congenital and acquired infection from some

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developed countries, most recently the United States, as is confirmed by the articles in this supplement. The
present article summarizes the clinical syndrome of CRS, the process by which the vaccine was developed,
and the history leading up to elimination, as well as the possible extension of elimination on a wider scale.

The importance of congenital rubella infection was rec- diabetes mellitus, and thyroiditis. Moreover, although
ognized in the United States and elsewhere in 1941, cataracts, cochlear atrophy, and patent ductus arter-
after the ophthalmologist Norman Gregg linked epi- iosus were prevalent in typical CRS, other manifesta-
demic congenital cataracts in Australia to intrauterine tions in the eye, ear, and heart were found to occur
rubella [1]. Landmark articles by Greenberg et al. [2] frequently, including glaucoma, central auditory im-
in the United States, Manson et al. [3] in the United perception, and peripheral pulmonic stenosis [7].
Kingdom, and Lundstrom in Sweden [4] established Those of us who were practicing pediatrics or ob-
congenital rubella as a prevalent and serious disease, stetrics during those years remember with poignancy the
changing rubella from a minor rash disease to a major many tragedies we witnessed as families struggled with
threat in pregnancy. decisions about therapeutic abortions and severely dam-
At first, cataracts, deafness, and congenital heart dis-
aged infants. In Philadelphia, I calculated that at the
ease were the only identifying characteristics of con-
height of the epidemic 1% of all births were affected [8].
genital rubella, but, in the spring of 1963, an epidemic
Meanwhile, the cell culture revolution that began
of rubella started in Europe and subsequently spread
after the Second World War was applied to the study
to the United States in 1964 and 1965, leaving thou-
of rubella in the early 1960s. Two laboratories succeeded
sands of damaged infants in its wake [5]. Studies of
in detecting the presence of rubella virus: that of Weller
these infants revealed that congenital rubella syndrome
(CRS) has many manifestations and affects virtually all and Neva [9] in Boston and that of Parkman, Buescher,
organ systems [6, 7]. In addition to affecting 3 core and Artenstein [10] in Bethesda. In Boston, rubella
organsthe optic lens, the cochlea, and the heart virus was isolated by detecting subtle changes in human
CRS was recognized as a cause of pathology in the brain, amnion cells, whereas in Bethesda the workers used a
lungs, liver, spleen, kidney, bone marrow, bones, and novel technique of viral interference. When samples
endocrine organs. This anatomic pathology was asso- containing rubella virus were inoculated on cultures of
ciated with encephalitis, mental retardation, pneumo- African green monkey kidney (AGMK) cells, the virus
nia, hepatitis, thrombocytopenia, metaphyseal defects, grew without cytopathic effect, but the cells secreted
interferon. Challenge of the AGMK cultures with en-
teroviruses such as echovirus 11 revealed interference
Reprints or correspondence: Dr. Stanley A. Plotkin, Sanofi Pasteur, 4650 Wismer with their readily detected cytopathic effect. This tech-
Rd., Doylestown, PA 18901 (Stanley.Plotkin@Sanofipasteur.com). nique became widely used in virology laboratories.
Clinical Infectious Diseases 2006; 43:S1648
Fortunately, the isolation of rubella virus came just
 2006 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2006/4309S3-0008$15.00 before the 19631965 rubella epidemic, permitting ac-

S164 CID 2006:43 (Suppl 3) Plotkin


curate virologic and serologic diagnosis and elucidation of dis- United States. At the same time, RA 27/3 was licensed in Eu-
ease pathogenesis. Many key features of rubella and CRS were rope. The reason for this difference is of historical interest. At
recognized, including the following [7, 11]: the time, there was a prejudice in the American regulatory
1. Replication of the virus in the throat for periods of 2 agency against a human cell strain, on the grounds that it might
3 weeks contain some hypothetical contaminating agent [22]. Some-
2. Viremia at high levels, particularly during the second what illogically, primary cultures from animals were thought
week of infection, terminated by the appearance of antibodies to be preferable. Ironically, over the years, human diploid cell
3. Clinically inapparent rubella virus infection in as many strains (first developed by Leonard Hayflick and Paul Moorhead
as a one-third of infected individuals [23] at the Wistar Institute) have become the reference standard
4. Correlation between the presence of serum antibodies for fully characterized cells free of contaminants.
and resistance to rubella virus infection Over the next decade, accumulating evidence led to changes
5. Viral infection of the placenta in the United States. First, the duck embryo and dog kidney
6. Panembryonic infection of fetuses after viremic infec- vaccine strains caused significant joint reactions [2427]. Second,
tions in their mothers reinfection on exposure to wild rubella virus was demonstrated
7. Confirmed rubella during the first trimester of preg- frequently with all strains except the RA 27/3 vaccine [2830].
nancy resulted in damage to 50%90% of fetuses, with declin- Third, the good safety record of the RA 27/3 vaccine in Europe,
ing percentages through the second trimester [12, 13] plus the majority opinion of scientists, led the US Food and Drug

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8. Cell death found in key organs of the fetus, together Administration to license RA 27/3. Important pressure for this
with inhibition of cellular mitosis and vascular endothelial decision came from Dorothy Horstmann at Yale, who was con-
damage vinced by her comparative studies of rubella vaccines [31], and
9. Excretion of virus at birth by babies with CRS, who by Maurice Hilleman at Merck, who sought a better rubella strain
continued to excrete virus for months, serving as vectors of for measles-mumps-rubella (MMR) vaccine.
transmission to others Over the past 30 years, the properties of the RA 27/3 vaccine
10. Seronegativity in 15% of American women of child- have been well documented. Seroconversion is regularly in-
bearing age, with higher or lower percentages in other parts of duced in 195% of vaccinees after subcutaneous injection [32
the world, depending on social conditions and population den- 34], and the strain can also be given intranasally [35, 36]. Data
sity. Thus, in crowded urban areas, rubella virus infection was on protection against natural rubella matches the antibody data.
relatively continual in children, but women were usually im- Persistence of protection has been somewhat controversial, be-
mune, whereas in some island populations epidemics were spo- cause some studies have shown 190% presence of antibodies
radic, and a high proportion of women were susceptible. in subjects vaccinated many years before [3739], whereas other
The devastating consequences of the rubella epidemic left no studies show eventual loss of antibodies in as many as one-
doubt that a vaccine was needed, and many groups set to work. third of vaccinees [40]. Although rubella vaccine is now com-
The common denominator was attenuation by passage in cell monly given twice in MMR vaccine and a second dose effec-
culture, since it had become clear with other viruses that such tively boosts vaccinees who have become seronegative [41], it
passage usually resulted in selection for lower virulence in vivo. is not clear how important this is for rubella control. No doubt,
Parkman, Meyer, and colleagues [14] attenuated rubella virus the sensitivity of antibody detection is an important factor in
in AGMK cell cultures (HPV-77), Hilleman et al. [15] in duck the evaluation of antibody persistence, but in any case, there
embryo cells (HPV-77/DEV), Prinzie et al. [16] in rabbit kidney is no evidence yet that vaccinated populations lose protection
(Cendehill), and I and my colleagues [17] in a human diploid with time. That said, it will be necessary to continue evaluation
fibroblast cell strain. The HPV-77 virus developed by Parkman of the duration of protection to cope with possible reintroduc-
was also adapted for commercial use in dog kidney cell cultures. tions of rubella into vaccinated populations. Anamnestic re-
One feature of the human diploid fibroblast vaccine (RA 27/ sponses may protect even if serum antibodies disappear, and,
3) that differed from the others was the adaptation of the strain additionally, RA 27/3 vaccine induces IgA secretory antibodies
to growth at 30C [1820]. The idea behind this was to rapidly in the nasopharynx [36].
induce attenuation, on the basis of my previous experience with With regard to safety, seronegative adult women are prone
attenuated poliovirus strains [21], following the work of others to acute transient arthalgia and arthritis after vaccination [28,
showing that replication at low temperatures selected against 42], but the idea that such reactions lead to chronic joint prob-
virulence. By the 25th passage in a human diploid cell strain, lems has not been supported by controlled studies [43, 44].
RA 27/3 had clearly become attenuated for humans. Subclinical thrombocytopenia may occur after vaccination [45].
All of the live attenuated vaccines except RA 27/3, the human Of great importance is the fact that extensive postvaccination
diploid cell vaccine, were licensed in 1969 and 1970 in the surveillance has not turned up any instance of teratogenic effect

History of Rubella Elimination CID 2006:43 (Suppl 3) S165


by RA 27/3 administered inadvertently to pregnant women [11, [58]. The high immunogenicity of RA 27/3 vaccine was con-
46, 47]. firmed in Oman [59]. The former Soviet states of Central Asia
With the availability of virologic and serologic tools, it be- are adopting vaccination [60]. Thailand and Malaysia have in-
came possible to elucidate the epidemiological profile of rubella troduced MMR vaccine into their vaccination schedule. Japan
and CRS [5]. Transmission occurs from respiratory secretions, has recently decided to make rubella a target through the use
and implantation of the virus probably occurs in the naso- of measles-rubella vaccine. Rubella vaccine production is just
pharynx [7]. The average number of transmissions from a case beginning in China.
of rubella in developed countries is between 3 and 8 [48, 49]. Sub-Saharan Africa remains a problem, both for epidemi-
In developed societies, infection occurs in collectivities of chil- ological and economic reasons. The incidence of CRS is poorly
dren, who may infect their parents. However, adult-to-adult documented, except for data from Ghana [61] and South Africa
transmission is also common, as is experienced among military [62]. The cost of vaccines is also an issue. However, at this
recruits, on cruise ships, and even among Wall Street traders point, rubella-containing combinations are being manufactured
[50]. Seropositivity in women of childbearing age varies be- in the developing world and can be purchased for !50 cents/
tween 85% and 95%, depending on when rubella disease was dose. Results of cost-benefit analyses favor vaccination, partic-
last introduced. In urban areas, epidemics occur with a certain ularly since there are no additional costs of administration when
periodicity, averaging 7 years [51]. rubella vaccine is used in combination with measles vaccine
When rubella vaccination became feasible, both the United [63]. Moreover, aerosol administration of measles and rubella

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States and the United Kingdom embarked on vaccination pro- combinations in mass campaigns has been shown to be feasible
grams. In the United States, the strategy was to vaccinate in- in Mexican studies [64].
fants, so that eventually the reservoir in childhood would be An important strategic issue concerns a possible paradoxical
abolished [52]. In contrast, the United Kingdom decided on a effect, in which vaccinating only infants reduces infection of
program of vaccinating adolescent girls [53]. Both strategies nonpregnant women by circulating rubella virus and, therefore,
were partial successes, in that CRS incidence began to decrease. results in an increase in their susceptibility to residual exposures
However, both were also partial failures, because in the United during later pregnancy [48]. Although the issue is only tem-
States pregnant women were still being exposed to rubella in porarybecause with time the infants become immunized
children and adults, and in the United Kingdom unvaccinated adultsit can be dealt with by a single mass campaign of
girls who refused vaccination were still exposed to rubella cases vaccination of women (or both sexes) up to 39 years of age.
because of circulation of virus in the male population and Catch-up vaccination of children up to 15 years of age will also
children. Each country revised its strategy to include both uni- greatly reduce the risk of a paradoxical effect.
versal immunization of infants and targeted vaccination of ad- The articles in this supplement recount the elimination of
olescent girls and adult women. Military recruits and health rubella and CRS from the United States. After a brief recru-
care workers were also singled out for vaccination [54]. descence in the early 1990s, elimination became possible
Meanwhile, a second dose of MMR vaccine became standard, through increased vaccination coverage, the institution of a
and the Scandinavian countries began systematic efforts to universal second dose of MMR vaccine, and the efforts of Mex-
eliminate rubella. Finland was a leader in this respect and, by ico and other Latin American countries to vaccinate against
maintenance of high coverage and monitoring by serologic test- rubella. The latter efforts reduced the introduction of rubella
ing, succeeded in eliminating rubella completely [55]. virus into the United States by immigrants. At this point, the
Elimination of rubella and CRS is now a goal throughout major sources of importation are Asia and Europe.
the Western Hemisphere, promoted by the Pan American On 29 October 2004, the Centers for Disease Control and
Health Organization [56]. The importance of rubella and CRS Prevention convened the meeting at which the accompanying
elimination became obvious when laboratory studies of rash papers were presented, against the background of few or no
disease incident to measles elimination campaigns revealed the reports of rubella activity from the 50 states and the virtual
high prevalence of rubella virus infections. absence of reported CRS. It seemed propitious to examine the
More recently, EURO (European Region of the WHO) has situation to determine whether rubella virus was or was not
chosen to attempt elimination of rubella [57]. Whereas north- still circulating. The clinical, laboratory, and epidemiological
ern Europe has already done the job, low vaccination rates in evidence supported the absence of rubella virus. A committee
southern and eastern Europe have resulted in persistent disease. of experts then decided on the basis of the evidence that rubella
However, increasing pressure put on the countries in those areas is no longer endemic in the United States. There are reasons
will inevitably result in elimination. to be optimistic about the eventual elimination of rubella from
Rubella vaccination is also beginning in developing countries, the world. We have the tools to do it, and only the political
where the incidence of CRS is also thought to be considerable will is required. Elimination now has been accomplished in the

S166 CID 2006:43 (Suppl 3) Plotkin


United States and in several other developed countries. One virus grown in human fibroblasts: evidence for reduced nasopharyngeal
excretion. Am J Epidemiol 1967; 86:46877.
hopes that elimination will succeed in more and more regions, 20. Plotkin SA, Buser F. History of RA27/3 rubella vaccine. Rev Infect Dis
eventually resulting in the eradication, once and for all, of a 1985; 7(Suppl 1):S778
threat to the birth of healthy infants. 21. Plotkin SA, Norton TW, Cohen BJ, Koprowski H. A type 3 attenuated
poliovirus genetically stable after human intestinal passage. Proc Soc
Exp Biol Med 1961; 107:829934.
Acknowledgment 22. Sabin APSA. Discussion on session V. Proceedings of the International
Conference on Rubella Immunization. Amer J Dis Child 1969; 118:
Supplement sponsorship. This article was published as part of a sup- 37880.
plement entitled The Evidence for the Elimination of Rubella and Con- 23. Hayflick L, Moorehead PS. The serial cultivation of human diploid
genital Rubella Syndrome in the United States: A Public Health Achieve- cell strains. Exp Cell Res 1961; 26:585621.
ment, sponsored by the Centers for Disease Control and Prevention. 24. Barnes EK, Altman R, Austin SM, Dougherty WJ. Joint reactions in
Potential conflicts of interest. S.A.P. was listed on a now-expired patent children vaccinated against rubella. II. Comparison of three vaccines.
on the RA 27/3 rubella vaccine strain. He is an employee of Sanofi Pasteur Am J Epidemiol 1972; 95:5966.
and consultant to Merck, both producers of the vaccine. 25. Kilroy AW, Schaffner W, Fleet WF Jr, Lefkowitz LB Jr, Karzon DT,
Fenichel GM. Two syndromes following rubella immunization: clinical
observations and epidemiological studies. JAMA 1970; 214:228792.
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