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

S164 CID 2006:43 (Suppl 3) Plotkin

curate virologic and serologic diagnosis and elucidation of dis-
ease pathogenesis. Many key features of rubella and CRS were
recognized, including the following [7, 11]:
1. Replication of the virus in the throat for periods of 2
3 weeks
2. Viremia at high levels, particularly during the second
week of infection, terminated by the appearance of antibodies
3. Clinically inapparent rubella virus infection in as many
as a one-third of infected individuals
4. Correlation between the presence of serum antibodies
and resistance to rubella virus infection
5. Viral infection of the placenta
6. Panembryonic infection of fetuses after viremic infec-
tions in their mothers
7. Confirmed rubella during the first trimester of preg-
nancy resulted in damage to 50%90% of fetuses, with declin-
ing percentages through the second trimester [12, 13]
8. Cell death found in key organs of the fetus, together
with inhibition of cellular mitosis and vascular endothelial
damage
9. Excretion of virus at birth by babies with CRS, who
continued to excrete virus for months, serving as vectors of
transmission to others
10. Seronegativity in 15% of American women of child-
bearing age, with higher or lower percentages in other parts of
the world, depending on social conditions and population den-
sity. Thus, in crowded urban areas, rubella virus infection was
relatively continual in children, but women were usually im-
mune, whereas in some island populations epidemics were spo-
radic, and a high proportion of women were susceptible.
The devastating consequences of the rubella epidemic left no
doubt that a vaccine was needed, and many groups set to work.
The common denominator was attenuation by passage in cell
culture, since it had become clear with other viruses that such
passage usually resulted in selection for lower virulence in vivo.
Parkman, Meyer, and colleagues [14] attenuated rubella virus
in AGMK cell cultures (HPV-77), Hilleman et al. [15] in duck
embryo cells (HPV-77/DEV), Prinzie et al. [16] in rabbit kidney
(Cendehill), and I and my colleagues [17] in a human diploid
fibroblast cell strain. The HPV-77 virus developed by Parkman
was also adapted for commercial use in dog kidney cell cultures.
One feature of the human diploid fibroblast vaccine (RA 27/
3) that differed from the others was the adaptation of the strain
to growth at 30C [1820]. The idea behind this was to rapidly
induce attenuation, on the basis of my previous experience with
attenuated poliovirus strains [21], following the work of others
showing that replication at low temperatures selected against
virulence. By the 25th passage in a human diploid cell strain,
RA 27/3 had clearly become attenuated for humans.
All of the live attenuated vaccines except RA 27/3, the human
diploid cell vaccine, were licensed in 1969 and 1970 in the
United States. At the same time, RA 27/3 was licensed in Eu-
rope. The reason for this difference is of historical interest. At
the time, there was a prejudice in the American regulatory
agency against a human cell strain, on the grounds that it might
contain some hypothetical contaminating agent [22]. Some-
what illogically, primary cultures from animals were thought
to be preferable. Ironically, over the years, human diploid cell
strains (first developed by Leonard Hayflick and Paul Moorhead
[23] at the Wistar Institute) have become the reference standard
for fully characterized cells free of contaminants.
Over the next decade, accumulating evidence led to changes
in the United States. First, the duck embryo and dog kidney
vaccine strains caused significant joint reactions [2427]. Second,
reinfection on exposure to wild rubella virus was demonstrated
frequently with all strains except the RA 27/3 vaccine [2830].
Third, the good safety record of the RA 27/3 vaccine in Europe,
plus the majority opinion of scientists, led the US Food and Drug
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Administration to license RA 27/3. Important pressure for this
decision came from Dorothy Horstmann at Yale, who was con-
vinced by her comparative studies of rubella vaccines [31], and
by Maurice Hilleman at Merck, who sought a better rubella strain
for measles-mumps-rubella (MMR) vaccine.
Over the past 30 years, the properties of the RA 27/3 vaccine
have been well documented. Seroconversion is regularly in-
duced in 195% of vaccinees after subcutaneous injection [32
34], and the strain can also be given intranasally [35, 36]. Data
on protection against natural rubella matches the antibody data.
Persistence of protection has been somewhat controversial, be-
cause some studies have shown 190% presence of antibodies
in subjects vaccinated many years before [3739], whereas other
studies show eventual loss of antibodies in as many as one-
third of vaccinees [40]. Although rubella vaccine is now com-
monly given twice in MMR vaccine and a second dose effec-
tively boosts vaccinees who have become seronegative [41], it
is not clear how important this is for rubella control. No doubt,
the sensitivity of antibody detection is an important factor in
the evaluation of antibody persistence, but in any case, there
is no evidence yet that vaccinated populations lose protection
with time. That said, it will be necessary to continue evaluation
of the duration of protection to cope with possible reintroduc-
tions of rubella into vaccinated populations. Anamnestic re-
sponses may protect even if serum antibodies disappear, and,
additionally, RA 27/3 vaccine induces IgA secretory antibodies
in the nasopharynx [36].
With regard to safety, seronegative adult women are prone
to acute transient arthalgia and arthritis after vaccination [28,
42], but the idea that such reactions lead to chronic joint prob-
lems has not been supported by controlled studies [43, 44].
Subclinical thrombocytopenia may occur after vaccination [45].
Of great importance is the fact that extensive postvaccination
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,
46, 47].
With the availability of virologic and serologic tools, it be-
came possible to elucidate the epidemiological profile of rubella
and CRS [5]. Transmission occurs from respiratory secretions,
and implantation of the virus probably occurs in the naso-
pharynx [7]. The average number of transmissions from a case
of rubella in developed countries is between 3 and 8 [48, 49].
In developed societies, infection occurs in collectivities of chil-
dren, who may infect their parents. However, adult-to-adult
transmission is also common, as is experienced among military
recruits, on cruise ships, and even among Wall Street traders
[50]. Seropositivity in women of childbearing age varies be-
tween 85% and 95%, depending on when rubella disease was
last introduced. In urban areas, epidemics occur with a certain
periodicity, averaging 7 years [51].
When rubella vaccination became feasible, both the United
States and the United Kingdom embarked on vaccination pro-
grams. In the United States, the strategy was to vaccinate in-
fants, so that eventually the reservoir in childhood would be
abolished [52]. In contrast, the United Kingdom decided on a
program of vaccinating adolescent girls [53]. Both strategies
were partial successes, in that CRS incidence began to decrease.
However, both were also partial failures, because in the United
States pregnant women were still being exposed to rubella in
children and adults, and in the United Kingdom unvaccinated
girls who refused vaccination were still exposed to rubella cases
because of circulation of virus in the male population and
children. Each country revised its strategy to include both uni-
versal immunization of infants and targeted vaccination of ad-
olescent girls and adult women. Military recruits and health
care workers were also singled out for vaccination [54].
Meanwhile, a second dose of MMR vaccine became standard,
and the Scandinavian countries began systematic efforts to
eliminate rubella. Finland was a leader in this respect and, by
maintenance of high coverage and monitoring by serologic test-
ing, succeeded in eliminating rubella completely [55].
Elimination of rubella and CRS is now a goal throughout
the Western Hemisphere, promoted by the Pan American
Health Organization [56]. The importance of rubella and CRS
elimination became obvious when laboratory studies of rash
disease incident to measles elimination campaigns revealed the
high prevalence of rubella virus infections.
More recently, EURO (European Region of the WHO) has
chosen to attempt elimination of rubella [57]. Whereas north-
ern Europe has already done the job, low vaccination rates in
southern and eastern Europe have resulted in persistent disease.
However, increasing pressure put on the countries in those areas
will inevitably result in elimination.
Rubella vaccination is also beginning in developing countries,
where the incidence of CRS is also thought to be considerable
S166 CID 2006:43 (Suppl 3) Plotkin
[58]. The high immunogenicity of RA 27/3 vaccine was con-
firmed in Oman [59]. The former Soviet states of Central Asia
are adopting vaccination [60]. Thailand and Malaysia have in-
troduced MMR vaccine into their vaccination schedule. Japan
has recently decided to make rubella a target through the use
of measles-rubella vaccine. Rubella vaccine production is just
beginning in China.
Sub-Saharan Africa remains a problem, both for epidemi-
ological and economic reasons. The incidence of CRS is poorly
documented, except for data from Ghana [61] and South Africa
[62]. The cost of vaccines is also an issue. However, at this
point, rubella-containing combinations are being manufactured
in the developing world and can be purchased for !50 cents/
dose. Results of cost-benefit analyses favor vaccination, partic-
ularly since there are no additional costs of administration when
rubella vaccine is used in combination with measles vaccine
[63]. Moreover, aerosol administration of measles and rubella
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combinations in mass campaigns has been shown to be feasible
in Mexican studies [64].
An important strategic issue concerns a possible paradoxical
effect, in which vaccinating only infants reduces infection of
nonpregnant women by circulating rubella virus and, therefore,
results in an increase in their susceptibility to residual exposures
during later pregnancy [48]. Although the issue is only tem-
porarybecause with time the infants become immunized
adultsit can be dealt with by a single mass campaign of
vaccination of women (or both sexes) up to 39 years of age.
Catch-up vaccination of children up to 15 years of age will also
greatly reduce the risk of a paradoxical effect.
The articles in this supplement recount the elimination of
rubella and CRS from the United States. After a brief recru-
descence in the early 1990s, elimination became possible
through increased vaccination coverage, the institution of a
universal second dose of MMR vaccine, and the efforts of Mex-
ico and other Latin American countries to vaccinate against
rubella. The latter efforts reduced the introduction of rubella
virus into the United States by immigrants. At this point, the
major sources of importation are Asia and Europe.
On 29 October 2004, the Centers for Disease Control and
Prevention convened the meeting at which the accompanying
papers were presented, against the background of few or no
reports of rubella activity from the 50 states and the virtual
absence of reported CRS. It seemed propitious to examine the
situation to determine whether rubella virus was or was not
still circulating. The clinical, laboratory, and epidemiological
evidence supported the absence of rubella virus. A committee
of experts then decided on the basis of the evidence that rubella
is no longer endemic in the United States. There are reasons
to be optimistic about the eventual elimination of rubella from
the world. We have the tools to do it, and only the political
will is required. Elimination now has been accomplished in the
United States and in several other developed countries. One
hopes that elimination will succeed in more and more regions,
eventually resulting in the eradication, once and for all, of a
threat to the birth of healthy infants.
Acknowledgment
Supplement sponsorship. This article was published as part of a sup-
plement entitled The Evidence for the Elimination of Rubella and Con-
genital Rubella Syndrome in the United States: A Public Health Achieve-
ment, sponsored by the Centers for Disease Control and Prevention.
Potential conflicts of interest. S.A.P. was listed on a now-expired patent
on the RA 27/3 rubella vaccine strain. He is an employee of Sanofi Pasteur
and consultant to Merck, both producers of the vaccine.
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