Rubella Viruses

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PERSPECTIVES IN MEDICAL VIROLOGY

Volume 15

Series Editors

A.J. Zuckerman
Royal Free and University College Medical School
University College London
London, UK

I.K. Mushahwar
Abbott Laboratories
Viral Discovery Group
Abbott Park, IL USA
 Rubella Viruses

Editors

Jangu Banatvala
King’s College London Medical School at Guy’s
King’s College and St Thomas’ Hospitals
London, UK

Catherine Peckham
Centre for Paediatric Epidemiology and Biostatistics
UCL Institute of Child Health
London, UK

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Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

Historical Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Molecular Virology of Rubella Virus

M.-H. Chen and J. Icenogle . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Clinical Features: Post-Natally Acquired Rubella

J.E. Banatvala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Laboratory Diagnosis of Rubella and Congenital Rubella

J.M. Best and G. Enders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Rubella Vaccine
S. Reef and S.A. Plotkin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Rubella Epidemiology: Surveillance to Monitor and Evaluate Congenital

Rubella Prevention Strategies
C. Peckham, P. Tookey and P. Hardelid . . . . . . . . . . . . . . . . . . . . 95
Future Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

List of Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
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 vii

Preface

Since its introduction in the 1960s, rubella vaccination has substantially changed
the epidemiology of rubella and congenital rubella nationally and internationally.
Worldwide, hundreds of thousands of congenital rubella births have been averted,
but the infection continues to inflict a considerable burden in many countries.
Different national and regional approaches to rubella control, the ease with which
infection can be imported across national boundaries, and the fact that infection is
usually mild and frequently asymptomatic, mean that the elimination of rubella will
be no easy task. Success in controlling rubella will depend on a sustained political
and economic commitment to vaccination and surveillance over the long term. This
book highlights the enormous challenges to be faced, through an up-to-date ap-
praisal of the molecular, clinical, laboratory and epidemiological features of rubella
and congenital rubella in the vaccine era.

Jangu Banatvala
London, UK

Catherine S. Peckham
Centre for Paediatric Epidemiology and Biostatistics
UCL Institute of Child Health
London, UK
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 ix

Historical Introduction

Rubella was originally known by its German name ‘‘Roteln’’ having been described
originally by two German physicians. For many years German measles was con-
fused with other infections causing a rash, particularly measles and scarlet fever
and even today a diagnosis on clinical grounds alone is notoriously inaccurate (see
Chapter 2). German measles was, in due course, recognised as a distinct disease by
an International Congress in Medicine in London in 1881 and the infection des-
ignated as ‘‘rubella’’ was accepted at about that time (reviewed by Best and Ban-
atvala, 2004).

It was not until 1941 that an Australian ophthalmologist, Norman McAlister

Gregg in his epoch-making paper produced evidence, which showed that if ac-
quired in early pregnancy, rubella caused developmental defects in the fetus (Gregg,
1941). In 1941, there were extensive outbreaks of rubella among troops in training
in New South Wales, Victoria and Queensland, being mobilised during the Second
World War. Infection spread to the civilian population and it is possible that troops
x Historical Introduction

may have infected their wives on returning home prior to serving overseas. Gregg
noted the presence of cataracts, usually bilateral, microphthalmia and the ‘‘salt and
pepper’’ appearance of a characteristic retinopathy occurring in congenitally in-
fected infants. A high percentage of infants also had cardiac anomalies, failed to
thrive and in due course many were found to have severe perceptive deafness.
Gregg was the first to recognise that a virus infection in humans could result in
embryopathy and that damage was the result of infection acquired in early fetal life.
Although Gregg’s findings were not universally accepted initially, other retrospec-
tive studies, not only in Australia but in other countries, subsequently confirmed
his findings (reviewed by Hanshaw et al., 1985). The earlier studies were retro-
spective and, as might be expected, were at risk of overestimating the incidence of
defects, since the starting point for investigations was the delivery of infants with
congenital anomalies, whose mothers reported a rubella-like rash during preg-
nancy. However, prospective studies carried out in the 1950s and early 1960s, in
which the starting point was a mother with a rubella-like illness, rather than an
infant with congenital anomalies, revealed a much lower incidence of congenital
malformation, varying from 10% to 54% (Hanshaw et al., 1985). But such studies
underestimated the incidence of rubella-induced congenital anomalies, since they
did not then have the benefit of laboratory confirmation of the clinical diagnosis.
Undoubtedly, many women with rash in pregnancy were included and were de-
livered of healthy babies, but had infections other than rubella. However, subse-
quent studies showed that following virologically confirmed rubella in the first
trimester, the fetus is almost invariably infected, and about 80–85% of infants are
damaged (see Chapter 2). Thus, despite the limitations of the earlier retrospective
studies, the original observations were a reasonably accurate assessment of the risk
to the fetus following maternal rubella, but this was due to the fact that the ex-
tensive Australian epidemics in the 1940s were caused by rubella rather than by
other infections-inducing rashes.
Rubella virus was isolated for the first time in 1962 by two groups working
independently in the USA employing different cell culture techniques (Parkman et
al., 1962; Weller and Neva, 1962). This discovery led to the development of se-
rological tests, which could be used to determine rubella virus immunity, and
confirm or refute the clinical diagnosis of rubella among women who were exposed
to, or who developed rubella during pregnancy. Laboratory investigations were
now also available to diagnose, and be used during follow-up studies on infants
who had been exposed to rubella in utero.
In 1963/1964, the USA experienced one of the most extensive recorded out-
breaks of rubella, which led to a greater understanding of the pathogenesis of
congenitally acquired rubella as well as a fuller appreciation of the clinical features
and sequelae. It was estimated that somewhere of the order of 20,000–30,000 ru-
bella damaged babies resulted from this epidemic and that these infants experienced
a generalised and persistent infection, occurring not only in utero but extending into
infancy (see Chapters 2 and 3). Although it was thought that the wider spectrum of
anomalies noted among infants with congenitally acquired rubella following the
 Historical Introduction xi

1963/1964 epidemic, termed at that time ‘‘the expanded rubella syndrome’’, was a
new phenomenon, careful inspection of clinical notes of infants with congenitally
acquired disease from previous but smaller outbreaks showed that many of the so-
called new clinical features had been observed previously.
The extensive nature of the 1963/1964 rubella epidemic emphasised the impor-
tance of attempting to prevent infection by the development of vaccines, and during
1965/1966 attenuated vaccines were developed and the first vaccine trials started.
During the next few years, different vaccines were licensed and rubella vac-
cination programmes commenced in the USA, UK and subsequently in other parts
of the world (see Chapter 4) making congenitally acquired rubella a preventable
disease. Current vaccination programmes have reduced the incidence of rubella
markedly in many industrialised countries and WHO has now put forward pro-
grammes to eliminate rubella, not only in industrialised countries, but also in many
developing countries (see Chapters 4 and 5).
Table 1 illustrates some of the principal developments in the history of rubella.

Table 1
Main developments in history of rubella

1881 International Congress on Medicine recognised rubella as a

distinct disease
1941 Gregg in Australia recognises teratogenic effects
1962 Rubella virus isolated in cell culture. Neutralisation tests
developed
1963–1964 Extensive European and USA epidemics. 12.5 million rubella
cases, 11,000 fetal deaths and 20,000 CRS cases in USA
1969 and 1970 Attenuated rubella vaccines licensed in USA and UK (USA
universal childhood programme; UK selective vaccination of
prepubertal school girls)
1971 MMR licensed in USA
1978, 1979 and 1983 Severe UK rubella epidemics mostly involving adolescent and
young adult males but some pregnant women
1986 Rubella virus genome sequenced
1988 UK policy augmented by offering MMR to pre-school
children of both sexes
1989 USA introduced a two-dose vaccination at age 12–15 months
and at age 4–5 years or 11–12 years
1989–1991 Resurgence of rubella in USA
1996 In UK, schoolgirl vaccination discontinued but second dose
of MMR introduced for children aged 4–5 years
2000 WHO recommends immunisation policies for elimination of
CRS
2002 123 (57%) of 212 of countries and territories include rubella
vaccination in national immunisation programmes
Source: Modified from Lancet 2004; 363: 1127–1137.
xii Historical Introduction

References

Best JM, Banatvala JE, Rubella. In: Principles and Practice of Clinical Virology (Zuckerman
AJ, Banatvala JE, Pattison JR, Griffiths PD, Schoub BD, editors) Chapter 12, Chichester:
Published by John Wiley & sons; 2004; pp. 427–457.
Gregg NM. Congenital cataract following German measles in mother. Trans. Ophthalmol
Soc Aust 1941; 3: 35–46.
Hanshaw JB, Dudgeon JA, Marshall WC. Viral Diseases of the Fetus and Newborn. 2nd ed.
Philadelphia: W.B. Saunders; 1985.
Parkman PD, Buescher EL, Artenstein MS. Recovery of rubella virus from army recruits.
Proc Soc Exp Biol Med 1962; 111: 225–230.
Weller TH, Neva A. Propagation in tissue culture of cytopathic agents from patients with
rubella-like illness. Proc Soc Exp Biol Med 1962; 111: 215–225.
Rubella Viruses 1
Jangu Banatvala and Catherine Peckham (Editors)
r 2007 Elsevier B.V. All rights reserved
DOI 10.1016/S0168-7069(06)15001-6

Chapter 1

Molecular Virology of Rubella Virus

Min-Hsin Chen, Joseph Icenogle

Division of Viral Diseases, Centers for Disease Control and Prevention, 1600 Clifton
Road, Atlanta, GA 30333, USA

Introduction

Rubella virus is the sole member of the Rubivirus genus in the Togaviridae family,
which also includes the Alphavirus genus (Chantler et al., 2001). Alphaviruses and
rubella virus share a similar genetic organization and replication strategy. Alpha-
viruses are transmitted to humans by arthropods while rubella virus is transmitted
between humans; humans are the only known hosts for rubella virus. An incom-
plete list of alphaviruses and the human diseases they are known to cause is Ross
River virus (fever, arthritis, rash), Semliki Forest virus (fever, encephalitis),
Venezuelan Equine Encephalitis virus (fever, encephalitis), and Sindbis virus (fever,
arthritis, rash) (Griffin, 2001). There is little sequence homology between rubella
virus and any alphavirus, limiting the possibilities for studying the relationships
between rubella virus and alphaviruses by simple phylogenetic analysis. Since
rubella virus is more difficult to culture than some alphaviruses (e.g. Sindbis virus),
equivalent information for alphaviruses and rubella virus is often lacking. Thus, in
the present chapter, some information is presented from work done with alpha-
viruses and then extrapolations are made to rubella virus.
Rubella virus is a potent, infectious, teratogenic agent, which continues to cause
devastating epidemics of congenital rubella syndrome (CRS) in much of the world
(Cooper, 1985; Lee and Bowden, 2000). The virus was isolated in 1962 and by 1969
an attenuated, live vaccine was licensed (Parkman et al., 1962; Weller and Neva,
1962). Viruses isolated from CRS cases are identical to viruses from postnatal
rubella cases (Lee and Bowden, 2000). In utero infection with rubella virus in the
first trimester usually produces one or more of a set of specific pathologies in the
2 M.-H. Chen, J. Icenogle

fetus. Although there have been some molecular studies in cell lines directed toward
the pathogenesis of rubella virus, the molecular details of the pathogenesis (i.e. the
mechanism(s) of teratogenicity of rubella virus) in humans are poorly understood.

Structure of the virion

Rubella virus virions are particles about 70 nm in diameter with a lipid envelope
containing two viral glycoproteins, E1 and E2, and a nucleocapsid, containing the
positive-strand RNA molecule and the capsid protein, C (Dominguez et al., 1990;
Risco et al., 2003; Zheng et al., 2003c) (Fig. 1A). The structure of the rubella virion
has not been precisely determined by fitting crystallographic structures of the in-
dividual proteins into cryoelectron microscopic maps, as has been done for alpha-
virus virions (Zhang et al., 2002; Gibbons et al., 2004). These studies of the virion
structures of various alphaviruses have shown interactions between the C protein
and RNA, the E1–E2 glycoprotein heterodimers organized into trimers on the
virion surface, and the overall structure of the virion. Major conformational
changes in the E1–E2 heterodimer occur at low pH and upon interactions with
cells, exposing the fusion protein on the E1 protein of Sindbis virus (see Kuhn et al.,
2002 for discussion; Paredes et al., 2004). These studies likely provide an approx-
imate model for the structure of the rubella virion and conformational changes that
likely occur in the rubella virion (Fig. 2). One should also note that there are
significant similarities in structure and function between the large envelope protein
of alphaviruses and the envelope protein of flaviviruses, which are more distantly
related to the alphaviruses than is rubella virus (Modis et al., 2004).
The C proteins in the rubella virion exist as disulfide-linked homodimers,
(although the dimerization is not required for formation of viral particles (Lee
et al., 1996)). Analysis of the amino acid sequence of the rubella virus C protein
suggests that the N-terminal half of this protein interacts with RNA, because it is
hydrophilic and rich in prolines and arginines (reviewed in Frey, 1994). The major
RNA-binding domain in the C protein has been located within amino acid residues
28–56, but other regions, including the C-terminus, might also be involved in en-
hancing the interaction (Liu et al., 1996). The C-terminus of the C protein is very
hydrophobic and retains the putative signal peptide of the E2 protein (reviewed in
Frey, 1994). Therefore, the C proteins in virions are anchored to the viral mem-
brane by their C-termini, with the N-terminal regions inside the viral envelope and
likely contacting the RNA. Since the C proteins are bound to the viral membrane,
nucleocapsid assembly/disassembly for rubella virus may well occur by pathways
different from those of alphaviruses (see below). It is possible that the N-terminal
region of the C protein interacts with the cytoplasmic tail of E1 and is involved in
budding (Hobman et al., 1994).
The E1 and E2 glycoproteins exist as heterodimers in the rubella virion. The E1
protein is a class 1 transmembrane protein with three N-linked glycosylation sites in
the N-terminal half of the protein. Although glycosylation of E1 does influence the
Fig. 1 Electron micrographs from rubella virus infected Vero cell culture. Panel A. Electron micrograph
of rubella virus particles in infected Vero cell culture (isolate JV 13R-23) showing dense core and
surrounding lipid bilayer (one virion is indicated by arrow). The virus was isolated from human case of
rubella. (Electron micrograph by Dr. Elena I. Ryabchikova, Dr. G. I. Tiunnikov, and Dr. Vladimir S.
Petrov (State Research Center of Virology and Biotechnology VECTOR, Russia) with permission). Bar
corresponds to 60 nm. Panel B. Rubella virus replication complex in Vero cells. Each complex is a
modified lysosome-containing vesicles (arrow heads) that line the inner membrane of a cytopathic
vacuole (v). The rough endoplasmic reticulum is indicated by open arrows. The bar represents 200 nm.
Figure is from Lee et al. (1999), with permission. The closed arrows with tails indicate rubella virus core
particles, which were seen in association with the periphery of cytopathic vacuoles in this study, but this
observation was not found in another study (Risco et al., 2003).