Published Online August 16, 2013

Immunization to prevent congenital

cytomegalovirus infection
Stuart P. Adler*
Department of Microbiology, Medical College of Virginia Campus/Virginia Commonwealth University,
Richmond, VA, USA

Sources of data: Relevant published literature.

Areas of agreement: There are no biologic obstacles to immunization against fetal/
placental infection with CMV.
Areas of uncertainty: CMV vaccine trials may be difcult due to a lack of public
awareness of CMV. Vaccine trials that use fetal infection as an endpoint will be
prolonged, since vaccination will need to occur preconception.
Areas timely for developing research: Vaccines in preclinical development include
antigens of the CMV gB glycoprotein and the gH/gL UL128, 130 and 131
pentameric complex. These antigens induce antibodies that block viral entry into
broblasts and endothelial/epithelial cells. Vaccines immunogenic in animals
include an inactivated virus with a wild-type UL131 gene, a DNA vaccine using a
wild-type UL130 gene and peptide vaccines using peptides from UL130 and 131.
Conclusions: In spite of these potential obstacles, successful evaluation of CMV
vaccines is possible.

Keywords: cytomegalovirus/pregnancy/vaccines
Accepted: July 9, 2013

Introduction
*Correspondence address.
Department of
Microbiology, Medical
College of Virginia
Campus/Virginia
Commonwealth
University, PO Box 163,
Richmond, VA 23298, USA.
E-mail: [email protected]

In the USA and many other developed countries, of women of childbearing age, between 20 and 60% are seronegative and are thus susceptible to
cytomegalovirus (CMV). Between 0.5 and 2% of infants worldwide are
congenitally infected with CMV and about 90% of these infants are
asymptomatic and usually have no sequela. In developed countries,
10% of congenitally infected infants manifest a wide range of signs and
symptoms. In the USA alone, every year an estimated 50008000

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DOI:10.1093/bmb/ldt023

& The Author 2013. Published by Oxford University Press. All rights reserved.
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Introduction: A primary maternal cytomegalovirus (CMV) during pregnancy causes

newborn disease that includes hearing decit and/or mental retardation.

S. P. Adler

Sources of data
This review will describe experimental and natural history data on
CMV that indicate that the development of a CMV vaccine to prevent
congenital infection is feasible and should be highly effective. The
major barriers to a CMV vaccine are not a lack of vaccine candidates,
for there are now many, but rather the design and execution of vaccine
trials to demonstrate efficacy. The sources of data are published papers
cited in PubMed which are directly relevant to the feasibility of CMV
immunization.
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children develop mental retardation and hearing deficit associated with a

congenital CMV infection. Similar disease rates are postulated for
Europe. Congenital CMV infection causes the majority of non-hereditary
hearing loss.13 The range of mental impairment is broad, but few symptomatic infants develop an IQ of over 100.
Long-term severe mental impairment and severe neurosensory hearing
loss nearly always follow a primary maternal CMV infection in the first
half of pregnancy.4 In 1992, Fowler et al. observed that of 125 infants
with congenital infection who were born of mothers with a primary
CMV infection during pregnancy, sequela occurred in 25% of the
infants.2 This contrasted with an 8% rate for 64 infants with congenital
infection, but born of mothers who were CMV seropositive prior to pregnancy. None of the infected infants born of seropositive mothers developed severe sequelae. One report does describe significant sequelae
characteristic of congenital CMV infection among infants born of
mothers CMV seropositive before conception.5 Although the relative frequency of severe mental impairment and severe neurosensory hearing
loss associated with seropositive mothers remains unknown, it appears
that the original observations of Fowler et al. are correct and over 90% of
congenital disease occurs among women who acquire a primary CMV infection during pregnancy.
In 1999, the U.S. Institute of Medicine issued a comprehensive
report called Vaccines for the 21st Century: A tool for decision
making. The need for a CMV vaccine was among eight vaccines at
level one, the most favorable category.6 A CMV vaccine for prepregnant women to prevent congenital infection was given the highest
priority because it would be highly cost effective and yield the highest
health benefits measured in terms of quality-adjusted life years. This
assessment was based on immunizing women of childbearing age beginning in adolescence.

CMV vaccination

Areas of agreement

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Four types of evidence indicate that there are no naturally occurring biologic obstacles to a CMV vaccine. The first type of evidence comes from
animal studies. The guinea pig is the best model for studying congenital
CMV infection because guinea pig CMV (gpCMV) crosses the placenta
and infects guinea pig pups. Numerous studies using the guinea pig
model have observed that both active and passive immunization are effective at reducing pup mortality or preventing congenital infections.
Active vaccines have included live attenuated virus, killed virus vaccine
and recombinant vaccines.79 Passive immunization which includes both
hyperimmune sera and sera raised against the gB glycoprotein of gpCMV
has also been effective at reducing pup mortality and/or preventing congenital infection.1012 A gpCMV vaccine that stimulates only cellular
immune responses is effective in the guinea pig model.13 Thus, in the
guinea pig model, the induction of immunity to gpCMV in susceptible
dames by a variety of different vaccine mechanisms all favorably affect
the natural history of this infection in guinea pigs.
The second type of evidence supporting the feasibility of immunization
against CMV is the natural history of CMV congenital infection in
humans. The majority of severe and long-term neurologic damage occurs
when a woman sustains a primary infection with CMV in the first half of
pregnancy. In this situation, the placenta becomes enlarged, inflamed and
dysfunctional and if infected, the fetus suffers intrauterine hypoxia and
malnourishment which is associated with long-term mental impairment.14,15 If a womans first CMV infection occurs during the first half of
pregnancy, the CMV transmission rate from mother to the fetus is about
50% and approximately one-third of these will have severe neurologic
impairment and/or hearing deficit.16 For women infected with CMV
before pregnancy, the transmission rate to the fetus is only 0.52% and
at least 90% of these congenital-infected infants will be normal at birth
and develop normally.
Globally an estimated 80% or more of women of childbearing age are
CMV seropositive, so CMV infections among women CMV seropositive
before pregnancy are important because these mothers may be an appropriate group for immunization. CMV infections among mothers who are
seropositive to CMV before pregnancy and have a congenitally infected
infant are called recurrent maternal infections and they have been associated with maternal acquisition of antibodies to new isolates of CMV,
suggesting an attractive hypothesis that maternal reinfection occurs and
results in congenital infection.17,18 There are case reports of maternal recurrent infections being associated with serve long-term neurologic
damage but the true frequency with which this occurs is unkown.5 For

S. P. Adler

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hearing deficit, however, the frequency of hearing deficit among infants

born after a primary maternal infection and the frequency among infants
born after a recurrent maternal infection are known and they are similar
(about 10%).19,20 The frequency, however, of severe/profound and progressive hearing deficit is much greater among infants born of mothers
with a primary infection during pregnancy.19
Maternal seropositivity before pregnancy is also a marker of protection
the fetus from congenital infection. In one study women immune to CMV
prior to a second pregnancy had a 1% congenital infection rate for a subsequent pregnancy compared with a 3% rate for women who were seronegative prior to the birth of second child, suggesting prior immunity induced
by wild-type CMV protects the fetus from infection.21 Thus, for seropositive women, an important question is: would immunization enhance the
protection offered by naturally acquired immunity? The answer is:
perhaps. The gB/MF59 vaccine when give to seropositive women boosts
antibody and CD4+ responses to CMV that are sustained for at least one
year.22 Hopefully, these vaccine-induced enhanced responses will be associated with protection of the fetus from congenital infection.
A third type of evidence indicating the feasibility of CMV immunization is that immunity induced by natural infection reduces the rate of reinfection in immunocompetent adults. This has been demonstrated
elegantly in two studies.23,24 One study monitored 38 seronegative and
42 seropositive women who had a young child shedding CMV that was
acquired in daycare.23 Of the 38 seronegative women, 45% acquired a
CMV infection from their child, whereas of the 42 seropositive women,
only 3 (7%) became infected with CMV. This study shows that the immunity provided by natural infection is substantial. If vaccine-induced
immunity was comparable with that induced by a wild-type infection, a
93% protection rate for a CMV vaccine would certainly be acceptable.
Another study demonstrating the protective effect of natural immunity
was an experimental challenge study.24 The elegance of this study emanated from the simplicity of its design, the paucity of subjects needed and
the clarity of the results. The study design and results are shown in
Table 1. Three groups of subjects were injected with varying doses of the
low-passage Toledo strain of CMV which is not attenuated. The three
groups were seronegative subjects, seropositive subjects and subjects who
had previously received 1000 PFU of the high-passage Towne strain of
CMV, an attenuated vaccine strain. The results show that seropositive
subjects became reinfected with Toledo but only at high doses of challenge virus compared with seronegative subjects. Those who had received
the 1000 PFU of Towne vaccine were partially protected compared with
naturally seropositive subjects. 1000 PFU of Towne vaccine is a low dose.
The fourth type of evidence indicating the feasibility of immunization
against CMV is from an observational non-randomized Phase I study of

CMV vaccination

Table 1 Challenge of human subjects with the Toledo unattenuated strain of CMV (from
Yamamoto et al. 18)
Immune status of study subjects by
parameter evaluated*

10

100

4/4
4/4
4/4

2/2
2/2
2/2

0/5
1/5
0/5

1/7
3/7
4/7

0/2
0/2
0/2

0/5
0/5
1/5

1000

3/5
5/5
3/5

Twelve subjects were seropositive after receiving the attenuated Towne vaccine.
Number of subjects affected over the total number tested.

passive immunization of pregnant women who acquired a CMV infection

during pregnancy.16 CMV hyperimmune globulin (Cytotect Biotest,
Dreieich, Germany) was used to prevent fetal infection in mothers who
had a primary CMV infection but who did not have amniocentesis to
confirm fetal infection. Of 126 women who had a primary infection
during pregnancy and who did not receive passive immunization, 57%
had CMV-infected fetuses compared with only 16% of women who
received passive immunization. CMV hyperimmune globulin was also
used to treat fetuses infected in utero. 16 Of 45 women who had primary
CMV during pregnancy and whose infants were congenitally infected
in utero as determined by amniocentesis, only one (3%) of 31 who
received CMV hyperimmune globulin had an infant that was symptomatic at birth and developed seqeulae at two years of age compared with 7 of
14 (50%) women who did not receive immunoglobulin. These observations have been supported by two recent subsequent studies.25,26 The
observed efficacy of passive immunization is consistent with the natural
history studies and animal studies described above. The data are also consistent with the success of passive immunization during pregnancy for
other viral infections such as measles, varicella and hepatitis A and B.
Thus, all of the available data indicate that CMV immunity is substantial but imperfect and that re-infection of naturally seropositive individuals will depend on the dose and exposure frequency. Therefore, the
best CMV vaccine is unlikely to be 100% effective. The efficacy of a
CMV vaccine will depend on study design and subjects as well as dose
and route of administration.
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Seronegative
Clinical
Laboratory signs (from Yamamoto et al. 18)
Infection
Towne (3 log10 PFU)
Clinical
Laboratory signs
Infection
Seropositive
Clinical
Laboratory signs
Infection

Toledo challenge dose (PFU)

S. P. Adler

Areas of uncertainty

Table 2 Power analysis for Phase III efcacy trials for the prevention of congenital CMV
disease by immunizing seronegative women by study endpoint
Endpoint

Maternal infection
Transmission
to the fetus

Disease in the
newborn

Vaccine efcacy = 80%

Vaccine efcacy = 50%

Rate for
placebo
arm (%)

Rate for
vaccine
arm (%)

Total no. of
subjects
needed

Rate for
placebo
arm (%)

Rate for
vaccine
arm (%)

Total no. of
subjects
needed

50*
12
4
3
2
1
0.4
0.2

10
2.4
1
0.075
0.5
0.25
0.08
0.04

48
264
976
1310
1976
3404
8542
17 154

50*
12
4
3
2
1
0.04
0.2

25
6
2
1.5
1
0.5
0.02
0.1

130
776
2476
3326
5028
10 128
25 434
50 940

Assumes an equal number of vaccine and placebo subjects with an alpha of 0.05 and a beta of 0.8.
Calculated by the method of Fleiss.47
*The approximate annual infection rate for mothers with a young child shedding CMV.27,29

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CMV vaccine efficacy trials may be biased by many factors including behavioral changes, route of transmission (oral or venereal), exposure frequency and possible viral genotypic heterogeneity that may affect
transmission rates. These variables have to be considered in a CMV
vaccine efficacy trial. CMV vaccine trials should be directed toward highrisk women. Lower socioeconomic seronegative African-American
women are at high risk.21 These women who are between pregnancies
have a congenital infection rate of 3% or about threefold higher than
low-risk women. Seronegative women with a child in daycare are also at
high risk. The overall infection rate for this group is about 8%; however,
for women who have a child at home aged <2 years that is excreting
CMV, the child-to-mother transmission rate is 50% over 1 year.27 We
have observed that two-thirds of women with a child in daycare will
become pregnant within 2 years of enrolling a child in day care, and the
average age of the youngest child in daycare at the time of maternal conception is about 18 months. The average time from enrollment of one
child in daycare and the birth of another is 27 months. This information
is very useful when designing vaccine trials that will enroll high-risk prepregnant women.28
Table 2 presents a statistical power analysis indicating the number of
subjects that will have to be studied in various types of CMV vaccine efficacy trials depending on one of three possible outcome variables to be
assessed: the rate of maternal infection, the rate of congenital infection
and the frequency of newborn disease. For this table, two levels of
vaccine efficacy were assumed, either 80% or 50%. The table shows that

CMV vaccination

if a vaccine prevented maternal infection with 80% efficacy, as few as 48

subjects could be required for an efficacy trial. On the other hand, if a
vaccine is only 50% effective and disease in the newborn is the endpoint,
as many as 50000 pregnant women may need to be enrolled in an efficacy
trial. A trial of this size is probably impractical. A more practical trial and
one that may be required for licensure would be one that uses the congenital infection rate as the primary end point. In this case, it will be necessary to enroll between 3400 and 10 000 pre-pregnant women and
their newborns in a vaccine efficacy trial.

For maximal public health impact, a CMV vaccine for infants and toddlers is optimal since contact with young children at home is the primary
source of infection among seronegative pregnant women.29 CMVinfected young children aged <2 years excrete virus in urine and saliva for
prolonged periods of up to 4 years. Immunization of young children
should ideally prevent CMV acquisition by the children and should
induce durable life-long immunity. If immunization of young children
reduces the duration of viral excretion or reduces the quantity of virus
shed, which may reduce the frequency of or prevent child-to-mother
transmission.
In contrast to vaccine trials with women as subjects, vaccine trials with
infants and toddlers as subjects will require small numbers of subjects
and an initial observation for a year or less. We have observed repeatedly
that an average of 25% of infants in daycare will acquire CMV infection
from another daycare enrollee.29 If a vaccine is 80% effective in preventing infection, only a total of 116 total infants will be needed to demonstrate efficacy. If the vaccine is only 50% effective, the number of infants
required would increase to 306.
Infants and toddlers have excellent antibody responses to CMV that are
sustained for up to 3 years, which if protective, may reduce the frequency
of either child-to-child transmission or child-to-mother transmission.
Unlike Towne vaccine which induces antibody levels in infants comparable with those induced in adults, the gB/MF59 vaccine when administered to infants and toddlers induces antibody responses six- to eightfold
higher than those induced in adults.30 These observations with both
vaccines suggest that the vaccination of young children may be quite
effective.
Finally, we have observed that infants and toddlers that shed CMV for
prolonged periods have normal CMV-specific CD8+ responses to CMV
but greatly diminished CMV-specific CD4+ responses.31,32 Therefore, it
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Infants and toddlers

S. P. Adler

may be necessary that a CMV vaccine for infants and toddlers induce
CMV-specific CD4+ responses to be effective.

Areas timely for developing research

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There are currently two CMV vaccines in Phase II studies. One is the
CMV gB/MF59 vaccine, which is disulfide-linked glycoprotein complex
(gB) with 130 and 55 kDa components.33 The gB complex is a major
component of the envelope glycoprotein of human CMV. The gB
complex contains at least seven neutralizing epitopes. In human convalescent sera antibodies to gB are abundant. Monoclonal antibodies against
gB neutralize both wild-type viral isolates and laboratory-adapted
strains. The gB proteins have been expressed in CHO cells and, when
administered with the adjuvant MF/59, induce high levels of neutralizing
antibodies in animals and humans. In both animals and humans, gB also
contains epitopes that stimulate T lymphocytes cytotoxic for CMV. Thus,
gB/MF59 is the most likely candidate for a subunit vaccine. Three doses
are required and the vaccine is safe and immunogenic in adults and
infants.
The other vaccine in a Phase I human trial is TowneToledo chimeras.
Towne is a live attenuated vaccine used extensively in clinical trials and is
safe.34 It does not reactivate in either healthy volunteers or immunosuppressed patients. It has limited reactogenicity. The vaccine is not shed and
does not produce viremia. The vaccine is given a single subcutaneous
dose, is safe and stimulates neutralizing antibodies comparable with
those induced by wild-type virus. Towne-induced antibody levels are sustained for 84 months or longer. Towne vaccine also induces limited cellular immune responses.35,36
Toledo is a CMV isolate that is not attenuated and causes illness when
given in high doses.24 Four TowneToledo chimeras were produced and
each obtained part of its genome from Towne and part from Toledo. This
was done in an attempt to enhance the immunogenicity of Towne
without sacrificing safety. The TowneToledo chimera were safe in seropositive subjects and are now being evaluated in seronegative subjects.37
CMV has historically been cultured using human fibroblasts. Viral isolates from humans are cell-associated and attain low titers (103 PFU/
ml). Growth properties improve upon serial passage in fibroblasts.
Laboratory-adapted high-passage strains such as Towne and AD169
grow in fibroblasts to high titers (107 PFU/ml) of extracellular virus.
Neutralizing antibodies prevent cells from becoming infected by
binding to virion proteins necessary for viral attachment and entry. The
ability of a vaccine to induce neutralizing antibodies is critical to efficacy.
The CMV epitopes that induce neutralizing activity are partially known.

CMV vaccination

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That antibodies to gB comprise over half of the fibroblast entry neutralizing activity in human sera made gB an early candidate for subunit vaccines and an important component for live attenuated vaccine candidates.
However, other viral glycoprotein complexes also contain neutralizing
epitopes, including gH/gL and gM/gN.38,39 As noted below, fibroblastbased neutralizing assays fail to identify major neutralizing epitopes that
are specific to other cell types and in fact most of the neutralizing antibodies in human sera are induced by non-gB proteins and these antibodies block entry into endothelial and epithelial cells.40 Thus, the ability
to induce neutralizing antibodies to a range of neutralizing epitopes, not
just gB, is a potential advantage.
Viral entry into epithelial and endothelial cells occurs by a mechanism
different from that of fibroblast entry. Entry into fibroblasts occurs by
pH-independent receptor-mediated fusion at the cell surface that is
mediated by gB and gH/gL. In contrast, entry into epithelial, endothelial
and other cell types uses a pH-dependent endocytic entry pathway in
which virus first attaches to the cell surface, is endocytosed and only
achieves fusion and entry to the cytoplasm upon acidification of the endosome. This pathway requires proteins gB, gH/gL and also UL128, UL130
and UL131.
Hahn et al. showed that viral genes UL128, UL130 and UL131 are
needed for endothelial entry.41 They further found that fibroblastadapted non-endothelial tropic strains contain mutations in at least one
of these three genes. Towne strain, for example, contains a two-bp insertion causing a frame shift in UL130, whereas AD169 contains a one-bp
insertion in UL131. Both Towne and AD169 could be adapted for
growth in endothelial cells, and in both instances, the frame shift mutations in UL130 or UL131 were repaired.41 Subsequent papers showed
that this genetic basis of endothelial tropism extends also to epithelial
and dendritic cell tropisms.42,43
CMV vaccines tested in clinical trials include Towne vaccine, the
TowneToledo chimeras discussed above, an alpha virus replicon with
gB as the antigen, the gB/MF59 vaccine, a gB vaccine produced by
GlaxoSmithKline and a DNA vaccine using gB and pp65. pp65 is viral
protein that is a potent inducer of CD8+ responses directed against CMV.
These vaccines are all poor inducers of antibodies that block viral entry
into endothelial/epithelial cells.44
In a Phase II clinical trial, the gB/MF59 vaccine was only 50% effective
at preventing primary infection among young women with a child at
home.45 This was a surprisingly good result, given gB is a poor inducer of
antibodies that block entry into endothelial/epithelial cells. Thus, current
vaccines in pre-clinical development have focused on including antigens
of the gH/gL UL128, 130 and 131 pentameric complex. Current vaccines
immunogenic in animal studies include an inactivated AD169 which has

S. P. Adler

been repaired in the UL131 gene, a DNA vaccine using a wild-type

UL130 gene and peptide vaccines using peptides from UL130 and 131.46

Conclusions

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3
4
5

6
7

8
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Even though all of the available data indicate that a CMV vaccine to
prevent congenital disease should be easily achievable, progress in evaluating CMV vaccines has been greatly impeded by a lack of public awareness of CMV. This lack of public awareness means that obstetricians are
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CMV vaccination

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