1038 • CID 2004:38 (1 April) • EDITORIAL COMMENTARY

E D I T O R I A L C O M M E N T A R Y

Congenital Cytomegalovirus Infectionand Its Prevention

Stanley A. PlotkinDepartment of Pediatrics, University of Pennsylvania, Philadelphia, and Aventis Pasteur, Doylestown, Pennsylvania

(See the article by Fowler et al. on pages 1035-7)

Received 23 December 2003; accepted 23 December 2003;electronically published 15 March 2004.

Reprints or correspondence: Dr. Stanley A. Plotkin, AventisPasteur, 4650 Wismer Rd., Doylestown, PA 18901 (Stanley.Plotkin@Aventis.com).

Clinical Infectious Diseases 2004; 38:1038–9� 2004 by the Infectious Diseases Society of America. Allrights reserved.1058-4838/2004/3807-0022$15.00

Whether likened to a “changeling demon”

[1] or to the “troll of transplantation” [2],

the human cytomegalovirus (HCMV) has

long been known to exact a heavy toll on

morbidity and mortality rates among

newborn children and immunosuppres-

sed individuals. A recent analysis by the

Institute of Medicine of the National

Academy of Sciences placed the develop-

ment of a vaccine against HCMV in its

highest category of priority: vaccines that

would actually save money for society

once they were applied [3]. The same

conclusion was reached in a previous

analysis [4].

The fact that, throughout the world, an

average of ∼1% of all infants are infected

with HCMV in utero is not widely ap-

preciated, nor are the sequelae of deafness

and mental retardation. This ignorance

probably derives from the late detection

of most of the sequelae, aside from the

occasional classic case of “cytomegalic in-

clusion disease” and the difficulty of

confirming by virological or serological

analysis the relation between those se-

quelae and intrauterine infection. Never-

theless, it appears that more infants are

damaged perennially by HCMV infection

than by Haemophilus influenzae type b

meningitis or by congenital rubella before

vaccination eliminated those menaces [5].

Epidemiological studies of women who

were seropositive or seronegative for

HCMV at the time of conception have

shown that the risk to the fetus due to

primary infection in the mother is greater

than that due to recurrent infection. A

prior study by Fowler et al. [6] showed a

transmission rate of 12.7% from mothers

with primary infection but only 1% from

immune women, which suggests a 92%

protection by immunity, if one assumes

equal rates of exposure in the 2 groups.

Fetal infection transmitted from immune

women is generally thought to be less se-

vere [6–8], but that idea is by no means

universally accepted, and some investiga-

tors believe that the severity of disease in

infants born to immune women is iden-

tical to that in infants born to nonimmune

women [9, 10]. If this were true, there

would be no merit to immunizing women

against HCMV infection, because their

risk of giving birth to an infected infant

would be the same. On the other hand, if

this were true, congenital CMV disease

should be common in developing coun-

tries in which the rate of seropositivity is

high among women. So far, that has not

been demonstrated.

This crucial controversy has induced

doubt about the wisdom of developing a

vaccine, although vaccine development is

far advanced [11, 12]. Indeed, there are

many reports that fetal damage may occur

in infants born to seropositive mothers,

confirming that even preconceptional

natural immunity does not always prevent

transplacental infection [13]. The second

infections in these instances appear to

have derived from reinfection of the

mothers with a new HCMV strain [14].

Although the occurrence of such cases

is beyond question, 2 explanations have

been offered to justify continued vaccine

development for seronegative women. It

has been argued that, first, despite recur-

rent infections, prior maternal immunity

confers a protection rate of up to 68%

[6]—and perhaps even higher [15]—on

the fetus; and second, that the presence of

maternal antibodies does not necessarily

equate with maternal cellular immunity,

and that the latter factor may be more

important than the former. Thus, we may

not be measuring the protective immune

response.

Now Fowler et al. [16] offer a third ex-

planation, which may account for some

of the prior observations of infection that

occurred despite maternal immunity at

the time of pregnancy. They provide evi-

dence that preconceptional maternal in-

fection may pose a persistent risk. Women

in whom HCMV seroconversion occurred

within 2 years of pregnancy (as deter-

by guest on August 21, 2011

cid.oxfordjournals.orgD

ownloaded from

EDITORIAL COMMENTARY • CID 2004:38 (1 April) • 1039

mined by analysis of cord serum samples

obtained during 2 consecutive successive

deliveries) had a 4-fold higher risk of de-

livering a congenitally infected baby than

did mothers whose prior pregnancy oc-

curred 12 years before the most recent

pregnancy. Assuming that the risk of ex-

posure to CMV was equally distributed

over time, this suggests that infection dur-

ing the 2 years before conception poses a

risk for the fetus. A similar trend was

seen among infants delivered by sero-

immune mothers but did not reach sta-

tistical significance.

In other words, women infected

months before pregnancy may harbor the

virus at a site from which the newly con-

ceived fetus can be infected. The occult

site could be persistently infected uterine

cells or macrophages that reactivate infec-

tion anywhere in the body. This opens an

avenue of needed research to determine

where the reservoir may be. If infection

before pregnancy is a risk for the fetus,

the potential value of vaccination would

be augmented, and there would be a

strong argument for offering a vaccine to

female adolescents, prepubertal girls, and

young married women years before they

intend to become pregnant.

Meanwhile, HCMV vaccine develop-

ment is moving forward. The live atten-

uated Towne strain, recombinants of the

Towne strain, subunit gB glycoprotein,

canarypox vector vaccines, and DNA vac-

cines are all being tested in the clinical

setting [11, 12]. Phase 2 efficacy trials in-

volving women whose infants are in day

care will be possible, because such women

are subject to high rates of CMV infection

[17]. But ultimately, phase 3 trials involv-

ing women who intend to become preg-

nant in the near future will be necessary.

The estimated size of such trials is quite

feasible, but if Fowler et al. [16] are correct

in asserting that women who seroconvert

before pregnancy are also at risk, the num-

ber of subjects needed to show efficacy

would be reduced. In any event, there is

an urgent need for studies of preconcep-

tional CMV infection in other populations

and at other geographical sites to confirm

the findings of Fowler et al. [16].

References

1. Plotkin SA. Vaccination against cytomegalo-virus, the changeling demon. Pediatr InfectDis J 1999; 18:313–25.

2. Balfour HH Jr. Cytomegalovirus: the troll oftransplantation. Arch Intern Med 1979; 139:279–80.

3. Institute of Medicine Committee. Cytomeg-alovirus. In: Stratton KR, Durch JS, LawrenceRS, eds. Vaccines for the 21st century, 2000:165–71.

4. Porath A, McNutt RA, Smiley LM, Weigle KA.Effectiveness and cost benefit of a proposedlive cytomegalovirus vaccine in the preventionof congenital disease. Rev Infect Dis 1990; 12:31–40.

5. Demmler GJ. Congenital cytomegalovirus in-fection. Semin Pediatr Neurol 1994; 1:36–42.

6. Fowler KB, Stagno S, Pass RF. Maternal im-munity and prevention of congenital cyto-megalovirus infection. JAMA 2003; 289:1008–11.

7. Stagno S, Pass RF, Dworsky ME, et al. Con-genital cytomegalovirus infection: the relativeimportance of primary and recurrent mater-nal infection. N Engl J Med 1982; 306:945–9.

8. Fowler KB, Stagno S, Pass RF, Britt WJ, BollTJ, Alford CA. The outcome of congenital cy-tomegalovirus infection in relation to mater-nal antibody status. N Engl J Med 1992; 326:663–7.

9. Boppana SB, Rivera LB, Fowler KB, Mach M,Britt WJ. Intrauterine transmission of cyto-megalovirus to infants of women with pre-conceptional immunity. N Engl J Med 2001;344:1366–71.

10. Gaytant MA, Rours GI, Steegers EA, GalamaJM, Semmekrot BA. Congenital cytomegalo-virus infection after recurrent infection: casereports and review of the literature. Eur J Pe-diatr 2003; 162:248–53.

11. Gonczol E, Plotkin S. Development of a cy-tomegalovirus vaccine: lessons from recentclinical trials. Expert Opin Biol Ther 2001; 1:401–12.

12. Pass RF, Burke RL. Development of cytomeg-alovirus vaccines: prospects for prevention ofcongenital CMV infection. Semin Pediatr In-fect Dis 2002; 13:196–204.

13. Morris DJ, Sims D, Chiswick M, Das VK,Newton VE. Symptomatic congenital cyto-megalovirus infection after maternal recurrentinfection. Pediatr Infect Dis J 1994; 13:61–4.

14. Boppana SB, Pass RF, Britt WJ. Virus-specificantibody responses in mothers and their new-born infants with asymptomatic congenitalcy-tomegalovirus infections. J Infect Dis 1993;167:72–7.

15. Plotkin S. Natural vs. vaccine-acquired im-munity to cytomegalovirus. JAMA 2003; 289:1008–11.

16. Fowler KB, Stagno S, Pass RF. Interval betweenbirths and risk of cytomegalovirus infection.Clin Infect Dis 2004; 38:1035–7 (in this issue).

17. Adler SP. Molecular epidemiology of cyto-megalovirus: evidence for viral transmissionto parents from children infected at a day carecenter. Pediatr Infect Dis 1986; 5:315–8.

by guest on August 21, 2011

cid.oxfordjournals.orgD

ownloaded from