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The Journal of Infectious Diseases
EDITORIAL COMMENTARY
40 Years Is Long Enough!
Gail J. Demmler Harrison
Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston
(See the major article by Adler et al on pages 1341–8.)
Keywords.
CMV; CMV vaccine; congenital infection.
Received and accepted 5 August 2016; published online 11
August 2016.
Correspondence: G.J. Demmler Harrison, Department of
Pediatrics, Baylor College of Medicine, Attending Physician,
Texas Children′s Hospital, 1102 Bates St, Feigin Center Ste
1150, Houston, TX 77030 ([email protected]).
The Journal of Infectious Diseases® 2016;214:1297–9
© The Author 2016. Published by Oxford University Press for
the Infectious Diseases Society of America. All rights reserved.
For permissions, e-mail [email protected].
DOI: 10.1093/infdis/jiw367
a vaccine candidate alone, but, when
teamed with Towne as genetically constructed recombinants, 4 Towne/Toledo
chimeric live virus next-generation vaccine candidates were produced [4, 5]. In
a previous article by Heineman et al, published in a 2006 issue of The Journal of Infectious Diseases, it was shown that these
chimeric vaccine candidates were safe in
CMV-seropositive subjects, laying the
groundwork for the work by Adler et al
in this issue, where results of the first
phase 1 dose-escalation trial of the 4 chimeras in CMV-seronegative, healthy
adult men are reported [5, 6]. All 4 chimeras were safe, well tolerated, and not excreted in bodily fluids, and chimera 4
led the pack as the most immunogenic
in producing CMV seroconversion. But
more work must be done, because the
chimera 4 seroconversions were not
robust or long lasting in the lower doses
studied, leading future investigators to
most likely study higher doses in more
subjects to establish the optimal dosage
of the leading chimera vaccine candidate.
If successful, initial target groups for
CMV vaccination might include adolescent girls or young women, to prevent
CMV infection during childbearing
years [7].
Because of the concerns that a live
CMV vaccine may not be immunogenic,
may be transmitted to other individuals,
may be transmitted from the vaccinated
mother to her fetus, may reactivate and
cause disease at some point in time, or
may exhibit an oncogenic potential and
potentiate cancer or other illnesses in
vaccine recipients, other approaches to
CMV vaccine development have been
studied. These approaches, with varying
degrees of success, include subunit
CMV glycoprotein B (gB) adjuvanted
with MF59, which induces neutralizing
antibodies; CMV phosphoprotein 65
(pp65) peptide–based vaccines, which induce cytotoxic T-cell vaccines for use in
therapeutic vaccination of immune compromised hosts; canarypox CMV recombinants ALVAC-CMV (gB) and ALVACCMV ( pp65), which appear to induce
neutralizing antibody and cytotoxic Tlymphocyte responses; CMV DNA plasmids containing genes for gB and pp65;
and dense bodies containing key CMV
immunogenic antigens [3, 8]. However,
it is not likely that a single-protein or single-component inactivated CMV vaccine
will be a successful vaccine candidate.
Therefore, strategies that use multiple
components that target different or multiple aspects of the exceedingly complex
viral replicative cycle of CMV, such as
the gH/gL/UL128/UL130/UL131 pentameric complex compromising 5 viral
proteins, should be pursued [9]. Since
these proteins appear to be missing
from many CMV vaccine strains after
multiple laboratory passages, it provides
a potential explanation for the modest
successes for live CMV vaccine candidates so far studied.
So why do we continue to pursue the
elusive CMV vaccine, live virus or otherwise? First, CMV infection is a major yet
thus far neglected public health problem,
affecting men, women, and children
around the world [10]. Congenital CMV
infection is the most common congenital
viral infection and a leading cause of
deafness and vision loss and developmental and motor disabilities. A CMV vaccine
to prevent primary infection or reduce
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In 1975, Stanley Plotkin and coworkers
developed one of the first live attenuated
cytomegalovirus (CMV) vaccines, called
Towne 125, which was isolated from a
congenitally infected infant and attenuated by cell culture passage and plaque
purification [1]. Hundreds of subjects,
including renal transplant recipients
and healthy men and women, received
the early investigational vaccine [2, 3].
The studies showed that the Towne
CMV vaccine was safe; induced both humoral immunity, including neutralizing
antibody, and cellular immunity, including cytotoxic T cells; and provided protection against CMV disease. However, it fell
short in preventing CMV infection when
compared to immunity from wild-type
virus infection and failed at producing
long-term measurable immunity, suggesting it was too attenuated to be effective.
Several live attenuated vaccines are
successfully being used for prevention of
diseases, including varicella, caused by varicella zoster virus, a herpesvirus cousin of
CMV, as well as measles, mumps, and rubella. In addition, the live oral poliovirus
vaccine has helped eradicate polio in almost all parts of the world. Why has a successful live CMV vaccine been so elusive?
A nonattenuated, more virulent Toledo
strain of CMV was found unsuitable to be
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the ability of CMV to reinfect individuals
with apparent immunity.
If a promising CMV vaccine candidate
is identified in successful phase 1/2 trials,
how do we efficiently enroll eligible
study subjects in large phase 3 efficacy
trials? Phase 3 trials evaluating a CMV
vaccine for prevention of congenital
CMV infection, for example, will need
to screen hundreds of thousands of individuals to identify the thousands of
CMV-seronegative subjects needed to
evaluate the safety and efficacy of the vaccine candidate for prevention of congenital CMV infection and disease. Because
CMV infection is relatively common and
CMV seroprevalence ranges from 50% to
80% in many populations, a rapid, accurate,
cost-effective, and preferably point-of-care
serodiagnostic test will be needed to easily
screen and identify CMV-seronegative
subjects and enroll them in these trials. In
addition, a serologic assay that can differentiate reinfection from reactivation would
further enhance the knowledge gained
from CMV vaccine trials.
CMV also has a so-called image problem. It remains the most common virus
most people have never heard of. Public
awareness about CMV infection and disease needs improvement. Most individuals have heard of HIV, Ebola virus, or
Zika virus, but only one fifth of individuals have heard of the more common
CMV [14]. For a CMV vaccine candidate
to be accepted, the public who will be receiving the vaccine must understand that
they would benefit from the vaccine.
Although research of all promising
CMV vaccines should continue vigorously,
what can be done now to reduce CMV infection in vulnerable populations, such as
pregnant women or immune compromised hosts? A popular and practical
so-called CMV knowledge vaccine alternative can be used now, especially in
pregnant women at risk for acquiring
CMV. The components of this preventive
measure are CMV awareness and 3 simple
hygiene precautions. CMV is transmitted
through close contact with body secretions, including saliva and urine. Toddlers
EDITORIAL COMMENTARY
and young children often silently shed
CMV and may transmit infection to
their pregnant mothers. Studies have
shown that, through education on hygiene
precautions such as careful hand washing
after diaper changes, wiping runny noses
and mouth drool, avoiding kissing toddlers on or around the mouth, and avoiding sharing food or drink with other
children, there is a significant reduction
in the risk of CMV transmission and infection [15–17]. Public health officials
support these preventive measures, and
many states (eg, Utah, Texas, Hawaii,
Connecticut, and Tennessee), frustrated
by the lack of CMV awareness in their
communities, have now passed CMV education laws to facilitate the dissemination
of information about CMV diagnosis
and prevention strategies [18, 19].
It is said that good things come to
those who wait. The babies affected
by congenital CMV, as well as others
who also experience the effects of CMV
disease, have waited long enough. Let’s
hope good things come soon.
Note
Potential conflict of interest. Author certifies
no potential conflicts of interest. The author has
submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the
editors consider relevant to the content of the
manuscript have been disclosed.
References
1. Plotkin SA, Furukawa T, Zygraich N, Huygelen C.
Candidate cytomegalovirus strain for human vaccination. Infect Immun 1975; 12:521–7.
2. Plotkin SA, Starr SE, Friedman HM, et al. Protective
effects of Towne cytomegalovirus vaccine against
low-passage cytomegalovirus administered as a
challenge. J Infect Dis 1989; 159:860–5.
3. Plotkin S. The history of vaccination against cytomegalovirus. Med Microbiol Immunol 2015;
204:247–54.
4. Quinnan GV, Delery MRA, Rook AH, et al. Comparative virulence and immunogenicity of the
Towne strain and a nonattenuated strain of cytomegalovirus. Ann Intern Med 1984; 101:478–83.
5. Heineman TC, Schleiss M, Bernstein D, et al.
A phase I study of 4 live, recombinant human
cytomegalovirus Towne/Toledo chimeric vaccines.
J Infect Dis 2006; 193:1350–60.
6. Adler SP, Manganello A.-M, Lee R, et al. A Phase 1
study of 4 live, recombinant human cytomegalovirus
Towne/Toledo chimera vaccines in cytomegalovirusseronegative men. J Infect Dis 2016; 214:1341–8.
7. Lanzieri T, Bialek S, Ortega –Sanchez I, Gambhir M.
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epidemiology of congenital cytomegalovirus infection. Vaccine 2014; 32:3780–6.
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recurrent CMV infections in pregnant
women would substantially reduce the
burden of congenital CMV disease. Second, prevention of primary CMV infection or suppression of reactivation or
reinfection in solid-organ and marrow
transplant recipients or individuals with
human immunodeficiency virus (HIV)
infection, with or without AIDS, or
other immune disorders would substantially reduce the CMV disease burden in
these vulnerable populations, in whom
CMV may cause life- and sight-threatening disease. Finally, a more theoretical but
potentially highly significant reason for
seeking a vaccine is that CMV has been
associated with the development of
atherosclerosis, the burden of which a
CMV vaccine may some day reduce.
The need for a CMV vaccine was so compelling and the results of cost-benefit
analyses were so favorable that a CMV
vaccine was deemed a high priority by
the Institute of Medicine and the National Vaccine Advisory Committee vaccine
prioritization reports for the 21st century
[11, 12]. Soon thereafter, in 2000, a US
government–sponsored meeting proposed activities to support CMV vaccine
development, and in 2012, another summit of diverse experts from government
agencies, industry, academic and research
institutions, public advocacy groups, and
professional societies met to address the
issues surrounding CMV vaccine development and increase efforts to create a
vaccine [13]. So clearly, an effective
CMV vaccine is a desirable and, hopefully, attainable goal.
What are the stumbling blocks in our
way to a successful CMV vaccine? Despite
its ubiquity, CMV remains relatively poorly
understood. More studies on the epidemiology, virology, and immunology of CMV
infections are still needed to help define
correlates of immunity for protection of
the placenta and fetus to protect against
congenital CMV infection, to expand our
limited understanding of the viral antigens
important for protective antibodies, and to
solve the conundrum of lifelong CMV persistence in apparently immune hosts and
8. Pass R, Zhang C, Evans A, et al. Vaccine prevention
of maternal CMV infection. N Engl J Med 2009;
360:1190–9.
9. Freed D, Tang Q, Tang A, et al. Pentameric complex
of viral gpH is the primary target for potent neutralization by a human CMV vaccine. Proc Natl Acad
Sci U S A 2013; 110: E4997–5005.
10. Kirby T. Congenital cytomegalovirus-a neglected
health problem. Lancet 2016; 16:900–1.
11. Stratton KR, Durch J, Lawrence RS, eds.
Vaccines for the 21st century: a tool for
decision making. Washington, DC: Institute
of Medicine Report, National Academy Press,
2000.
12. Arvin A, Fast P, Myers M, et al. Vaccine development to prevent cytomegalovirus disease: report
from the National Vaccine Advisory Committee.
Clin Infect Dis 2004; 39:233–9.
13. Krause P, Bialek S, Boppana S, et al. Priorities for
CMV vaccine development. Vaccine 2013; 32:4010.
14. Cannon M. Congenital cytomegalovirus (CMV) epidemiology and awareness. J Clin Virol 2009; 46
(suppl 4):S6–10.
15. Adler S, Finney J, Manganello A, Best A. Prevention
of child to mother transmission of cytomegalovirus
among pregnant women. J Pediatr 2004; 145:485–91.
16. Vauloup-Fellous C, Picone O, Cordier A, et al.
Does hygiene counseling have an impact on the
rate of cytomegalovirus primary infection during
pregnancy? Results of a 3-year prospective study
in a French hospital. J Clin Virol 2009; 46(suppl
4):S49–53.
17. Revello M, Tibaldi C, Masuelli G, et al. Prevention of
primary cytomegalovirus infection in pregnancy.
EBiomedicine 2015; 2:1205–10.
18. Demmler-Harrison G. Congenital cytomegalovirus:
public health action towards awareness, prevention
and treatment. J Clin Virol 2009; 46(suppl 4):
S1–5.
19. Demmler G, Yow M. Congenital cytomegalovirus
disease-20 years is long enough. N Engl J Med
1992; 326:702–3.
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