salman alfarisi

7212019 salman alfarisi

httpslidepdfcomreaderfullsalman-alfarisi 112

Immunization to prevent congenital

cytomegalovirus infection

Stuart P Adler

Department of Microbiology Medical College of Virginia CampusVirginia Commonwealth UniversityRichmond VA USA

Introduction A primary maternal cytomegalovirus (CMV) during pregnancy causes

newborn disease that includes hearing de1047297cit andor mental retardation

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 dif1047297cult 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 gHgL UL128 130 and 131

pentameric complex These antigens induce antibodies that block viral entry into

1047297broblasts and endothelialepithelial 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 cytomegaloviruspregnancyvaccines

Accepted July 9 2013

Introduction

In the USA and many other developed countries of women of childbear-ing age between 20 and 60 are seronegative and are thus susceptible tocytomegalovirus (CMV) Between 05 and 2 of infants worldwide arecongenitally infected with CMV and about 90 of these infants areasymptomatic and usually have no sequela In developed countriessim10 of congenitally infected infants manifest a wide range of signs andsymptoms In the USA alone every year an estimated 5000ndash8000

British Medical Bulletin 2013 107 57ndash68

DOI101093bmbldt023

amp The Author 2013 Published by Oxford University Press All rights reserved

For permissions please e-mail journalspermissionsoupcom

Correspondence address

Department of

Microbiology Medical

College of Virginia

CampusVirginia

Commonwealth

University PO Box 163

Richmond VA 23298 USA

E-mail sadlervcuedu

Published Online August 16 2013



children develop mental retardation and hearing deficit associated with acongenital CMV infection Similar disease rates are postulated forEurope Congenital CMV infection causes the majority of non-hereditaryhearing loss1ndash3 The range of mental impairment is broad but few symp-tomatic infants develop an IQ of over 100

Long-term severe mental impairment and severe neurosensory hearingloss nearly always f ollow a primary maternal CMV infection in the firsthalf of pregnancy4 In 1992 Fowler et al observed that of 125 infantswith congenital infection who were born of mothers with a primaryCMV infection during pregnancy sequela occurred in 25 of theinfants2 This contrasted with an 8 rate for 64 infants with congenitalinfection but born of mothers who were CMV seropositive prior to preg-nancy None of the infected infants born of seropositive mothers devel-oped severe sequelae One report does describe significant sequelaecharacteristic of congenital CMV infection among infants born of mothers CMV seropositive before conception5 Although the relative fre-quency of severe mental impairment and severe neurosensory hearingloss associated with seropositive mothers remains unknown it appearsthat the original observations of Fowler et al are correct and over 90 of congenital disease occurs among women who acquire a primary CMV in-fection during pregnancy

In 1999 the US Institute of Medicine issued a comprehensivereport called ldquoVaccines for the 21st Century A tool for decisionmakingrdquo The need for a CMV vaccine was among eight vaccines atlevel one the most favorable category6 A CMV vaccine for pre-pregnant women to prevent congenital infection was given the highest

priority because it would be highly cost effective and yield the highesthealth benefits measured in terms of quality-adjusted life years Thisassessment was based on immunizing women of childbearing age be-ginning in adolescence

Sources of data

This review will describe experimental and natural history data onCMV that indicate that the development of a CMV vaccine to preventcongenital infection is feasible and should be highly effective Themajor barriers to a CMV vaccine are not a lack of vaccine candidatesfor there are now many but rather the design and execution of vaccinetrials to demonstrate efficacy The sources of data are published paperscited in PubMed which are directly relevant to the feasibility of CMVimmunization

S P Adler

58 British Medical Bulletin 2013107



Areas of agreement

Four types of evidence indicate that there are no naturally occurring bio-logic obstacles to a CMV vaccine The first type of evidence comes fromanimal studies The guinea pig is the best model for studying congenital

CMV infection because guinea pig CMV (gpCMV) crosses the placentaand infects guinea pig pups Numerous studies using the guinea pigmodel have observed that both active and passive immunization are ef-fective at reducing pup mortality or preventing congenital infectionsActive vaccines have included live attenuated virus killed virus vaccineand recombinant vaccines7ndash9 Passive immunization which includes bothhyperimmune sera and sera raised against the gB glycoprotein of gpCMVhas also been eff ective at reducing pup mortality andor preventing con-genital infection10ndash12 A gpCMV vaccine that stimulates only cellularimmune responses is effective in the guinea pig model13 Thus in the

guinea pig model the induction of immunity to gpCMV in susceptibledames by a variety of different vaccine mechanisms all favorably affectthe natural history of this infection in guinea pigs

The second type of evidence supporting the feasibility of immunizationagainst CMV is the natural history of CMV congenital infection inhumans The majority of severe and long-term neurologic damage occurswhen a woman sustains a primary infection with CMV in the first half of pregnancy In this situation the placenta becomes enlarged inflamed anddysfunctional and if infected the fetus suffers intrauterine hypoxia andmalnourishment which is associated with long-term mental impair-ment1415 If a womanrsquos first CMV infection occurs during the first half of pregnancy the CMV transmission rate from mother to the fetus is about50 and approximately one-third of these will have severe neurologicimpairment andor hearing deficit16 For women infected with CMVbefore pregnancy the transmission rate to the fetus is only 05ndash2 andat least 90 of these congenital-infected infants will be normal at birthand develop normally

Globally an estimated 80 or more of women of childbearing age areCMV seropositive so CMV infections among women CMV seropositivebefore pregnancy are important because these mothers may be an appro-priate group for immunization CMV infections among mothers who are

seropositive to CMV before pregnancy and have a congenitally infectedinfant are called recurrent maternal infections and they have been asso-ciated with maternal acquisition of antibodies to new isolates of CMVsuggesting an attractive hypothesis that maternal reinfection occurs andresults in congenital infection1718 There are case reports of maternal re-current infections being associated with serve long-term neurologicdamage but the true frequency with which this occurs is unkown5 For

CMV vaccination

British Medical Bulletin 2013107 59



hearing deficit however the frequency of hearing deficit among infantsborn after a primary maternal infection and the frequency among infantsborn after a recurrent maternal infection are known and they are similar(about 10)1920 The frequency however of severeprofound and pro-gressive hearing deficit is much greater among infants born of mothers

with a primary infection during pregnancy19

Maternal seropositivity before pregnancy is also a marker of protectionthe fetus from congenital infection In one study women immune to CMVprior to a second pregnancy had a 1 congenital infection rate for a subse-quent pregnancy compared with a 3 rate for women who were seronega-tive prior to the birth of second child suggesting prior immunity inducedby wild-type CMV protects the fetus from infection21 Thus for seroposi-tive women an important question is would immunization enhance theprotection offered by naturally acquired immunity The answer isperhaps The gBMF59 vaccine when give to seropositive women boostsantibody and CD4+ responses to CMV that are sustained for at least oneyear22 Hopefully these vaccine-induced enhanced responses will be asso-ciated with protection of the fetus from congenital infection

A third type of evidence indicating the feasibility of CMV immuniza-tion is that immunity induced by natural infection reduces the rate of re-infection in immunocompetent adults This has been demonstratedelegantly in two studies2324 One study monitored 38 seronegative and42 seropositive women who had a young child shedding CMV that wasacquired in daycare23 Of the 38 seronegative women 45 acquired aCMV infection from their child whereas of the 42 seropositive womenonly 3 (7) became infected with CMV This study shows that the im-

munity provided by natural infection is substantial If vaccine-inducedimmunity was comparable with that induced by a wild-type infection a93 protection rate for a CMV vaccine would certainly be acceptable

Another study demonstrating the protective effect of natural immunitywas an experimental challenge study24 The elegance of this study ema-nated from the simplicity of its design the paucity of subjects needed andthe clarity of the results The study design and results are shown inTable 1 Three groups of subjects were injected with varying doses of thelow-passage Toledo strain of CMV which is not attenuated The threegroups 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 seropositivesubjects became reinfected with Toledo but only at high doses of chal-lenge virus compared with seronegative subjects Those who had receivedthe 1000 PFU of Towne vaccine were partially protected compared withnaturally seropositive subjects 1000 PFU of Towne vaccine is a low dose

The fourth type of evidence indicating the feasibility of immunizationagainst CMV is from an observational non-randomized Phase I study of

S P Adler




passive immunization of pregnant women who acquired a CMV infectionduring pregnancy16 CMV hyperimmune globulin (Cytotect BiotestDreieich Germany) was used to prevent fetal infection in mothers whohad a primary CMV infection but who did not have amniocentesis toconfirm fetal infection Of 126 women who had a primary infectionduring pregnancy and who did not receive passive immunization 57had CMV-infected fetuses compared with only 16 of women who

received passive immunization CMV hyperimmune globulin was alsoused to treat fetuses infected in utero16 Of 45 women who had primaryCMV during pregnancy and whose infants were congenitally infectedin utero as determined by amniocentesis only one (3) of 31 whoreceived CMV hyperimmune globulin had an infant that was symptomat-ic at birth and developed seqeulae at two years of age compared with 7 of 14 (50) women who did not receive immunoglobulin These observa-tions have been supported by two recent subsequent studies2526 Theobserved efficacy of passive immunization is consistent with the naturalhistory studies and animal studies described above The data are also con-

sistent with the success of passive immunization during pregnancy forother viral infections such as measles varicella and hepatitis A and B

Thus all of the available data indicate that CMV immunity is substan-tial but imperfect and that re-infection of naturally seropositive indivi-duals will depend on the dose and exposure frequency Therefore thebest CMV vaccine is unlikely to be 100 effective The efficacy of aCMV vaccine will depend on study design and subjects as well as doseand route of administration

Table 1 Challenge of human subjects with the Toledo unattenuated strain of CMV (from

Yamamoto et al18)

Immune status of study subjects by

parameter evaluatedToledo challenge dose (PFU)

10 100 1000

Seronegative

Clinical 44dagger 22

Laboratory signs (from Yamamoto et al18) 44 22

Infection 44 22

Towne (3 log10 PFU)

Clinical 05 17

Laboratory signs 15 37

Infection 05 47

Seropositive

Clinical 02 05 35

Laboratory signs 02 05 55

Infection 02 15 35

Twelve subjects were seropositive after receiving the attenuated Towne vaccinedagger

Number of subjects affected over the total number tested

CMV vaccination




Areas of uncertainty

CMV vaccine efficacy trials may be biased by many factors including be-havioral changes route of transmission (oral or venereal) exposure fre-quency and possible viral genotypic heterogeneity that may affect

transmission rates These variables have to be considered in a CMVvaccine efficacy trial CMV vaccine trials should be directed toward high-risk women Lower socioeconomic seronegative African-Americanwomen are at high risk21 These women who are between pregnancieshave a congenital infection rate of 3 or about threefold higher thanlow-risk women Seronegative women with a child in daycare are also athigh risk The overall infection rate for this group is about 8 howeverfor women who have a child at home aged lt2 years that is ex cretingCMV the child-to-mother transmission rate is 50 over 1 year27 Wehave 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 theaverage age of the youngest child in daycare at the time of maternal con-ception is about 18 months The average time from enrollment of onechild in daycare and the birth of another is 27 months This informationis very useful when designing vaccine trials that will enroll high-risk pre-pregnant women28

Table 2 presents a statistical power analysis indicating the number of subjects that will have to be studied in various types of CMV vaccine effi-cacy trials depending on one of three possible outcome variables to beassessed the rate of maternal infection the rate of congenital infectionand the frequency of newborn disease For this table two levels of vaccine efficacy were assumed either 80 or 50 The table shows that

Table 2 Power analysis for Phase III ef1047297cacy trials for the prevention of congenital CMV

disease by immunizing seronegative women by study endpoint

Endpoint Vaccine ef1047297cacy = 80 Vaccine ef1047297cacy= 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

Maternal infection 50 10 48 50 25 130

12 24 264 12 6 776

Transmission

to the fetus

4 1 976 4 2 2476

3 0075 1310 3 15 3326

2 05 1976 2 1 5028

1 025 3404 1 05 10 128

Disease in the

newborn

04 008 8542 004 002 25 434

02 004 17 154 02 01 50 940

Assumes an equal number of vaccine and placebo subjects with an alpha of 005 and a beta of 08

Calculated by the method of Fleiss47

The approximate annual infection rate for mothers with a young child shedding CMV2729

S P Adler




if a vaccine prevented maternal infection with 80 efficacy as few as 48subjects could be required for an efficacy trial On the other hand if avaccine is only 50 effective and disease in the newborn is the endpointas many as 50000 pregnant women may need to be enrolled in an efficacytrial 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 con-genital infection rate as the primary end point In this case it will be ne-cessary to enroll between 3400 and 10 000 pre-pregnant women andtheir newborns in a vaccine efficacy trial

Infants and toddlers

For maximal public health impact a CMV vaccine for infants and tod-dlers is optimal since contact with young children at home is the primarysource of infection among seronegative pregnant women29 CMV-infected young children aged lt2 years excrete virus in urine and saliva forprolonged periods of up to 4 years Immunization of young childrenshould ideally prevent CMV acquisition by the children and shouldinduce durable life-long immunity If immunization of young childrenreduces the duration of viral excretion or reduces the quantity of virusshed which may reduce the frequency of or prevent child-to-mothertransmission

In contrast to vaccine trials with women as subjects vaccine trials withinfants and toddlers as subjects will require small numbers of subjects

and an initial observation for a year or less We have observed repeatedlythat an average of 25 of infants in daycare will acquire CMV infectionfrom another daycare enrollee29 If a vaccine is 80 effective in prevent-ing infection only a total of 116 total infants will be needed to demon-strate efficacy If the vaccine is only 50 effective the number of infantsrequired would increase to 306

Infants and toddlers have excellent antibody responses to CMV that aresustained for up to 3 years which if protective may reduce the frequencyof either child-to-child transmission or child-to-mother transmissionUnlike Towne vaccine which induces antibody levels in infants compar-

able with those induced in adults the gBMF59 vaccine when adminis-tered to infants and toddlers induces antibody responses six- to eightfoldhigher than those induced in adults30 These observations with bothvaccines suggest that the vaccination of young children may be quiteeffective

Finally we have observed that infants and toddlers that shed CMV forprolonged periods have normal CMV-specific CD8+ responses to CMVbut greatly diminished CMV-specific CD4+ responses3132 Therefore it

CMV vaccination




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

Areas timely for developing research

There are currently two CMV vaccines in Phase II studies One is theCMV gBMF59 vaccine which is disulfide-linked glycoprotein complex(gB) with 130 and 55 kDa components33 The gB complex is a majorcomponent of the envelope glycoprotein of human CMV The gBcomplex contains at least seven neutralizing epitopes In human convales-cent sera antibodies to gB are abundant Monoclonal antibodies againstgB neutralize both wild-type viral isolates and laboratory-adaptedstrains The gB proteins have been expressed in CHO cells and whenadministered with the adjuvant MF59 induce high levels of neutralizingantibodies in animals and humans In both animals and humans gB alsocontains epitopes that stimulate T lymphocytes cytotoxic for CMV ThusgBMF59 is the most likely candidate for a subunit vaccine Three dosesare required and the vaccine is safe and immunogenic in adults andinfants

The other vaccine in a Phase I human trial is TownendashToledo chimerasTowne is a live attenuated vaccine used extensively in clinical trials and issafe34 It does not reactivate in either healthy volunteers or immunosup-pressed patients It has limited reactogenicity The vaccine is not shed anddoes not produce viremia The vaccine is given a single subcutaneousdose is safe and stimulates neutralizing antibodies comparable with

those induced by wild-type virus Towne-induced antibody levels are sus-tained for 84 months or longer Towne vaccine also induces limited cellu-lar immune responses3536

Toledo is a CMV isolate that is not attenuated and causes illness whengiven in high doses24 Four TownendashToledo chimeras were produced andeach obtained part of its genome from Towne and part from Toledo Thiswas done in an attempt to enhance the immunogenicity of Townewithout sacrificing safety The TownendashToledo chimera were safe in sero-positive subjects and are now being evaluated in seronegative subjects37

CMV has historically been cultured using human fibroblasts Viral iso-

lates from humans are cell-associated and attain low titers (sim103

PFU ml) Growth properties improve upon serial passage in fibroblastslsquoLaboratory-adaptedrsquo high-passage strains such as Towne and AD169grow in fibroblasts to high titers (sim107 PFUml) of extracellular virus

Neutralizing antibodies prevent cells from becoming infected bybinding to virion proteins necessary for viral attachment and entry Theability of a vaccine to induce neutralizing antibodies is critical to efficacyThe CMV epitopes that induce neutralizing activity are partially known

S P Adler




That antibodies to gB comprise over half of the fibroblast entry neutraliz-ing activity in human sera made gB an early candidate for subunit vac-cines and an important component for live attenuated vaccine candidatesHowever other viral glycoprotein complexes also contain neutralizingepitopes including gHgL and gMgN3839 As noted below fibroblast-

based neutralizing assays fail to identify major neutralizing epitopes thatare specific to other cell types and in fact most of the neutralizing anti-bodies in human sera are induced by non-gB proteins and these anti-bodies block entry into endothelial and epithelial cells40 Thus the abilityto induce neutralizing antibodies to a range of neutralizing epitopes notjust gB is a potential advantage

Viral entry into epithelial and endothelial cells occurs by a mechanismdifferent from that of fibroblast entry Entry into fibroblasts occurs bypH-independent receptor-mediated fusion at the cell surface that ismediated by gB and gHgL In contrast entry into epithelial endothelialand other cell types uses a pH-dependent lsquoendocytic entryrsquo pathway inwhich virus first attaches to the cell surface is endocytosed and onlyachieves fusion and entry to the cytoplasm upon acidification of the endo-some This pathway requires proteins gB gHgL and also UL128 UL130and UL131

Hahn et al showed that viral genes UL128 UL130 and UL131 areneeded for endothelial entry41 They further found that fibroblast-adapted non-endothelial tropic strains contain mutations in at least oneof these three genes Towne strain for example contains a two-bp inser-tion causing a frame shift in UL130 whereas AD169 contains a one-bpinsertion in UL131 Both Towne and AD169 could be adapted for

growth in endothelial cells and in both instances the frame shift muta-tions in UL130 or UL131 were repaired41 Subsequent papers showedthat this genetic basis of endothelial tropism extends also to epithelialand dendritic cell tropisms4243

CMV vaccines tested in clinical trials include Towne vaccine theTownendashToledo chimeras discussed above an alpha virus replicon withgB as the antigen the gBMF59 vaccine a gB vaccine produced byGlaxoSmithKline and a DNA vaccine using gB and pp65 pp65 is viralprotein that is a potent inducer of CD8+ responses directed against CMVThese vaccines are all poor inducers of antibodies that block viral entry

into endothelialepithelial cells44

In a Phase II clinical trial the gBMF59 vaccine was only 50 effectiveat preventing primary infection among young women with a child athome45 This was a surprisingly good result given gB is a poor inducer of antibodies that block entry into endothelialepithelial cells Thus currentvaccines in pre-clinical development have focused on including antigensof the gHgL UL128 130 and 131 pentameric complex Current vaccinesimmunogenic in animal studies include an inactivated AD169 which has

CMV vaccination




been repaired in the UL131 gene a DNA vaccine using a wild-typeUL130 gene and peptide vaccines using peptides from UL130 and 13146

Conclusions

Even though all of the available data indicate that a CMV vaccine toprevent congenital disease should be easily achievable progress in evalu-ating CMV vaccines has been greatly impeded by a lack of public aware-ness of CMV This lack of public awareness means that obstetricians areunfamiliar with CMV infections during pregnancy including diagnosisand management and thus our knowledge of the prevalence and inci-dence of CMV infections is incomplete Lack of public awareness meansthat vaccine trials are not given high priority by granting agencies and thepharmaceutical companies Although CMV infections are common 90

of those infected develop no symptoms and hence development of symp-toms cannot be used as an endpoint for vaccine trials Also with enhancedpublic awareness of CMV recruitment into vaccine trials would begreatly facilitated If the public were demanding a CMV vaccine a CMVvaccine to prevent congenital infection would most likely be availablenow

In spite of these difficulties evaluation of CMV vaccines is possible andlikely when considered against similar obstacles encountered by severalother recently licensed vaccines such as the human papilloma and rota-virus vaccines

References

1 Morton CC Nance WE Newborn hearing screeningmdasha silent revolution N Engl J Med 2006182151ndash64

2 Fowler KB Stagno S Pass RF et al The outcome of congenital CMV infection in relation to

maternal antibody status N Engl J Med 1992326663ndash7

3 Adler SP Congential cytomegalovirus screening Pediatr Infect Dis J 2005241105ndash06

4 Stagno S Pass RF Cloud G et al Primary cytomegalovirus infection in pregnancy incidence

transmission to fetus and clinical outcome JAMA 19862561904ndash8

5 Boppanna SB Fowler KB Stagno S et al Symptomatic congenital cytomegalovirus infection in

infants born of mothers with preexisting immunity to cytomegalovirus Pediatrics

199910455ndash66 Stratton K Durch J Lawrence R Vaccines for the 21st Century A Tool for Decisionmaking

Vol 1 Washington DC National Academy Press 2001 476

7 Schleiss MR Bourne N Stroup G et al Protection against congenital cytomegalovirus infection

and disease in guinea pigs conferred by a purified recombinant glycoprotein B vaccine J Infect Dis 20041891374ndash81

8 Schleiss MR Animal models of congenital cytomegalovirus infection an overview of progress in

the characterization of guinea pig cytomegalovirus J Clin Virol 20022S37ndash49

9 Bia FJ Miller SA Lucia HL et al Vaccination against transplacental cytomegalovirus transmis-

sion vaccine reactivation and efficacy in guinea pigs J Infect Dis 1984149355ndash62

S P Adler




10 Chatterjee A Harrison CJ Britt WJ et al Modification of maternal and congenital cytomegalo-

virus infection anti-glycoprotein b antibody transfer in guinea pigs J Infect Dis 2001

183547ndash53

11 Bratcher DF Bourne N Bravo FJ et al Effect of passive antibody on congenital cytomegalovirus

infection in guinea pigs J Infect Dis 1995172944ndash50

12 Bia FJ Griffith BP Tariso M et al Vaccination for the prevention of maternal and fetal infection

with guinea pig cytomegalovirus J Infect Dis 1980142732ndash8

13 Schleiss MR Lacayo JC Belkaid Y et al Preconceptual administration of an alphavirus repliconUL83 (pp65 homolog) vaccine induces humoral and cellular immunity and improves pregnancy

outcome in the guinea pig model of congenital cytomegalovirus infection J Infect Dis2007195789ndash98

14 Maidji E Nigro G Tabata T et al Antibody treatment promotes compensation for human

cytomegalovirus-induced pathogenesis and a hypoxia-like condition in placentas with congeni-

tal infection Am J Pathol 20101771298ndash310

15 La Torre R Nigro G Mazzocco M et al Placental enlargement in women with a primary mater-

nal cytomegalovirus infection is associated with fetal and neonatal disease Clin Infect Dis

200643994ndash1000

16 Nigro G Adler SP La Torre R et al Passive immunization during pregnancy for congenital

cytomegalovirus infection N Engl J Med 20053531350ndash6

17 Boppana SB Rivera LB Fowler KB et al Intrauterine transmission of cytomegalovirus to infants

of women with preconceptional immunity N Engl J Med 20013441366ndash

7118 Yamamoto AY Mussi-Pinhata MM Boppana SB Human cytomegalovirus reinfection is asso-

ciated with intrauterine transmission in a highly cytomegalovirus-immune maternal population

Am J Obstet Gynecol 2010202297ndash8

19 Ross SA Fowler KB Ashrith G et al Hearing loss in children with congenital cytomegalovirus

infection born to mothers with preexisting immunity J Pediatr 2006148332ndash6

20 de Vries JJ van Zwet EW Dekker FW et al The apparent paradox of maternal seropositivity as

a risk factor for congenital cytomegalovirus infection a population-based prediction model

Rev Med Virol 2013 doi101002rmv1744

21 Fowler KB Stagno S Pass RF Maternal immunity and prevention of congenital cytomegalo-

virus infection JAMA 20032891008ndash11

22 Sabbaj S Pass RF Goepfert PA et al Glycoprotein B vaccine is capable of boosting both anti-

body and CD4 T-cell responses to cytomegalovirus in chronically infected women J Infect Dis20112031534ndash41

23 Adler SP Starr SE Plotkin SA et al Immunity induced by a primary cytomegalovirus infection

protects against secondary infection among women of childbearing age J Infect Dis199517126ndash32

24 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 1989159860ndash5

25 Nigro G Adler SP Parruti G et al Immunoglobulin therapy of fetal cytomegalovirus infection

occurring in the first half of pregnancy ndash a case-control study of the outcome in children J Infect Dis 2012205215ndash2

26 Visentin S Manara R Milanese L et al Early primary CMV infection in pregnancy maternal

hyperimmune globulin therapy improves childrenrsquos outcome at one year Clin Infect Dis

201255497ndash503

27 Adler SP Cytomegalovirus and child day care risk factors for maternal infection Pediatr Infect Dis J 199110590ndash4

28 Marshall BC Adler SP The frequency of pregnancy and exposure to cytomegalovirus (CMV)infections among women with a young child in day care Am J Obs Gyn 2009200161ndash5

29 Adler SP Finney JW Manganello AM et al Prevention of child-to-mother transmission of

cytomegalovirus among pregnant women J Pediatr 2004145485ndash91

30 Mitchell DK Holmes SJ Burke RL et al Immunogenicity of a recombinant human cytomegalo-

virus (CMV) gB vaccine in seronegative toddlers Pediatr Infect Dis J 200221133ndash8

31 Chen SF Tu WW Sharp MA et al Antiviral CD8 T cells in the control of primary human

cytomegalovirus infection in early childhood J Infect Dis 20041891619ndash27

32 Tu W Chen S Sharp M et al Persistent and selective deficiency of CD4+ T cell immunity to

cytomegalovirus in immunocompetent young children J Immunol 20041723260ndash7

CMV vaccination




33 Frey SE Harrison C Pass RF et al Effects of antigen dose and immunization regimens on anti-

body responses to a cytomegalovirus glycoprotein b subunit vaccine J Infect Dis

19991801700ndash3

34 Adler SP Hempfling SH Starr SE et al Evaluation of the safety and immunogenicity of the

Towne strain of cytomegalovirus among women of childbearing age and children Pediatr Infect Dis J 199817200ndash6

35 Jacobson MA Sinclair E Bredt B et al Safety and immunogenicity of Towne cytomegalovirus

vaccine with or without adjuvant recombinant interleukin 12 Vaccine 2006245311ndash1936 Jacobson MA Sinclair E Bredt B et al Cytomegalovirus (CMV) antigen-specific CD4+ and

CD8+ T cell proliferation and IFN gamma responses in CMV-seronegative recipients of Towne

CMV vaccine J Clin Virol 200635332ndash7

37 Heineman TC Schleiss M Bernstein DI et al A phase 1 study of 4 live recombinant human

cytomegalovirus TowneToledo chimeric vaccines J Infect Dis 20061931350ndash60

38 Urban M Klein M Britt WJ et al Glycprotein H of human cytomegalovirus is a major antigen

for the neutralizing humoral immune response J Gen Virol 1996771537ndash47

39 Shimamura M Mach M Britt WJ Human cytomegalovirus infection elicits a glycoprotein M

(gM)gN-specific virus-neutralizing antibody response J Virol 2006804591ndash600

40 Fouts AE Chan P Stephan JP et al Antibodies against the gHgLUL128UL130UL131

complex comprise the majority of the anti-cytomegalovirus (anti-CMV) neutralizing antibody

response in CMV hyperimmune globulin J Virol 2012867444ndash7

41 Hahn G Revello MG Patrone M et al Human cytomegalovirus UL131-128 genes are indis-pensable for virus growth in endothelial cells and virus transfer to leukocytes J Virol 20047810023ndash33

42 Gerna G Percivalle E Lilleri D et al Dendritic-cell infection by human cytomegalovirus is

restricted to strains carrying functional UL131-128 genes and mediates efficient viral antigen

presentation to CD8+ T cells J Gen Virol 200586275ndash84

43 Wang D Shenk T Human cytomegalovirus UL131 open reading frame is required for epithelial

cell tropism J Virol 20057910330ndash8

44 Cui X Meza BP Adler SP et al Cytomegalovirus vaccines fail to induce epithelial entry neutral-

izing antibodies comparable to natural infection Vaccine 2008265760ndash6

45 Pass RF Zhang C Evans A et al Vaccine prevention of maternal cytomegalovirus infection

N Engl J Med 20093601191ndash9

46 Sauer A Saccoccioa F Cui X et al Peptides from cytomegalovirus UL130 and UL131 proteins

induce high titer antibodies that block viral entry into mucosal epithelial cells Vaccine

2011292705ndash1

47 Fleiss JL Statistical Methods for Rates and Proportions (2nd edn) New York Wiley 1981

S P Adler




children develop mental retardation and hearing deficit associated with acongenital CMV infection Similar disease rates are postulated forEurope Congenital CMV infection causes the majority of non-hereditaryhearing loss1ndash3 The range of mental impairment is broad but few symp-tomatic infants develop an IQ of over 100

Long-term severe mental impairment and severe neurosensory hearingloss nearly always f ollow a primary maternal CMV infection in the firsthalf of pregnancy4 In 1992 Fowler et al observed that of 125 infantswith congenital infection who were born of mothers with a primaryCMV infection during pregnancy sequela occurred in 25 of theinfants2 This contrasted with an 8 rate for 64 infants with congenitalinfection but born of mothers who were CMV seropositive prior to preg-nancy None of the infected infants born of seropositive mothers devel-oped severe sequelae One report does describe significant sequelaecharacteristic of congenital CMV infection among infants born of mothers CMV seropositive before conception5 Although the relative fre-quency of severe mental impairment and severe neurosensory hearingloss associated with seropositive mothers remains unknown it appearsthat the original observations of Fowler et al are correct and over 90 of congenital disease occurs among women who acquire a primary CMV in-fection during pregnancy

In 1999 the US Institute of Medicine issued a comprehensivereport called ldquoVaccines for the 21st Century A tool for decisionmakingrdquo The need for a CMV vaccine was among eight vaccines atlevel one the most favorable category6 A CMV vaccine for pre-pregnant women to prevent congenital infection was given the highest

priority because it would be highly cost effective and yield the highesthealth benefits measured in terms of quality-adjusted life years Thisassessment was based on immunizing women of childbearing age be-ginning in adolescence

Sources of data

This review will describe experimental and natural history data onCMV that indicate that the development of a CMV vaccine to preventcongenital infection is feasible and should be highly effective Themajor barriers to a CMV vaccine are not a lack of vaccine candidatesfor there are now many but rather the design and execution of vaccinetrials to demonstrate efficacy The sources of data are published paperscited in PubMed which are directly relevant to the feasibility of CMVimmunization

S P Adler




Areas of agreement







CMV vaccination












S P Adler









Yamamoto et al18)



10 100 1000

Seronegative



Infection 44 22

Towne (3 log10 PFU)

Clinical 05 17


Infection 05 47

Seropositive

Clinical 02 05 35


Infection 02 15 35



CMV vaccination












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


12 24 264 12 6 776

Transmission

to the fetus

4 1 976 4 2 2476

3 0075 1310 3 15 3326

2 05 1976 2 1 5028

1 025 3404 1 05 10 128

Disease in the

newborn

04 008 8542 004 002 25 434

02 004 17 154 02 01 50 940




S P Adler













CMV vaccination














S P Adler












CMV vaccination





Conclusions




References

















S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler




Areas of agreement







CMV vaccination












S P Adler









Yamamoto et al18)



10 100 1000

Seronegative



Infection 44 22

Towne (3 log10 PFU)

Clinical 05 17


Infection 05 47

Seropositive

Clinical 02 05 35


Infection 02 15 35



CMV vaccination












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


12 24 264 12 6 776

Transmission

to the fetus

4 1 976 4 2 2476

3 0075 1310 3 15 3326

2 05 1976 2 1 5028

1 025 3404 1 05 10 128

Disease in the

newborn

04 008 8542 004 002 25 434

02 004 17 154 02 01 50 940




S P Adler













CMV vaccination














S P Adler












CMV vaccination





Conclusions




References

















S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler












S P Adler









Yamamoto et al18)



10 100 1000

Seronegative



Infection 44 22

Towne (3 log10 PFU)

Clinical 05 17


Infection 05 47

Seropositive

Clinical 02 05 35


Infection 02 15 35



CMV vaccination












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


12 24 264 12 6 776

Transmission

to the fetus

4 1 976 4 2 2476

3 0075 1310 3 15 3326

2 05 1976 2 1 5028

1 025 3404 1 05 10 128

Disease in the

newborn

04 008 8542 004 002 25 434

02 004 17 154 02 01 50 940




S P Adler













CMV vaccination














S P Adler












CMV vaccination





Conclusions




References

















S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler









Yamamoto et al18)



10 100 1000

Seronegative



Infection 44 22

Towne (3 log10 PFU)

Clinical 05 17


Infection 05 47

Seropositive

Clinical 02 05 35


Infection 02 15 35



CMV vaccination












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


12 24 264 12 6 776

Transmission

to the fetus

4 1 976 4 2 2476

3 0075 1310 3 15 3326

2 05 1976 2 1 5028

1 025 3404 1 05 10 128

Disease in the

newborn

04 008 8542 004 002 25 434

02 004 17 154 02 01 50 940




S P Adler













CMV vaccination














S P Adler












CMV vaccination





Conclusions




References

















S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler












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


12 24 264 12 6 776

Transmission

to the fetus

4 1 976 4 2 2476

3 0075 1310 3 15 3326

2 05 1976 2 1 5028

1 025 3404 1 05 10 128

Disease in the

newborn

04 008 8542 004 002 25 434

02 004 17 154 02 01 50 940




S P Adler













CMV vaccination














S P Adler












CMV vaccination





Conclusions




References

















S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler













CMV vaccination














S P Adler












CMV vaccination





Conclusions




References

















S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler














S P Adler












CMV vaccination





Conclusions




References

















S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler












CMV vaccination





Conclusions




References

















S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler





Conclusions




References

















S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler






183547ndash53












200643994ndash1000

























201255497ndash503











CMV vaccination






19991801700ndash3




























2011292705ndash1


S P Adler






19991801700ndash3




























2011292705ndash1


S P Adler


salman alfarisi

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