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Transmission of Vaccine-StrainVaricella-Zoster Virus: ASystematic ReviewMona Marin, MD,a Jessica Leung, MPH,a Anne A. Gershon, MDb

abstractCONTEXT: Live vaccines usually provide robust immunity but can transmit the vaccine virus.OBJECTIVE: To assess the characteristics of secondary transmission of the vaccine-strainvaricella-zoster virus (Oka strain; vOka) on the basis of the published experience with use oflive varicella and zoster vaccines.

DATA SOURCES: Systematic review of Medline, Embase, the Cochrane Library, Cumulative Index toNursing and Allied Health Literature, and Scopus databases for articles publishedthrough 2018.

STUDY SELECTION: Articles that reported original data on vOka transmission from persons whoreceived vaccines containing the live attenuated varicella-zoster virus.

DATA EXTRACTION: We abstracted data to describe vOka transmission by index patient’s immunestatus, type (varicella or herpes zoster) and severity of illness, and whether transmission waslaboratory confirmed.

RESULTS: Twenty articles were included. We identified 13 patients with vOka varicella aftertransmission from 11 immunocompetent varicella vaccine recipients. In all instances, thevaccine recipient had a rash: 6 varicella-like and 5 herpes zoster. Transmission occurredmostly to household contacts. One additional case was not considered direct transmissionfrom a vaccine recipient, but the mechanism was uncertain. Transmission from vaccinatedimmunocompromised children also occurred only if the vaccine recipient developed a rashpostvaccination. Secondary cases of varicella caused by vOka were mild.

LIMITATIONS: It is likely that other vOka transmission cases remain unpublished.

CONCLUSIONS: Healthy, vaccinated persons have minimal risk for transmitting vOka to contactsand only if a rash is present. Our findings support the existing recommendations for routinevaricella vaccination and the guidance that persons with vaccine-related rash avoid contactwith susceptible persons at high risk for severe varicella complications.

aNational Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; and bDepartment of Pediatrics, Vagelos College of Physicians andSurgeons, Columbia University, New York, New York

Dr Marin conceptualized and designed the study, reviewed the articles, drafted the initial manuscript, and reviewed and revised the manuscript; Ms Leung participatedin the design of the study, reviewed the articles, and reviewed and revised the manuscript; Dr Gershon provided substantial contribution to the interpretation of thedata and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountablefor all aspects of the work.

To cite: Marin M, Leung J, Gershon AA. Transmission of Vaccine-Strain Varicella-Zoster Virus: A Systematic Review. Pediatrics. 2019;144(3):e20191305

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Varicella, caused by the varicella-zoster virus (VZV), is highlycontagious. Although generally a mildchildhood disease, seriouscomplications (including death) canoccur, most commonly in infants,adults, and immunocompromisedpersons.1 Varicella was an importantcause of morbidity and mortality inthe United States before theintroduction of varicella vaccination(1996), with ∼4 million cases, 10 500to 13 000 hospitalizations, and 100 to150 deaths annually.2 In the 1970s,30% of children with leukemia whocontracted varicella developedviscerally disseminated disease, with7% mortality.3 In the era of antiviraltherapy, prognoses improved withtreatment administered early in thecourse of illness, but deaths continueto occur. Varicella during pregnancycan cause congenital disease in thefetus or severe varicella in thenewborn or can lead to herpes zoster(HZ) in early childhood.4 Nosocomialtransmission of VZV often disruptshealth care facilities’ operations.5,6

VZV exposures among patients andhealth care personnel can be timeconsuming and costly even when theydo not result in transmission.

Vaccination effectively preventsdisease transmission in communityand health care settings. To addressthe burden of varicella, a liveattenuated vaccine was developed inthe 1970s7 and licensed in the UnitedStates in 1995. Varicella vaccines arecontraindicated forimmunocompromised persons orpregnant women, but theseindividuals may benefit indirectlyfrom vaccination of householdcontacts and health care workers whocare for them.2 Several formulationsof varicella vaccines, all containingthe live attenuated virus, are availableworldwide but are recommended forroutine use in only a limited numberof countries. Since 2006, a liveattenuated zoster vaccine, whichcontains the same VZV strain asvaricella vaccines but at a higher

potency, has been available toprevent HZ.

Live attenuated vaccines usuallyprovide more robust immunity thanvaccines containing inactivatedviruses but can, in rare instances,transmit the vaccine virus. Millions ofpersons are vaccinated with varicellavaccine each year in the United States,including routine vaccinations andvaccination of close contacts ofpersons at high risk for severevaricella; therefore, tracking thecharacteristics of secondarytransmission of vaccine-strain VZV(Oka strain; abbreviated as vOka) isimportant. We reviewed theexperience reported in the literaturewith the use of live VZV vaccinesadministered to healthy andimmunocompromised persons toaddress this question.

METHODS

We defined secondary transmissionof the vaccine strain as transmissionof vOka from a person who had everreceived a vaccine containing liveattenuated VZV to a contact.Transmission was determined by theauthors of the articles bydocumentation of (1) laboratoryconfirmation of vOka from the rashesof the vaccinated index case andsecondary case(s), (2) laboratoryconfirmation of the virus from thesecondary case’s rash similar to thatin the vaccine received by the indexcase, or (3) seroconversion ofcontacts of vaccine recipients in theabsence of a rash or other VZVexposure of the contact. Some authorsreported transmission based only ontemporal association betweenvaccination and the disease in thecontact of a vaccine recipient. Thosereports were classified in this articleas unsubstantiated transmissionbecause no or insufficient laboratorytesting was performed to documentvOka; additionally, in some reports,the epidemiological assessment didnot provide support for transmission

from the vaccine recipient or did notaccord with the biology of varicella,especially the incubation period.

We searched Medline, Embase, theCochrane Library, and the CumulativeIndex to Nursing and Allied HealthLiterature (CINAHL) databases forarticles published, in any language,from database inception throughDecember 31, 2018. The completesearch strategy is described inSupplemental Table 3. Two authorsreviewed each title and abstract todetermine if the article included anyinformation on transmission of vOka.For articles that passed this initialscreen, we reviewed the full text. Wealso reviewed references thatdescribed transmission of vOkaidentified from the reference sectionof the articles retrieved by thedatabase search. Only articles thatincluded original reports of vOkatransmission were retained.

Two authors abstracted data ondisease presentation and immunestatus of the index case (ie, varicellavaccine recipient), number ofsecondary cases, transmission setting,how transmission was determined,interval between vaccination and rashonset in the index case, intervalbetween rash onset in the index andsecondary case(s), characteristics ofthe disease and immune status of thesecondary case(s), whether the indexand secondary case(s) werelaboratory confirmed, and vaccinemanufacturer. We describe vOkatransmission by immune status of theindex patient (immunocompetent orimmunocompromised), type(varicella or HZ) and severity ofillness this patient had, and whethervOka transmission was laboratoryconfirmed.

RESULTS

We screened 378 nonduplicatearticles and identified 98 for full-textreview; this included 1 study knownby the authors to be published afterthe literature search was completed.8

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After excluding 72 articles, 26 metinclusion criteria for our review(Fig 1). Six articles reported interimresults on 2 studies. To describeinstances of secondary transmission,we included only the last reportsfrom these 2 studies; when specificinformation of interest was notincluded in the last publications, weabstracted data from the earlierpublications. A total of 20 articleswere included in our review.

Articles originated from the UnitedStates (n = 15), Australia (n = 2),China (n = 1), Japan (n = 1), andEurope (n = 1; country not reported);publication years were 1981–2019.

Most articles described transmissionof vOka after receipt of Varivax(Merck varicella vaccine), which islicensed in the United States, likelybecause large clinical trials amongimmunocompromised andimmunocompetent children wereconducted in the United States beforelicensure of the vaccine, and theUnited States has the longest-runningroutine varicella vaccination program.Transmission of vOka from recipientsof other varicella vaccines(SmithKline and/or GlaxoSmithKlineor Biken) also occurred.9–12 Of note,all available varicella vaccines exceptthe vaccine used in Korea contain liveattenuated VZV derived from the

same parental seed stock of vOka. Allreports of vOka transmissionfollowed receipt of a first dose of thevaricella vaccine; no transmissionwas reported from recipients of thelive zoster vaccine.

Overall, we identified 13 cases ofconfirmed transmission of vOka from11 immunocompetent vaccinerecipients with a rash.8–17 Oneadditional case was not considereddirect transmission from a vaccinerecipient, but the mechanism wasuncertain.18 In the largest study ofimmunocompromised children, therate of transmission of vOka was 23%from vaccine recipients whodeveloped rash after vaccination and0% if the vaccine recipient did notdevelop a rash.19

vOka Transmission FromImmunocompetent Varicella VaccineRecipients

Transmission Resulting in ClinicalVaricella Among Contacts

Five articles reported 6 instances oftransmission of vOka from animmunocompetent varicella vaccinerecipient who developeda varicellalike rash soon aftervaccination (Table 1).10,14–17 In 5instances, transmission occurred inthe household; 1 occurred ina chronic care facility. Eightsecondary cases occurred from the 6vaccinated individuals, all withlaboratory-confirmed vOka. Of thevaccinated individuals, 2 were adultsand 4 were children, and alldeveloped a vesicular rash 12 to24 days after vaccination; rash wasmild (2–40 lesions) with 1 exception(.500 lesions). Contacts whodeveloped varicella were morevariable in age (range 4 months–39years) and with no reportedimmunocompromising conditions.Rash in the contacts developed 16 to21 days after rash onset in the indexcases and was mild (median 25–30lesions; range 10–100; 1 with .100lesions).

FIGURE 1Study selection.

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Five articles reported 5 instances oftransmission of vOka from animmunocompetent varicella vaccinerecipient who developed vOka HZafter vaccination (Table 2).8,9,11–13 In4 instances, transmission occurred inthe household; 1 occurred in school.Five secondary varicella casesoccurred. No immunocompromisingconditions were reported in theinfected contacts. Index cases werechildren (age 20 months–5 years)who developed HZ 8 months to2 years after varicella vaccination.Contacts who developed varicellaranged in age from 2 to 35 years.Rash in the contacts developed 14 to19 days after HZ rash onset in theindex cases, and the number oflesions ranged from 10 to 20 to“uncountable” (median 50–100); 1contact had mild meningismus but nofocal neurologic signs.8

Seroconversion Among Contacts ofVaricella Vaccine Recipients as a Proxyfor Transmission

In clinical trials of the varicellavaccine, seroconversion in siblings ofhealthy vaccinated children was

examined. The siblings were varicellasusceptible and vaccinated witha placebo.20 Six (1%) of 439 placeborecipients seroconverted withouthaving developed a rash; none oftheir varicella-vaccinated siblingsdeveloped a rash. Serological data ofthe vaccine recipient and sibling whoreceived the placebo suggested that 3of 6 seroconverters received thevaccine mistakenly in lieu of theirsibling.20 An alternative explanationis that the serological test usedyielded false-positive results, not anuncommon occurrence.21,22

Other Mechanism of Transmission

Kluthe et al18 reported a case ofneonatal varicella (50–60maculopapular and vesicular lesions)with vOka diagnosed 22 days aftermaternal postpartum vaccination.The mother did not have a rash, butthe newborn was in the room whenthe mother was vaccinated; themechanism of transmission remainsundetermined, but the most plausiblemode of transmission was deemedaerosolization when the vaccine-filedsyringe was cleared of air bubbles

rather than transmission from themother.

vOka Transmission FromImmunocompromised VaricellaVaccine Recipients Resulting inClinical Varicella or SeroconversionWithout Rash in the Contact

Several publications described casereports or observational studies oftransmission of vOka aftervaccination of immunocompromisedchildren.17,19,23–25 In these studies,authors attributed disease orseroconversion without rash amongunvaccinated siblings to vOka,although laboratory confirmation ofvOka causing the rash was not alwaysobtained (or could not be obtained incases of seroconversion). Exposuresto varicella or HZ were closelymonitored, and if no other knownexposures were reported, rash in thevaccinated sibling was considered thelikely source for the rash orseroconversion in the contacts.

Because immunocompromisedpersons are at high risk for severevaricella, the US National Institutes ofHealth supported a clinical trial of

TABLE 1 vOka Transmission From Immunocompetent Varicella Vaccine Recipients: Transmission From a Varicella Vaccine Recipient Who Developeda Varicella-like Rash Soon After Vaccination

Author Vaccinated Person or Index Case Secondary Case(s)a

LaRussa et al10 38-y-old developed a rash with 30 scattered lesions (25 vesicles) 12 dafter receipt of an investigational varicella vaccine; low-grade feverwith no other systemic symptoms

2.5- and 8-y-old children developed rashes with 30 lesions (5vesicles) and 100 lesions (20 vesicles), respectively, 16 d afteronset of mother’s rash; 1 child had low-grade fever with noother systemic symptoms

Tsolia et al17 Healthy sibling (secondary case, age not reported) contact of hisvaccinated sibling with leukemia; vOka rash with 40 lesions 18 dafter vaccination of his immunocompromised sibling

Healthy sibling (age not reported) developed a rash with 11lesions 18 d after his healthy sibling’s rash

Grossberg et al14 16-y-old resident of a chronic care facility developed fever andvaricella-like rash (.500 vesicular lesions) 15 d postvaccination;clinically immunocompetent but with multiple chronic medicalconditions, including profound mental retardation, spasticquadriplegia, and seizures

Immunocompetent 12-y-old resident of the facility developed a 2-d vesicular rash with 15 lesions and mild fever 19 d after rashonset in the index case; 39-y-old health care worker developeda vesicular rash with 10 lesions and a 1-d fever of 38.4°C 21 dafter rash onset in the index case. Both secondary patientsreported a history of varicella during childhood

Sharrar et al16 1-y-old developed 2 vesicular lesions 14 d postvaccination 4-mo-old sibling developed a rash with 25 lesions 19 d after indexcase rash onset

1 y-old developed 12 vesicular lesions 17 d postvaccination 35-y-old (father) developed .100 lesions 17 d after index caserash onset

Sharrar et at16 andSalzman et al15

1-y-old developed ∼30 vesicular lesions 24 d postvaccination 30-y-old pregnant mother (gestation 5–6 wk) developed 100vesicular lesions with no fever 16 d after index case rash onset;mother terminated the pregnancy. Fetal tissue was negative forVZV by PCR

Includes 1 instance in which transmission did not occur directly from a vaccinated person but from a contact of a vaccinated person who developed rash postvaccination17; the contactdeveloped vOka varicella-like rash. PCR, polymerase chain reaction.a vOka was laboratory confirmed in all secondary cases.


varicella vaccine inimmunocompromised childrenduring the 1980s26; 575 childrenwith acute lymphocytic leukemia(ALL) in remission were vaccinated.19

A vaccine-associated rash (mean 77lesions) occurred a median of 30 days(range 7–41) after the first dose in40% of children in whomchemotherapy was suspended for1 week before and 1 week aftervaccination and 10% of those whohad completed their chemotherapybefore vaccination.17 Of 93 varicella-susceptible (laboratory-confirmed)healthy siblings exposed to a vaccinerecipient with leukemia witha vaccine-associated rash,transmission was reported in 21(23%); of these, 16 developed a rash14 to 22 days after rash onset in thevaccinated sibling (vOka was isolatedfrom 4), and 5 had onlyseroconversion by fluorescentantibody to membrane antigen(FAMA) assay.19 The rash amongcontacts was mild, with a mean of 38lesions (median 12; range 1–200) andno systemic symptoms. Transmissionof vOka correlated with the numberof skin lesions in the vaccinatedsibling; vaccine recipients whotransmitted the virus to susceptibleexposed siblings had a mean of 195lesions (median 110) compared with43 lesions (median 15) among those

who did not transmit (P = .006).17 Nospread of vOka was documented (byFAMA) among 124 siblings exposedto a vaccine recipient without rashafter the first dose27; there was noevidence of transmission to 72siblings exposed to a vaccinerecipient who received a second dose,including 10 siblings exposed toa vaccine recipient with a rash.27

Similar experiences were reported bya case report and 2 smaller studies(Supplemental Table 4).23–25

Reports of Unsubstantiated vOkaTransmission

Six instances of alleged butunsubstantiated transmission of vOkaafter vaccination ofimmunocompetent persons havebeen reported (SupplementalTable 5).17,25,28–31

DISCUSSION

Spread of vOka as documented in theliterature illustrates both potentialfor vaccine virus transmission andcharacteristics associated with thespread, with applicability in clinicalpractice. We found that transmissionof the vaccine virus from healthyvaccine recipients is rare. To date,only 13 cases from 11immunocompetent vaccine recipientshave been reported, most commonly

among household contacts. Anadditional few alleged instances ofvOka transmission were suspectedbut not confirmed by appropriatelaboratory testing. These rareinstances of transmission occured inthe context of large numbers ofvaricella vacine used; in the UnitedStates alone, .140 million doses ofvaricella vaccine were distributedduring 1995–2013.32 Transmission ofvOka resulting in clinical varicellawas reported only from vaccinerecipients who developed a rash aftervaccination. Putative mechanismsother than rash (eg, aerosolization ofthe vaccine during administration toanother patient) would be even morerare. Secondary cases of varicellacaused by vOka have beentypically mild.

Rash after varicella vaccination isuncommon; ∼4% of children and 6%of adolescent and adult vaccinerecipients develop a rash aftervaccination, and not all are vaccineassociated.33 The rarity of the rashand subsequent transmission fromvaccinated healthy persons supportuse of varicella vaccine for routineimmunization. They also indicate thesafety of vaccination of close contactsof susceptible persons at high risk forsevere varicella who themselves havecontraindications for vaccination.

TABLE 2 vOka Transmission From Immunocompetent Varicella Vaccine Recipients: Transmission From a Varicella Vaccine Recipient Who Developed vOkaHZ After Vaccination

Author Vaccinated Person or Index Case Secondary Case(s)

Goulleret et al9 20-mo-old developed HZ 5 mo after varicellavaccination

35-y-old (father) developed a generalized varicella-like rash, positive for vOka, with anuncountable number of lesions 14 d after HZ onset; father reported varicella inchildhood

Otsuka et at11 3-y-old developed HZ 2 y after varicella vaccine 2-y-old unvaccinated brother had a rash with 10–20 papulovesicles and fever 19 d afterHZ onset; DNA sequence of skin lesion specimens from the brother matched those ofvOka in vaccine received by his older sibling

Gan et al12 5-y-old developed HZ 13 mo after varicellavaccination

23-y-old (teacher) developed varicella with 50–100 vesicular lesions and a 1-d, low-grade fever 17 d later after HZ onset; molecular typing of DNA from vesicular fluidfrom the teacher’s rash showed vOka with the same characteristics as the vaccinereceived by the child

Brunell andArgaw13

3-y-old developed HZ 5 mo after varicella vaccination Brother (age not reported) who received varicella vaccine at the same time developed∼50 vesicular lesions 14 d after HZ onset in his sibling; virus isolated from his skinlesions was confirmed as vOka

Davidson andBroom8

2-y-old developed HZ 8 mo after varicella vaccination(measles-mumps-rubella-varicella vaccine)

28-y-old (mother) developed a maculopapular and vesicular rash in a nondermatomaldistribution 2 wk after HZ onset; mother also had mild meningismus but no focalneurologic signs. Cerebrospinal fluid culture result was positive for VZV; vOka wasidentified in skin lesion specimens from both daughter and mother


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Considering the high infectivity of thewild-type virus (secondary householdattack rate of ∼87%), assessingevidence of immunity to varicella offamily members and other closecontacts (eg, health care workers) ofsusceptible immunocompromisedpersons and subsequent vaccinationof contacts without evidence ofimmunity is recommended.2,34 Thisscenario will occur more frequentlyas more conditions, including cancer,organ transplant comorbidities, andautoimmune conditions, are treatedwith immunosuppressive therapy.The benefits of herd immunity forimmunocompromised persons vastlyoutweigh the risk of secondarytransmission of vOka to thosepatients. It may, however, be prudentto avoid preparation of varicellavaccine with a susceptibleimmunocompromised person,pregnant woman, or newborn presentin the room with the individual beingimmunized.18 In general, ifa susceptible, immunocompromisedperson is exposed to a person whohas a vaccine-related rash, passiveimmunization is not needed becausedisease associated with the vaccinevirus is expected to be mild.2 Someexperts, however, advise that passiveimmunization can be considered ona case-by-case basis in the face ofvOka exposure depending on thedegree of immunocompromise forsusceptible immunocompromisedpersons.

Transmission of vOka from vaccinerecipients without a rash has beenexceedingly rare, possiblynonexistent. This is consistent withthe rarity of respiratory spread ofwild-type VZV. To date, there is noevidence of respiratory spread of thevaccine virus, and cultures ofnasopharyngeal and throat specimensfrom vaccine recipients have notyielded vOka.26,35,36

Although varicella vaccine is notrecommended forimmunocompromised persons,experience from the clinical trial of

varicella vaccine inimmunocompromised children isinstructive. In this trial, transmissionoccurred only if the vaccine recipientshad a rash and it was positivelycorrelated with vaccine recipients’number of skin lesions; the more skinlesions were present, the more likelytransmission occurred.17 Amonghealthy persons, varicella-relatedrash after vaccination besides beinguncommon typically manifests withonly a few lesions (median 2–5).33

Because of the low number of lesions,the risk for vOka transmission is thusexpected to be low for healthyvaccine recipients even if theydevelop a rash. In instances oftransmission of vOka from varicella-like rashes postvaccination inimmunocompetent persons, vaccinerecipients tended to have morelesions (median 30), but 2 had 2 and12 lesions, respectively. Thesefindings support the guidance thatbecause of potential for transmission,vaccine recipients with a vaccine-related rash avoid contact for theduration of the rash with personswithout evidence of varicellaimmunity at high risk for severecomplications.2,34

When transmission occurred fromhealthy vaccine recipients, thesecondary cases developed a rash 14to 21 days after rash onset in thevaccine recipient. Diseasepresentation was mild with fewerlesions (median of 50 in the 13secondary patients), shorter durationof illness, and no or low fever. Onesecondary patient had mildmeningismus but no focal neurologicsigns.8 These characteristics supportinfection with attenuated virus; inimmunocompromised persons whowere vaccinated, infection with thevaccine virus has also been reportedto be milder than infection with wild-type virus.27 Oka strain has not beendemonstrated to revert to wild-typeVZV.17,24 Similarly, inimmunocompromised contacts ofvaccinated persons, if the virus is

transmitted, illness is unlikely to besevere unless the patient is severelyimmunocompromised.37 Nonetheless,persons with immunocompromisingconditions, regardless of degree ofimmunosuppression, should avoidcontact with vaccine recipients whodevelop postvaccination rash.2

Live attenuated VZV in the varicellavaccine can establish latent infectionand subsequently reactivate as HZ.Risk for HZ development is lowerafter vaccination than after naturalVZV infection among both healthyand immunocompromised children; 1large study reported a 78% lower HZrisk in healthy vaccinated childrenthan in those unvaccinated.38 Invaricella vaccine recipients, HZ can becaused by vaccine or wild-typestrains. We identified 5 cases ofsecondary transmission of vOka fromimmunocompetent vaccine recipientswith HZ, indicating that vaccinerecipients who later develop HZ mayrarely transmit vOka to susceptiblechildren or adults. Therefore, nomatter what strain of virus isinvolved, patients with HZ should beconsidered contagious and infectioncontrol precautions followed.39

Our study has several limitations. Wereport all cases of vaccine-straintransmission as they were classifiedby the authors. Some publishedreports relied on seroconversion dataalone as a proxy for vaccine-straintransmission, although we found fewcase reports based on seroconversionin the absence of rash. Additionally,we classified as unsubstantiatedtransmission the few putativeinstances of vOka transmission notconfirmed by appropriate laboratorytesting. Because of the limitednumber of cases and absence ofa denominator, we were unable tocalculate rates of vOka transmissionfrom healthy vaccine recipients. It islikely that other cases remainunreported in the literature; however,were this an important phenomenon,we believe more signals would havebeen present.


Pre- and postlicensure studies haveshown that the varicella vaccine issafe, immunogenic, and effective inhealthy persons and certain groups ofimmunocompromised patients.40,41

Routine varicella vaccination hassignificantly reduced morbidity andmortality. In the United States, during2 decades of programimplementation, incidence declinedby 93% to 98% and hospitalizationsand deaths by .93%.37,42,43 Globally,most studies have documented.80% reduction in hospitalizationsand deaths44 after varicellavaccination. Review of the datasuggests that healthy, vaccinatedpersons have minimal risk fortransmitting the vaccine virus tocontacts, particularly in the absenceof vaccine rash in the vaccine

recipient. Transmission occurredfrom vaccine recipients whodeveloped a varicella-like rash or HZafter vaccination and wasdocumented in close-contact settings(homes, long-term care facilities, andschools). Our findings support theexisting recommendations for routinevaricella vaccination and the guidancethat persons with vaccine-relatedrash, particularly health carepersonnel and household contacts ofimmunocompromised persons, avoidcontact for the duration of the rashwith persons without evidence ofimmunity who are at high risk forsevere complications.2,34

ACKNOWLEDGMENTS

We thank Centers for Disease Controland Prevention colleagues JoannaTaliano for performing the literaturesearch and Mary Ann Hall, MPH, foreditorial review of the article.

ABBREVIATIONS

ALL: acute lymphocytic leukemiaCINAHL: Cumulative Index to

Nursing and AlliedHealth Literature

FAMA: fluorescent antibody tomembrane antigen

HZ: herpes zostervOka: vaccine-strain varicella-

zoster virus (Oka strain)VZV: varicella-zoster virus

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and

Prevention or the US Department of Health and Human Services.

DOI: https://doi.org/10.1542/peds.2019-1305

Accepted for publication Jun 3, 2019

Address correspondence to Mona Marin, MD, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mail Stop H24-5, Atlanta, GA 30333. E-mail: zsn8@

cdc.gov

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2019 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: Dr Gershon receives National Institutes of Health funding (R01DK03094) and has a contractual relationship with Merck through

the Varicella Zoster Virus Identification Program; Drs Marin and Leung have indicated they have no potential conflicts of interest to disclose.

REFERENCES

1. LaRussa PS, Marin M. Varicella-ZosterVirus, 20th ed. Philadelphia, PA:Elsevier; 2016

2. Marin M, Güris D, Chaves SS, Schmid S,Seward JF; Advisory Committee onImmunization Practices, Centers forDisease Control and Prevention (CDC).Prevention of varicella:recommendations of the AdvisoryCommittee on Immunization Practices(ACIP). MMWR Recomm Rep. 2007;56(RR):1–40

3. Feldman S, Hughes WT, Daniel CB.Varicella in children with cancer:

seventy-seven cases. Pediatrics. 1975;56(3):388–397

4. Gnann JW Jr. Varicella-zoster virus:prevention through vaccination. ClinObstet Gynecol. 2012;55(2):560–570

5. Kellie SM, Makvandi M, Muller ML.Management and outcome ofa varicella exposure in a neonatalintensive care unit: lessons for thevaccine era. Am J Infect Control. 2011;39(10):844–848

6. Weber DJ, Rutala WA, Parham C. Impactand costs of varicella prevention ina university hospital. Am J PublicHealth. 1988;78(1):19–23

7. Takahashi M, Otsuka T, Okuno Y, Asano Y,Yazaki T. Live vaccine used to preventthe spread of varicella in children inhospital. Lancet. 1974;2(7892):1288–1290

8. Davidson N, Broom J. Vaccine strainvaricella zoster virus transmittedwithin a family from a child withshingles results in varicella meningitisin an immunocompetent adult. InternMed J. 2019;49(1):132–133

9. Goulleret N, Mauvisseau E, Essevaz-Roulet M, Quinlivan M, Breuer J. Safetyprofile of live varicella virus vaccine(Oka/Merck): five-year results of the


https://doi.org/10.1542/peds.2019-1305mailto:[email protected]:[email protected]

European Varicella Zoster VirusIdentification Program (EU VZVIP).Vaccine. 2010;28(36):5878–5882

10. LaRussa P, Steinberg S, Meurice F,Gershon A. Transmission of vaccinestrain varicella-zoster virus froma healthy adult with vaccine-associatedrash to susceptible household contacts.J Infect Dis. 1997;176(4):1072–1075

11. Otsuka T, Gomi Y, Inoue N, Uchiyama M.Transmission of varicella vaccine virus,Japan. Emerg Infect Dis. 2009;15(10):1702–1703

12. Gan L, Wang M, Yang S, Gershon AA,Chen JJ. Transmission of varicellavaccine virus to a non-family memberin China. Vaccine. 2011;29(11):2015–2017

13. Brunell PA, Argaw T. Chickenpoxattributable to a vaccine viruscontracted from a vaccinee with zoster.Pediatrics. 2000;106(2). Available at:www.pediatrics.org/cgi/content/full/106/2/E28

14. Grossberg R, Harpaz R, Rubtcova E,et al. Secondary transmission ofvaricella vaccine virus in a chronic carefacility for children. J Pediatr. 2006;148(6):842–844

15. Salzman MB, Sharrar RG, Steinberg S,LaRussa P. Transmission of varicella-vaccine virus from a healthy 12-month-old child to his pregnant mother.J Pediatr. 1997;131(1 pt 1):151–154

16. Sharrar RG, LaRussa P, Galea SA, et al.The postmarketing safety profile ofvaricella vaccine. Vaccine. 2000;19(7–8):916–923

17. Tsolia M, Gershon AA, Steinberg SP, GelbL; National Institute of Allergy andInfectious Diseases Varicella VaccineCollaborative Study Group. Liveattenuated varicella vaccine: evidencethat the virus is attenuated and theimportance of skin lesions intransmission of varicella-zoster virus.J Pediatr. 1990;116(2):184–189

18. Kluthe M, Herrera A, Blanca H, et al.Neonatal vaccine-strain varicella-zostervirus infection 22 days after maternalpostpartum vaccination. Pediatr InfectDis J. 2012;31(9):977–979

19. Gershon AA, LaRussa P, Steinberg S. Thevaricella vaccine. Clinical trials inimmunocompromised individuals.

Infect Dis Clin North Am. 1996;10(3):583–594

20. Weibel RE, Neff BJ, Kuter BJ, et al. Liveattenuated varicella virus vaccine.Efficacy trial in healthy children. N EnglJ Med. 1984;310(22):1409–1415

21. Saiman L, LaRussa P, Steinberg SP, et al.Persistence of immunity to varicella-zoster virus after vaccination ofhealthcare workers. Infect Control HospEpidemiol. 2001;22(5):279–283

22. Michalik DE, Steinberg SP, Larussa PS,et al. Primary vaccine failure after 1dose of varicella vaccine in healthychildren. J Infect Dis. 2008;197(7):944–949

23. Arbeter AM, Granowetter L, Starr SE,et al. Immunization of children withacute lymphoblastic leukemia with liveattenuated varicella vaccine withoutcomplete suspension of chemotherapy.Pediatrics. 1990;85(3):338–344

24. Brunell PA, Geiser CF, Novelli V, Lipton S,Narkewicz S. Varicella-like illnesscaused by live varicella vaccine inchildren with acute lymphocyticleukemia. Pediatrics. 1987;79(6):922–927

25. Hughes P, LaRussa P, Pearce JM, et al.Transmission of varicella-zoster virusfrom a vaccinee with leukemia,demonstrated by polymerase chainreaction. J Pediatr. 1994;124(6):932–935

26. Gershon AA, Steinberg SP, Gelb L, et al.Live attenuated varicella vaccine.Efficacy for children with leukemia inremission. JAMA. 1984;252(3):355–362

27. Gershon AA, Steinberg S, Gelb L, et al. Amulticentre trial of live attenuatedvaricella vaccine in children withleukaemia in remission. Postgrad MedJ. 1985;61(suppl 4):73–78

28. Huang W, Hussey M, Michel F.Transmission of varicella to a gravidavia close contacts immunized withvaricella-zoster vaccine. A case report.J Reprod Med. 1999;44(10):905–907

29. Kim A, Papademetriou M, Soe EP,Feldman DM. Perils of prednisone:varicella hepatitis in a previouslyhealthy man. Am J Gastroenterol. 2016;111:S861–S862

30. Scanlon-Kohlroser CA, Fan PY, PrimackW, Stoff JS. Primary varicella after

transplantation. Am J Kidney Dis. 2002;39(6):1310–1312

31. To E. Transmission of chickenpox fromVaricella zoster vaccination is possible.Aust Fam Physician. 2001;30(5):417

32. Willis E, Marko A, Marin M, et al.Pregnancy registry for varicella-zostervirus-containing vaccines: 18-yearsummary of pregnancy outcomes[abstract]. Open Forum Infect Dis. 2014;1(1):S307

33. Merck & Co, Inc. Varivax [PackageInsert]. Whitehouse Station, NJ: Merck& Co, Inc; 2012

34. American Academy of Pediatrics.Varicella-Zoster Virus Infections. In:Kimberlin DW, ed. Red Book: 2018-2021Report of the Committee on InfectiousDiseases, 31st ed. Elk Grove Village, IL:American Academy of Pediatrics; 2018:pp 869–883

35. Diaz PS, Au D, Smith S, et al. Lack oftransmission of the live attenuatedvaricella vaccine virus toimmunocompromised children afterimmunization of their siblings.Pediatrics. 1991;87(2):166–170

36. Brunell PA, Shehab Z, Geiser C, WaughJE. Administration of live varicellavaccine to children with leukaemia.Lancet. 1982;2(8307):1069–1073

37. Leung J, Marin M. Update on trends invaricella mortality during the varicellavaccine era-United States, 1990-2016.Hum Vaccin Immunother. 2018;14(10):2460–2463

38. Weinmann S, Naleway AL, Koppula P,et al. Incidence of herpes zoster amongchildren: 2003-2014. Pediatrics. 2019;144(1):e20182917

39. Siegel JD, Rhinehart E, Jackson M,Chiarello L; Health Care InfectionControl Practices Advisory Committee.2007 Guideline for isolationprecautions: preventing transmissionof infectious agents in health caresettings. Am J Infect Control. 2007;35(10suppl 2):S65–S164

40. Marin M, Meissner HC, Seward JF.Varicella prevention in the UnitedStates: a review of successes andchallenges. Pediatrics. 2008;122(3)Available at: www.pediatrics.org/cgi/content/full/122/3/e744


http://www.pediatrics.org/cgi/content/FUll/106/2/E28http://www.pediatrics.org/cgi/content/FUll/106/2/E28http://www.pediatrics.org/cgi/content/FUll/122/3/e744http://www.pediatrics.org/cgi/content/FUll/122/3/e744

41. Marin M, Marti M, Kambhampati A,Jeram SM, Seward JF. Global varicellavaccine effectiveness: a meta-analysis.Pediatrics. 2016;137(3):e20153741

42. Lopez AS, Zhang J, Marin M.Epidemiology of varicella during the 2-

dose varicella vaccination program -United States, 2005-2014. MMWR MorbMortal Wkly Rep. 2016;65(34):902–905

43. Leung J, Harpaz R. Impact of thematuring varicella vaccination programon varicella and related outcomes in

the United States: 1994-2012. J PediatricInfect Dis Soc. 2016;5(4):395–402

44. Varela FH, Pinto LA, Scotta MC. Globalimpact of varicella vaccinationprograms. Hum Vaccin Immunother.2019;15(3):645–657


DOI: 10.1542/peds.2019-1305 originally published online August 30, 2019; 2019;144;Pediatrics

Mona Marin, Jessica Leung and Anne A. GershonTransmission of Vaccine-Strain Varicella-Zoster Virus: A Systematic Review

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DOI: 10.1542/peds.2019-1305 originally published online August 30, 2019; 2019;144;Pediatrics

Mona Marin, Jessica Leung and Anne A. GershonTransmission of Vaccine-Strain Varicella-Zoster Virus: A Systematic Review

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