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  • Transmission of Vaccine-Strain Varicella-Zoster Virus: A Systematic Review Mona 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-strain varicella-zoster virus (Oka strain; vOka) on the basis of the published experience with use of live varicella and zoster vaccines.

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

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

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

    RESULTS: Twenty articles were included. We identified 13 patients with vOka varicella after transmission from 11 immunocompetent varicella vaccine recipients. In all instances, the vaccine recipient had a rash: 6 varicella-like and 5 herpes zoster. Transmission occurred mostly to household contacts. One additional case was not considered direct transmission from a vaccine recipient, but the mechanism was uncertain. Transmission from vaccinated immunocompromised children also occurred only if the vaccine recipient developed a rash postvaccination. 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    LIMITATIONS: It is likely that other vOka transmission cases remain unpublished.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 contacts and only if a rash is present. Our findings support the existing recommendations for routine varicella vaccination and the guidance that persons with vaccine-related rash avoid contact with 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 and Surgeons, 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 participated in the design of the study, reviewed the articles, and reviewed and revised the manuscript; Dr Gershon provided substantial contribution to the interpretation of the data and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for 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

    PEDIATRICS Volume 144, number 3, September 2019:e20191305 REVIEW ARTICLE by guest on July 8, 2021www.aappublications.org/newsDownloaded from

  • Varicella, caused by the varicella- zoster virus (VZV), is highly contagious. Although generally a mild childhood disease, serious complications (including death) can occur, most commonly in infants, adults, and immunocompromised persons.1 Varicella was an important cause of morbidity and mortality in the United States before the introduction of varicella vaccination (1996), with ∼4 million cases, 10 500 to 13 000 hospitalizations, and 100 to 150 deaths annually.2 In the 1970s, 30% of children with leukemia who contracted varicella developed viscerally disseminated disease, with 7% mortality.3 In the era of antiviral therapy, prognoses improved with treatment administered early in the course of illness, but deaths continue to occur. Varicella during pregnancy can cause congenital disease in the fetus or severe varicella in the newborn or can lead to herpes zoster (HZ) in early childhood.4 Nosocomial transmission of VZV often disrupts health care facilities’ operations.5,6

    VZV exposures among patients and health care personnel can be time consuming and costly even when they do not result in transmission.

    Vaccination effectively prevents disease transmission in community and health care settings. To address the burden of varicella, a live attenuated vaccine was developed in the 1970s7 and licensed in the United States in 1995. Varicella vaccines are contraindicated for immunocompromised persons or pregnant women, but these individuals may benefit indirectly from vaccination of household contacts and health care workers who care for them.2 Several formulations of varicella vaccines, all containing the live attenuated virus, are available worldwide but are recommended for routine use in only a limited number of countries. Since 2006, a live attenuated zoster vaccine, which contains the same VZV strain as varicella vaccines but at a higher

    potency, has been available to prevent HZ.

    Live attenuated vaccines usually provide more robust immunity than vaccines containing inactivated viruses but can, in rare instances, transmit the vaccine virus. Millions of persons are vaccinated with varicella vaccine each year in the United States, including routine vaccinations and vaccination of close contacts of persons at high risk for severe varicella; therefore, tracking the characteristics of secondary transmission of vaccine-strain VZV (Oka strain; abbreviated as vOka) is important. We reviewed the experience reported in the literature with the use of live VZV vaccines administered to healthy and immunocompromised persons to address this question.

    METHODS

    We defined secondary transmission of the vaccine strain as transmission of vOka from a person who had ever received a vaccine containing live attenuated VZV to a contact. Transmission was determined by the authors of the articles by documentation of (1) laboratory confirmation of vOka from the rashes of the vaccinated index case and secondary case(s), (2) laboratory confirmation of the virus from the secondary case’s rash similar to that in the vaccine received by the index case, or (3) seroconversion of contacts of vaccine recipients in the absence of a rash or other VZV exposure of the contact. Some authors reported transmission based only on temporal association between vaccination and the disease in the contact of a vaccine recipient. Those reports were classified in this article as unsubstantiated transmission because no or insufficient laboratory testing was performed to document vOka; additionally, in some reports, the epidemiological assessment did not provide support for transmission

    from the vaccine recipient or did not accord with the biology of varicella, especially the incubation period.

    We searched Medline, Embase, the Cochrane Library, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases for articles published, in any language, from database inception through December 31, 2018. The complete search strategy is described in Supplemental Table 3. Two authors reviewed each title and abstract to determine if the article included any information on transmission of vOka. For articles that passed this initial screen, we reviewed the full text. We also reviewed references that described transmission of vOka identified from the reference section of the articles retrieved by the database search. Only articles that included original reports of vOka transmission were retained.

    Two authors abstracted data on disease presentation and immune status of the index case (ie, varicella vaccine recipient), number of secondary cases, transmission setting, how transmission was determined, interval between vaccination and rash onset in the index case, interval between rash onset in the index and secondary case(s), characteristics of the disease and immune status of the secondary case(s), whether the index and secondary case(s) were laboratory confirmed, and vaccine manufacturer. We describe vOka transmission by immune status of the index patient (immunocompetent or immunocompromised), type (varicella or HZ) and severity of illness this patient had, and whether vOka transmission was laboratory confirmed.

    RESULTS

    We screened 378 nonduplicate articles and identified 98 for full-text review; this included 1 study known by the authors to be published after the literature search was completed.8

    2 MARIN et al by guest on July 8, 2021www.aappublications.org/newsDownloaded from

    https://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2019-1305/-/DCSupplemental/

  • After excluding 72 articles, 26 met inclusion criteria for our review (Fig 1). Six articles reported interim results on 2 studies. To describe instances of secondary transmission, we included only the last reports from these 2 studies; when specific information of interest was not included in the last publications, we abstracted data from the earlier publications. A total of 20 articles were included in our review.

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

    Most articles described transmission of vOka after receipt of Varivax (Merck varicella vaccine), which is licensed in the United States, likely because large clinical trials among immunocompromised and immunocompetent children were conducted in the United States before licensure of the vaccine, and the United States has the longest-running routine varicella vaccination program. Transmission of vOka from recipients of other varicella vaccines (SmithKline and/or GlaxoSmithKline

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