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American Academy of Pediatrics
Article

Near Real-Time Surveillance to Assess the Safety of the 9-Valent Human Papillomavirus Vaccine

James G. Donahue, Burney A. Kieke, Edwin M. Lewis, Eric S. Weintraub, Kayla E. Hanson, David L. McClure, Elizabeth R. Vickers, Julianne Gee, Matthew F. Daley, Frank DeStefano, Rulin C. Hechter, Lisa A. Jackson, Nicola P. Klein, Allison L. Naleway, Jennifer C. Nelson and Edward A. Belongia
Pediatrics December 2019, 144 (6) e20191808; DOI: https://doi.org/10.1542/peds.2019-1808
James G. Donahue
Marshfield Clinic Research Institute, Marshfield, Wisconsin;
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Burney A. Kieke
Marshfield Clinic Research Institute, Marshfield, Wisconsin;
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Edwin M. Lewis
Kaiser Permanente Northern California, Oakland, California;
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Eric S. Weintraub
Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, Georgia;
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Kayla E. Hanson
Marshfield Clinic Research Institute, Marshfield, Wisconsin;
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David L. McClure
Marshfield Clinic Research Institute, Marshfield, Wisconsin;
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Elizabeth R. Vickers
Marshfield Clinic Research Institute, Marshfield, Wisconsin;
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Julianne Gee
Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, Georgia;
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Matthew F. Daley
Kaiser Permanente Colorado, Aurora, Colorado;
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Frank DeStefano
Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, Georgia;
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Rulin C. Hechter
Kaiser Permanente Southern California, Pasadena, California;
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Lisa A. Jackson
Kaiser Permanente Washington, Seattle, Washington; and
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Nicola P. Klein
Kaiser Permanente Northern California, Oakland, California;
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Allison L. Naleway
Kaiser Permanente Northwest, Portland, Oregon
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Jennifer C. Nelson
Kaiser Permanente Washington, Seattle, Washington; and
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Edward A. Belongia
Marshfield Clinic Research Institute, Marshfield, Wisconsin;
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  • FIGURE 1
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    FIGURE 1

    Histogram of weekly counts of 9vHPV vaccinations administered in the VSD population from the week starting on October 4, 2015, through the week starting on October 1, 2017, by age and sex.

  • FIGURE 2
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    FIGURE 2

    Distribution of days to onset of appendicitis in the 42-day risk window after administration of 9vHPV vaccine among boys 9 to 17 years old.

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    TABLE 1

    Characteristics of Prespecified Adverse Events

    Medical SettingPostvaccination Risk Window, dFirst Episode in What Period?Primary Comparison Groupa
    Uncommon or rare adverse event
     AnaphylaxisED, inpatient0–2First in 42 dHistoric
     AppendicitisED, inpatient1–42First in 42 dHistoric
     PancreatitisED, inpatient1–42First everHistoric
     GBSOutpatient, ED, inpatient1–42First in 42 dHistoric
     CIDPOutpatient, ED, inpatient1–180First everHistoric
     SeizureED, inpatient0–42First in 42 d and first everConcurrent
     StrokeED, inpatient0–42First in 42 dHistoric
     VTEOutpatient, ED, inpatient1–42First in 1 yHistoric
    Common adverse event
     Allergic reactionsOutpatient, ED, inpatient0–2 for ED and inpatient,1–2 for outpatientFirst in 42 dConcurrent
     Injection site reactionsOutpatient, ED, inpatient1–6First in 42 dConcurrent
     Nonspecific reactionsOutpatient, ED, inpatient0–6First in 42 dConcurrent
     SyncopeOutpatient, ED, inpatientDay 0First in 2 dConcurrent
    • ↵a Concurrent comparison group: visits during which comparator vaccines were administered, with analytic strata defined by age (in 1-y increments), site, sex, and week of the vaccination visit. Two historic comparison groups (2007–2014) were used: general VSD population and vaccinated VSD population, vaccinated with comparator vaccines.

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    TABLE 2

    Summary of Uncommon Adverse Events in Selected Subgroups Evaluated With Historical Comparison Groups Using MaxSPRT and CMaxSPRT

    AEType of SPRT AnalysisaSubgroup, Sex, Age Group in yNo. Observed VaccinationsNo. Observed AENo. Comparator Vaccinations, Historical PeriodNo. AEs in the Historical PeriodNo. Expected AEsRRTest StatisticCritical ValuebSignal
    AnaphylaxisMaximizedMale, 9–17334 3810——0.9002.7No
    CMaxMale, 9–17334 38101 053 6422—002.6No
    AppendicitisMaximizedMale, 9–1778 88533——25.61.30.973.5No
    CMaxMale, 9–1778 885331 053 642312—1.41.63.8No
    GBSMaximizedFemale, 18–26128 6450——0.6002.6No
    CMaxFemale, 18–26128 6450431 4013—002.7No
    PancreatitisMaximizedMale, 18–2651 9448——2.63.13.72.9Yes
    CMaxMale, 18–2651 9448349 96629—1.91.13.4No
    SeizuresMaximizedFemale, 9–17304 38444——115.20.403.8No
    CMaxFemale, 9–17304 38444698 263105—1.003.7No
    StrokeMaximizedFemale, 18–26128 6455——4.91.002.9No
    CMaxFemale, 18–26128 6455431 40111—1.50.32.9No
    VTEMaximizedFemale, 18–26128 6458——9.80.803.1No
    CMaxFemale, 18–26128 6458431 40154—0.503.4No
    • Results were extracted from the final report (week starting October 1, 2017) for all events except for pancreatitis, which comes from the week when it first signaled (week 71). CIDP was not included because there were no events during the study period. AE, adverse event; CMax, conditional maximized; SPRT, sequential probability ratio test; —, not applicable.

    • ↵a MaxSPRT: analyses were conducted in combination with the general VSD population historic comparison group (2007–2014). CMaxSPRT: analyses were conducted in combination with the historic VSD population vaccinated with comparator vaccines (2007–2014).

    • ↵b Critical values are threshold values of the test statistic above, in which the null hypothesis would be rejected.

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    TABLE 3

    Summary of Common Adverse Events Using ESA in Subgroups Evaluated With the Concurrent Comparison Group

    Adverse EventSubgroup, Sex, Age Group in y, 9vHPV DoseWeek When First SignaledNo. 9vHPV Vaccinations in SubgroupNo. Total CasesaNo. Exposed CasesaRRP
    Allergic reactionbFemale, 9–17, ED or inpatient, any82242 72633262.7.04
    Female, 9–17, outpatient, anyNo signalc242 72686600.8.75
    Female, 9–17, ED or inpatient, dose 194109 89626172.8.04
    Female, 9–17, outpatient, dose 1No signald109 89682501.2.28
    Female, 18–26, outpatient, dose 28633 11838151.9.04
    Female, 18–26, ED or inpatient, dose 2No signale33 118810.4.92
    AppendicitisfMale, 9–17, dose 38473 12250302.1.03
    Male, 9–17, anyNo signalg271 679103811.5.09
    Male, 9–17, dose 1No signalg106 74147251.4.23
    Male, 9–17, dose 2No signalg91 15647261.5.23
    Injection site reactionMale, 9–17, dose 32623 40929182.5.03
    Nonspecific reactionMale, 18–26, dose 32540543295.0.04
    Male, 18–26, dose 13413 22814911.1.04
    Female, 18–26, dose 15026 71171341.7.03
    Female, 18–26, any105128 8062151261.3.04
    SyncopeFemale, 18–26, any2528 23498671.8.007
    Female, 18–26, dose 12512 24565352.0.004
    Female, 18–26, dose 23110 92460251.7.04
    • Results were extracted from the report for the week when the adverse event first signaled. NS, no signal.

    • ↵a Cases in a specific subgroup are only counted for analytic strata with ≥1 case (either exposed or not), ≥1 9vHPV vaccine, and ≥1 comparator vaccine, in which analytic strata are defined by age (in 1-y increments), site, sex, and week of the vaccination visit.

    • ↵b Diagnoses were made in the ED or inpatient setting or in the outpatient setting.

    • ↵c No signal was detected for this subgroup. Data were extracted from the report for the week when allergic reaction signaled for girls 9 to 17 y old with any dose in the ED or inpatient setting.

    • ↵d No signal was detected for this subgroup. Data were extracted from the report for the week when allergic reaction signaled for girls 9 to 17 y old with dose 1 in the ED or inpatient setting.

    • ↵e No signal was detected for this subgroup. Data were extracted from the report for the week when allergic reaction signaled for women 18 to 26 y old with dose 2 in the outpatient setting.

    • ↵f Appendicitis was classified as an uncommon adverse event in this study, but a statistical signal was detected with ESA, and it is therefore included here.

    • ↵g No signal was detected for this subgroup. Data were extracted from the report for the week when appendicitis signaled for boys 9 to 17 y old with dose 3.

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Pediatrics
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1 Dec 2019
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Near Real-Time Surveillance to Assess the Safety of the 9-Valent Human Papillomavirus Vaccine
James G. Donahue, Burney A. Kieke, Edwin M. Lewis, Eric S. Weintraub, Kayla E. Hanson, David L. McClure, Elizabeth R. Vickers, Julianne Gee, Matthew F. Daley, Frank DeStefano, Rulin C. Hechter, Lisa A. Jackson, Nicola P. Klein, Allison L. Naleway, Jennifer C. Nelson, Edward A. Belongia
Pediatrics Dec 2019, 144 (6) e20191808; DOI: 10.1542/peds.2019-1808

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Near Real-Time Surveillance to Assess the Safety of the 9-Valent Human Papillomavirus Vaccine
James G. Donahue, Burney A. Kieke, Edwin M. Lewis, Eric S. Weintraub, Kayla E. Hanson, David L. McClure, Elizabeth R. Vickers, Julianne Gee, Matthew F. Daley, Frank DeStefano, Rulin C. Hechter, Lisa A. Jackson, Nicola P. Klein, Allison L. Naleway, Jennifer C. Nelson, Edward A. Belongia
Pediatrics Dec 2019, 144 (6) e20191808; DOI: 10.1542/peds.2019-1808
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