Real-world evidence of quadrivalent meningococcal conjugate vaccine safety in the United States: a systematic review

Figures & data

Figure 1. Article selection flow chart

Table 1. Real-world post-licensure studies of the safety of MenACWY in the U.S

Study setting	Study design	Exposure	Outcomes	Comparison group	Follow-up/Look back period	Study population	Sample size	Available demographic and indication information	Results	Key conclusion	Reference
VAERS: National U.S.	Spontaneous reporting	MenACWY-D	Pregnancy-specific and non-pregnancy specific maternal, fetal, and infant outcomes	None	None	All ages	103 adverse event reports	Median (range) maternal age: 17 years (13–31)	Spontaneous abortion: 17 (16.5%); Urinary tract infections (4; 3.9%); fever with vomiting (3; 2.9%); 1 major congenital anomaly.	No concerning patterns identified.	Zheteyeva et al., 2013^Citation15
Kaiser Permanente Southern California	Cohort	MenACWY-CRM	Spontaneous and induced abortion, preterm birth, low birth weight, major congenital malformations (MCM)	None	Through pregnancy outcome	Pregnant adolescents-young adults aged 11–21 years	92 individuals	Hispanic: 68.5%; Mean age (SD): 18.9 (1.73)	Prevalence of spontaneous abortions: 18.2%; among live born infants – preterm: 14.5%; low birth weight: 9.1%; MCM: 1.8%	Prevalence estimates appear to be comparable with U.S. background prevalence estimates.	Becerra-Culqui et al., 2020^Citation16
VAERS: National U.S.	Spontaneous reporting	MenACWY-CRM	Adverse events; serious adverse events; prespecified conditions: anaphylaxis, facial nerve palsy, GBS; death	None	None	All ages	2,614 adverse event reports	11–18 years: 74% of reports	67 reports classified as serious, including 1 death. Most events were non-serious. Anaphylaxis and syncope most common reports – already known risk factors following any vaccine. Non-serious reports of vaccination during 14 pregnancies – 11 had no birth outcome information and 3 had uncomplicated pregnancies/births.	Many of the most frequent AEs were consistent with the data from pre-licensure trials.	Myers et al., 2017^Citation17
Kaiser Permanente Northern California	Self-controlled risk interval; cohort	MenACWY-D	Emergency department visits, hospitalizations, pre-specified conditions in outpatient setting (Bell’s palsy, GBS, etc.) within pre-defined risk window or during 6 month follow-up window; pregnancy outcomes	1) Self-controlled: 31–60 days post-vaccination; 2) matched by age, sex, receipt of comparison vaccine during same month of MenACWY-D recipient but in prior year	Follow up through 6 months; Risk interval: 0–30 days post-vaccination	Adolescents/teenagers aged 11–16 years; Teenagers aged 17–18 years; Adults aged 19–29 years; 30–55 years; >55 years	31,561 vaccine recipients	11–16 years: 67.8%; Caucasian: 41.1%, Hispanic: 17.2%	21outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Two serious adverse events were considered possibly related to vaccination-new onset diabetes and juvenile rheumatoid arthritis; 0.38/1,000 person months febrile illness within 30 day risk window. Pregnancy exposure (n = 25; 18 available data): 12 live births, 5 elective abortions, 1 fetal death	Did not identify any new short- or long-term safety concerns	Hansen et al., 2017^Citation18
Kaiser Permanente Southern California	Cohort	MenACWY-CRM	ED visits, Hospitalizations; Diagnosis groups	None	6 months post- vaccination	Infants/toddlers aged 2–23 months	138 individuals	Race/ethnicity: 59.4% African American Indication: 54.3% travel, 39.1% anatomic or functional asplenia (including sickle cell disease), 3.6% unknown 2.9% DiGeorge syndrome	Incidence rate of ED visits: 0.6/person-year (95% CI: 0.5–0.8); hospitalizations: 0.4/person-year (CI: 0.3–0.5); ED to hospital transfers 0.1/person-year (CI: 0.1–0.3); 29.0% of recipients had an incident diagnosis; fever and acute upper respiratory infections were most common diagnoses.	No suggestion of safety concerns	Becerra-Culqui et al., 2020^Citation19
Kaiser Permanente Northern California	Self-controlled risk interval	MenACWY-D	≤30 days post-vaccination: ED visits, hospitalizations; prespecified conditions in outpatient setting (neurological conditions, hypersensitivity reactions, new onset autoimmune disease); deaths	Self-controlled: 9–23 month olds 31–75 day comparison; 2–10 year olds 31–60 day comparison	Follow-up range 6 months to 3.5 years post-vaccination	Infants/toddlers aged 9–23 months; children aged 2–10 years	116 infants/toddlers; 1,421 children	9–23 month olds: Race/ethnicity: Black- 40.5%. Indication: 62.1% travel-related, 32.8% unknown/parental request, 1.7% sickle cell, 1.7% hydrocele, 0.9% congenital heart disease, 0.9% congenital immunity syndrome, 2–10 year olds indication: 69.5% unknown/parental request, 25.6% travel-related, 3.1% sickle cell disease, 1.5% thalassemia, 1.2% asplenia, 0.6% other hemoglobinopathy, 0.6% hereditary spherocytosis, 0.1% Complement deficiency, 0.1% Hereditary elliptocytosis, 0.1% HIV	9–23 month olds: 7 ED visits by 7 subjects, no hospitalizations, no outpatient outcomes, no deaths; 2–10 year olds: 105 ED visits in 86 subjects, 26 hospitalizations in 16 subjects within 6 months. No elevated IRR in risk-interval analyses.	9–23 month olds: No significant safety findings; 2–10 year olds: Inpatient cellulitis/abscess, although not near the injection area.	Hansen et al., 2018^Citation20
Kaiser Permanente Southern California	Cohort	MenACWY-CRM	26 prespecified events of interest (i.e., neurologic, rheumatologic, hematologic, endocrine, renal, pediatric infectious diseases) and SMAE in ED and inpatient visits.	None	Follow-up through 1 year post-vaccination	Children 2–10 years	327 individuals	Hispanic: 36.1%, Black: 27.2% Indications: 42.8% routine, 31.8% ravel-related, 17.1% other/unknown, 5.6% functional or anatomic asplenia, 2.8% possible exposure to meningitis	1 confirmed new onset of asthma with onset 237 days after concomitant vaccination with typhoid vaccine (IR: 4.1/1,000 person-years); 94 SMAE incident events but only 16 could be vaccine related. Only 4 children experienced events within 30 days of vaccination (pneumonia, febrile convulsion).	No new safety concerns associated with vaccination	Tartof et al., 2017^Citation21
VAERS: National U.S.	Spontaneous reporting	MenACWY-D	GBS	None	Not applicable	Adolescents/teenagers 11–19 years	17 cases with GBS	Not reported	Incidence rate calculation: 20/100,000 person-months	Larger study is necessary to provide a definitive assessment of MenACWY-D and GBS association.	Centers for Disease Control and Prevention (CDC), 2006^Citation22
VSD network sites and 5 other U.S. Health Plans (Velentgas et al.)	Cohort	MenACWY-D	GBS	Velentgas et al.’s background rate of 0.55 chart-confirmed GBS case per 100,000 unexposed person-years	Risk window: 1–42 days	Adolescents/teenagers aged 11–19 years	2,321,590 doses	Not reported	One-sided 95% CI, upper bound: 1.29 GBS cases per 1 million vaccinations	If there is an increased risk of GBS associated with MenACWY-D, it is likely to amount to less than 0.66 excess case per million adolescents vaccinated.	Yih et al., 2012^Citation23
5 U.S. health plans: Aetna, Healthcore, Inc. (Wellpoint), Highmark, Inc., OptumInsight (UnitedHealthcare), Kaiser Permanente Center for Health Research, Hawaii	Cohort	MenACWY-D	GBS	43 days and later, after vaccination	Follow-up varied: disenrolled, turned 22 years, or study end date	Adolescents-young adults 11–21 years	1.4 million vaccinations	11–13 years: 36.2%, 14–16 years: 23.9%, 17–18 years: 16.0%, 19–21 years: 23.9%	No confirmed GBS case occurred within 42 days of MenACWY-D vaccination. The GBS incidence rate outside the 42-day postimmunization window was 0.45 cases per 100,000 person-years (95% CI, 0.24–0.75). Among those with no record of immunization, the rate was 0.55 (95% CI: 0.41–0.69).	No evidence of increased risk associated with the MenACWY-D vaccine	Velentgas et al., 2012^Citation24
Kaiser Permanente Northern California	Cohort	MenACWY-D	Recurrent GBS	None	Not predefined	Persons aged ≥5 years with GBS with subsequent vaccination	550 GBS total cases; 7 GBS cases before MenACWY-D vaccination	Not reported	No single recurrence of GBS that can be associated with MenACWY-D vaccination.	Vaccination does not increase the risk of recurrent GBS, although insufficient sample size.	Baxter et al., 2012^Citation25
Kaiser Permanente Southern California	Self-controlled case series	MenACWY-CRM	26 prespecified events of interest including neurologic, rheumatologic, hematologic, endocrine, renal, pediatric infectious diseases	Self-controlled; Comparison window starts after risk window up to 1 year post-vaccination	Follow-up through 1 year post-vaccination	11–21 years	48,899 individuals	Hispanic: 49.2%, White: 29.8%	The relative incidence for Bell’s palsy: 5.0, 95% CI: 1.4–17.8 among individuals who received other vaccines concomitantly	Temporal association between Bell’s palsy and receipt of MenACWY-CRM given concomitantly with other vaccines	Tseng et al., 2017^Citation26
VAERS: National U.S.	Spontaneous reporting	MenACWY-D	Syncope	Syncope reports to VAERS during 2002–2004, before vaccine approval	Not applicable	Persons aged ≥5 years	463 syncope reports	Female: 61.1%; 11–18 years: 47.3%;	33 (7.1%) of the 463 postvaccination syncope reports during 2005–2007 were coded as serious; the percentage was not substantially different from the corresponding 20 (9.9%) serious reports during the 2002–2004 comparison period	Syncope was associated with at least one of the following recommended adolescent vaccines: MenACWY-D, Tdap, and HPV	Centers for Disease Control and Prevention, 2008^Citation27
Kaiser Permanente Colorado and Denver Health	Cohort	MenACWY	Syncope	None	Up to 15 minutes post-vaccination	Teenagers 13–17 years	28,495 doses	Not available	1 chart confirmed event; 1.15 chart-confirmed events/10,000 doses (0.36–3.65)	Syncopal rates after adolescent vaccines appear lower than those anecdotally reported by clinic staff.	Narwaney et al., 2017^Citation28
Kaiser Permanente Northern California	Case-centered analysis	MenACWY-D	Bell’s Palsy	All patient members similar to each case in age and sex (risk set)	12 months prior to diagnosis	Persons ≤18 years	233 Bell’s palsy cases with 12 month history of any vaccination	Hispanic: 46.2%; Female: 60.5%	8 Bell’s palsy cases with 12 months history of meningococcal vaccination	No association between Bell’s palsy and any vaccine during risk intervals 1–56 days prior to diagnosis.	Rowhani-Rahbar et al., 2012^Citation29
VSD: Group Health (Seattle, WA), KP Northern California, KP Northwest, KP Colorado; Marshfield Clinic (Marshfield, WI), HealthPartners (Minneapolis, MN)	Cohort	MenACWY-D	Medically attended local reactions	None	0–6 days post-vaccination	Children-young adults 9–26 years	49,278 vaccinations	Not available	9 validated local reactions; 1.8 events per 10,000 vaccinations (95% CI: 0.8, 3.5)	Risks were low and comparable to previous studies. Reactions were not severe.	Jackson et al., 2009^Citation30
Kaiser Permanente (KP) Southern California, KP Northern California, KP Colorado, KP Northwest, KP Washington, Marshfield Clinic Research Foundation (Wisconsin).	Tree-temporal scan statistic data mining	MenACWY-D	Thousands of potential adverse event diagnoses and diagnosis groupings within pre-defined risk windows.	Remaining days within the 1–56 day follow-up period but outside of the risk interval	Risk intervals starting 1–21 days after vaccination and ending 2–42 days later	Adolescents/teenagers aged 11–18 years	1,253,403 first doses	Not available	3 groups with AE signals at risk window of 1–42 days post-vaccination: 47 fever cases (1–2 days), 229 urticaria cases (4–14 days), 48 pleurisy cases (21–32 days)	Detected signals for 2 expected groups: Diseases of the skin and subcutaneous tissue; fever, and urticaria; Pleurisy results were new but further examination suggested it was likely a false signal	Li et.al., 2018^Citation31
Dana Farber Cancer Institute	Cohort	MenACWY-D	Adverse events, not specified	None	60 days post-vaccination	Adults aged ≥18 years; vaccination 12-months post hematopoietic cell transplantation	67 individuals	Median age: 58 years (range, 21–77); 58.2% male Indication: 100% hematopoietic cell transplant recipients	No AEs documented	No suggestion of safety concerns	Cheng et al., 2018^Citation32

Abbreviations: AE: Adverse event; Cl: confidence interval; ED: Emergency department; GBS: Guillain Barre syndrome; IR: Incidence rate; IRR: Incidence rate ratio; HIV: Human immunodeficiency virus; HPV: Human papillomavirus vaccine; KP: Kaiser Permanente; SAE: Serious adverse event; SMAEs: Serious medically attended events; Tdap: Tetanus- diphtheria-pertussis vaccine; VAERS: Vaccine Adverse Event Reporting System; VSD: Vaccine Safety Datalink

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