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

ABSTRACT

Two quadrivalent meningococcal conjugate vaccines (MenACWY) that prevent invasive meningococcal disease caused by N. meningitidis serogroups A, C, Y, and W have been licensed in the U.S. in the past 10–15 years. We systematically reviewed published studies conducted in the U.S. to evaluate the real-world safety evidence of meningococcal conjugate vaccines. We performed a literature search in PubMed of publications from 01/01/2005 to 02/29/2020 and identified 18 studies meeting inclusion criteria. Populations included high-risk persons aged 2 months to 10 years, adolescents/adults aged ≥11 years, pregnant populations, and hematopoietic cell transplant recipients. We extracted information about study setting, study design, exposure, outcomes, comparison group, follow-up/look back period, study population, sample size, available demographic/indication information, results, key conclusion, and reference. These published studies found no new significant safety concerns related to MenACWY. Consideration for future research includes a post-licensure safety evaluation of a new MenACWY product approved in April 2020.

KEYWORDS:

• Meningococcal conjugate vaccines
• post-licensure
• safety
• real-world evidence

Background

Invasive meningococcal disease (IMD) is a severe acute bacterial infection, and in the vast majority of cases is caused by five serogroups of Neisseria meningitidis (A, B, C, W, Y).¹ In the U.S., serogroups B, C, and Y are most prevalent, while serogroup A is rarely isolated.² The overall incidence of meningococcal disease during the ten-year period between 2006 and 2015 was approximately 0.26 cases per 100,000 people in the U.S. with a decrease in incidence by 2015 (0.12 cases per 100,000 people).³ Incidence varies by age; infants younger than one year have the highest incidence of meningococcal disease (0.73 cases per 100,000) and overall case fatality is approximately 15%.³ Morbidity from the disease is also high, with 11 to 27% of survivors experiencing significant sequelae, including neurologic and/or orthopedic disability, allergic complications, myocarditis, and hearing loss.^4–7

In the U.S., three quadrivalent meningococcal conjugate vaccines (MenACWY) that prevent invasive meningococcal disease (IMD) caused by N. meningitidis serogroups A, C, Y, and W have been licensed – MenACWY-D (Menactra; Sanofi Pasteur, Swiftwater, PA), MenACWY-CRM (Menveo; GlaxoSmithKline, Middlesex, United Kingdom), and MenACWY-TT (MenQuadfi; Sanofi Pasteur, Swiftwater, PA). MenACWY-D was licensed in 2005 and is approved as a single dose administration to persons 2–55 years of age and as a 2-dose series in children 9–23 months of age.^8,9 MenACWY-CRM, a quadrivalent meningococcal oligosaccharide diphtheria CRM₁₉₇ conjugate vaccine, was licensed in 2010 and is approved as a single dose administration in persons 2–55 years of age and as a multi-dose series in children 2–23 months of age.¹⁰ MenACWY-TT, a quadrivalent meningococcal tetanus toxoid-conjugated vaccine, was licensed in April 2020 and is approved as a single dose administration in persons 2 years of age and older.¹¹ However, MenACWY-TT is not yet recommended for use in the U.S. by the Advisory Committee on Immunization Practices (ACIP). Therefore, this paper focuses on MenACYW-D and MenACWY-CRM only, as there were no post-licensure observational studies available for MenACWY-TT.

The Centers for Disease Control and Prevention’s (CDC) ACIP recommends routine vaccination with MenACWY to all persons 11 to 12 years of age with a booster dose at age 16 years.⁸ However, recommendations for infants, children (2–10 years), and adults (≥19 years) is limited to administration among those at increased risk for meningococcal disease.⁸ MenACWY-CRM can be administered as early as 2 months of age while MenACWY-D has a minimum age of 9 months. Individuals at increased risk include those who have persistent complement component deficiencies (e.g., C5-C9, properdin, factor H, or factor D); those exposed to a community outbreak attributable to a vaccine serogroup; and those who travel to or reside in countries where meningococcal disease is hyperendemic or epidemic.^1,8 Additional groups at increased risk include persons who have functional or anatomic asplenia (including sickle cell disease) or HIV infection. However, among children 23 months and younger with these indications, MenACWY-CRM is the only MenACWY vaccine that is recommended.¹²

A few reviews of the post-licensure safety of MenACWY have been published. Keshavan et al. (2018) published a review of the clinical experience with MenACWY-CRM that consisted of 4 new safety surveillance studies published since a previous review in 2011.¹³ Myers and McNeil (2017) published a commentary focusing on the post-licensure safety experience of MenACWY-D and MenACWY-CRM.¹⁴ Since these two reports, additional real-world¹⁵ post-licensure safety studies of MenACWY vaccines have been published based on U.S. populations, including the safety experience of infants/toddlers not previously studied, as well as pregnant women. We undertook a systematic review of published studies to evaluate the real-world evidence of MenACWY safety in the U.S., with a focus on the most recent studies.

Methods

We performed a literature search in PubMed of publications from January 1, 2005 to February 29, 2020. Study inclusion criteria included studies conducted in the U.S that examined the observational post-licensure safety of any of the two MenACWY vaccines (MenACWY-D and MenACWY-CRM) recommended by the ACIP (MenACWY-TT had not yet been licensed and was not included). We first used the terms ‘meningococcal’ ‘conjugate’ ‘vaccine’ ‘safety’ to search all fields. Second, we conducted a separate targeted search of the title/abstract using the terms ‘meningococcal’ ‘vaccine’ ‘safety’ ‘united states’ excluding hits with ‘serogroup B’ ‘serogroup C’ and ‘trial.’ Finally, we manually searched the references cited by Myers et al. for additional references not captured in our systematic PubMed search findings.¹⁴

One author (TAB) conducted the systematic review of the literature and assessed study eligibility. One other author (ZS) completed a quality control check to verify the study eligibility of 1) a 20% random sample of those publications identified in the first step of the systematic search, and 2) all publications determined by the first author to meet study inclusion criteria. Any discrepancies by the two authors were brought to the other authors for a final decision to include/exclude publications for review (HT, LSS).

We extracted information regarding study setting, study design, exposure, outcomes, comparison group, follow-up/look back period, study population, sample size, available demographic/indication information, results, key conclusion, and reference (author, publication year).

Results

The PubMed search resulted in 309 published papers that were manually reviewed for eligibility. Of these, 12 original studies met the eligibility criteria (Figure 1). Studies were excluded because they were not post-licensure, not about a meningococcal vaccine approved for use in the U.S., or were studies based outside of the U.S. One additional study was identified from the targeted PubMed search. Five additional studies were added from the Myers et al. review that were not captured in the original PubMed search because they reflected larger vaccine safety assessments and did not exclusively evaluate safety of MenACWY vaccines.

Figure 1. Article selection flow chart

Of the 18 studies selected in the first review, the secondary review identified 2 studies that did not meet inclusion criteria because they were broader safety evaluations of vaccines and it was unclear whether specific MenACWY vaccine safety analyses were conducted. However, the authors decided to include the papers after tertiary review. The papers reported on specific safety outcomes after meningococcal vaccination, but sample size limited the ability to conduct further analyses. In the random sample of papers identified in the first step (n = 60), the secondary reviewer confirmed appropriate exclusion of all the excluded papers (Table 1). Of the included publications, 67% (n = 12) were observational studies (e.g., cohort, self-controlled, case-centered, or tree-temporal scan designs) and 22% (n = 4) were analyses of spontaneous reports from the Vaccine Adverse Event Reporting System (VAERS). VAERS is a national vaccine safety surveillance system co-administered by the CDC and the U.S. Food and Drug Administration (FDA) and is reliant on passive reporting of inadvertent exposures and/or adverse events.

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

MenACWY during pregnancy

Although the vaccines are not approved for use in pregnant women, inadvertent exposure can occur, often in the early gestational period when the status of pregnancy may be unknown. Four studies to date have evaluated the safety of MenACWY vaccines during pregnancy, two of which were reviewed by Myers et al.^16–19

One of the earlier studies, conducted by Zheteyeva et al., looked at adverse events during pregnancy after inadvertent exposure to MenACWY-D and found 17 (16.5%) spontaneous abortions and one congenital anomaly (1%; aqueductal stenosis and severe ventriculomegaly) among 103 exposed pregnant women reported to the VAERS.¹⁶ The authors stated that the patterns were not concerning based on background prevalence of the outcomes. The other study was also a VAERS analysis of 14 pregnant women exposed to MenACWY-CRM, in which only 3 reports included limited information on birth outcomes that were in all cases normal.¹⁸

After the Myers et al. review, there was a third study, a large evaluation of MenACWY-D safety conducted within a large integrated health care system that identified 25 pregnancy exposures. Of these, 18 had available outcome data: 12 live births (including birth of an infant with a dermoid cyst), 5 elective abortions, and 1 fetal death.¹⁹ The authors stated that this was not suggestive of an increased risk of pregnancy complications or an unusual pattern of adverse events among their infants, although this study included very few exposed pregnancies. The latest study evaluated MenACWY-CRM exposure in 92 pregnant women within a large integrated health care system. It was based on a cohort of vaccinated young women 11–21 years old who consequently became pregnant within 28 days of vaccination or were pregnant at the time of vaccination.¹⁷ In this study, the prevalence of spontaneous and induced abortions, preterm birth, low birth weight, and major congenital malformations were comparable with U.S. background prevalence estimates.¹⁷

MenACWY in infants and toddlers

Only two studies have assessed the post-licensure safety of MenACWY vaccines specifically in infants and toddlers, one in MenACWY-D recipients and the other in MenACWY-CRM recipients.^20,21 Both studies evaluated emergency department (ED) visits and hospitalizations as outcomes. Becerra-Culqui et al. assessed all-cause ED visits/hospitalizations and associated diagnoses up to 6 months post MenACWY-CRM vaccination in 138 high-risk individuals 2–23 months of age and found comparable rates of ED/hospitalization visits in available published data, suggesting no safety concerns.²⁰ Hansen et al. assessed 30-day ED visits/hospitalizations, pre-specified conditions in the outpatient setting, and death following MenACWY-D vaccination in 116 infants/toddlers 9–23 months of age. Compared to outcomes in a 31–75 days post-vaccination period, they found no new safety concerns in relation to outcomes reported in clinical trials.²¹

MenACWY in children 2–10 years

Two studies have specifically reviewed safety events among children 2–10 years old. In addition to evaluating outcomes in infant/toddlers, Hansen et al. reviewed safety outcomes following MenACWY-D among children 2–10 years old.²¹ The only significantly elevated outcome was cellulitis/abscess in the inpatient setting, although the two cases did not appear near the injection site and thus were determined to be unrelated to vaccination. Tartof et al. evaluated safety outcomes following MenACWY-CRM in 327 children.²² Among pre-specified events of interest, they found 1 confirmed new onset case of asthma, although it was 237 days post-vaccination. Only 4 children experienced events in the ED or inpatient settings within 30 days of vaccination. Findings were consistent with the events reported after vaccination with MenACWY-CRM from clinical trials described in the MenACWY-CRM package insert.¹⁰

MenACWY in adolescents and adults

Several studies have evaluated the safety of MenACWY vaccines in adolescents and young adults, and many of these studies have been reviewed by Myers et al.¹⁴ Briefly, early reports raised concerns about an association between MenACWY-D and Guillain-Barre syndrome (GBS).²³ It was estimated in 2012 that if such a risk existed, it was no more than 0.66 excess cases per 1 million adolescents vaccinated.²⁴ In the same year, Velentgas et al. published an evaluation of the risk of GBS among 1.4 million Men-ACWY-D vaccinations in 5 U.S. health plans, finding 0 GBS cases occurring within a 42-day window post-vaccination. They concluded that there was no evidence of an increased risk of GBS associated with MenACWY-D.²⁵ Baxter et al. measured the recurrence of GBS following any vaccination, including 7 individuals who had GBS prior to MenACWY-D vaccination. They found 0 recurrences of GBS after MenACWY-D vaccination.²⁶ In 2017, Myers et al. reported finding 4 confirmed cases of GBS out of 2,614 VAERS data reports after MenACWY-CRM vaccination.¹⁸ However, 2 individuals had a viral illness prior to onset of GBS symptoms, and the authors stated that they did not observe disproportionate reporting for this condition in the data mining analysis. No cases of GBS were observed in evaluations of 48,499 MenACWY-CRM recipients and 31,561 MenACWY-D recipients in large integrated health care systems.^19,27

Postvaccination syncope was reported to VAERS in 2005–2007 following vaccination with MenACWY-D and other routine adolescent vaccines (Tdap, HPV).²⁸ Syncope was also reported to VAERS in 2010–2015 following vaccination with MenACWY-CRM.¹⁸ There were 141 (7%) syncope reports in 11–18 year olds and 5 serious reports of vasovagal syncope. One additional study-based assessed vaccine-associated syncope in adolescents 13–17 years of age.²⁹ They found only 1 chart-confirmed case of syncope following 28,495 MenACWY doses. However, syncopal rates after adolescent vaccination were lower than what was anecdotally reported by clinic staff, suggesting an underestimation of events.

In 2012, Rowhani-Rahbar et al. published a case-centered analysis of Bell’s palsy after any vaccination among children ≤18 years old.³⁰ In this analysis, 8 Bell’s palsy cases were identified among individuals with history of MenACWY-D receipt in the prior year. In a consolidated group analysis of “any vaccine,” no association with Bell’s palsy was found during any of the risk intervals within 1–56 days following vaccination. Later in 2017, Tseng et al. observed a temporal association between occurrence of Bell’s palsy and receipt of MenACWY-CRM concomitantly administered with other vaccines.²⁷ In that study, 8 cases of Bell’s palsy occurred in the risk window, primarily between 5 and 10 weeks after vaccination. The authors suggested the need for further investigation of the association between MenACWY-CRM and Bell’s palsy, one reason being that the increased risk was only found in those who received other vaccines concomitantly and the association with concomitant vaccines could not be ruled out. All 8 Bell’s palsy cases resolved completely. In a cohort study of MenACWY-D and in a report of MenACWY-CRM based on VAERS data, no significantly increased risk of Bell’s palsy or facial nerve palsy was detected.^18,19

Other safety outcomes following MenACWY vaccines have been reported. Jackson et al. found that the risk of local reactions was low and comparable to previous studies, occurring in 1.8 out of 10,000 MenACWY-D vaccinations.³¹ Signals from a tree-temporal scan study among 11–18 year olds included diseases of the skin and subcutaneous tissue, fever, and urticaria after vaccination with MenACWY-D, all of which were already documented in pre-licensure studies.³³ However, this study found a signal for pleurisy 21–32 days post-vaccination. A post-hoc exploration found that 60% of the cases had an International Classification of Diseases-9^th edition diagnosis code for conditions that could cause pleurisy (i.e., trauma, pneumonia, asthma, injury, surgery, etc.), suggesting that it could have been a false signal, although further investigation is warranted.³³

Not many studies have looked at safety events among an older vaccine recipient population, except when included in a safety evaluation of a larger age group.^{16,18,19,26,28} However, Cheng et al evaluated the safety of MenACWY-D after hematopoietic cell transplantation (HCT) in a study population (n = 67) with a median age of 58 years. HCT, also known as bone marrow or stem cell transplantation, is a treatment for cancer and other conditions.³² In this study, no adverse events were documented within 60 days of vaccine administration.³⁴

Discussion

This systematic review of the real-world evidence of the safety of MenACWY vaccines in the U.S. provides an updated safety assessment of these vaccines, particularly among high-risk infants, toddlers, and children 2–10 years. One additional safety study of MenACWY-CRM in pregnant women has been added to the literature since the last review in 2017. While early reports detected safety concerns regarding GBS and syncope in adolescent and young adult vaccine recipients, only Bell’s palsy was subsequently detected as a potential safety concern when MenACWY-CRM was received concomitantly with other vaccines. However, two later studies (one on MenACWY-D and one on MenACWY-CRM) did not find increased risks of Bell’s palsy following MenACWY vaccination regardless of co-administration with other vaccines.

The real-world post-licensure safety assessment of MenACWY in infants, toddlers, and children 2–10 years at high-risk of contracting meningococcal disease is important. While pre-licensure clinical trials were conducted in healthy individuals, MenACWY has been recommended in high-risk children post-licensure. The three published post-licensure studies including these high-risk populations found no new safety concerns potentially related to MenACWY vaccination, although the outcomes were often sporadic. However, gathering a large sample size of high-risk-vaccinated individuals was a challenge considering the indicated conditions for vaccination (medical or high risk of exposure) can be rare. For example, only 116 and 138 infant/toddlers over a course of 3 years met inclusion criteria for the two separate studies conducted at Kaiser Permanente Northern California (KPNC) and Kaiser Permanente Southern California (KPSC), respectively.^20,21 In addition, 1,421 and 327 children 2–10 years of age, respectively, were included in the two childhood vaccination safety assessments, although “healthy” children receiving an early dose of a routine MenACWY dose typically given at age 11–12 years per ACIP recommendations were also included.^21,22 Nevertheless, these studies conducted in large-integrated health care settings had unique strengths. Safety assessments of MenACWY-CRM, one in infant/toddlers (2–23 months) and the other in children (2–10 years) included detailed chart reviews to improve accuracy in assessing eligibility and identifying incident safety outcome information, which was feasible with smaller sample sizes.^20,22 The study design of the MenACWY-D safety assessment in children 9 months to 10 years of age gathered comparison data allowing for a direct comparison of outcomes and calculations of association estimates.²¹

Although MenACWY vaccines are not approved for use in pregnant women, four studies in total have published findings on this population, two studies of VAERS data and two cohort studies. Findings were not suggestive of an increased risk of pregnancy- or birth-related adverse events. Inadvertent exposure can occur in pregnant young women, often in the early gestational period when the status of pregnancy may be unknown. All the evaluations of MenACWY exposure during pregnancy were descriptive in nature with no comparison group. However, a unique feature of the study of 92 pregnant women included the systematic identification of MenACWY exposure and pregnancy and birth outcomes that were chart reviewed in detail.¹⁷ This is in contrast to the two studies based on VAERS data that relied on passive reporting of inadvertent exposure and/or adverse events with limited access to medical records for detailed review.^16,18 Detailed review of outcomes was also limited in the evaluation of 25 exposed pregnancies with outcome data only available for 18 women.

Real-world safety studies are necessary and the only way to evaluate vaccines in the public after they have been licensed. MenACWY vaccine safety has been mainly evaluated via VAERS reports or in health care settings. Four studies have been conducted using the VAERS system, 4 have been exclusively conducted at Kaiser Permanente Southern California (MenACWY-CRM), 4 exclusively at Kaiser Permanente Northern California (MenACWY-D), a large Vaccine Safety Datalink (VSD) data mining study involving 1.25 million MenACWY-D doses, and a combined analysis of over 2 million MenACWY-D doses from the VSD and 5 U.S. health plans to assess the association between MenACWY-D and GBS. The study settings complement each other. For example, VAERS studies have the highest potential for selection bias since they are reliant on passive reporting, without clear population denominators for the calculation of rates. However, VAERS is valuable for signal detection that triggers larger follow-up studies in large health care systems, such as in the case of GBS and syncope after MenACWY-D vaccination.^23,28 Systematic evaluation of vaccine safety is needed especially among high-risk groups for which MenACWY is recommended. Although small sample size or lack of an adequate comparison group has been an issue for studies of high-risk populations, these studies still provide valuable real-world evidence of MenACWY, not otherwise available pre-licensure or systematically in VAERS.

Post-licensure studies have generated reassuring real-world evidence of the safety of MenACWY vaccines. This review included post-licensure safety studies for MenACWY-D and MenACWY-CRM, which have been used in the U.S. for 15 and 10 years, respectively. Because of the potential limitation that the sample size of high-risk populations and pregnant women receiving these vaccines is still small, constant monitoring of the safety of these vaccines in this population is warranted. Consideration for future research includes the post-licensure safety evaluation of MenACWY-TT, a newly licensed MenACWY vaccine for which safety has been evaluated in 5 double-blind, randomized clinical trials.¹¹

Disclosure of potential conflicts of interest

This work was supported by Kaiser Permanente Southern California.

TBC, LSS, ZS and HFT received research funding from GSK for meningococcal vaccine studies and other unrelated vaccine studies. LSS, HFT, and ZS received research support from Novavax for studies unrelated to this paper. HFS and LSS received research support from Seqirus for studies unrelated to this paper. LSS and ZS received research support from Dynavax for studies unrelated to this paper. HFT received research support from Genentech for studies unrelated to this paper. ZS received research support from Gilead for studies unrelated to this paper.

Additional information

Funding

This work was supported by the Kaiser Permanente Southern California.