Safety Surveillance of Bivalent Meningococcal Group B Vaccine, Vaccine Adverse Event Reporting System, 2014–2018

Abstract

Background

In October 2014, MenB-FHbp (Trumenba, Pfizer) became the first meningococcal group B vaccine licensed in the United States. It is approved for use in individuals aged 10–25 years. Our objective was to evaluate the safety of MenB-FHbp postlicensure.

Methods

The Vaccine Adverse Event Reporting System (VAERS) is a national passive vaccine safety surveillance system. We analyzed US VAERS reports for MenB-FHbp received from the date of licensure in October 2014 through December 2018. We described the characteristics of the persons and adverse events (AEs) reported and calculated reporting rates using the number of doses distributed. We used empirical Bayesian data mining to identify AEs reported at least twice as often as expected compared with all other vaccines.

Results

VAERS received 2106 reports involving MenB-FHbp, representing 698 reports per million doses distributed. The median age of vaccinees was 17 years, and 55% were female. MenB-FHbp was given simultaneously with other vaccines in 37% of reports. Most reports (57%) described AEs that started on the day of or day after vaccination. The most common AEs reported were pyrexia (27%), headache (25%), and pain (16%). There were 44 serious reports (2% of all reports), among which 42 reported a hospitalization. Data mining identified disproportional reporting of headache, pyrexia, chills, and myalgia.

Conclusions

The AEs most commonly or disproportionately reported following MenB-FHbp were consistent with those identified in clinical trials as described in the US package insert. We did not identify any new safety issues.

Meningococcal disease is caused by Neisseria meningitidis and includes sepsis and meningitis. MenACWY vaccine has been recommended for adolescents in the United States since 2005 to prevent meningococcal disease caused by N. meningitidis serogroups A, C, W, and Y [1]. For the period 2006 through 2015, meningococcal serogroup B (MenB) was the most common cause of meningococcal disease in the United States [2]. The first MenB vaccine was licensed in the United States in 2014 (Trumenba, Pfizer). Trumenba is called bivalent because it contains 2-Factor H binding protein (FHbp) variants (hereafter referred to as MenB-FHbp). MenB-FHbp is approved in the United States for use in individuals aged 10 through 25 years and is administered by intramuscular injection as either a 2- or 3-dose series, with the first and last doses given 6 months apart [3]. The Advisory Committee on Immunization Practices (ACIP) recommends the 3-dose series of MenB-FHbp for people aged ≥10 years who are at increased risk for MenB disease because of an outbreak, persistent complement component deficiencies (including persons receiving a complement inhibitor drug), anatomic or functional asplenia (including sickle cell disease), and for microbiologists [4]. The ACIP states that adolescents and young adults not at increased risk for MenB disease may be vaccinated based on shared clinical decision-making using a 2-dose series, with the preferred ages being 16 through 18 years [5, 6].

The safety of MenB-FHbp has been evaluated in 11 clinical studies that included 15 227 individuals who received at least 1 dose of MenB-FHbp [3, 7–11]. Among those aged 10 through 18 years, 87% had injection site pain after the first dose, which lasted an average (range) of 2 (1–17) days. Myalgia was experienced by 24%. Injection site pain, fever, and headache were more common in MenB-FHbp recipients than in control subjects. The safety of MenB-FHbp was also assessed in 1081 college students during a mass vaccination campaign done in response to a MenB outbreak; adverse event (AE) rates were similar to the clinical trial results, and most AEs resolved within 7 days [12]. Our objective was to evaluate the postlicensure safety of MenB-FHbp in the United States using the Vaccine Adverse Event Reporting System (VAERS).

METHODS

VAERS is a public health surveillance and pharmacovigilance system managed by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) [13]. VAERS accepts reports of AEs following immunization submitted using a standardized form. Anyone may submit a report; vaccine manufacturers and health care providers are required to report. Multiple reports from 1 or more sources regarding the same person and vaccination episode are consolidated into a single record. AE descriptions are submitted in free text and coded using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) [14]. A report may contain more than 1 AE and may involve more than 1 vaccine administered at the same time. Reports are classified as serious if the patient outcome results in hospitalization, prolongation of existing hospitalization, life-threatening illness, disability, death, or congenital anomaly or birth defect [15]. Copies of medical records are routinely requested for US serious reports [13].

For this evaluation, we included US reports of MenB-FHbp that were received by VAERS from October 29, 2014 (the date MenB-FHbp was licensed in the United States), through December 31, 2018. We performed descriptive analyses using SAS 9.4 (SAS Institute Inc., Cary, North Carolina, USA) to examine the characteristics of the vaccinated persons, vaccines, and reported AEs. We requested US dose distribution data from the manufacturer and calculated reporting rates by dividing the number of VAERS reports by the number of doses distributed. We conducted empirical Bayesian data mining analyses using Oracle’s Empirica Signal System to detect disproportionality in AE reporting for MenB-FHbp compared with all other vaccines in the VAERS database. We conducted analyses restricted to persons aged 10 through 25 years controlling for age group, sex, and year the report was received, including all reports and serious reports only. We also conducted data mining analyses by age group for all ages, controlling for sex and year in which the report was received in VAERS. We calculated the empirical Bayes geometric mean (EBGM) and 90% confidence interval for each vaccine–AE combination. We defined disproportionate reporting as an EBGM with a lower bound of the confidence interval ≥2 [16, 17].

We manually reviewed all reports coded as serious and any reports that might have represented selected conditions of interest in order to confirm or classify the event and extract additional clinical details. Conditions of interest were identified using coded variables and supplemented with free text search. During the manual review process, we consolidated reports for the same person/vaccination episode that had not previously been consolidated. We reclassified the serious designation when the information provided contradicted the initial classification, and we identified the primary AE leading to the report being classified as serious. We classified AEs using Brighton Collaboration case definitions when available [18–20]. We selected conditions of interest based on the following rationale: (1) AEs of interest with vaccination in general, including anaphylaxis, syncope, potential shoulder injury, Guillain-Barré syndrome (GBS), and potential autoimmune diseases; (2) AEs for which a potential association with a MenB vaccine has been suggested in prior literature; MenB-4C (Bexsero, GSK), the second MenB vaccine licensed in the United States, also contains an FHbp, so we included conditions from the MenB-4C literature: nephrotic syndrome [21], diseases associated with Factor H autoantibodies [22], and vaccination in persons receiving eculizumab [23]; (3) reports of meningococcal disease; (4) reports involving persons with preexisting conditions for which limited prior vaccine safety data are available (ie, pregnancy and persons at increased risk for MenB disease); (5) vaccination errors.

Patient Consent Statement

As a public health surveillance activity, VAERS is exempt from institutional review board and informed consent requirements.

RESULTS

During our assessment period, there were 2106 US MenB-FHbp VAERS reports. The vaccinees were female in 55% of reports. When age was reported (in 78% of reports), the median age (range) was 17 (0–81) years, and 97% were aged 10–25 years and 68% were aged 16–18 years. In 41 reports, the person vaccinated was outside the indicated age range; among 8 persons aged <10 years, 6 received MenB-FHbp as the wrong vaccine because of administration error, and the reason for vaccination in the other 2 was not stated; among 33 persons >25 years of age, 7 received MenB-FHbp because they were at increased risk for MenB disease, 1 received the wrong vaccine because of administration error, and the reason for vaccination in the remainder was not stated. MenB-FHbp was the only vaccine listed in 1318 (63%) reports. Table 1 shows additional report characteristics.

Table 1.

Characteristics of Persons, Vaccines, and Adverse Events Among all MenB-FHbp Reports (n = 2106)

Characteristic	No.	%a
Age group, y
≤9	8	0.4
10–15	142	7
16–18	1039	49
19–25	302	14
≥26	33	1.6
Unknown	582	28
Sex
Female	1149	55
Male	723	34
Unknown	234	11
Persons with risk factors for MenB diseaseb
Complement component deficiencies	1	0.05
Receiving eculizumab	0	0
Anatomic or functional asplenia	8	0.4
Sickle cell disease	1	0.05
Microbiologist	1	0.05
MenB disease outbreak setting	10	0.5
Dose number in MenB-FHbp series
1	1034	49
2	241	11
3	36	2
4 c	2	0.1
Unknown	793	38
Other vaccines on same dayd,e
Any	788	37
MenACWY	447	21
HPV	288	14
Influenza	139	7
Hepatitis A	73	3
Tdap	60	3
Adverse event onset, days postvaccination
0 f	854	41
1	327	16
≥2	143	7
Unknown	782	37
Serious reportb,d	44	2
Hospitalization	42	2
Prolongation of existing hospitalization	0	0
Life-threatening illness	3	0.1
Disability or permanent damage	0	0
Death	0	0
Congenital anomaly or birth defect	0	0
Reporter
Manufacturer	1040	49
Health care professional	768	36
Patient or parent/guardian	111	5
Other or unknown	187	9

Abbreviations: HPV, human papillomavirus; MenACWY, meningococcal serogroups A, C, W, and Y; MenB, meningococcal serogroup B; Tdap, tetanus-diphtheria-acellular pertussis.

^aPercentages may not add up to 100% due to rounding.

^bThis characteristic was confirmed by manual review of reports.

^cMenB-FHbp is approved as either a 2- or 3-dose series; the reason for the fourth dose in 1 report was because the third dose had been given too soon, and the reason was not stated in the other report.

^dCategories are not mutually exclusive.

^eOnly the most common simultaneously received vaccines are shown.

^fThe day of vaccination is referred to as day 0.

Among all reports, 1033 different MedDRA PTs were coded, with a median (range) of 3 (1–121) PTs per report. The most common PTs were pyrexia, headache, and pain (Table 2). When the PTs for injection site reactions (ISRs) were grouped, 576 (27%) reports included an ISR, and 134 (6%) reported only an ISR. Two MenB-FHbp ISRs were classified as serious due to hospitalization. One met the Brighton case definition level 1 criteria for a local reaction at or near the injection site; the other was initially treated as possible cellulitis but was later assessed to be an ISR. There were 27 nonserious reports of cellulitis, which is not considered an ISR, mostly described as in the arm or at the injection site.

Table 2.

The Most Common MedDRA Preferred Terms Characterizing Adverse Events Among MenB-FHbp Reports^a

All MenB-FHbp Reports (n = 2106)			MenB-FHbp Without Other Vaccines (n = 1318)
Preferred Term	No.	%	Preferred Term	No.	%
Pyrexia	560	27	Pyrexia	354	27
Headache	515	25	Headache	338	26
Pain	346	16	Pain	230	18
Chills	327	16	Injection site pain	223	17
Nausea	322	15	Chills	221	17
Injection site pain	321	15	Nausea	199	15
Injection site erythema	268	13	Injection site erythema	175	13
Pain in extremity	254	12	Pain in extremity	168	13
Fatigue	251	12	Fatigue	166	13
Dizziness	243	12	Erythema	127	10
Erythema	202	10	Injection site swelling	124	9
Injection site swelling	187	9	Dizziness	121	9
Vomiting	186	9	Myalgia	114	9
Myalgia	159	8	Vomiting	103	8
Malaise	140	7	Malaise	91	7

Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; MenB-FHbp, Bivalent Meningococcal Group B Vaccine.

^aPreferred terms are not mutually exclusive.

Manual review of 59 reports initially coded as serious confirmed 44 as serious (2% of all reports). The most common primary diagnoses or symptoms among serious reports were pyrexia and headache (Table 3).

Table 3.

Primary Adverse Events Among Serious MenB-FHbp Reports (n = 44)^a

Primary System/Organ/Class	No.	Preferred Term for Primary Diagnosis or Symptom Reported, No.
Blood and lymphatic system disorders	2	Leukocytosis (1), leukopenia and thrombocytopenia (1)
Gastrointestinal disorders	1	Volvulus of bowel (1)
General disorders and administration site conditions	16	Asthenia (1), chest pain (1), chills (1), malaise (1), pyrexia (11), swelling (1)
Immune system disorders	1	Hypersensitivity (1)
Infections and infestations	3	Cellulitisb (1), meningitis aseptic (1), pneumonia (1)
Nervous system disorders	15	Guillain-Barre syndrome (2c), headache (8), seizure (2), syncope (3)
Psychiatric disorders	3	Conversion disorder (1), psychogenic seizure (1), psychotic behavior (1)
Renal and urinary disorders	1	Nephritis (1)
Vascular disorders	2	Shockd (2)

Abbreviation: MenB-FHbp, Bivalent Meningococcal Group B Vaccine.

^aThe primary diagnosis or symptom reported as an adverse event was determined by manual review.

^bThe cellulitis was at the injection site of another vaccine; MenB-FHbp was not given in the same limb.

^cThese 2 reports were submitted by different reporters and appear to be about the same person, but there was insufficient information reported to definitively consolidate them into a single record.

^dNo etiology was identified in either case of shock.

There were 3 018 899 MenB-FHbp doses distributed during our assessment period. There were 698 MenB-FHbp VAERS reports per million doses distributed and 15 serious reports per million doses distributed.

Data Mining

We identified disproportional reporting of 4 PTs with MenB-FHbp among persons aged 10–25 years (Table 4). Data mining for all ages stratified by age group identified the same PTs in the age group 10–17 years, and 1 of those (chills) in the age group 18–25 years (data not shown). Analysis restricted to serious reports did not identify disproportional reporting.

Table 4.

Adverse Events Disproportionately Reported With MenB-FHbp Among Persons 10 Through 25 Years of Age

Preferred Term	MenB-FHbp Reports, No.	Empirical Bayes Geometric Mean (90% CI)a
Chills	255	3.79 (3.40–4.20)
Myalgia	136	2.61 (2.25–3.03)
Pyrexia	413	2.43 (2.24–2.63)
Headache	417	2.28 (2.10–2.46)

Abbreviation: MenB-FHbp, Bivalent Meningococcal Group B Vaccine.

^aIf the lower bound of the 90% confidence interval is ≥2, then this is considered a potential signal that may need further evaluation.

Conditions of Interest

We identified 5 reports of GBS (1 was potentially a duplicate but had insufficient identifying information to definitively consolidate). Details such as age and timing of onset postvaccination were only reported for 2 cases, which were classified as Brighton levels 3 and 4, respectively. The first was a 21-year-old female evaluated as an outpatient for weakness starting 36 days postvaccination who later reported improvement; she had also received inactivated influenza vaccine and had an upper respiratory infection before symptom onset. The other case was reported in a 17-year-old male with symptom onset on day 24 postvaccination; he was hospitalized for 4 days and later recovered.

We identified 1 report of a potential autoimmune disease other than GBS. An 18-year-old female experienced blurry vision that began 4 days following vaccination and was diagnosed with bilateral anterior uveitis. Her symptoms improved following treatment with topical ophthalmic corticosteroid, and she had normal visual acuity on follow-up, though the condition had not resolved after 1 year. She had streptococcal pharyngitis diagnosed 4 days before vaccination.

There were no reports of meningococcal disease. There were 19 reports of patients who had a lumbar puncture (10 with hospitalization and 9 in the emergency department) and 2 more that declined; most (68%) were done to test for meningitis in patients with signs or symptoms such as fever or headache.

There were 20 reports involving individuals with risk factors for MenB disease (Table 1); the AEs reported were similar to those among all other reports. We identified 3 reports involving pregnant women, none of whom reported an AE.

We identified 51 reports of errors related to administration of MenB-FHbp (Table 5); 37% of these reports were submitted by 1 clinic regarding repeated instances of administering MenB-FHbp instead of MenACWY. When discounting the multiple reports from that clinic, the most common type of error reported was MenB-FHbp administered instead of another intended vaccine (MenACWY, PCV13, HepB, or Tdap). When HepB or PCV13 was the intended vaccine, this error resulted in MenB-FHbp being administered to a person younger than the indicated age. A 1-month-old female who received MenB-FHbp instead of HepB developed fever 1 day after vaccination and was admitted to intensive care with a diagnosis of aseptic meningitis. This was the only serious AE associated with a vaccination error. Most error reports (73%) did not involve an AE. The AEs reported with a vaccination error were common AEs that were not apparently related to the type of error, with the exception of 1 report of subcutaneous administration in which the patient was diagnosed with cellulitis. In most reports, a reason why the error occurred was not stated. Reporting rates and additional details for other conditions of interest are shown in Table 5.

Table 5.

Conditions of Interest Among MenB-FHbp Reports

Condition	Reviewed, No.	Confirmed, No.	Details	Reporting Rate per Million Dosesa
Anaphylaxis	6	6	• Brighton level: 1 (n = 1), 2 (n = 2), 4 (n = 3).	2
			• Dose: 1 (n = 4), unknown (n = 2).
			• Onset: 0 min, 5 min, 30 min, 3 h (n = 2), unknown.
			• Simultaneous vaccines (n = 2).
Syncope	168	168	• Age: median 17 (range 11–64) y.	56
			• Simultaneous vaccines: 62%.
			• Onset: within minutes (64%), later same day (16%), next day or later (7%), unknown (13%).
			• Resulted in injury (15%): concussion (n = 10), laceration (n = 3), dental (n = 2).
Potential shoulder injury (in MenB-FHbp arm)	1	0	• There was 1 report of subdeltoid bursitis, but 2 providers did not agree on the diagnosis.	0
Guillain-Barré syndrome	6	5 b	• Brighton level: 3 (n = 1), 4 (n = 4).	2
			• Onset: 24 days (n = 1), 36 days (n = 1), unknown (n = 3).
Potential autoimmune diseases	1	1	• Anterior uveitis.	0.3
Factor H autoantibody-associated conditions	1	0	N/A	0
Nephrotic syndrome and other renal conditions	14	5	• Nephrotic syndrome due to minimal change disease (n = 1).	2
			• Acute nephritic syndrome (n = 1).
			• Shock with acute renal failure (n = 1).
			• Urinary tract infection (n = 1).
			• Gross hematuria (no additional diagnostic details, n = 1).
Eculizumab exposure	2	0	• One report mentioned eculizumab, but the patient was not started on the drug before vaccination.	0
Meningococcal disease	0	0	N/A	0
Pregnancy	12	3	• Age: range 16–17 y.	N/A
			• None knew they were pregnant at time of vaccination.
			• Exposure during trimester: 1 (n = 1), 2 (n = 1), unknown (n = 1).
			• No adverse events reported.
Vaccination errors associated with MenB-FHbp	76	51	• Wrong vaccine administered (MenB-FHbp instead of another intended vaccine, n = 34).	17
			• Interchange of vaccine products (MenB-FHbp and MenB-4C in series, n = 6). • Expired vaccine administered (n = 3).
			• Vaccine administered at inappropriate site (thigh, n = 2; buttock, n = 1).
			• Incorrect route of vaccine administration (subcutaneous, n = 1).
			• Inappropriate schedule of administration (3rd dose given too soon, n = 1).
			• Product storage error (vaccine was frozen, n = 1).
			• Syringe leak (n = 1).
			• Wrong patient received vaccine (child during group visit for 3 siblings, n = 1).

Abbreviations: MenB-4C, four-component Meningococcal Group B Vaccine; MenB-FHbp, Bivalent Meningococcal Group B Vaccine; N/A, not applicable.

^aRate of confirmed reports per million doses distributed.

^bThis confirmed case count includes 1 likely duplicate report; however, insufficient identifying information was submitted to definitively consolidate the report.

DISCUSSION

We evaluated domestic VAERS reports for MenB-FHbp received during the first 4 full years following licensure in the United States. The AEs most commonly or disproportionately reported following MenB-FHbp were consistent with the AEs identified in prelicensure studies and described in the US package insert. Serious reports were rare, representing 2% of all MenB-FHbp reports and 15 reports per million doses distributed.

Anaphylaxis, syncope, and shoulder injury can occur with any injectable vaccine. The reporting rate for anaphylaxis following MenB-FHbp was 2 per million, which is similar to VAERS reporting rates for other vaccines [24]. We found syncope in 8% of MenB-FHbp reports and did not find any confirmed reports of potential shoulder injury. Syncope and shoulder injury are thought to be related to the injection procedure rather than to the vaccine ingredients [25]. The CDC provides guidance on proper vaccine administration, and adherence to these guidelines could help prevent shoulder injury and injury from syncope [26, 27].

An association between GBS and influenza vaccine was first identified in 1976, and GBS has since been assessed as a potential AE following other vaccines [25]. GBS onset within 42 days after vaccination has been considered a plausible risk period. The background rate of GBS among persons aged 10–19 years in the United States has been estimated to be 7.5 cases per million person-years [28]. The expected number of GBS cases that would occur by chance alone within 42 days after vaccination for the number of MenB-FHbp doses distributed is 2.61. We identified 5 GBS reports following MenB-FHbp (1 of which might be a duplicate), but only 2 reported symptom onset within 42 days. Data mining did not detect disproportional reporting of GBS with MenB-FHbp compared with other vaccines. Overall, these data do not suggest an increased occurrence of GBS following MenB-FHbp.

We identified 1 report of a potential autoimmune disease, a case of uveitis. The patient had a streptococcal infection before vaccination. Poststreptococcal syndrome has been proposed as a cause of uveitis based on case reports [29]. This case highlights the difficulty of establishing a causal association between vaccination and an AE in an individual, particularly when the patient has other relevant concurrent exposures. A standardized algorithm to assess causality after individual adverse events is available that can assist in collecting and interpreting patient data [30].

A theoretical safety issue for autoimmune disease had previously been proposed based on serologic studies of Factor H autoantibodies detected postvaccination in animals [31]. Factor H is a human plasma protein that inhibits the alternative complement pathway (a part of the innate immune system). The 2 antigens in MenB-FHbp are variants of the bacterial FHbp [3]. Immunization with MenB-4C, which also contains an FHbp, was found to induce autoantibodies against human Factor H [22]. Factor H autoantibodies have been found in persons with several complement-mediated diseases including atypical hemolytic-uremic syndrome, membranoproliferative glomerulonephritis, C3 glomerulopathies, and membranous nephropathy [32–34]. Our VAERS review did not identify any reports of the aforementioned conditions following MenB-FHbp. There was 1 report of acute nephritic syndrome; a final diagnosis was not reported, but the patient had normal complement levels, suggesting a non-complement-mediated pathology.

Nephrotic syndrome can be caused by several different types of renal diseases and is not associated with Factor H [35]. Active vaccine safety surveillance following a MenB-4C mass vaccination campaign in Quebec, Canada, identified 4 cases of nephrotic syndrome in children aged 2–5 years, which was interpreted as possibly being greater than the expected number of cases of this condition [21]. In the United States, MenB vaccines are neither indicated nor recommended for children under 10 years of age. We identified 1 report of nephrotic syndrome in a 14-year-old male with minimal change disease, which is an idiopathic condition.

Persons receiving eculizumab (a monoclonal antibody drug that inhibits complement component 5) are at increased risk of meningococcal disease and should receive meningococcal vaccines at least 2 weeks before initiating the drug [36, 37]. Health Canada released a safety warning in 2016 stating that persons receiving eculizumab for paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome are potentially at increased risk of hemolysis or anemia when vaccinated with MenB-4C [23]. Our VAERS review did not identify any reports of individuals receiving eculizumab before MenB-FHbp vaccination; therefore, we cannot draw any conclusions about this group. We identified 9 reports involving individuals at increased risk of MenB disease due to underlying medical conditions. We did not identify any safety issues specific to these groups, but the number of persons was small.

VAERS sometimes receives reports of cases of the disease a vaccine is intended to prevent (which the reporter might consider a vaccine failure). We did not identify any reports of meningococcal disease following MenB-FHbp. There were several reports of individuals who had emergency department visits or hospitalizations during which meningitis was considered in the differential diagnosis due to symptoms such as fever or headache, with or without rash. The majority of these events occurred on the day of or day after vaccination. Headache and fever can be associated with MenB-FHbp but might be concerning for meningitis, particularly in persons vaccinated in response to a MenB outbreak, as specified in some VAERS reports.

MenB-FHbp administration during pregnancy has not been studied in clinical trials [3]. We identified 3 reports of unintended MenB-FHbp vaccination during pregnancy, none of which reported an AE. Information on the safety of MenB-FHbp vaccination during pregnancy remains limited.

Vaccination errors are preventable and have previously been reported for other types of vaccines [38]. In our review, the most common error identified was MenB-FHbp inadvertently administered instead of another intended vaccine. Our VAERS assessment only included reports for individuals who received MenB-FHbp, so we did not assess how often inadvertent administration of another vaccine instead of MenB-FHbp was reported. Health care systems and providers should implement prevention strategies to minimize vaccination errors and may benefit from learning about errors reported by others [38].

Strengths of our safety assessment include use of the VAERS database, which receives information about the use of vaccines in routine clinical practice. Due to its national scope, VAERS draws on data from a large number of people, allowing it to detect rare adverse events [13]. However, as a passive reporting system, VAERS is subject to several limitations, including reporting bias, sometimes incomplete information in reports, and lack of a comparator group [13]. For these and other reasons, VAERS data generally cannot establish the causality of a vaccine for reported AEs. Failure to report AEs could lead to undercounting of events. For example, with other vaccines, VAERS was estimated to capture from 13% to 76% of expected anaphylaxis cases, a rare but clinically significant adverse event, whereas VAERS may capture <1% of common nonserious adverse events [39]. As we observed in this assessment, submission of reports for the same event from multiple sources with insufficient information to consolidate reports could lead to overcounting of events. While dose distribution information provides context to the number of reports received, reporting rates are crude measures that do not represent the true incidence of AEs because of the potential for under-reporting of AEs and imprecise denominator data (on number of persons actually vaccinated).

In summary, our review of VAERS did not identify any new safety issues for MenB-FHbp. Safety data for pregnant women and persons with preexisting medical conditions remain limited. The number of persons in the United States who have received a MenB vaccine to date is relatively small compared with other types of vaccines. As of 2018, 17% of adolescents had received at least 1 dose of MenB vaccine by 17 years of age [40]. There are 2 brands of MenB vaccine approved for use in the United States. ACIP recommendations state that either MenB vaccine can be used and that the same vaccine product must be used for all doses [1]. The adverse events for the other MenB vaccine (MenB-4C) described in the prescribing information and commonly reported to VAERS are similar to those for MenB-FHbp [1]. Continued safety monitoring is warranted for MenB vaccines, particularly for rare AEs. Health care professionals and others should continue to report clinically significant AEs following MenB vaccines to VAERS [41].