A comprehensive review of clinical and real-world safety data for the four-component serogroup B meningococcal vaccine (4CMenB)

Figures & data

Table 1. Summary of key safety findings in key clinical trials.

	Ref	Study design	Country/countries	Study population	Safety endpoints and most frequent AEs within 7 days
Study 1	[37]	Phase III 4CMenB + RV* MenC + RV* RV* only	Germany, Austria, Italy, Finland, Czech Republic	Infants aged 2, 4, 6 months; 12-month booster with MMRV (N = 2627); safety sub study (N = 1003)	Observer-blinded AEs after primary dose
					Systemic			Local
						4CMenB + RV	RV ± MenC		4CMenB + RV‡	RV ± MenC
					Irritability	93%	76–83%	Injection site tenderness	87%	53–68%
					Unusual crying	85%	64–72%	Erythema	83%	53–74%
					Sleepiness	87%	72%	Induration	77%	46–75%
					Fever (≥38.5°C)	65%	32–34%	Swelling	47%	17–34%
Study 2	[28]	Phase III 4CMenB + RV^† RV^† only	Taiwan	Infants aged 2, 4, 6, and 12 months (booster) (N = 225)	Solicited AEs across all vaccinations
					Systemic			Local
						4CMenB + RV	RV		4CMenB + RV‡	RV
					Irritability	52–75%	22–44%	Injection site tenderness	48–51%	7–16%
					Persistent crying	42–65%	21–41%	Erythema	36–42%	4–21%
					Sleepiness	26–53%	13–45%	Induration	36–43%	8–24%
					Fever (≥38.0°C)	44–51%	8–17%	Swelling	23–36%	4–14%
Study 3	[32]	Phase III 4CMenB 4CMenB + MenACWY-CRM MenACWY-CRM	Mexico, Argentina	Infants aged 3, 5, 7, and 13 months (N = 750)	Solicited AEs across all vaccinations
					Systemic			Local
						4CMenB (+MenACWY-CRM)	MenACWY-CRM		4CMenB (+MenACWY-CRM‡)	MenACWY-CRM
					Persistent crying	43–58% (41–52%)	27–36%	Local tenderness	60–70% (62–68%)	27–31%
					Irritability	37–54% (38–47%)	28–37%	Erythema	44–46% (36–43%)	16–21%
					Sleepiness	19–35% (18–29%)	16–23%	Induration	44–50% (41–46%)	9–14%
					Fever (≥38.0°C)	18–25% (17–26%)	4–11%	Swelling	37–38% (34–37%)	9–10%
Study 4	[34]	Phase II/III 4CMenB (1-, 2-, or 6-month intervals) Placebo	Chile	Adolescents aged 11–17 years (N = 1631)	Solicited AEs across all vaccinations (cumulative)
					Systemic			Local
						4CMenB	Placebo		4CMenB	Placebo
					Malaise	51%	30%	Pain	86%	60%
					Headache	42%	27%	Erythema	51%	29%
					Fever (≥38.0°C)	4%	2%	Induration	40%	20%
Study 5	[30]	Phase II 4CMenB (ic RV) 4CMenB + RV (concomitant 2, 4, 6 months and accelerated 2, 3, 4 months)* RV*	UK, Belgium, Germany, Czech Republic, Italy, Spain	Infants aged 2–7 months (N = 1885)	Parent-recorded AEs across all vaccinations
					Systemic			Local
						4CMenB (ic RV) (4CMenB + RV)	RV		4CMenB ic RV (4CMenB + RV)‡	RV
					Irritability	53–63% (66–79%)	44–57%	Erythema	66–67% (62–70%)	47–58%
					Sleepiness	37–61% (54–73%)	38–59%	Pain	51–60% (56–66%)	29–38%
					Fever (≥38.0°C)	26–41% (44–62%)	23–36%	Induration	50–54% (45–54%)	17–43%
Study 6	[33]	Phase II 4CMenB + RV ± antipyretic MenC vaccine	Argentina, Chile, Czech Republic, Hungary	Infants aged 2, 3, 4, and 12 months (N = 558)	Solicited AEs across all vaccinations
					Systemic			Local
						4CMenB + RV	MenC		4CMenB site	RV site
					Irritability	64–75%	43–46%	Tenderness	56–75%	51–67%
					Fever (≥38.0°C)	49–62%	23–34%	Erythema	57–61%	37–55%
					Sleepiness	41–66%	42–52%	Induration	47–57%	29–48%
Study 7	[31]	Phase II open label 4CMenB (three doses: baseline, 2 months and 6 months) MenACWY-CRM 1 month later	Italy, Germany	At-risk adults aged 18–50 years (N = 54)	Solicited AEs across all vaccinations after ≥ 1 dose
					Systemic			Local
						4CMenB	MenACWY-CRM		4CMenB	MenACWY-CRM
					Malaise	30–52%	28%	Pain	95–99%	25%
					Myalgia	28–48%	12%	Erythema	42–55%	22%
					Headache	28–42%	22%	Induration	42–58%	12%
					Fever	6%	5%
Study 8	[29]	Phase II open label 4CMenB (three doses: baseline and after 2 and 6 months) + MenACWY-CRM (baseline)	UK	At-risk adults aged 18–65 years (N = 38)	Solicited AEs across all vaccinations
					Systemic			Local (after each visit)
						4CMenB + MenACWY-CRM (BL)	4CMenB (doses 2/3)		4CMenB‡	MenACWY-CRM
					Headache	38%	16–18%	Pain	95–100%	21%
					Nausea	26%	14–18%	Induration	41–47%	5%
					Fever	<5%	5–7%	Erythema	19–42%	5%
Study 9	[36]	Phase I 4CMenB (three doses) rMenB + OMV (Norway) rMenB	Switzerland	Adults aged 18–40 years (N = 70)	Solicited AEs across all vaccinations
					Systemic			Local
						4CMenB	rMenB ± OMV		4CMenB‡	rMenB ± OMV
					Myalgia	85%	75–90%	Injection site pain	100%	85–100%
					Headache	58%	45–60%	Induration	68%	50–58%
					Chills	50%	20–65%	Erythema	39%	20–42%
					Fever	12%	0–5%

^*DtaP, IPV, hepatitis B plus Hib and PCV7.

^†DtaP, IPV, hepatitis B plus Hib, PCV13, and MMRV.

^‡Site after any vaccination dose of 4CMenB.

4CMenB, 4-component serogroup B meningococcal vaccine; AE, adverse event; BL, baseline; DtaP, diphtheria-tetanus-acellular pertussis; Hib, Haemophilus influenzae type b; ic, intercalated (RV given separately at 3, 5, and 7 months rather than concomitantly); IPV, inactivated polio; MenACWY-CRM, quadrivalent serogroups A, C, W, Y-cross-reactive material 197 conjugate meningococcal vaccine; MenC, meningococcal serogroup C; MMRV, measles-mumps-rubella-varicella; OMV, outer membrane vesicle; PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; Ref, reference; rMenB, serogroup B meningococcal vaccine incorporating recombinant antigens; RV, routine vaccines.

Table 2. Summary of key safety findings from real-world surveillance and outbreak studies.

Study	Ref	Country	Study population	Key safety data		Summary of findings
Prospective surveillance safety study after ~ 3 million doses of 4CMenB, including co-administration (2015–2017)	[46]	UK	Infants aged 8 weeks, 16 weeks, 12 months (N = 1.29 million)	N = 902 suspected adverse reaction reports		No safety concerns were found Vaccine was well accepted by parents and 95% received their second dose 4CMenB introduction did not reduce compliance with other routine vaccinations Safety assessment indicates a favorable benefit–risk profile for 4CMenB
				Systemic	Fever (40%, of which 37% was in infants aged 8 weeks, 13% in those aged 12 weeks, and 17% in those aged 16 weeks) Similar rates of seizures (6%) within 7 days of routine immunization seen in the periods before and after 4CMenB introduction
				Local	Injection site or local skin reaction (41%) with a persistent local mass/nodule seen in ~20% of cases
PMS study of 4CMenB (93% co-administered) in routine care focused on seizures (2015–2018)	[47]	UK	Children aged 1–18 months (N = 107,231)	AEs after 194,929 doses (primary outcomes were seizures, febrile seizures, and Kawasaki disease). Adjusted incidence rate ratios (all 4CMenB exposures): Seizures: 1.43 (95% CI 1.02, 2.02) Febrile seizures: 1.72 (95% CI 1.0, 2.75) Kawasaki disease: ND (insufficient cases)		Study showed few cases of the primary outcomes after vaccinations, including 4CMenB, with an increased risk of seizures and febrile seizures (not attributable to specific vaccination)
Population-based short-term active AE surveillance after 4CMenB vaccination, including co-administration (2014–2015)	[48]	Canada	Aged ≤20 years (N = 59,098)	Reported AEs (solicited for fever) following Doses 1 and 2		Reactogenicity profile was consistent with that seen in clinical trials, with no unexpected AEs seen Acceptable safety and risk-benefit based on short-term data in view of high regional need for vaccination against serogroup B meningococcal disease
				Systemic	Fever in 11% (Dose 1) and 13% (Dose 2); 0.6% reported a temperature > 40°C (highest incidence in infants <2 years old); in children aged <10 years, >2 doses of acetaminophen prophylaxis significantly reduced fever incidence on Days 1–2 after Doses 1 and 2
				Local	Injection site reaction in 3–4% Malaise in 3–5%
PMS study (2013–2016) after 4CMenB vaccination	[49]	Germany	All ages (N = 664)	Spontaneous reporting of N = 1960 AEs over all case reports		The established safety profile from clinical studies was confirmed in the spontaneous reports, with no new safety issues identified
				Systemic	Fever in 39% of infants and toddlers, 25% of children, 12% of adolescents, and 6% of adults Headache in 0% of infants and toddlers, 28% of children, and 40–50% of adults and adolescents
				Local	Higher PRRs for local reactions with 4CMenB vs other vaccines: injection site pain (3.88 vs 0.68–1.02), induration (7.89 vs 1.26–1.92), swelling (3.5 vs 1.54–2.04), and site pain (3.88 vs 0.68–1.02)
Surveillance and outbreak report; 4CMenB vaccination (2016)	[50]	France	Aged 2 months to 24 years (N = 2222)	N = 152 reports of AEs after 4062 first doses and 1840 second doses (parent and GP data collection): AE incidence was low (309 AEs reported, with only 4 considered medically relevant) – none classed as severe by WHO criteria		Tolerance of 4CMenB was considered good during the campaign AEs conformed with the Summary of Product Characteristics, and no SAEs were seen Overall, the safety profile was reassuring as this was the first use of 4CMenB in a vaccination campaign in France
				Systemic	Not reported
				Local	81% (local or loco-regional reaction)
Surveillance and outbreak report; 4CMenB vaccination (2015)	[51]	US	Aged 17–21 years (N > 5000)	Passive collection of AEs after 9853 4CMenB doses: One SAE possibly related to 4CMenB (rhabdomyolysis)		No concerning patterns of AEs following vaccination were observed
Post-licensure passive surveillance system case series (2015–2018)	[52]	US	Aged 10–25 years	N = 1867 reports after 5.6 million doses (332 per million) 40% involved co-administration Majority (96%) of reports were non-serious		No new safety issues Large majority were non-serious and consistent with clinical studies and package insert
				Systemic	Most common were pyrexia (16%) and headache (16%)
				Local	Most commonly injection site pain (22%); disproportionate reporting of injected limb mobility decreased secondary to injection site reactions
Post-marketing surveillance following 4CMenB alone or co-administered (2014–2019)	[53]	Italy	Median age of people with AE was 30 months (range 2–394 months)	N = 214 spontaneous reports of AEs after 807,446 doses, of which 58 were SAEs and 31 had a consistent causal association with vaccination		Good safety profile reported in a large population after mass vaccination with 4CMenB
				Systemic	Fever/hyperpyrexia reporting rate 12.9 (2.6 serious/causal) × 100,000 doses
				Local	Injection site reactions reporting rate 17.0 (0.4 serious/causal) × 100,000 doses
South Australian Vaccine Safety Surveillance System (2017–2018)	[45]	South Australia	Median age 16 years (N = 30,522)	N = 193 AEs in 187 students after 58,637 doses of 4CMenB (reporting rate 0.33% [95% CI 0.28, 0.39]) Nine SAEs reported – all were considered either possibly or probably related to vaccination (product or procedure) o Two medically significant (frozen shoulder, fever/malaise/raised liver enzymes) o Seven hospitalizations (dehydration, fever/malaise, vasovagal episode, biphasic anaphylaxis, bilateral central scotoma, type 1 diabetes, immunization stress-related response)		Reporting rates provided real-world evidence of the safety of 4CMenB in this age group
				Systemic	Most common were headache (99/193 [51%]) and nausea (61/193 [32%])
				Local	Most common was injection site reaction (126/193 [65%])

Note: 4CMenB, 4-component serogroup B meningococcal vaccine; AE, adverse event; CI, confidence interval; GP, general practitioner; ND, not determined; PMS, post-marketing surveillance; PRR, proportional reporting ratio; SAE, serious adverse event; WHO, World Health Organization.

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