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

ABSTRACT

Introduction

Neisseria meningitidis causes invasive meningococcal disease and, globally, significant morbidity, with serogroup B (MenB) being the most common cause of endemic disease and outbreaks in several regions. Extensive use of the four-component serogroup B meningococcal vaccine (4CMenB; Bexsero, GSK) and its inclusion in immunization programs in several countries have generated substantial safety data during the 9 years since its first authorization in 2013.

Areas covered

4CMenB safety data from clinical trials and post-marketing surveillance studies (2011 to 2022), and spontaneously reported adverse events of medical interest from the GSK global safety database. We discuss these safety findings in relation to the benefit of 4CMenB vaccination and implications for further enhancing vaccine confidence.

Expert opinion

4CMenB has been consistently well tolerated across clinical trials and post-licensure surveillance studies, despite a higher incidence of fever reported in infants than with other pediatric vaccines. Surveillance data have not identified any significant safety issues, consistent with an acceptable safety profile of 4CMenB. These findings highlight the need to balance the risk of relatively common, transient, post-immunization fever with the benefit of affording protection that reduces the risk of uncommon but potentially fatal meningococcal infection.

Plain Language Summary

The four-component serogroup B meningococcal vaccine 4CMenB (Bexsero®, GSK) was licensed in 2013 and has acquired substantial safety evidence through clinical trial and real-world data. Availability of real-world and clinical 4CMenB safety evidence is important to help address vaccination hesitancy. This comprehensive review of safety data, from 9 years of 4CMenB use including recent data from the real world, shows no significant safety issues in a variety of age groups. Data show that transient fever may occur after vaccination. Invasive meningococcal disease, although rare, can be life-threatening. Abundant safety data from this review can help reassure individuals and healthcare providers on the use of 4CMenB.

KEYWORDS:

• 4CMenB
• clinical trials
• meningococcal serogroup B vaccine
• safety
• surveillance

1. Introduction

Invasive meningococcal disease (IMD), the most significant and serious consequence of infection with the bacterium Neisseria meningitidis, is a major cause of morbidity and mortality around the world [1,2]. The case fatality rate of IMD ranges from 4% to 20% (the pooled overall rate is 8%) and is dependent on age and serogroup, being higher in adolescents and young adults than in infants [3]. Sequelae that can be serious and lifelong, including limb amputations and cognitive impairment, may be seen in up to 20% of survivors [1,2,4–6].

Meningococcal serogroups are defined by the antigenic structure of their polysaccharide capsule, and six serogroups (A, B, C, W, X, and Y) represent the most frequent causes of IMD [7]. The epidemiology of IMD is unpredictable; currently, meningococcal serogroup B (MenB) is an increasingly common cause of endemic disease and outbreaks in Europe, Australia, and North America. In the United States (US), 60% of IMD cases in children aged <5 years are caused by MenB [8]; in Europe, MenB accounts for 51% of cases across all age groups below 65 years [9]; and MenB is also prevalent in Latin America, particularly among infants [2].

Immunization programs with protein–polysaccharide conjugate vaccines have been used for several decades to control IMD caused by serogroups A, C, W, and Y. However, the capsular polysaccharide of MenB is poorly immunogenic in humans, which necessitated the development of vaccines based on subcapsular, surface-expressed proteins [7,10,11]. The four-component MenB vaccine, 4CMenB (Bexsero; GSK), was developed using reverse vaccinology based on whole-genome sequencing and comprises recombinant MenB antigens that are conserved across strains and induce bactericidal antibodies [11,12]. Another vaccine, MenB-FHbp (Trumenba; Pfizer), which contains recombinant-derived Factor H binding protein derived from two representative strains, is also available [10].

4CMenB was approved in the European Union in 2013 for individuals aged ≥2 months and in the US in 2015 for individuals aged 10–25 years [13,14]. The vaccine is now approved in >50 countries (GSK, data on file). MenB-FHbp was approved in the US in 2014 for individuals aged 10–25 years and in Canada (aged 10–25 years), Australia (aged ≥10 years), and Europe (aged ≥10 years) in 2017 [15–18]. 4CMenB is included in routine infant (aged ≤12 months) immunization programs in 10 European Union countries, and is the only MenB vaccine used in infants in the region [19–21]. The implementation of 4CMenB vaccination in national or regional immunization programs has had a substantial impact on MenB disease burden across several countries, with reductions in case numbers of 71–100% in vaccine-eligible populations after follow-up periods of 2–5 years [22–27]. Reported vaccine effectiveness estimates from five countries range from 59% to 100% in infants, and from 50% to 100% in children and adolescents [25].

Here, we report the results of a comprehensive review of 4CMenB safety data from clinical trials conducted globally in approximately 9000 individuals, including infants and adolescents [28–37], and data from post-marketing active and passive surveillance for adverse events (AEs) following vaccinations carried out over the 9 years since its licensure in 2013.

2. Methods

PubMed and Embase searches encompassing publications from 2011 to 2022 were carried out using the search query terms described in Appendix 1. In addition, spontaneously reported AEs of medical interest following 4CMenB vaccination, as of September 6, 2022, were extracted from the GSK global safety database as described in Appendix 1.

3. Results

From a total of 1790 references, we identified 229 references for potential review and inclusion in this analysis, of which 88 are reviewed herein.

3.1. Safety of 4CMenB in clinical trials

3.1.1. Infants and children

In infants and children aged <2 years, the most common local and systemic adverse reactions observed in clinical trials were injection site tenderness and erythema, fever, and irritability (Table 1) [28,30,32,33,37]. Data from four Phase II and III clinical trials conducted in >5000 infants where 4CMenB was co-administered with routine vaccines (Studies 1, 2, 5, and 6; Table 1) showed that post-vaccination fever is more frequent than for routine vaccines alone, including pertussis-containing vaccines and pneumococcal conjugate vaccine (PCV) [28,30,33,37]. A randomized Phase III study conducted in 750 infants (Study 3, Table 1) demonstrated a lower incidence of fever (18–25% [17–26% when 4CMenB is combined with MenACWY-CRM]) [32] than other Phase III studies (44–77%) [28,37]. However, Study 3 (Table 1) differed from other Phase III trials in that the infants were older (the series started at 3 months rather than 2 months) and 4CMenB was co-administered with MenACWY-CRM rather than pertussis-containing vaccines or PCV, which are known to exacerbate the febrile response [32,38]. In a large (N = 1885) multicenter Phase II study (Study 5, Table 1) in infants, fever was seen frequently following 4CMenB vaccination alone (26–41%) and even more frequently (44–62%) when it was co-administered with routine vaccines (including in an accelerated schedule); rates with routine vaccines alone were 23–36% [30]. In Study 5, hospital admission due to fever within 2 days of vaccination rarely occurred (six cases from 1885 infants randomized into intervention and control groups), and there was one case of febrile seizure 2 days after the second 4CMenB dose [30].

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.

In two pivotal Phase III trials (Studies 1 and 2, Table 1), healthy infants received three doses of 4CMenB at 2, 4, and 6 months, and a booster at 12 months. Fever was commonly reported in both studies, where peak temperatures were noted to have occurred within the first 6 hours after vaccination [28,37]. Peak temperatures returned to normal within 24–48 hours in Study 1 [37]. In Study 1, which included open-label (n = 2627) and observer-blind (n = 1003) phases, fever was twice as common in infants aged 2–6 months who received 4CMenB together with routine vaccines (diphtheria-tetanus-acellular pertussis [DTaP], inactivated poliovirus, hepatitis B plus Haemophilus influenzae type b, and seven-valent pneumococcal vaccine) than in those who received routine vaccines alone or together with the meningococcal serogroup C (MenC) vaccine (65.3% vs 32.2% and 33.7%) [37]. In Study 1, antipyretic use was more frequent (93% [2302/2478]) in individuals receiving 4CMenB co-administered with routine vaccines than in those receiving routine vaccines alone (71% [471/659]). In the observer-blind portion of Study 1, medical attention for fever was sought for 5.3% of infants in the 4CMenB plus routine vaccines group and 2.8% of infants in the routine vaccines only group, whereas in the open-label part of the study, when parents were aware which vaccine was administered and were able to anticipate and manage fever without medical intervention, these values were lower (1.4% vs 1.8%, respectively) [37]. After a fourth (booster) dose of 4CMenB alone at 12 months in 4CMenB-primed children, the frequency of fever within 6 h was similar (31–32%) to that reported when 4CMenB was given with the measles-mumps-rubella-varicella (MMRV) vaccine, although this group displayed the characteristic increase in temperature associated with MMRV, which peaks 9 days after vaccination [37]. Overall, fever was less common in children (aged ≥12 months) who received a booster dose in Study 1 (32% in children aged 12 months following a 4CMenB booster dose within 6 h of vaccination compared with 65% of infant 4CMenB recipients), with no documentation of high fever (>40°C) in those who received 4CMenB alone [37].

The effect of prophylactic antipyretics, such as acetaminophen (paracetamol), on the reactogenicity of routine infant vaccines and 4CMenB vaccine was evaluated in a randomized Phase II study (Study 6, Table 1) [33]. Prophylactic acetaminophen was shown to reduce post-vaccination reactions by 51–65% without compromising immunogenicity, and medically attended visits were rare in this study. Post-vaccination fever was shown to be transient, generally resolving 24–48 hours after administration [33].

Although an increased risk of fever when 4CMenB is co-administered with routine vaccines has been established [13], one study analyzing data from three European randomized clinical trials [30,37] introduced an interaction effect to statistically analyze the incidence of AEs across separate visits versus co-administration [39]. When such an interaction was accounted for in the analysis of data from >5000 infants in the three trials, the cumulative incidence of fever was less with co-administration of 4CMenB and routine vaccines (76%) compared with separate administration (86%). The same study also showed that those with a history of reactogenic AEs were at a significantly higher risk of presenting with the same AE with subsequent vaccinations; however, severity was not usually increased [39].

Febrile seizures were rarely reported following 4CMenB in the primary Phase III studies; the only two cases that occurred were considered to probably be related to 4CMenB by the investigator (where one was a complex febrile seizure case in a child with an underlying neurological condition) [37]. Febrile seizures were not reported in the randomized Phase III Study 2 (N = 225) [28].

Systemic reactions other than fever occurring within 7 days of any dose, including irritability, sleepiness, and unusual crying, were more frequent in infants aged 2–6 months who received a primary series of 4CMenB with routine vaccines, compared with routine vaccines alone or routine vaccines plus MenC (Study 1, Table 1) [37]. The most frequently reported solicited systemic AE in Study 2 was irritability in both the 4CMenB plus routine vaccines and the routine vaccines groups (Table 1) [28].

Mild-to-moderate local reactogenicity in infants has been observed across Phase II and III clinical trials [28,30,32–34,37]. In Study 1, the incidence of local reactions was higher with 4CMenB versus routine vaccines alone in infants aged 2–6 months (Table 1) [37]. The most frequent reaction to 4CMenB plus other routine vaccines was tenderness (87% vs 53–59% for routine vaccines only), which was severe (i.e. crying when moved) in 29% of cases (vs 6–8% for routine vaccines only) [37]. Pooled reactogenicity profiles indicated that injection site reactions were most frequent on the day of vaccination and decreased the next day. Erythema, induration, and swelling were frequently reported, but <1% were severe. In Study 1, booster doses of 4CMenB in children aged 12 months elicited lower occurrences of all injection site reactions. Local and systemic reactions common in infants, such as tenderness, erythema, and irritability, were less frequent following a booster dose compared with the primary 4CMenB plus routine vaccines (e.g. irritability was 68–73% vs 93% in the primary series) [37].

In children aged 35 months to 12 years, safety profiles were similar between booster and catch-up groups, but solicited local and systemic AEs tended to decrease with subsequent catch-up doses [40]. In Phase II (Study 5) and Phase III (Study 2) trials of 4CMenB and routine vaccines in healthy infants, severe erythema, swelling, or induration at any vaccination sites were rare (<1%), but local pain or tenderness were more common after a dose of 4CMenB compared with control vaccines (local erythema 36–70% vs 4–58%; Table 1) [28,30]. In Study 3 in infants, solicited local reactions were all higher in the 4CMenB alone and concomitant (with MenACWY-CRM) groups, compared with the MenACWY-CRM alone group (tenderness: 60–70% for 4CMenB and 62–68% with 4CMenB plus MenACWY-CRM vs 27–31% for MenACWY-CRM alone) [32]. The incidence of these solicited local reactions did not increase with subsequent vaccinations in any of the groups (Table 1), and both 4CMenB and MenACWY-CRM were well tolerated when either co-administered or administered alone in infants; in addition, no safety issues were observed [32].

A meta-analysis of randomized trials [41] identified higher rates of local reactions with 4CMenB compared with routine vaccinations (e.g. injection site pain 74% with 4CMenB vs 52% for an investigational three-protein recombinant MenB vaccine and 54% for control vaccines), but these have generally been mild-to-moderate and short-lasting [41,42]. Overall, this analysis of published studies found that the incidence of potentially vaccine-related acute serious AEs (including those that are life-threatening or require hospitalization) reported in those receiving 4CMenB (5.4 per 1000 individuals) was higher than seen after routine vaccines (1.2 per 1000 individuals). The most frequently reported serious AE was febrile convulsions (seven events after vaccination with 4CMenB [n = 7209 over 13 datasets] and one after control vaccine [n = 1640 over 8 datasets]). The authors concluded that 4CMenB had an acceptable short-term safety profile [41].

Across clinical trials, there have been rare reports of Kawasaki disease, an acute vasculitis that primarily affects children aged <5 years, among infant recipients of 4CMenB [30,37]. There were two confirmed and one unconfirmed case in Phase III Study 1, with no episodes occurring after the booster dose at 12 months [37]. Two cases were reported in the Phase II Study 5, one of which was considered by the reporting investigator to be possibly related to 4CMenB [30]. The number of cases of Kawasaki disease in these studies was too small for a comparison against the background incidence based on clinical trial data alone, requiring much larger samples in the real-world setting (data discussed in the next section).

There were no deaths defined as potentially vaccine-related in 13 clinical trials (N > 7000) [41]. No cases of sudden infant death syndrome (SIDS) – defined as death within the first 2 years of life and without etiology after autopsy [43] – were reported in Phase II or III trials (Studies 1–3, 5, 6) carried out in infants [28,30,32,33,37].

3.1.2. Adolescents and adults

In a Phase II/III study in adolescents (Study 4, Table 1), the most commonly reported systemic reactions were malaise (51% vs 30%) and headache (42% vs 27%) in vaccine versus placebo groups, respectively [34]. This study demonstrated that, compared with the rates reported in infants, fever occurs infrequently in adolescents (4%) [34] and at-risk adults (Study 7; Table 1) [31], rarely requiring medical attention (<1%) [34] and with antipyretic/analgesic therapy being sought infrequently (9–19%) [31]. Similarly, in a Phase II study (Study 8, Table 1) of 38 adult, at-risk, healthy laboratory workers receiving 4CMenB co-administered with the MenACWY-CRM vaccine, the most common solicited systemic reactions were nausea or headache, whereas fever was rare (Table 1) [29]. In this and other studies, local reactions of pain, erythema, and induration were more frequent after 4CMenB than MenACWY-CRM (Studies 7 and 8) or placebo (Study 4). For example, in Study 8, local reactions of erythema, pain, and induration were up to eight times higher following 4CMenB compared with MenACWY-CRM injection (Table 1), and injection site reaction was the most common solicited systemic reaction related to 4CMenB (21%) [29]. A similar safety profile for 4CMenB was seen in a randomized Phase II study (N = 500) comparing an investigational pentavalent MenABCWY vaccine with 4CMenB plus MenACWY-CRM in adolescents and young adults aged 10–25 years [44].

A Phase IV cluster-randomized controlled trial of senior high school students who were vaccinated (N = 30,522) had the potential to provide a clearer representation of real-world safety compared with the solicited AE rates from Studies 4, 7, and 8 by adopting a spontaneous reporting system for AEs following immunization. In this study, self-reported fever following 4CMenB was rare (<1%) and the majority of fevers were short-lived [45]. The study showed that other systemic AEs following immunization, such as chills, headache, malaise, and lethargy, were also uncommon and were resolved by the time of follow-up [45]. In this population of adolescents, injection site reactions that manifested as pain, swelling, or tenderness were the most common spontaneously reported AEs following 4CMenB vaccination (Table 2). Injection site reactions accounted for 65% (126/193) of all AEs reported, with an incidence (pain, swelling, tenderness) of 0.24% after dose 1 and 0.12% after dose 2 [45]. Severe local reaction was rarely reported and the hospitalization rate per dose administered was 0.01%; the overall reporting rate provided reassuring evidence of 4CMenB safety and indicated good tolerability in this age group [45].

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.

A prospective Phase IV study evaluated the safety of 4CMenB in 72 adult patients in special situations (including anatomic and functional asplenia, immunodeficiency with high risk or prior history of IMD) and found that an acceptable safety profile was seen despite a higher frequency of fever (12.5%) than expected from previous studies in healthy individuals [54].

3.2. Safety data in real-world settings: surveillance and observational studies

3.2.1. Infants and children

A comprehensive prospective surveillance in the UK has assessed the safety of 4CMenB over a 20-month period, during which approximately 3 million doses were given to an estimated 1.3 million infants (aged 2–18 months) as part of the national immunization program (NIP) [46]. The study was based on the UK Yellow Card Scheme and Clinical Practice Research Datalink, a passive safety surveillance system through which healthcare professionals and members of the public can report a spontaneous suspected adverse reaction to any vaccine or medicinal product directly to the Medicines and Healthcare products Regulatory Agency by post, online, or via a smartphone application. During the surveillance period, 902 reports were received, equivalent to 0.3 per 1000 doses administered, which was lower than expected (based on background incidence and numbers vaccinated), potentially due to raised awareness of possible reactogenicity and acetaminophen use as prophylaxis [46]. The most frequently reported AEs were injection site reaction (41%) and fever (40%) (Table 2) [46]. Most reports of acute febrile reactions, local reactions, and other suspected adverse reactions were expected and typical of Yellow Card reporting for routine vaccines administered to children in the same age group. The only unexpected finding in this surveillance was the high proportion of local reactions (160/366 [44%]) described as a persistent injection site nodule, usually without other local symptoms [46].

Another surveillance study, based on a general practitioner database in the UK [55], showed a small increase in infant fever consultations following the introduction of 4CMenB in the NIP. When compared with the 2 years prior to vaccine introduction, all-cause fever rates increased 1.6-fold in infants eligible for the first dose of 4CMenB (at 7–10 weeks of age) and 1.5-fold in those eligible for the second dose (at 15–18 weeks of age) [55]. The authors noted that other factors may have influenced higher consultation rates at that time, including a heightened threshold of concern based on limited experience with the new 4CMenB vaccine program at the time [55]. Febrile seizures were reported to be rare in the same UK study in the 3-year period of vaccination, with only 12 cases recorded in the general practitioner database, acknowledging the fact that for seizures, parents are usually more likely to take their infants to hospital emergency departments than contact primary care services [55]. In two retrospective reviews of hospitalized preterm infants in the UK, 4CMenB was associated with fever and occasionally with undertaking of investigations for sepsis and administration of intravenous antibiotics [56,57]; however, related AEs occurring within 48 hours were attenuated with routine prophylactic acetaminophen, and the administration of antibiotics was reduced [56]. Retrospective reviews of UK hospital records showed an increase in healthcare presentations (accident and emergency departments and subsequent admissions) with AEs following introduction of 4CMenB in the UK NIP [58–60]. In one study, it was reported that after 4CMenB introduction, the number of infants presenting with routine-vaccination-related AEs had increased from 1/972 doses to 1/295 doses at the 2-month immunization episode and from 1/7043 to 1/881 at the 4-month episode, requiring more frequent attendance by clinicians [60].

Real-world surveillance studies have also provided greater insight into the safety profile of the vaccine and reassuring data on rarer AEs reported in clinical studies. In a large UK study [46], there were 55 reports of seizure (6% of all AE reports) compared with an expected 137 seizure reports within 7 days of the first dose, an expected 78 after the second dose, and an expected 199 after the booster dose based on background (pre−4CMenB) incidence of seizures, translating to an age-adjusted observed-to-expected ratio of 0.13 (95% confidence interval [CI] 0.10, 0.17). Rates of seizures within 7 days of routine immunization were reported to be similar in the periods before and after 4CMenB introduction (10.6 per 100,000 vs 13.8 per 100,000 at 2 months of age [incidence rate ratio (IRR) 1.3]; 6.7 per 100,000 vs 10.2 per 100,000 at 4 months of age [IRR 1.53]; 34.1 per 100,000 vs 43.1 per 100,000 at the 12-month dose [IRR 1.26] for the periods before and after 4CMenB introduction, respectively) [46]. An observational study (2015–2018), including more than 100,000 children aged 1–18 months within the routine UK immunization program, based on The Health Improvement Network (THIN) database patient records (electronic primary healthcare records) reported adjusted incidence rate ratios (outcome specific risk period compared with baseline period) of 1.43 (95% CI 1.02, 2.02) for seizures and 1.72 (95% CI 1.08, 2.75) for febrile seizures [47]. These estimates represent a summary risk for these AEs as 4CMenB was co-administered with other routine vaccines in the majority of the infants (93% of study subjects), so the observed increase in the risk of seizures and febrile seizures could not be attributed to any specific vaccine by the authors [47].

The surveillance in the UK also reported to have observed no evidence of an increased risk of Kawasaki disease after the first 3 million doses of 4CMenB administered to infants during 2015–2017 [46]. There were only three reports of Kawasaki disease (<1% of all reports) among 1.4 million vaccinated infants and based on a conservative background incidence of Kawasaki disease an observed-to-expected ratio amounted to 1.40 (95% CI 0.29, 4.08) with wide confidence intervals [46]. Results from the THIN database study supported these findings, reporting that there were insufficient Kawasaki cases to estimate a risk ratio (≤5 episodes in the primary risk period of 1.6 person-years and in the baseline period of 8.0 person-years) [47]. A limitation of this study was the unfeasibility of assessing potential causality of events, as co-administration of 4CMenB with other routine vaccinations was the foremost routine practice [47]. A self-controlled case series analysis of over 500 cases from a national database in England also showed no evidence of an increased risk of Kawasaki disease specifically related to 4CMenB vaccination, with a relative incidence of 1.03 (95% CI 0.51, 2.05) after the first or second 4CMenB doses and 0.64 (95% CI 0.08, 5.26) after the third dose [61].

In the UK surveillance study of 4CMenB, there were very few (three) cases of SIDS within 3 days following vaccination in children aged 2–4 months (observed-to-expected ratio 0.44 [95% CI 0.12, 1.14]) [46]. Although SIDS typically occurs during a vaccination-intensive period in infancy, a causal association between routine vaccinations and SIDS has been refuted in several studies [43]. Nonetheless, surveillance studies monitor SIDS, and the UK study has examined this for 4CMenB and showed that the incidence of SIDS was within the projected incidence level, with no evidence of an increased risk [46].

A large-scale population-based surveillance study conducted in Quebec, Canada, followed the mass vaccination of almost 60,000 individuals from 2 months to 20 years of age in response to the high regional incidence of IMD caused by MenB [48]. With the exception of fever, the 7-day reactogenicity profile was consistent with the clinical trial data (Table 2). Rates of fever were lower than reported in clinical trials, probably attributable to less rigorous non-systematic monitoring or reporting of fever and wide use of prophylactic acetaminophen, which was recommended especially for infants; antipyretic use was reported for 90% of children aged <2 yearsand nearly 65% of older children. The overall vaccination coverage of two doses of 4CMenB was high (77%) and the vaccine safety was concluded to be acceptable [48].

An active post-marketing surveillance identified two cases of febrile seizures within 7 days of immunization (both requiring hospitalization) among 49,000 vaccinees in Quebec, Canada [62]. In the same ecological study, four cases of nephrotic syndrome were also reported. The nephrotic syndrome cases occurred in children aged 2–5 years within 12 months post-vaccination, with the hospitalization rate among children aged 1–9 years in the vaccinated region estimated to be 3.6-fold higher than the rest of the province for the same period and 8.3-fold higher than during the 8 years prior to the immunization program [62]. Prompted by these cases reported in Canada, another study in the UK analyzed infant hospital admission data from 2005 to 2019 to compare nephrotic syndrome cases before and after the introduction of the 4CMenB vaccine in the UK program. This study found no evidence of an increased risk of nephrotic syndrome, with incidence ratios of 0.81 and 1.18 for the 6–11 months and 12–17 months age groups, respectively [63]. Although the nephrotic syndrome cases seen in Canada were in children older than those who were routinely vaccinated in the UK, an increased risk would be expected to be detected based on the large number of doses administered in the UK [63]. The observations in the Canadian study were therefore not confirmed in the large UK study, and moreover, the causative mechanisms of nephrotic syndrome have not been established yet [62,64].

A post-marketing passive surveillance study in Germany found that fever was reported more frequently in infants and toddlers following immunization compared with older individuals (Table 2), consistent with age-specific background incidence rates [49]. In the same study, the proportional reporting ratio (PRR) for febrile convulsion (n = 12 [0.6%]; PRR 5.51) was consistent with the increased PRR for pyrexia and clinical trial findings. In accordance with findings in the UK, only one case of Kawasaki disease was reported in the 3 years of German surveillance.

A post-marketing surveillance study in Italy after 807,446 doses of 4CMenB administered from 2014 to 2019 reported fever (reporting rate 2.6 per 100,000 doses) among the most frequently reported AEs, and neurological symptoms, of which hypotonic – hyporesponsive episodes were the most frequent (reporting rate 0.9 per 100,000 doses), as serious AEs with a causal association with immunization (Table 2) [53]. The reported incidence of fever was consistent with the known safety profile of 4CMenB documented in the Summary of Product Characteristics [13].

Overall, observational studies carried out in the UK, Germany, Italy, and Canada concluded that there were no safety issues identified after widespread use of 4CMenB in infants, confirming the safety data from the clinical trials [46,48,49,53]. These studies also reported finding no link between the 4CMenB vaccine and rarer AEs, such as febrile seizures and Kawasaki disease. Surveillance studies incorporating wider age ranges, beyond infants, have reported that injection site reactions (pain, swelling, induration) and malaise were the most commonly reported AEs following 4CMenB vaccination, with rates higher than those reported after vaccination with MenC or PCV (Table 2) [48–50].

A study of data on solicited AEs collected after vaccination, based on questionnaires in a clinical study in healthy (36% of participants) and high-risk (64% of participants) children with chronic medical conditions, reported that the incidences of AEs, including fever and local reactions, were lower than those reported in primary clinical trials [65]. Moreover, the occurrence of AEs was similar in healthy and high-risk children. Clinical testing of serum from children with complement deficiencies has been carried out to measure immune response levels before and after routine vaccination with 4CMenB, and within this study context no safety issues were reported among the participating healthy children or those with complement deficiency, further supporting the recommendation for 4CMenB vaccination for this indication [66].

3.2.2. Adolescents and adults

Post-marketing surveillance studies including adolescent and adult vaccinees have confirmed a lower incidence of fever in older individuals compared with infants [48,49]. There were higher PRRs for local reactions with 4CMenB compared with MenC and PCV across all age groups (Table 2) [49], although PCV is given only to those aged <2 years, potentially confounding comparisons of local reactogenicity across ages. Data from post-marketing surveillance studies are consistent with the known safety profile of 4CMenB, with no safety issues [48–50]. Age-related differences in AEs other than fever, such as headache (44% in adults and adolescents vs 28% in children and 0% [i.e. unable to be reported] in infants, in a German surveillance study) [49], were expected, due to limitations associated with self-reporting of symptoms in infant and very young children [49]. In a US epidemiologic study following an outbreak in New Jersey, no concerning patterns of AEs were identified among students aged 17–21 years, although one case of rhabdomyolysis – a potentially serious muscle-injury-related syndrome – was reported after a second dose and considered, by the reporting investigator, to be possibly related to the vaccine [51].

3.3. AEs of medical interest from GSK spontaneous reporting

From the time of 4CMenB licensure in 2013 until September 2022, >74 million doses of 4CMenB were distributed globally and GSK received 29,724 spontaneous safety reports during continuous monitoring, describing the occurrence of 72,140 AEs following 4CMenB vaccination (a dose-related AE reporting rate of <0.1%). Of these, SIDS, Kawasaki disease, and seizures (including febrile seizures) were considered AEs of medical interest (defined as events of scientific and medical significance for the product and pediatric vaccines in general) and assessed against relevant Brighton Collaboration (BC) definitions, as applicable [67].

3.3.1. Sudden infant death syndrome

Sixteen spontaneous reports of SIDS have been received following 4CMenB vaccination (0.03 reports per 100,000 doses). These cases were reported by healthcare professionals and concerned infants aged between 8 weeks and 16 months. In these reports, sudden death occurred within the 4 days following vaccination. Seven reports were assessed as BC Level 2–3 (probable and possible, respectively; defined in Appendix 2). Based on an analysis of all relevant reported information it was concluded that, despite the temporal relationship, SIDS reports presented either insufficient information to assess causality or included confounding factors, such as the co-administration of multiple vaccines on the same day.

3.3.2. Kawasaki disease

Eighty cases of Kawasaki disease (see Appendix 1 for search strategy) were reported spontaneously following 4CMenB vaccination (0.114 cases per 100,000 doses). Most cases were reported by healthcare professionals and referred to infants and children aged ≤11 years. In 38 reports, disease onset was within 10 days following vaccination, which is regarded as too short an interval for a disease that may be immune mediated. Five cases were assessed as BC Level 1 (definite; defined in Appendix 2) for Kawasaki disease [68]. In 33 reports, the outcome was reported as resolving, resolved, or recovered, and only 2 reported sequelae. Overall, all the reports of Kawasaki disease presented insufficient information for adequate medical assessment or included relevant confounding factors.

3.3.3. Seizures, including febrile seizures

Of the 869 spontaneous reports of seizure (see Appendix 1 for search strategy) following 4CMenB vaccination, 536 described the occurrence of febrile seizure (0.72 cases per 100,000 doses). Most cases concerned infants and children and were reported by healthcare professionals. In 447 reports, disease onset occurred within 10 days of vaccine administration; among these, 23 reports were assessed as BC Level 1–3 (definite, probable, and possible, respectively; defined in Appendix 2) for generalized convulsion. Most of these reports lacked key information for adequate medical assessment or presented relevant confounding factors.

4. Conclusion

In clinical trials of 4CMenB conducted in infants and children, the most common local and systemic adverse reactions are injection site reactions, together with fever and irritability, whereas malaise and headache are most common in adolescents and adults. Clinical trial data show a higher incidence of fever and local reactions in infants aged <6 months compared with other pediatric vaccines [28,30,33,37]. The incidence of potential vaccine-related acute serious AEs in those receiving 4CMenB is low, although pooled rates (per 1000 individuals based on a meta-analysis) are significantly higher than in those following routine vaccines. Despite this, the safety profile of 4CMenB is confirmed to be acceptable, including in vulnerable patient populations at higher risk of mortality and complications from IMD.

The occurrence of the few Kawasaki cases, initially identified as a possible concern based on pooled clinical trial datasets, was not shown to be linked to 4CMenB in the real-world studies; nonetheless, monitoring is ongoing [41,42,46]. Similarly, febrile convulsions have rarely been reported for recipients in the clinical development program, having similar incidence to that seen with other routine vaccines. Indeed, seizures and specifically febrile seizures (triggered by vaccine-induced fever) have been observed in routine childhood vaccine recipients; febrile seizures are the most common type of non-epileptic seizures following immunization [69]. These findings have been corroborated by post-marketing spontaneous reporting of AEs of medical interest as part of pharmacovigilance, although these data do not allow conclusions regarding potential causality.

Overall, pharmacovigilance data have provided valuable safety information that, when combined with data from observational studies, have confirmed the acceptable safety profile of 4CMenB in various age groups.

5. Expert opinion

Fever is a very common AE following 4CMenB immunization, especially in infants and children, and its frequency is increased following co-administration with other routine vaccinations. Several studies have shown either a lower than expected (based on background incidence and numbers vaccinated) reporting rate of AEs, including fever, or small increases in fever consultations for infants. Importantly, for 4CMenB, there is a need to balance the risk of relatively common, but transient, post-immunization fever (also seen with other pediatric vaccines) with the benefit of affording protection against an uncommon but severe disease that may result in death or lifelong debilitating sequalae [30]. Although there has been an impact on healthcare presentations with AEs following routine introduction of 4CMenB [58–60], parental education and awareness campaigns on expected post-vaccination fever could offer reassurance and may minimize their seeking healthcare assistance [60]. Several studies highlight that there is a need for further guideline development that might reduce the number of potentially unnecessary invasive investigations related to vaccine reactogenicity that may be performed in vaccinated infants with AEs following immunization [58,70,71]. This especially applies where local or regional guidance may result in a low threshold for further clinical investigation of the potential cause of infant fever. An appropriate pediatric dosage of acetaminophen is considered safe in infants, and guidance promoting its use has been issued by healthcare organizations, such as the UK NHS [72]. However, recommending bodies generally state that there is no need for major focus on the management of fever that can generally be regarded as a physiological signal rather than a direct illness [33].

Several countries recommend co-administration of 4CMenB with routine infant vaccines [21,73,74]. Although 4CMenB appears to be less reactogenic when administered separately [30], reactogenicity should be balanced against benefits of co-administration in terms of improved timeliness and vaccine uptake rates. In addition to the widespread recommendation for the administration of prophylactic acetaminophen, it is important to communicate the transient nature of reactogenicity to parents and vaccinees as an established element of routine immunization programs against this serious disease. It is notable that, in a discrete choice experiment, parents and adolescents preferred a mild fever over no fever following 4CMenB vaccination, and it was hypothesized that this was because they felt that this was evidence the vaccine was ‘working’ and were more concerned about the effectiveness of the 4CMenB vaccine than potential side effects [75].

In active and passive surveillance studies reviewed herein, no increase has been detected in the rates of AEs considered of significant medical interest, such as SIDS, Kawasaki disease, and seizures (including febrile seizures). It is particularly important that these continuous studies lessen any potential concerns related to these types of rare, but clinically significant, AEs for which uncertainty about incidence and causality could prove to be limiting factors in vaccination compliance. Overall, these post-implementation surveillance studies alleviate potential concerns about AEs, especially after the first dose, which otherwise may have led parents to avoid further vaccinations for their infants and compromise prevention from the disease.

Article highlights

• We carried out a comprehensive review of safety data from 9 years of 4CMenB use, including safety reported in clinical trials, post-marketing surveillance studies, and spontaneously reported adverse events of medical interest from the GSK safety database.

• 4CMenB was well tolerated across clinical trials and surveillance studies despite a higher incidence of transient fever in infants than seen with other pediatric vaccines.

• Surveillance data have not identified any significant safety issues in a variety of age groups, and are consistent with the known safety profile of 4CMenB.

• Invasive meningococcal disease, although rare, can be life-threatening. The data from this review should help to reassure patients and healthcare providers about the acceptable safety profile of 4CMenB.

Abbreviations

4CMenB	=	Four-component serogroup B meningococcal vaccine
AE	=	Adverse event
BC	=	Brighton Collaboration
BL	=	Baseline
CI	=	Confidence interval
DTaP	=	Diphtheria-tetanus-acellular pertussis
GP	=	General practitioner
GSKMQ	=	GSK MedDRA Query
Hib	=	Haemophilus influenzae type b
ic	=	Intercalated
IMD	=	Invasive meningococcal disease
IPV	=	Inactivated polio
MedDRA	=	Medical Dictionary for Regulatory Activities
MenACWY-CRM	=	Quadrivalent serogroups A, C, W, Y-cross-reactive material 197 conjugate meningococcal vaccine
MenB	=	Meningococcal serogroup B
MenC	=	Meningococcal serogroup C
MMRV	=	Measles-mumps-rubella-varicella
ND	=	Not determined
NIP	=	National immunization program
OMV	=	Outer membrane vesicle
PCV	=	Pneumococcal conjugate vaccine
PMS	=	Post-marketing surveillance
PRR	=	Proportional reporting ratio
PT	=	Preferred terms
rMenB	=	Serogroup B meningococcal vaccine incorporating recombinant antigens
RV	=	Routine vaccines
SAE	=	Serious adverse event
SIDS	=	Sudden infant death syndrome
SMQ	=	Standard MedDRA query
THIN	=	The Health Improvement Network
WHO	=	World Health Organization

Declaration of interest

WY Sohn, R Bekkat-Berkani, A Banzhoff, S Cenci, and V Abbing-Karahagopian are employees of the GSK group of companies and hold shares in the GSK group of companies as part of their employee remuneration. E Occhipinti is an employee of the GSK group of companies. G S Marshall has received consulting fees from GSK, Merck, Moderna, Pfizer, Sanofi, and Seqirus, and the University of Louisville has received contracts for vaccine clinical trials sponsored by GSK, Merck, Pfizer, Sanofi, and Seqirus, where G S Marshall was an investigator. H S Marshall is an investigator on investigational vaccine trials sponsored by Novartis, Pfizer, and Iliad. Her institution has received funding from industry, including GSK, Pfizer, and Sanofi-Pasteur for investigator-led vaccine research. She does not receive any personal payments from industry. J H Conway has received consulting fees from GSK, Merck, Moderna, Pfizer, and the University of Wisconsin, and has received contracts for vaccine clinical trials sponsored by Moderna, GSK, Sanofi, and AstraZeneca, where J H Conway was an investigator. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript.

Authors’ contributions

All authors participated in the development and review of the manuscript and approved the final version. The corresponding author had final responsibility to submit for publication. Drafts were developed by a professional publication writer according to the recommendations, documentation, and outline provided by the lead author.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Trademarks

Bexsero is a trademark of the GSK group of companies. Trumenba is a trademark of Pfizer Inc.

Acknowledgments

The authors thank Daniela Toneatto for her valued input and OPEN Health Communications (London, UK) for editorial assistance in the preparation of this manuscript, with financial support from GSK. This work has been presented in part at the European Society for Paediatric Infectious Diseases (ESPID) Annual Meeting 2023; 8–12 May 2023; Lisbon, Portugal and Online.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14760584.2023.2222015.

Additional information

Funding

GSK funded all costs associated with the development and the publishing of this manuscript. There were no personal payments to co-authors for their time or contribution.