Leaflet BEXSERO suspension for injection in pre-filled syringe
Indicated for: prevention of meningococcal disease
Route of administration: injectable
Substance: meningococcal group B vaccine (recombinant, adsorbed) (vaccine)
ATC: J07AH09 (Antiinfectives for systemic use | Bacterial vaccines | Meningococcal vaccines)
Risk of severe allergic reaction. Seek urgent medical help if serious symptoms occur.
This medicine is subject to additional monitoring.
Store in the refrigerator as instructed in the leaflet.
Store protected from light.
The group B meningococcal vaccine (recombinant, adsorbed) is used to prevent infections caused by Neisseria meningitidis serogroup B, a bacterium that can cause meningitis and septicemia. The vaccine contains recombinant proteins derived from serogroup B, which stimulate the immune system to produce specific antibodies against this serogroup.
The vaccine is administered intramuscularly, usually in two or three doses, depending on the patient's age and the recommended vaccination schedule. It is particularly indicated for infants, adolescents, and individuals at increased risk of infection.
Common side effects include pain at the injection site, fever, fatigue, and irritability. In rare cases, severe allergic reactions may occur.
The group B meningococcal vaccine (recombinant, adsorbed) is an essential preventive measure for reducing the incidence of meningococcal diseases caused by serogroup B, helping to protect vulnerable populations and prevent severe complications associated with these infections.
General data about BEXSERO
- Substance: meningococcal group B vaccine (recombinant, adsorbed)
- Date of latest medicines list: 01-06-2026
- Product code: W62936001
- Pharmaceutical form: suspension for injection in pre-filled syringe
- Quantity: 1
- Product type: Original
- Price: 493.24 RON
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Leaflet BEXSERO
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Contents of the package leaflet for the medicine BEXSERO suspension for injection in pre-filled syringe
1. NAME OF THE MEDICINAL PRODUCT
Bexsero suspension for injection in pre-filled syringe
Meningococcal group B Vaccine (rDNA, component, adsorbed)
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One dose (0.5 ml) contains:
Recombinant Neisseria meningitidis group B NHBA fusion protein 1, 2, 3 50 micrograms
Recombinant Neisseria meningitidis group B NadA protein 1, 2, 3 50 micrograms
Recombinant Neisseria meningitidis group B fHbp fusion protein 1, 2, 3 50 micrograms
Outer membrane vesicles (OMV) from Neisseria meningitidis group B 25 microgramsstrain NZ98/254 measured as amount of total protein containing the PorA P1.4 21 produced in E. coli cells by recombinant DNA technology2 adsorbed on aluminium hydroxide (0.5 mg Al3+)3 NHBA (Neisserial Heparin Binding Antigen), NadA (Neisseria adhesin A), fHbp(factor H binding protein)
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Suspension for injection.
White opalescent liquid suspension.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Bexsero is indicated for active immunisation of individuals from 2 months of age and older againstinvasive meningococcal disease caused by Neisseria meningitidis group B. The impact of invasivedisease in different age groups as well as the variability of antigen epidemiology for group B strains indifferent geographical areas should be considered when vaccinating. See section 5.1 for informationon protection against specific group B strains. The use of this vaccine should be in accordance withofficial recommendations.
4.2 Posology and method of administration
Table 1. Summary of posology
Intervals
Age at first dose Primary Immunisation between Booster
Primary Doses
Three doses each Not less Yes, one doseof 0.5 ml than 1 month between 12 and 15 months of
Infants, 2 months age with an interval of atto 5 months a least 6 months between the
Two doses Not less primary series and boostereach of 0.5 ml than 2 months dose b, c
Yes, one dose in the second
Infants, 6 months Two doses each Not less year of life with an intervalto 11 months of 0.5 ml than 2 months of at least 2 months betweenthe primary series andbooster dose c
Yes, one dose with an
Children, 12 months Two doses each Not less interval of 12 monthsto 23 months of 0.5 ml than 2 months to 23 months between theprimary series and boosterdose c
Children, 2 years A booster dose should beto 10 years considered in individuals at
Two doses each Not less continued risk of exposure to
Adolescents of 0.5 ml than 1 month meningococcal disease,(from 11 years) and based on officialadults* recommendations da The first dose should be given no earlier than 2 months of age. The safety and efficacy of
Bexsero in infants less than 8 weeks of age has not yet been established. No data are available.b In case of delay, the booster should not be given later than 24 months of age.c See section 5.1. The need for and timing of further booster doses has not yet been determined.d See section 5.1.
* There are no data in adults above 50 years of age.
Method of administrationThe vaccine is given by deep intramuscular injection, preferably in the anterolateral aspect of the thighin infants or in the deltoid muscle region of the upper arm in older subjects.
Separate injection sites must be used if more than one vaccine is administered at the same time.
The vaccine must not be injected intravenously, subcutaneously or intradermally and must not bemixed with other vaccines in the same syringe.
For instructions on the handling of the vaccine before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.
As with other vaccines, administration of Bexsero should be postponed in subjects suffering from anacute severe febrile illness. However, the presence of a minor infection, such as cold, should not resultin the deferral of vaccination.
Do not inject intravascularly.
As with all injectable vaccines, appropriate medical treatment and supervision should always bereadily available in case of an anaphylactic event following the administration of the vaccine.
Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-relatedreactions may occur in association with vaccination as a psychogenic response to the needle injection(see section 4.8). It is important that procedures are in place to avoid injury from fainting.
This vaccine should not be given to individuals with thrombocytopenia or any coagulation disorderthat would contraindicate intramuscular injection, unless the potential benefit clearly outweighs therisk of administration.
As with any vaccine, vaccination with Bexsero may not protect all vaccine recipients.
Bexsero is not expected to provide protection against all circulating meningococcal group B strains(see section 5.1).
As with many vaccines, healthcare professionals should be aware that a temperature elevation mayoccur following vaccination of infants and children (less than 2 years of age). Prophylacticadministration of antipyretics at the time of and closely after vaccination can reduce the incidence andintensity of post-vaccination febrile reactions. Antipyretic medication should be initiated according tolocal guidelines in infants and children (less than 2 years of age).
Individuals with impaired immune responsiveness, whether due to the use of immunosuppressivetherapy, a genetic disorder, or other causes, may have reduced antibody response to activeimmunisation.
Immunogenicity data are available in individuals with complement deficiencies, asplenia, or splenicdysfunctions (see section 5.1).
Individuals with familial complement deficiencies (for example, C3 or C5 deficiencies) andindividuals receiving treatments that inhibit terminal complement activation (for example, eculizumab)are at increased risk for invasive disease caused by Neisseria meningitidis group B, even if theydevelop antibodies following vaccination with Bexsero.
There are no data on the use of Bexsero in subjects above 50 years of age and limited data in patientswith chronic medical conditions.
The potential risk of apnoea and the need for respiratory monitoring for 48-72 hours should beconsidered when administering the primary immunisation series to very premature infants(born ≤ 28 weeks of gestation) and particularly for those with a previous history of respiratoryimmaturity. As the benefit of vaccination is high in this group of infants, vaccination should notbe withheld or delayed.
Kanamycin is used in early manufacturing process and is removed during the later stages ofmanufacture. If present, kanamycin levels in the final vaccine are less than 0.01 micrograms per dose.
The safe use of Bexsero in kanamycin-sensitive individuals has not been established.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Bexsero can be given concomitantly with any of the following vaccine antigens, either as monovalentor as combination vaccines: diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b,inactivated poliomyelitis, hepatitis B, heptavalent pneumococcal conjugate, measles, mumps, rubella,varicella, and meningococcal groups A, C, W, Y conjugate.
Clinical studies demonstrated that the immune responses of the co-administered routine vaccines wereunaffected by concomitant administration of Bexsero, based on non-inferior antibody response rates tothe routine vaccines given alone. Inconsistent results were seen across studies for responses toinactivated poliovirus type 2 and pneumococcal conjugate serotype 6B and lower antibody titers to thepertussis pertactin antigen were also noted, but these data do not suggest clinically significantinterference.
Due to an increased risk of fever, tenderness at the injection site, change in eating habits andirritability when Bexsero was co-administered with the above vaccines, separate vaccinations can beconsidered when possible. Prophylactic use of paracetamol reduces the incidence and severity of feverwithout affecting the immunogenicity of either Bexsero or routine vaccines. The effect of antipyreticsother than paracetamol on the immune response has not been studied.
Concomitant administration of Bexsero with vaccines other than those mentioned above has not beenstudied.
When given concomitantly with other vaccines Bexsero must be administered at separate injectionsites (see section 4.2).
4.6 Fertility, pregnancy and lactation
Insufficient clinical data on exposed pregnancies are available.
The potential risk for pregnant women is unknown. Nevertheless, vaccination should not be withheldwhen there is a clear risk of exposure to meningococcal infection.
There was no evidence of maternal or foetal toxicity, and no effects on pregnancy, maternal behaviour,female fertility, or postnatal development in a study in which female rabbits received Bexsero atapproximately 10 times the human dose equivalent based on body weights.
Breast-feedingInformation on the safety of the vaccine to women and their children during breast-feeding is notavailable. The benefit-risk ratio must be examined before making the decision to immunise duringbreast-feeding.
No adverse reactions were seen in vaccinated maternal rabbits or in their offspring through day 29 oflactation. Bexsero was immunogenic in maternal animals vaccinated prior to lactation, and antibodieswere detected in the offspring, but antibody levels in milk were not determined.
FertilityThere are no data on fertility in humans.
There were no effects on female fertility in animal studies.
4.7 Effects on ability to drive and use machines
Bexsero has no or negligible influence on the ability to drive and use machines. However, some of theeffects mentioned under section 4.8 “Undesirable effects” may temporarily affect the ability to drive oruse machines.
4.8 Undesirable effects
The safety of Bexsero was evaluated in 17 studies including 10 randomised controlled clinical trialswith 10 565 subjects (from 2 months of age) who received at least one dose of Bexsero. Among
Bexsero recipients, 6 837 were infants and children (less than 2 years of age), 1 051 were children(2 to 10 years of age) and 2 677 were adolescents and adults. Of the subjects who received primaryinfant series of Bexsero, 3 285 received a booster dose in the second year of life.
In infants and children (less than 2 years of age) the most common local and systemic adversereactions observed in clinical trials were tenderness and erythema at the injection site, fever andirritability.
In clinical studies in infants vaccinated at 2, 4 and 6 months of age, fever (≥ 38 °C) was reportedby 69% to 79% of subjects when Bexsero was co-administered with routine vaccines (containing thefollowing antigens: pneumococcal 7-valent conjugate, diphtheria, tetanus, acellular pertussis, hepatitis
B, inactivated poliomyelitis and Haemophilus influenzae type b) compared with 44% to 59% ofsubjects receiving the routine vaccines alone. Higher rates of antipyretic use were also reported forinfants vaccinated with Bexsero and routine vaccines. When Bexsero was given alone, the frequencyof fever was similar to that associated with routine infant vaccines administered during clinical trials.
When fever occurred, it generally followed a predictable pattern, with the majority resolving by theday after vaccination.
In adolescents and adults, the most common local and systemic adverse reactions observed were painat the injection site, malaise and headache.
No increase in the incidence or severity of the adverse reactions was seen with subsequent doses of thevaccination series.
Tabulated list of adverse reactionsAdverse reactions (following primary immunisation or booster dose) considered as being at leastpossibly related to vaccination have been categorised by frequency.
Frequencies are defined as follows:
Very common: (≥1/10)
Common: (≥1/100 to <1/10)
Uncommon: (≥1/1,000 to <1/100)
Rare: (≥1/10,000 to <1/1,000)
Very rare: (<1/10,000)
Not known: (cannot be estimated from the available data)
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
In addition to reports in clinical trials, worldwide voluntary reports of adverse reactions received for
Bexsero since market introduction are included in the list. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not always possible to reliably estimate theirfrequency and they are consequently listed with the frequency unknown.
Infants and children (up to 10 years of age)
Blood and lymphatic system disordersNot known: lymphadenopathy
Immune system disordersNot known: allergic reactions (including anaphylactic reactions)
Metabolism and nutrition disordersVery common: eating disorders
Nervous system disordersVery common: sleepiness, unusual crying, headache
Uncommon: seizures (including febrile seizures)
Not known: hypotonic-hyporesponsive episode, meningeal irritation (signs of meningeal irritation,such as neck stiffness or photophobia, have been sporadically reported shortly after vaccination. Thesesymptoms have been of mild and transient nature)
Vascular disordersUncommon: pallor (rare after booster)
Rare: Kawasaki syndrome
Gastrointestinal disordersVery common: diarrhoea, vomiting (uncommon after booster)
Skin and subcutaneous tissue disordersVery common: rash (children aged 12 to 23 months) (uncommon after booster)
Common: rash (infants and children 2 to 10 years of age)
Uncommon: eczema
Rare: urticaria
Musculoskeletal and connective tissue disordersVery common: arthralgia
General disorders and administration site conditionsVery common: fever (≥ 38 °C), injection site tenderness (including severe injection site tendernessdefined as crying when injected limb is moved), injection site erythema, injection site swelling,injection site induration, irritability
Uncommon: fever (≥ 40 °C)
Not known: injection site reactions (including extensive swelling of the vaccinated limb, blisters at oraround the injection site and injection site nodule which may persist for more than one month)
Adolescents (from 11 years of age) and adults
Blood and lymphatic system disordersNot known: lymphadenopathy
Immune system disordersNot known: allergic reactions (including anaphylactic reactions)
Nervous system disordersVery common: headache
Not known: syncope or vasovagal responses to injection, meningeal irritation (signs of meningealirritation, such as neck stiffness or photophobia, have been sporadically reported shortly aftervaccination. These symptoms have been of mild and transient nature)
Gastrointestinal disordersVery common: nausea
Skin and subcutaneous tissue disordersNot known: rash
Musculoskeletal and connective tissue disordersVery common: myalgia, arthralgia
General disorders and administration site conditionsVery common: injection site pain (including severe injection site pain defined as unable to performnormal daily activity), injection site swelling, injection site induration, injection site erythema, malaise
Not known: fever, injection site reactions (including extensive swelling of the vaccinated limb, blistersat or around the injection site and injection site nodule which may persist for more than one month)
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
Experience of overdose is limited. In the event of overdose, monitoring of vital functions and possiblesymptomatic treatment is recommended.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: meningococcal vaccines, ATC code: J07AH09
Mechanism of actionImmunisation with Bexsero is intended to stimulate the production of bactericidal antibodies thatrecognize the vaccine antigens NHBA, NadA, fHbp, and PorA P1.4 (the immunodominant antigenpresent in the OMV component) and are expected to be protective against Invasive Meningococcal
Disease (IMD). As these antigens are variably expressed by different strains, meningococci thatexpress them at sufficient levels are susceptible to killing by vaccine-elicited antibodies. The
Meningococcal Antigen Typing System (MATS) was developed to relate antigen profiles of differentstrains of meningococcal group B bacteria to killing of the strains in the serum bactericidal assay withhuman complement (hSBA). A survey of approximately 1 000 different invasive meningococcal group
B isolates collected during 2007-2008 in 5 European countries showed that, depending on the countryof origin, between 73% and 87% of meningococcal group B isolates had an appropriate MATS antigenprofile to be covered by the vaccine. Overall, 78% (95% CI: 63-90) of the approximately 1 000 strainswere potentially susceptible to vaccine-induced antibodies.
Clinical efficacyThe efficacy of Bexsero has not been evaluated through clinical trials. Vaccine efficacy has beeninferred by demonstrating the induction of serum bactericidal antibody responses to each of thevaccine antigens (see section Immunogenicity). Vaccine effectiveness and impact have beendemonstrated in real-world settings.
Impact of vaccination on disease incidence
In the UK, Bexsero was introduced into the national immunisation programme (NIP) in September 2015using a two-dose schedule in infants (at 2 and 4 months of age) followed by a booster dose (at 12 monthsof age). In this context, Public Health England (PHE) conducted a 3-year observational study at thenational level covering the entire birth cohort.
After three years of the programme, a statistically significant reduction of 75% [Incidence Rate Ratio(IRR) 0.25 (95% CI: 0.19-0.36)] in MenB IMD cases was observed in vaccine-eligible infants,irrespective of the infants’ vaccination status or predicted meningococcal group B strain coverage.
In South Australia, more than 30 000 students aged 16 through 19 years (from 91% of high schools),received two doses of Bexsero with a one- to three-month interval. In an interrupted time-seriesanalysis, a statistically significant reduction of 71% (95% CI: 15-90) in MenB IMD cases wasobserved in the two years of follow-up (July 2017-June 2019).
ImmunogenicitySerum bactericidal antibody responses to each of the vaccine antigens NadA, fHbp, NHBA and
PorA P1.4 were evaluated using a set of four meningococcal group B reference strains. Bactericidalantibodies against these strains were measured by the Serum Bactericidal Assay using human serumas the source of complement (hSBA). Data are not available from all vaccine schedules using thereference strain for NHBA.
Most of the primary immunogenicity studies were conducted as randomized, controlled, multicenter,clinical trials. Immunogenicity was evaluated in infants, children, adolescents and adults.
Immunogenicity in infants and children
In infant studies, participants received three doses of Bexsero either at 2, 4 and 6 or 2, 3 and 4 monthsof age and a booster dose in their second year of life, as early as 12 months of age. Sera were obtainedboth before vaccination, one month after the third vaccination (see Table 2) and one month afterbooster vaccination (see Table 3). In an extension study the persistence of the immune response wasassessed one year after the booster dose (see Table 3). The immunogenicity after two or three dosesfollowed by a booster has been evaluated in infants 2 months to 5 months of age in another clinicalstudy. The immunogenicity after two doses has been also documented in another study ininfants 6 months to 8 months of age at enrolment (see Table 4).
Previously unvaccinated children also received two doses in the second year of life, with antibodypersistence being measured at one year after the second dose (see Table 4).
Immunogenicity in infants 2 months to 5 months of age
Three-dose primary series followed by a booster
Immunogenicity results at one month after three doses of Bexsero administeredat 2, 3, 4 and 2, 4, 6 months of age are summarised in Table 2. Bactericidal antibody responses onemonth after the third vaccination against meningococcal reference strains were high against the fHbp,
NadA and PorA P1.4 antigens at both Bexsero vaccination schedules. The bactericidal responsesagainst the NHBA antigen were also high in infants vaccinated at the 2, 4, 6-month schedule, but thisantigen appeared to be less immunogenic at the 2, 3, 4-month schedule. The clinical consequences ofthe reduced immunogenicity of the NHBA antigen at this schedule are not known.
Table 2. Serum bactericidal antibody responses at 1 month following the third dose of
Bexsero given at 2, 3, 4 or 2, 4, 6 months of age
Antigen Study V72P13 Study V72P12 Study V72P162, 4, 6 months 2, 3, 4 months 2, 3, 4 months% seropositive* N=1 149 N=273 N=170fHbp (95% CI) 100% (99-100) 99% (97-100) 100% (98-100)hSBA GMT** 91 82 101(95% CI) (87-95) (75-91) (90-113)% seropositive N=1 152 N=275 N=165
NadA (95% CI) 100% (99-100) 100% (99-100) 99% (97-100)hSBA GMT 635 325 396(95% CI) (606-665) (292-362) (348-450)% seropositive N=1 152 N=274 N=171
PorA P1.4 (95% CI) 84% (82-86) 81% (76-86) 78% (71-84)hSBA GMT 14 11 10(95% CI) (13-15) (9.14-12) (8.59-12)% seropositive N=100 N=112 N=35
NHBA (95% CI) 84% (75-91) 37% (28-46) 43% (26-61)hSBA GMT 16 3.24 3.29(95% CI) (13-21) (2.49-4.21) (1.85-5.83)
* % seropositive = the percentage of subjects who achieved an hSBA ≥ 1:5.
** GMT = geometric mean titer.
Data on bactericidal antibody persistence at 8 months after Bexsero vaccination at 2, 3 and 4 monthsof age, and at 6 months after Bexsero vaccination at 2, 4 and 6 months of age (pre-booster time point)and booster data after a fourth dose of Bexsero administered at 12 months of age are summarised in
Table 3. Persistence of the immune response one year after the booster dose is also presented in
Table 3.
Table 3. Serum bactericidal antibody responses following a booster at 12 months of age aftera primary series administered at 2, 3 and 4 or 2, 4 and 6 months of age, andpersistence of bactericidal antibody one year after the booster
Antigen 2, 3, 4, 12 months 2, 4, 6, 12 monthspre-booster*% seropositive** (95% N=81 N=426
CI) 58% (47-69) 82% (78-85)hSBA GMT*** (95% CI) 5.79 (4.54-7.39) 10 (9.55-12)fHbp 1 month after booster N=83 N=422% seropositive (95% CI) 100% (96-100) 100% (99-100)hSBA GMT (95% CI) 135 (108-170) 128 (118-139)12 months after booster N=299% seropositive (95% CI) - 62% (56-67)hSBA GMT (95% CI) 6.5 (5.63-7.5)pre-booster N=79 N=423% seropositive (95% CI) 97% (91-100) 99% (97-100)hSBA GMT (95% CI) 63 (49-83) 81 (74-89)1 month after booster N=84 N=421
NadA % seropositive (95% CI) 100% (96-100) 100% (99-100)hSBA GMT (95% CI) 1 558 (1 262-1 923) 1 465 (1 350-1 590)12 months after booster N=298% seropositive (95% CI) - 97% (95-99)hSBA GMT (95% CI) 81 (71-94)pre-booster N=83 N=426% seropositive (95% CI) 19% (11-29) 22% (18-26)hSBA GMT (95% CI) 1.61 (1.32-1.96) 2.14 (1.94-2.36)1 month after booster N=86 N=424
PorA P1.4 % seropositive (95% CI) 97% (90-99) 95% (93-97)hSBA GMT (95% CI) 47 (36-62) 35 (31-39)12 months after booster N=300% seropositive (95% CI) - 17% (13-22)hSBA GMT (95% CI) 1.91 (1.7-2.15)pre-booster N=69 N=100% seropositive (95% CI) 25% (15-36) 61% (51-71)hSBA GMT (95% CI) 2.36 (1.75-3.18) 8.4 (6.4-11)1 month after booster % N=67 N=100
NHBA seropositive (95% CI) 76% (64-86) 98% (93-100)hSBA GMT (95% CI) 12 (8.52-17) 42 (36-50)12 months after booster N=291% seropositive (95% CI) - 36% (31-42)hSBA GMT (95% CI) 3.35 (2.88-3.9)
* pre-booster time point represents persistence of bactericidal antibody at 8 months after Bexserovaccination at 2, 3 and 4 months of age and 6 months after Bexsero vaccinationat 2, 4 and 6 months of age.
** % seropositive = the percentage of subjects who achieved an hSBA ≥ 1:5.
*** GMT = geometric mean titer.
A decline in antibody titers to PorA P1.4 and fHbp antigens (reaching 9%-10% and 12%-20% ofsubjects with an hSBA ≥ 1:5, respectively) has been observed in an additional study inchildren 4 years of age who received a full priming and booster schedule as infants. In the same studythe response to a further dose was indicative of immunological memory as 81%-95% of subjectsreached an hSBA ≥ 1:5 to PorA P1.4 and 97%-100% to fHbp antigens following further vaccination.
The clinical significance of this observation and the need for additional booster doses to maintainlonger term protective immunity has not been established.
Two-dose primary series followed by a booster
The immunogenicity after two primary doses (at 3 and a half and 5 months of age) or three primarydoses (at 2 and a half, 3 and a half and 5 months of age) of Bexsero followed by a booster dose ininfants starting vaccination between 2 and 5 months of age has been evaluated in an additional phase 3clinical study. The percentages of seropositive subjects (i.e. achieving an hSBA of at least 1:4) rangedfrom 44% to 100% one month after the second dose and from 55% to 100% one month after the thirddose. At one month following a booster administered 6 months after the last dose, the percentages ofseropositive subjects ranged from 87% to 100% for the two-dose schedule, and from 83% to 100% forthe three-dose schedule.
Antibody persistence was evaluated in an extension study in children 3 to 4 years of age. Comparablepercentages of subjects were seropositive at 2 to 3 years after being previously vaccinated with eithertwo doses followed by a booster of Bexsero (ranging from 35% to 91%) or three doses followed by abooster (ranging from 36% to 84%). In the same study the response to an additional dose administered2 to 3 years after the booster was indicative of immunological memory as shown by a robust antibodyresponse against all Bexsero antigens, ranging from 81% to 100% and from 70% to 99%, respectively.
These observations are consistent with adequate priming in infancy with both a two-dose and a three-dose primary series followed by a booster of Bexsero.
Immunogenicity in infants 6 to 11 months and children 12 to 23 months of age
The immunogenicity after two doses administered two months apart in children 6 months to 23 monthsof age has been documented in two studies whose results are summarised in Table 4. Against each ofthe vaccine antigens, seroresponse rates and hSBA GMTs were high and similar after the two-doseseries in infants 6-8 months of age and children 13-15 months of age. Data on antibody persistenceone year after the two doses at 13 and 15 months of age are also summarised in Table 4.
Table 4. Serum bactericidal antibody responses following Bexsero vaccination at 6 and 8 monthsof age or 13 and 15 months of age and persistence of bactericidal antibody one yearafter the two doses at 13 and 15 months of age
Age range6 to 11 12 to 23
Antigen months of age months of age
Age of vaccination6, 8 months 13, 15 months1 month after 2nd dose N=23 N=163% seropositive* (95% CI) 100% (85-100) 100% (98-100)fHbp hSBA GMT** (95% CI) 250 (173-361) 271 (237-310)12 months after 2nd dose N=68% seropositive (95% CI) - 74% (61-83)hSBA GMT (95% CI) 14 (9.4-20)1 month after 2nd dose N=23 N=164% seropositive (95% CI) 100% (85-100) 100% (98-100)
NadA hSBA GMT (95% CI) 534 (395-721) 599 (520-690)12 months after 2nd dose N=68% seropositive (95% CI) - 97% (90-100)hSBA GMT (95% CI) 70 (47-104)1 month after 2nd dose N=22 N=164% seropositive (95% CI) 95% (77-100) 100% (98-100)
PorA hSBA GMT (95% CI) 27 (21-36) 43 (38-49)
P1.4 12 months after 2nd dose N=68% seropositive (95% CI) - 18% (9-29)hSBA GMT (95% CI) 1.65 (1.2-2.28)1 month after 2nd dose N=46% seropositive (95% CI) - 63% (48-77)
NHBA hSBA GMT (95% CI) 11 (7.07-16)12 months after 2nd dose N=65% seropositive (95% CI) - 38% (27-51)hSBA GMT (95% CI) 3.7 (2.15-6.35)
* % seropositive = the percentage of subjects who achieved an hSBA ≥ 1:4 (in the 6 to 11 monthsrange of age) and an hSBA ≥ 1:5 (in the 12 to 23 months range of age).
** GMT = geometric mean titer.
Immunogenicity in children 2 to 10 years of age
The immunogenicity after two doses of Bexsero administered either one or two months apart inchildren 2 to 10 years of age has been evaluated in an initial phase 3 clinical study and its extension. Inthe initial study, whose results are summarised in Table 5, participants received two doses of Bexserotwo months apart. The seroresponse rates and hSBA GMTs were high after the two-dose schedule inchildren against each of the vaccine antigens (Table 5).
Table 5. Serum bactericidal antibody responses at 1 month following the second dose of
Bexsero given to children 2-10 years of age following a 0, 2-month schedule
Antigen 2 to 5 years of age 6 to 10 years of age% seropositive* N=99 N=287fHbp (95% CI) 100% (96-100) 99% (96-100)hSBA GMT** 140 112(95% CI) (112-175) (96-130)% seropositive N=99 N=291
NadA (95% CI) 99% (95-100) 100% (98-100)hSBA GMT 584 457(95% CI) (466-733) (392-531)% seropositive N=100 N=289
PorA P1.4 (95% CI) 98% (93-100) 99% (98-100)hSBA GMT 42 40(95% CI) (33-55) (34-48)% seropositive N=95 N=275(95% CI) 91% (83-96) 95% (92-97)
NHBAhSBA GMT 23 35(95% CI) (18-30) (29-41)
* % seropositive = the percentage of subjects who achieved an hSBA ≥ 1:4 (against referencestrains for fHbp, NadA, PorA P1.4 antigens) and an hSBA ≥ 1:5 (against reference strain for
NHBA antigen).
** GMT = geometric mean titer.
In the extension study, in which two doses of Bexsero were administered one month apart inunvaccinated children, high percentages of subjects were seropositive one month after the seconddose. An early immune response after the first dose was also evaluated. The percentages ofseropositive subjects (i.e. achieving an hSBA of at least 1:4) across strains ranged from 46% to 95% atone month after the first dose and from 69% to 100% at one month after the second dose (Table 6).
Table 6. Serum bactericidal antibody responses at 1 month following the second dose of
Bexsero given to children 2-10 years of age following a 0, 1-month schedule
Antigen 35 to 47 months of age 4 to 7 years of age 8 to10 years of age% seropositive* N=98 N=54 N=34fHbp (95% CI) 100% (96.3-100) 98% (90.1-99.95) 100% (89.7-100)hSBA GMT** 107 76.62 52.32(95% CI) (84-135) (54-108) (34-81)% seropositive N=98 N=54 N=34
NadA (95% CI) 100% (96.3-100) 100% (93.4-100) 100% (89.7-100)hSBA GMT 631 370.41 350.49(95% CI) (503-792) (264-519) (228-540)% seropositive N=98 N=54 N=33
PorA P1.4 (95% CI) 100% (96.3-100) 100% (93.4-100) 100% (89.4-100)hSBA GMT 34 30.99 30.75(95% CI) (27-42) (28-49) (20-47)% seropositive N=91 N=52 N=34(95% CI) 75% (64.5-83.3) 69% (54.9-81.3) 76% (58.8-89.3)
NHBAhSBA GMT 12 9.33 12.35(95% CI) (7.57-18) (5.71-15) (6.61-23)
* % seropositive = the percentage of subjects who achieved an hSBA ≥ 1:4 (against referencestrains for fHbp, NadA, PorA P1.4 antigens) and an hSBA ≥ 1:5 (against reference strain for
NHBA antigen).
** GMT = geometric mean titer.
The same extension study also evaluated antibody persistence and the response to a booster dose inchildren who received the two-dose primary series at 2-5 or 6-10 years of age. After 24-36 months, thepercentages of seropositive subjects (i.e. achieving an hSBA of at least 1:4) declined, ranging acrossstrains from 21% to 74% in children 4-7 years of age and from 47% to 86% in children 8-12 years ofage. The response to a booster dose administered 24-36 months after the primary series was indicativeof immunological memory as the percentages of seropositive subjects ranged across strains from 93%to 100% in children 4-7 years of age and from 96% to 100% in children 8-12 years of age.
Immunogenicity in adolescents (from 11 years of age) and adults
Adolescents received two doses of Bexsero with one, two or six-month intervals between doses; thesedata are summarised in Tables 7 and 8.
In studies with adults, data were obtained after two doses of Bexsero with a one-month or two-monthinterval between doses (see Table 9).
The vaccination schedules of two doses administered with an interval of one or two months showedsimilar immune responses in both adults and adolescents. Similar responses were also observed foradolescents administered two doses of Bexsero with an interval of six months.
Table 7. Serum bactericidal antibody responses in adolescents one month after two doses of
Bexsero administered according to different two-dose schedules and persistence ofbactericidal antibody 18 to 23 months after the second dose
Antigen 0, 1 months 0, 2 months 0, 6 months1 month after 2nd dose N=638 N=319 N=86% seropositive* 100% 100% 100%(95% CI) (99-100) (99-100) (99-100)hSBA GMT** 210 234 218fHbp (95% CI) (193-229) (209-263) (157-302)18-23 months after 2nd dose N=102 N=106 N=49% seropositive 82% 81% 84%(95% CI) (74-89) (72-88) (70-93)hSBA GMT 29 34 27(95% CI) (20-42) (24-49) (16-45)1 month after 2nd dose N=639 N=320 N=86% seropositive 100% 99% 99%(95% CI) (99-100) (98-100) (94-100)hSBA GMT 490 734 880
NadA (95% CI) (455-528) (653-825) (675-1 147)18-23 months after 2nd dose N=102 N=106 N=49% seropositive 93% 95% 94%(95% CI) (86-97) (89-98) (83-99)hSBA GMT 40 43 65(95% CI) (30-54) (33-58) (43-98)1 month after 2nd dose N=639 N=319 N=86% seropositive 100% 100% 100%(95% CI) (99-100) (99-100) (96-100)hSBA GMT 92 123 140
PorA (95% CI) (84-102) (107-142) (101-195)
P1.4 18-23 months after 2nd dose N=102 N=106 N=49% seropositive 75% 75% 86%(95% CI) (65-83) (66-83) (73-94)hSBA GMT 17 19 27(95% CI) (12-24) (14-27) (17-43)1 month after 2nd dose N=46 N=46 -% seropositive 100% 100%
NHBA (95% CI) (92-100) (92-100) -hSBA GMT 99 107(95% CI) (76-129) (82-140) -
* % seropositive = the percentage of subjects who achieved an hSBA ≥ 1:4.
** GMT = geometric mean titer.
In the study in adolescents, bactericidal responses following two doses of Bexsero were stratified bybaseline hSBA less than 1:4 or equal to or greater than 1:4. Seroresponse rates and percentages ofsubjects with at least a 4-fold increase in hSBA titer from baseline to one month after the second doseof Bexsero are summarised in Table 8. Following Bexsero vaccination, a high percentage of subjectswere seropositive and achieved 4-fold increases in hSBA titers independent of pre-vaccination status.
Table 8. Percentage of adolescents with seroresponse and at least 4-fold rise in bactericidaltiters one month after two doses of Bexsero administered according to differenttwo-dose schedules - stratified by pre-vaccination titers
Antigen 0, 1 months 0, 2 months 0, 6 monthspre-vaccination N=369 N=179 N=55% seropositive*nd titer < 1:4 100% (98-100) 100% (98-100) 100% (94-100)after 2 dose(95% CI) pre-vaccination N=269 N=140 N=31titer ≥ 1:4 100% (99-100) 100% (97-100) 100% (89-100)fHbppre-vaccination N=369 N=179 N=55% 4-fold increasend titer < 1:4 100% (98-100) 100% (98-100) 100% (94-100)after 2 dose(95% CI) pre-vaccination N=268 N=140 N=31titer ≥ 1:4 90% (86-93) 86% (80-92) 90% (74-98)pre-vaccination N=427 N=211 N=64% seropositivend titer < 1:4 100% (99-100) 99% (97-100) 98% (92-100)after 2 dose(95% CI) pre-vaccination N=212 N=109 N=22
NadA titer ≥ 1:4 100% (98-100) 100% (97-100) 100% (85-100)pre-vaccination N=426 N=211 N=64% 4-fold increasend titer < 1:4 99% (98-100) 99% (97-100) 98% (92-100)after 2 dose(95% CI) pre-vaccination N=212 N=109 N=22titer ≥ 1:4 96% (93-98) 95% (90-98) 95% (77-100)pre-vaccination N=427 N=208 N=64% seropositivend titer < 1:4 100% (98-100) 100% (98-100) 100% (94-100)after 2 dose(95% CI) pre-vaccination N=212 N=111 N=22titer ≥ 1:4 100% (98-100) 100% (97-100) 100% (85-100)
PorA P1.4pre-vaccination N=426 N=208 N=64% 4-fold increasend titer < 1:4 99% (98-100) 100% (98-100) 100% (94-100)after 2 dose(95% CI) pre-vaccination N=211 N=111 N=22titer ≥ 1:4 81% (75-86) 77% (68-84) 82% (60-95)pre-vaccination N=2 N=9% seropositivend titer < 1:4 100% (16-100) 100% (66-100) -after 2 dose(95% CI) pre-vaccination N=44 N=37titer ≥ 1:4 100% (92-100) 100% (91-100) -
NHBApre-vaccination N=2 N=9% 4-fold increasend titer < 1:4 100% (16-100) 89% (52-100) -after 2 dose(95% CI) pre-vaccination N=44 N=37titer ≥ 1:4 30% (17-45) 19% (8-35) -
* % seropositive = the percentage of subjects who achieved an hSBA ≥ 1:4.
Antibody persistence data for the study in adolescents were obtained in an extension phase 3 study. Atapproximately 7.5 years after the two-dose primary series, the percentages of subjects withhSBA ≥ 1:4 declined, ranging across strains from 29% to 84%. The response to a booster doseadministered 7.5 years after the primary series was indicative of immunological memory as thepercentages of subjects reaching an hSBA ≥ 1:4 across strains ranged from 93% to 100%.
The same study also evaluated antibody persistence data from an additional phase 3 initial study inadolescents. At approximately 4 years after the two-dose primary series, the percentages of subjectswith hSBA ≥ 1:5 generally declined from a range across strains of 68% to 100% after the second doseto a range across strains of 9% to 84%. The response to a booster dose administered 4 years after theprimary series was indicative of immunological memory as the percentages of subjects withhSBA ≥ 1:5 ranged across strains from 92% to 100%.
Table 9. Serum bactericidal antibody responses in adults after two doses of Bexseroadministered according to different two-dose schedules
Antigen 0, 1 months 0, 2 months1 month after 2nd dose N=28 N=46% seropositive* 100% 100%fHbp (95% CI) (88-100) (92-100)hSBA GMT** 100 93(95% CI) (75-133) (71-121)1 month after 2nd dose N=28 N=46% seropositive 100% 100%
NadA (95% CI) (88-100) (92-100)hSBA GMT 566 144(95% CI) (338-948) (108-193)1 month after 2nd dose N=28 N=46% seropositive 96% 91%
PorA P1.4 (95% CI) (82-100) (79-98)hSBA GMT 47 32(95% CI) (30-75) (21-48)
* % seropositive = the percentage of subjects who achieved an hSBA ≥ 1:4.
** GMT = geometric mean titer.
Serum bactericidal response to NHBA antigen has not been evaluated.
Immunogenicity in special populations
Children and adolescents with complement deficiencies, asplenia, or splenic dysfunction
In a phase 3 clinical study, children and adolescents 2 through 17 years of age with complementdeficiencies (40), with asplenia or splenic dysfunction (107), and age-matched healthy subjects (85)received two doses of Bexsero two months apart. At 1 month following the 2-dose vaccination course,the percentages of subjects with hSBA ≥ 1:5 in individuals with complement deficiencies and aspleniaor splenic dysfunction were 87% and 97% for antigen fHbp, 95% and 100% for antigen NadA, 68%and 86% for antigen PorA P1.4, 73% and 94% for antigen NHBA, respectively, indicating an immuneresponse in these immunocompromised subjects. The percentages of healthy subjects with hSBA ≥ 1:5were 98% for antigen fHbp, 99% for antigen NadA, 83% for antigen PorA P1.4, and 99% for antigen
NHBA.
5.2 Pharmacokinetic properties
Not applicable.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on repeated dose toxicity andreproductive and developmental toxicity studies.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride
Histidine
Sucrose
Water for injections
For adsorbent see section 2.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.
6.3 Shelf life
4 years
6.4 Special precautions for storage
Store in a refrigerator (2 °C - 8 °C).
Do not freeze.
Store in the original package in order to protect from light.
6.5 Nature and contents of container
0.5 ml of suspension in a pre-filled syringe (type I glass) with a plunger stopper (butyl rubber) andwith a rubber tip cap.
The tip cap and rubber plunger stopper of the pre-filled syringe are made with synthetic rubber.
Pack sizes of 1 and 10, with or without needles.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Upon storage a fine off-white deposit may be observed in the pre-filled syringe containing the suspension.
Before use, the pre-filled syringe should be well shaken in order to form a homogeneous suspension.
The vaccine should be visually inspected for particulate matter and discoloration prior toadministration. In the event of any foreign particulate matter and/or variation of physical aspect beingobserved, do not administer the vaccine. If two needles of different lengths are provided in the pack,choose the appropriate needle to ensure an intramuscular administration.
Instructions for the pre-filled syringe
Luer Lock Adaptor
Hold the syringe by the barrel, not by theplunger.
Plunger Unscrew the syringe cap by twisting it
Barrel anticlockwise.
Cap
Needle hub
To attach the needle, connect the hub to the Luer
Lock Adaptor and rotate a quarter turnclockwise until you feel it lock.
Do not pull the syringe plunger out of the barrel.
If it happens, do not administer the vaccine.
DisposalAny unused medicinal product or waste material should be disposed of in accordance with local requirements.
10. DATE OF REVISION OF THE TEXT
DD/MM/YYYY
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.