Bexero vaccine for the prevention of meningococcal infection suspension for injection 1 dose (0.5 ml/dose)

Instructions for use Bexero vaccine for the prevention of meningococcal infection, suspension for injection, 1 dose (0.5 ml/dose)

Composition

active ingredients: one dose (0.5 ml) contains:

1 was obtained using E. coli cells by recombinant DNA technology.

2 adsorbed on aluminum hydroxide (0.5 mg Al³+).

³ NHBA (Neisseria heparin-binding antigen), NadA (Neisseria adhesin A), fHbp (factor-H binding protein).

Excipients: aluminum hydroxide, sodium chloride, sucrose, histidine, water for injection.

Dosage form

Suspension for injection.

Main physicochemical properties: opalescent liquid (whitish suspension).

Pharmacotherapeutic group

Antibacterial vaccines. Vaccines for the prevention of meningococcal infection. ATX code J07A H09.

Pharmacological properties

Immunological and biological properties.

Pharmacodynamics

Mechanism of action

Immunization with BEXERO vaccine is designed to induce bactericidal antibodies that recognize the vaccine antigens NHBA, NadA, fHbp, and PorA P1.4 (an immunodominant antigen present in the OMV component) and is expected to protect against invasive meningococcal disease (IMD). Due to the variability in the expression of these antigens by different strains, meningococci that express them at sufficient levels are susceptible to the antibodies produced by the vaccine. The Meningococcal Antigen Detection System (MATS) was developed to correlate the antigen profiles of different strains of meningococcal serogroup B bacteria with the killing of the strains in the human complement-mediated serum bactericidal assay (hSBA). Studies of approximately 1000 different isolates of invasive serogroup B meningococci collected in 2007–2008. in 5 European countries, showed that, depending on the country of origin, 73–87% of meningococcal serogroup B isolates had the antigenic profile according to MATS that should be covered by the vaccine. Overall, 78% (95% confidence interval of 63–90%) of approximately 1000 strains were susceptible to vaccine-induced antibodies.

Clinical efficacy

The efficacy of BEXERO vaccine has not been evaluated in clinical trials. The conclusion of vaccine efficacy was made by demonstrating the induction of serum bactericidal antibody responses to each of the vaccine antigens (see Immunogenicity below).

Immunogenicity

Serum bactericidal antibody responses to each of the vaccine antigens NadA, fHbp, NHBA and PorA P1.4 were assessed using a set of four control strains of meningococci serogroup B. Bactericidal antibody levels against these strains were determined by the human complement-based serum bactericidal assay (hSBA). Data for all vaccination schedules using control strains for NHBA are not available.

Most of the primary immunogenicity studies were conducted using randomized, controlled, multicenter clinical trial designs. Immunogenicity was assessed in infants, children, and adults.

Immunogenicity in children

Children enrolled in the studies received three doses of BEXERO vaccine at 2, 4, and 6 or 2, 3, and 4 months of age, and a booster dose in the second year of life, but not earlier than 12 months of age. Sera were collected both before vaccination, one month after the third vaccination (see Table 1), and one month after the booster (see Table 2). The persistence of the immune response was assessed in an extension study one year after the booster (see Table 2). Another clinical study evaluated immunogenicity in children aged 2 to 5 months after administration of two or three doses followed by a booster. Immunogenicity after administration of two doses was also documented in another study in infants aged 6 to 8 months at the time of study enrollment (see Table 3).

Previously unvaccinated children also received two doses of vaccine in the second year of life, and antibody persistence was determined one year after the second dose (see Table 3).

Immunogenicity in children aged 2–5 months

Three-dose primary vaccination course with subsequent booster vaccination

The results of the immunogenicity assessment one month after the administration of three doses of BEXERO vaccine to children aged 2, 3, 4 and 2, 4, 6 months are presented in Table 1. One month after the third dose of vaccination, the level of bactericidal antibodies against the control meningococcal strains was high against the fHbp, NadA and PorA P1.4 antigens in both BEXERO vaccination schedules. The level of bactericidal antibodies against the NHBA antigen was also high in children vaccinated with the 2, 4, 6 month schedule, however, the immunogenicity of this antigen was lower in the 2, 3, 4 month schedule. The clinical consequences of the lower immunogenicity of the NHBA antigen in this vaccination schedule are unknown.

Table 1

Serum bactericidal antibody response 1 month after the third dose of vaccine

BEXERO administered at 2, 3, 4 or 2, 4, 6 months of age

Research V72P13

2, 4, 6 months

* % seropositive = percentage of individuals who achieved an hSBA titer ≥ 1:5.

** GMT = geometric mean titer.

Data on the persistence of bactericidal antibodies 8 months after vaccination with BEXERO vaccine at 2, 3 and 4 months of age, as well as 6 months after vaccination with BEXERO vaccine at 2, 4 and 6 months of age (control time point before booster vaccination) and data on booster vaccination after the fourth dose of BEXERO vaccine administered at 12 months of age are presented in Table 2. Data on the persistence of the immune response one year after booster vaccination are also presented in Table 2.

Table 2

Serum bactericidal antibody response after booster vaccination at 12 months of age

primary vaccination course at 2, 3 and 4 or 2, 4 and 6 months of age, as well as resistance

bactericidal antibodies one year after booster vaccination

* The pre-booster control time point represents bactericidal antibody persistence 8 months after vaccination with BEXERO vaccine at 2, 3, and 4 months of age and 6 months after vaccination with BEXERO vaccine at 2, 4, and 6 months of age.

** % seropositive = percentage of individuals who achieved an hSBA titer ≥ 1:5.

*** GMT = geometric mean titer.

In a follow-up study in 4-year-old children who received a complete primary vaccination course and a booster dose during the first year of life, a decrease in antibody titers against PorA P1.4 and fHbp antigens was observed (reaching 9–10% and 12–20% of individuals with hSBA titers ≥ 1:5, respectively). In the same study, the response to the booster dose was indicative of immunological memory, as 81–95% of individuals achieved hSBA titers ≥ 1:5 against PorA P1.4 antigen and 97–100% against fHbp antigen after subsequent vaccination. The clinical relevance of this observation and the need for additional booster doses to maintain long-term protective immunity have not been established.

Immunogenicity following a two-dose primary vaccination course (at 3.5 and 5 months of age) or a three-dose primary vaccination course (at 2.5, 3.5, and 5 months of age) of BEXERO followed by a booster dose in children initiated at 2–5 months of age was evaluated in an additional Phase 3 clinical study. The percentage of seropositive subjects (i.e. subjects achieving an hSBA titer of at least 1:4) was 44–100% one month after the second dose and 55–100% one month after the third dose. One month after the booster dose administered 6 months after the last dose, the percentage of seropositive subjects was 87–100% for the two-dose vaccination schedule and 83–100% for the three-dose vaccination schedule.

Antibody persistence was assessed in a follow-up study in children aged 3–4 years. Comparable percentages of subjects were seropositive 2–3 years after a previous vaccination with two doses followed by a booster dose of BEXERO (35% to 91%) or three doses followed by a booster dose (36% to 84%). In the same study, the response to a booster dose given 2–3 years after the booster dose was indicative of immunological memory, as demonstrated by persistent immune responses to all BEXERO antigens of 81–100% and 70–99%, respectively. These observations indicate sufficient primary vaccination in early childhood with both the two-dose and three-dose courses followed by a booster dose of BEXERO.

Immunogenicity in children aged 6–11 months and 12–23 months

Immunogenicity in children aged 6–23 months after two doses administered two months apart was documented in two studies, the results of which are presented in Table 4. Seroconversion rates and hSBA GMTs for each vaccine antigen were high and similar after two-dose courses in children aged 6–8 months and children aged 13–15 months. Data on antibody persistence one year after two doses administered at 13 and 15 months are also presented in Table 3.

Table 3

Serum bactericidal antibody response following vaccination with BEXERO at 6 and 8 months of age or 13 and 15 months of age, and persistence of bactericidal antibodies one year after administration of two doses at 13 and 15 months of age

* % seropositive = percentage of individuals who achieved hSBA titer ≥ 1:4 (in the age range 6–11 months) and hSBA ≥ 1:5 (in the age range 12–23 months).

** GMT = geometric mean titer.

Immunogenicity in children aged 2–10 years

Immunogenicity following two doses of BEXERO vaccine administered one or two months apart in children 2 to 10 years of age was evaluated in an initial Phase 3 clinical study and its extension. In the initial study, the results of which are presented in Table 4, participants received two doses of BEXERO vaccine administered two months apart. Seroconversion rates and hSBA GMTs for each of the vaccine antigens were high following the two-dose vaccination schedule in children.

Table 4

Serum bactericidal antibody response 1 month after the second dose of BEXERO vaccine in children aged 2–10 years following a 0.2-monthly dosing schedule

* % seropositive = percentage of individuals who achieved an hSBA titer ≥ 1:4 (against the control strains of the fHbp, NadA, PorA P1.4 antigens) and an hSBA titer ≥ 1:5 (against the control strain of the NHBA antigen).

** GMT = geometric mean titer.

In an extension study in which two doses of BEXERO were administered one month apart to unvaccinated children, a high percentage of subjects were seropositive one month after the second dose. Early immune responses following the first dose of vaccine were also assessed. The percentage of subjects seropositive (i.e., subjects achieving an hSBA titer of at least 1:4) by strain ranged from 46% to 95% one month after the first dose and from 69% to 100% one month after the second dose (Table 5).

Table 5

Serum bactericidal antibody response 1 month after the second dose of BEXERO vaccine in children aged 2–10 years following a 0.1-month dosing schedule

* % seropositive = percentage of individuals who achieved an hSBA titer ≥ 1:4 (against the control strains of the fHbp, NadA, PorA P1.4 antigens) and an hSBA titer ≥ 1:5 (against the control strain of the NHBA antigen).

** GMT = geometric mean titer.

In the same extension study, antibody persistence and response to booster vaccination were also assessed in children who received a two-dose primary vaccination course at ages 2–5 or 6–10 years. After 24–36 months, the percentage of seropositive individuals (i.e. individuals who achieved an hSBA titer of at least 1:4) decreased and for different strains was 21–74% in children aged 4–7 years and 47–86% in children aged 8–12 years. The response to booster vaccination 24–36 months after the primary vaccination course was indicative of immunological memory, as the percentage of seropositive individuals for different strains was 93–100% in children aged 4–7 years and 96–100% in children aged 8–12 years.

Immunogenicity in children (aged 11 years and older) and adults

Children received two doses of BEXERO vaccine with an interval of one, two, or six months between doses; these data are presented in Tables 6 and 7.

In studies in adults, data were obtained after administration of two doses of BEXERO vaccine with an interval of one or two months between doses (see Table 8).

The two-dose schedule, administered one or two months apart, produced similar immune responses in both adults and children. Similar responses were also observed in children who received two doses of BEXERO vaccine six months apart.

Table 6

Serum bactericidal antibody response in children one month after two doses of BEXERO vaccine administered in different two-dose schedules and persistence of bactericidal antibodies 18–23 months after the second dose

* % seropositive = percentage of individuals who achieved an hSBA titer ≥ 1:4.

** GMT = geometric mean titer.

In a study in children, bactericidal antibody levels after two doses of BEXERO were stratified by hSBA titer less than 1:4 or greater than 1:4. Seroconversion rates and the percentage of subjects with at least a 4-fold increase in hSBA titer from baseline within one month of the second dose of BEXERO are shown in Table 7. After vaccination with BEXERO, the percentage of seropositive subjects was high and a 4-fold increase in hSBA titer was achieved regardless of prior vaccination status.

Table 7

Percentage of children with seroconversion and a 4-fold increase in bactericidal antibody titer one month after administration of two doses of BEXERO vaccine according to different two-dose schedules, stratified by pre-vaccination titer

* % seropositive = percentage of individuals who achieved an hSBA titer ≥ 1:4.

The same study also evaluated antibody persistence data from an additional phase 3 study in children. Approximately 4 years after the two-dose primary vaccination course, the percentage of subjects achieving a titer ≥ 1:5 overall decreased from a range of 68–100% across strains after the second dose to a range of 9–84% across strains. The response to booster vaccination 4 years after the primary vaccination course was indicative of immunological memory, as the percentage of subjects with hSBA titers ≥ 1:5 across strains was 92–100%.

Table 8

Serum bactericidal antibody response in adults after two doses

BEXERO vaccines in different two-dose regimens

* % seropositive = percentage of individuals who achieved an hSBA titer ≥ 1:4.

** GMT = geometric mean titer.

The serum bactericidal antibody response to the NHBA antigen was not evaluated.

Immunogenicity in special patient groups

Children with complement deficiency, splenic aplasia, or splenic dysfunction

In a phase 3 clinical study, children aged 2 to 17 years with complement deficiency (40), splenic aplasia or splenic dysfunction (107) and age-matched healthy subjects (85) received two doses of BEXERO vaccine, 2 months apart. At 1 month after the 2-dose vaccination course, the percentage of subjects with hSBA titers ≥1:5 among subjects with complement deficiency and splenic aplasia or splenic dysfunction was 87% and 97% for fHbp antigen, 95% and 100% for NadA antigen, 68% and 86% for PorA P1.4 antigen, and 73% and 94% for NHBA antigen, respectively, indicating an immune response in these immunocompromised subjects. The percentages of healthy individuals with hSBA titers ≥1:5 were 98% for the fHbp antigen, 99% for the NadA antigen, 83% for the PorA P1.4 antigen, and 99% for the NHBA antigen.

The impact of vaccination on the incidence of disease

In the UK, BEXERO was introduced into the National Immunisation Programme (NIP) in September 2015 using a two-dose schedule (at 2 and 4 months of age) followed by a booster dose (at 12 months of age). In this context, Public Health England conducted a 3-year national observational study covering the entire birth cohort.

After three years of the program, there was a statistically significant 75% reduction [incidence rate 0.25 (95% CI: 0.19, 0.36)] in cases of IMD caused by Neisseria meningitidis serogroup B among children who met the vaccination criteria regardless of the child's vaccination status or predicted coverage of meningococcal serogroup B strains.

The European Medicines Agency has deferred the obligation to submit the results of studies with BEXERO in one or more subsets of the paediatric population for the prevention of meningococcal infection caused by Neisseria meningitidis serogroup B (see section 6.2 for information on the use of the vaccine in children).

Pharmacokinetics

Not applicable.

Preclinical safety data.

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity studies and studies of reproductive and developmental toxicity.

Indication

BEXERO is indicated for the active immunisation of individuals from 2 months of age against invasive meningococcal disease caused by Neisseria meningitidis serogroup B. Vaccination should take into account the impact of invasive disease in different age groups and the variability in the epidemiology of antigens for serogroup B strains in different geographical regions. For information on protection against specific serogroup B strains, see section 5.2. Immunological and biological properties. This vaccine should be administered in accordance with official recommendations.

Contraindication

Hypersensitivity to the active substances or to any of the excipients (see section "Composition").

Interaction with other medicinal products and other types of interactions

Use with other vaccines

BEXERO vaccine can be administered simultaneously with: any monovalent or combination vaccines against: diphtheria, tetanus, pertussis (acellular), Haemophilus influenzae type b, poliomyelitis (inactivated), hepatitis B;

Clinical studies have demonstrated that co-administration of BEXERO with routine pediatric vaccination did not affect the immune response elicited by the concomitant routine vaccines, as measured by no greater antibody response rate than routine vaccination alone. Studies have shown inconsistent results for responses to inactivated poliovirus type 2 and pneumococcal serotype 6B conjugate, and lower antibody titers to pertussis pertactin antigen have been observed, but these data do not indicate a clinically relevant effect.

Due to the increased risk of fever, injection site tenderness, changes in normal eating habits, and irritability when BEXERO is administered concomitantly with the above vaccines, separate administration of these vaccines may be considered. Prophylactic use of paracetamol reduces the incidence and severity of fever without affecting the immunogenicity of BEXERO or standard vaccines. The effect of antipyretics other than paracetamol on the immune response has not been studied.

Concomitant administration of BEXERO with other vaccines not listed above has not been studied.

When BEXERO is administered simultaneously with other vaccines, the injection site should be rotated (see section 4.2).

Application features

As with other vaccines, the administration of BEXERO should be postponed in patients with acute severe fever. The presence of a minor infection, such as a cold, is not a contraindication.

Do not administer the vaccine intravascularly.

As with all injectable vaccines, appropriate medical care and supervision should always be readily available in case of anaphylactic reactions following the administration of the vaccine. The vaccinated person should remain under the supervision of a healthcare professional for at least 30 minutes after vaccination.

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions such as psychogenic reaction to needle injection, may occur in connection with the administration of the vaccine (see section 4.8). This should be taken into account to prevent injury to the patient if they faint during vaccination.

This vaccine should not be administered to individuals with thrombocytopenia or any bleeding disorder that is a contraindication to intramuscular injection unless the potential benefit clearly outweighs the risk of administration.

As in the case