According to data published in the Boletín Epidemiológico Semanal, for the 2006–2007 period, the incidence rate of reported IMD cases (confirmed cases and suspected but unconfirmed cases) was 1.37 per 100,000 inhabitants, decreasing to 1.21 per 100,000 inhabitants in 20108 and to 0.93 per 100,000 in 2011.9

For serogroup B, the incidence was 0.77 per 100,000 inhabitants per year.7 The highest rates corresponded to children younger than 5 years (13 cases per 100,000 for infants younger than one year, and 4.3 cases per 100,000 inhabitants in the 1-to-4 year old age group).10

The incidence of IMD by serogroup B in Spain is slightly higher than the European mean, ranking fifth after Ireland, United Kingdom, Lithuania and Belgium in the European Union (EU), and second among the most populous countries.7 In terms of the total number of cases, Spain ranks third in Europe after the United Kingdom and France.7

The decline in the number of cases of serogroup B disease observed in recent years is similar to that seen in other European countries.8 Its cyclical nature requires strict surveillance in order to generate data towards the potential use of vaccines with different formulations, and to monitor the impact of the use of these vaccines. For example, in the 1975–1985 decade, meningococcal disease in Galicia reached rates of 30 cases per 100,000 inhabitants.8

It is estimated that between 10% and 14% of cases of IMD are fatal, and that between 8% and 20% to 30% of survivors suffer from long-term sequelae.11,12 In 2011, the mortality rate in Spain reached 13.6% (95% CI, 10.5%–17.2%), somewhat above the European mean (8.7%; 95% CI, 7.7%–9.6%), and was very similar across all age groups.7 The mortality was slightly lower in cases caused by serogroup B, but this must be interpreted with caution considering the low number of cases that are due to other individual serogroups.7

Some of the sequels associated to meningitis or meningococcal septicaemia are hearing loss, amputations, skin complications, psychosocial problems, hydrocephalus, other neurological and developmental disorders, and kidney failure.11,13

It is important that we consider the economic impact and the burden of hospitalisation that result from IMD in Spain. A study on the hospitalisations and deaths associated with IMD based on data from the Conjunto Mínimo Básico de Datos (mandatory basic set of data documented at discharge in Spain)14 between 1997 and 2008, showed an annual hospitalisation rate of 2.33 per 100,000 inhabitants with an associated direct annual cost of more than 5 million euro.14

For survivors affected by permanent sequelae, the latter put a considerable burden on them and their families from both an economic and a quality of life perspective that must be taken into account when deciding whether or not the vaccine should be included in the routine schedule. A study conducted in Spain showed that the short- and long-term costs associated with surviving patients that have sequelae from IMD constitute a considerable economic burden. The total cost for severe long-term sequelae associated with septicaemia amounts to 2,515,554 euro, and the cost for severe long-term sequelae associated with meningitis to 3,219,653 euro.15

According to the summary of product characteristics of the Bexsero® vaccine, currently approved in Europe and by extension in Spain, it is indicated for active immunisation against IMD caused by serogroup B N. meningitidis starting at 2 months of age.3 Thus, the vaccine is approved for administration in both healthy and at-risk individuals older than 2 months.16

The experience of 10 clinical trials that assessed the immunogenicity of this vaccine comprehended approximately 5800 individuals, of whom 4000 were children aged 2–24 months, 84 children aged 40–43 months, and 1738 adolescents or adults aged 11–55 years.8 These studies demonstrated that the vaccine is immunogenic and safe in all of these age groups, and that it induces immunological memory.

It is very difficult to demonstrate efficacy in clinical trials and population effectiveness in the prevention of a disease as rare as this one. Only the introduction of the vaccine in routine immunisation schedules and subsequent epidemiologic surveillance could prove its effectiveness in vaccinated and unvaccinated populations, similar to what occurred with the vaccines against group C meningococcus or Haemophilus influenzae type b. It is unlikely that it will be any different with the MenB. The effectiveness data from the United Kingdom will probably be the earliest evidence on this subject, as this country has already introduced the vaccine into its routine immunisation schedule.17 Furthermore, more data on the duration of immunogenicity will become available in upcoming years that may influence future changes in immunisation guidelines, as occurred with the meningococcal C vaccine.

The Meningococcal Antigen Typing System (MATS) is a method developed to assess the potential coverage of the 4CMenB vaccine against circulating strains of MenB, although it could be used for other vaccines. This method is used to find out the percentage of meningococcal strains that could be killed by the antibodies contained in the vaccine.

The MATS involves a vaccine antigen-specific enzyme-linked immunosorbent assay (ELISA) that detects qualitative and quantitative differences in the expression of these antigens. It measures both the immunologic cross-reactivity and quantity of the expressed NHBA, NadA and fHbp antigens. It also includes PorA genotyping information to assess the potential coverage associated with this antigen. The results obtained with the ELISA were correlated with the killing of strains by SBA.

In a study conducted with MenB strains isolated in several European countries (Germany, France, England and Wales, Italy, Norway, Spain and Portugal), MATS was used to predict that the 4CMenB vaccine would cover 73–87% of the strains.18 The data obtained in Spain, which included 300 strains, predicted a coverage of 69% (95% CI, 48.0–85.3%),18,19 slightly below the coverage estimated for the other European countries under study. The estimated coverage in Spain was similar to that of the United Kingdom (73%; 95% CI, 58%–87%), for which 535 strains were analysed.18

Based on the five epidemic seasons from 2007–2008 to 2011–2012, which resulted in 914 cases in children younger than 5 years and a total of 6933 disability-adjusted life years (DALYs), and considering the potential effectiveness percentage of 69% predicted by the MATS data, the vaccine could prevent up to 631 cases in the next five seasons and a total of 4784 DALYs in Spain for an assumed vaccine coverage of 100%.4

The safety of this vaccine has been evaluated in nine clinical trials that included a total of 4800 infants younger than 12 months, 1600 toddlers aged 12–24 months, 84 children aged 40–43 months, and 1738 adolescents and adults aged 11–55 years. The most frequent local and systemic adverse reactions observed in children younger than 24 months were pain and redness at the injection site, fever and irritability. Clinical trials in infants showed that the fever developed more frequently when the 4CMenB vaccine was coadministered with routine vaccines (61%) than when given alone (38%) or compared to routine vaccines administered alone (33%).16 The fever is usually mild, with onset in the first 6h and rarely lasting past 36–48h. A fever higher than 38.5°C was observed in 37% of children older than 12 months and in only 2–5% of adolescents.

When it comes to the use of antipyretics, one study showed that the prophylactic use of paracetamol reduced the likelihood of developing a fever and other local and systemic adverse effects without diminishing the immune response to the administered vaccines.20

The published literature shows that Bexsero® is compatible with routine vaccines, except for the meningococcal C vaccine,16,21 for which there is a study underway the results of which will be available in 2015. It is also authorised for coadministration with the pneumococcal 13-valent conjugate vaccine (Prevenar 13®), as well as the rotavirus22 and the varicella16 vaccines.

The AEMPS stated its position in regards to the vaccine on April 5, 2013: “Based on the lack of data on the clinical efficacy of this vaccine, combined with the present reduced incidence of serogroup B meningococcal disease, and awaiting post-authorisation data on its effectiveness, and in the absence, at the moment, of official recommendations for its use from the Directorate of Public Health, it is recommended that the Bexsero® vaccine be restricted to hospital use until the Directorate of Public Health, in the context of the Consejo Interterritorial del Sistema Nacional de Salud (Interterritorial Council of the National Health Service), establishes the objectives or policy to follow in the use of this vaccine”.5

Similarly, on June 20, 2013 the working group on MenB of the Ponencia de Programas y Registro de Vacunaciones del Ministerio de Sanidad, Servicios Sociales e Igualdad (Vaccination Programmes and Registry Communications Group of the Ministry of Health, Social Services and Equality) determined that “taking into account the available information and the epidemiological situation, the inclusion of this vaccine in the routine immunisation schedule is not considered justified at the present time. It is recommended that evaluation of this vaccine resumes once key information becomes available, especially as it pertains to clinical protection in geographical regions or countries in our area, and that a laboratory surveillance system is set up to determine the effectiveness of vaccination and the evolution of the N. meningitidis population. The healthcare authorities will evaluate the use of the vaccine in the event of outbreaks and isolated cases of serogroup B meningococcal disease”.4

Unfortunately, these arrangements make the situation of the Bexsero® vaccine in Spain totally different from that in the other European countries. In Spain, the vaccine has been available officially since August 13, 2014,23 but only in private and public hospital pharmacies. Which is to say, it cannot be acquired in community pharmacies.

Based on the directives of the Ministry of Health, at present the only official recipients of this vaccine are individuals with risk factors for IMD (individuals with a complement deficiency or undergoing treatment with eculizumab, with asplenia or severe splenic dysfunction, or with more than one prior episode of IMD, or laboratory staff that manipulate samples that may contain meningococci) or the vaccine can be used in the event of outbreaks.4,5 In the first case, recipients represent a very small percentage of the individuals that have this disease, so the expected impact of vaccination would be very small. Paradoxically, there is a lack of immunogenicity studies precisely in patients that are at risk for IMD, while there are studies in healthy individuals (younger than 50 years) for whom the vaccine has not been authorised in Spain.

The situation of the 4CMenB in the rest of the European Union (EU) countries is completely different, as all of them, unlike Spain, have authorised it for its unrestricted distribution in community and hospital pharmacies.

In the United Kingdom the vaccine has been included in the routine immunisation schedule. In March 2014 this country approved its inclusion in the immunisation programme with a 2+1 schedule (at 2, 4 and 12 months) after reviewing all the available documentation and analysing its cost-effectiveness.24

Poland and Austria are well ahead in the process of adding the vaccine to their immunisation schedules, and other countries and regions, such as the Czech Republic, Saxony (in Germany) or Apulia, Basilicata and Tuscany (in Italy) have already included it in theirs.

Other countries, such as Germany and France, are currently analysing all the available information.25,26

The possibility of routine vaccination of children younger than 24 months and adolescents 15–19 years of age as well as at-risk groups is being considered in Australia.27 In the United States the vaccine is yet to be approved by the Food an Drug Administration, but it was used on an emergency basis in over 14,000 students due to independent outbreaks of serogroup B meningococcal disease in two universities (Princeton and UC Santa Barbara).28,29 In Canada, which had a mean incidence rate of 0.57 cases per 100,000 inhabitants per year for the 2007–2011 period, it was decided to implement routine vaccination of the population aged 2 months to 20 years in Quebec.30

The vaccine is indicated for immunisation against IMD caused by serogroup B N. meningitidis starting at 2 months of age.3Table 3 shows the posology currently recommended in the summary of product characteristics approved by the EMA.16

Final considerations and recommendations of the Comité Asesor de Vacunas de la Asociación Española de Pediatría on the four-component meningococcal serogroup B vaccine (4CMenB)

Table 4 summarises the main data on group B meningococcal disease and its prevention by means of vaccination.

Table 5 presents the considerations and recommendations of the CAV-AEP on this vaccine at the time this paper was being written (August 2014). The committee believes that this vaccine has the profile of a routine vaccine that should be included in the schedules of every autonomous community in Spain, and that the vaccine should be available for its unrestricted distribution to any individual older than 2 months of age.