Neisseria meningitidis is an exclusively human pathogen, capable of causing severe infections such as invasive meningococcal disease (IMD)1. Age is an essential factor in the distribution of the risk associated with meningococcus, and therefore there is a higher risk of invasive disease in children, although there is a higher rate of carriers among adolescents and young adults2.

In 2014, 2,760 confirmed cases of IMD in Europe were reported to the European Centre for Disease Control and Prevention; this shows an annual incidence rate of 0.5 cases per 100,000 inhabitants. Of these cases, 64% were caused by a serogroup B meningococcus (MenB)3.

Currently there are six meningococcal vaccines marketed in Spain4: three monovalent vaccines against serogroup C (Menjugate®, Meningitec® and NeisVac-C®), two tetravalent vaccines against serogroups A, C, W and Y (Menveo® and Nimenrix®), and the four-component vaccine against the serogroup B identified with the acronym 4CMenB (Bexsero®). A new vaccine has been recently marketed against serogroup B, with the two antigenic variables of the FHbp protein (binding protein to factor H), known as MenB-FHbp (Trumenba®).

Currently, only the vaccine against serogroup C is included in the systematic child vaccination calendar in Spain, while the 4CMenB vaccine is only recommended and reimbursed under some special risk situations within the Spanish National Health System (SNS)5.

Vaccine safety and pharmacovigilance are two key elements in any vaccination program. Those clinical trials conducted on the 4CMenB vaccine show that the main adverse reactions (ARs) reported are pain and local erythema. Moreover, in the case of babies, fever >38 °C appears in 14% to 50% of the vaccinated group, and clearly higher figures will be reached (85%) if administered jointly with other vaccines6–11. It is worth highlighting that these clinical trials were conducted particularly with healthy children, adolescents and adults; however, and regardless of the clear indication of this vaccine for patients in special situations (anatomic and functional asplenia, and others), there are no studies so far dealing with safety in this group.

For this reason, the objective of this research is to understand the safety profile of 4CMenB vaccine in adult persons in special situations with recommendation of vaccination according to the Spanish NHS.

In total, the study included 72 patients who met the inclusion criteria. Of these, 54.2% (39) were male and 45.8% (33) were women. Their mean age was 52.5 years, with a ±18.0-year standard deviation.

Regarding the medical indication for vaccination against 4CMenB, the sample was distributed into: 81.9% (59) with anatomic asplenia, 12.5% (9) with previous IMD, 2.8% (2) on treatment with eculizumab, 1.4% (1) with common variable immunodeficiency in a lab staff in contact with N. meningitidis, and 1.4% (1) with functional asplenia due to graft-versus-host disease in a patient with allogeneic transplant of haematopoietic progenitors. On the other hand, 80.6% (58) were receiving treatment for some chronic disease at the time of vaccination, while 19.4% (14) were receiving no treatment.

The most frequent adverse reactions, appearing within the first 24 hours after vaccination with the first and second doses of Bexsero® were: local pain [80.6% (58) after the first dose and 77.8% (56) after the second dose], headache [20.8% (15) after the first dose and 18.10% (13) after the second dose] and fever >38°C [12.5% (9) after the first and second doses]. Figure 1 shows the frequency rate of all adverse reactions described at Bexsero®‘s product specifications for the first and second doses of the vaccine. No statistically significant differences were found between any of the variables studied. However, when comparing the adverse reactions identified in this study with those shown in Bexsero®‘s PS, some noteworthy differences can be observed. Thus, we can highlight the development of six adverse reactions that are not described in the PS of the vaccine for the >11-year-old and adult group, such as: fever >38 °C, somnolence, loss of appetite, irritability, vomiting and paleness (Table 1).

Figure 1.

Proportion of requested adverse reactions after the first and second doses of Bexsero®, with their 95% confidence interval, and statistical analysis of the differences between them (p values in italics). The number of patients who presented each one of the adverse reactions is shown in the table below the graph.

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Pain at the site of injection was evaluated at 24 hours of vaccination through an AVS on which each patient had been previously trained; 80.6% (58) and 77.8% (56) of patients reported local pain within the first 24 hours after vaccination with the first and second doses. The mean AVS score with the first dose was 3.22 (CI95%: 2.67-3.76) and 3.23 with the second dose (CI95%: 2.69-3.78). There were no statistically significant differences (p=0.979); however, there was a higher frequency of moderate pain with the first dose (AVS score 4-6), and of mild pain with the second dose (AVS score 1-3), as shown in Figure 2. It is worth highlighting that only two patients assigned a value >8 in the AVS to their pain both for the first and the second dose of the vaccine.

Figure 2.

Profile of pain reported in the injection site according to number of doses, at 24 hours after vaccination, according to the AVS scale: mild (1-3), moderate (4-6) or intense (7-10).

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Adverse reactions in the first seven days after vaccination (“not requested”) were analyzed with qualitative methodology. Of those 72 persons included in the research, only 2 reported no sign or symptom within the seven days after vaccination. On the contrary, the remaining 70 persons reported some adverse reaction, including: local pain [84.72% (61)], general malaise [63.11% (26)] and fever [22.22% (16)] within the first seven days after Bexsero®. The “latency” and “duration” variables could not be analyzed due to lack of record by patients. Table 2 shows the grouped outcomes.

It is worth noting that even though 80.6% of patients in the study were receiving chronic treatment due to their basal condition, the development of both local and systemic adverse reactions was attributed to vaccination, because symptoms were compatible both clinically and epidemiologically, and moreover, these were solved without any treatment interruption.

The only adverse reaction classified as severe, according to the clinically relevant criterion, was reported to the SEFV-H (Record No. 600167). This adverse reaction consisted in general malaise with nausea, dizziness, and unspecific abdominal discomfort; it lasted over three days and then disappeared.

Phase IV studies are essential in order to improve the detection of adverse pharmacological reactions. In most occasions, infrequent adverse reactions, or those appearing in specific patient subpopulations, are not identified in pre-marketing stages; therefore, post-marketing monitoring becomes specially relevant14,15. Many studies have been conducted with the 4CMenB vaccine in paediatric population, but not so many in the adult population, beyond those conducted in specific closed populations, such as university campuses or labs with staff at risk10,16,17. Therefore, we have a lack of clinical trials, not only in the adult population but specifically for the group of adults in special situations. For this reason, this present research represents a novelty in terms of studying the safety of this vaccine in the adult population in special situations.

The frequency of adverse reactions on the sample under study has been compared with the one stated in the product specifications12. It is worth highlighting that the PS states that the frequency rate of fever for the >11-year-old and adult group is unknown, while this study has recorded a frequency >10% for both doses. These results coincide with what other authors have described: they have also found, although with great variability, that the frequency of developing fever is higher than expected6,9.

A recent systematic review of the safety of the 4CMenB vaccine vs. Trumenba® (a recently marketed vaccine against meningococcus B) and vaccines routinely administered in children and adolescents, reached the conclusion that the most frequently reported severe adverse reactions were febrile seizures18. These results cannot be compared with this study that has been conducted in adults in special situations; besides, only one severe case was identified. It is worth noting that the same review found a 74% prevalence of pain at the injection site, and a 24% prevalence of fever18; both results are higher than those found in our research, although matching the Product Specifications of the vaccine for this group12. On the other hand, the quantitative evaluation of local pain through the AVS represents an innovation regarding previous studies on the safety of the 4CMenB vaccine. So far, authors such as Santolaya and Grossner used qualitative scales where pain was rated according to its intensity: mild, moderate or severe8,9. However, using a quantitative scale allows more accurate comparisons of local pain intensity, and this scale is the most frequently used in research associated with pain measurement19,20. No significant differences have been found in terms of pain intensity between the first and the second doses. Unlike what other authors have done, i.e. administering Bexsero® and placebo, or Bexsero® and other vaccines9, in this case both doses were administered in the same conditions, and therefore these results cannot be compared.

Finally, the main limitation in our study is sample size. In this sense, the implementation of inclusion criteria and vaccination conditions, as well as the target population chosen to conduct this research, made it difficult to obtain a large sample within a reasonable period of time; in the future, it could be considered to conduct multicentre studies.

Summing up, vaccination against meningococcus B with Bexsero® in adults in special situations shows a good safety profile; however, there is limited information available, given the low number of patients studied. The frequency of fever in this population is higher than expected for the same age group according to the Product Specifications. Local pain is the adverse reaction most frequently reported for both vaccine doses; however, pain intensity is low.

No funding.

No conflict of interests.