Meningococcal Vaccines

178 Review

Meningococcal Vaccines Halil Özdemir1, Ergin Çiftçi2 1Clinic of Pediatric Infectious Diseases, Konya Training and Research Hospital, Konya, Turkey 2Division of Pediatric Infection Diseases, Ankara University Faculty of Medicine, Ankara, Turkey

Abstract Invasive meningococcal disease is a serious and global life-threatening disease. It affects more than 500.000 people worldwide annually, with 50.000 deaths and 50.000-100.000 severe sequelae, despite treatment. Six serogroups (A, B, C, W135, X, and Y) account for the majority of cases of meningococcal disease worldwide. Meningococcal polysaccharide vaccines were introduced several decades ago and have led to the decline in the burden of disease. However, these vaccines have several limitations, including poor immunogenicity in infants and toddlers, short-lived protection, lack of immunologic memory and herd immunity, and negligible impact on nasopharyngeal carriage. The conjugation of polysaccharide vaccines has the potential to overcome these draw- backs. Herein, we reviewed the new information about the quadrivalent conjugated meningococcal vaccines and meningococcal serogroup B vaccines. (J Pediatr Inf 2014; 8: 178-86) Keywords: Conjugated meningococcal vaccines, meningococcal serogroup B vaccines, meningococcal infections, Neisseria meningitidis

A. Meningococcal Epidemiology coccal infections are still high despite early diag- and Serogroups nosis and appropriate therapy. Although mortality is reported as 10-14%, it may reach the Meningococcus has throughout the history sequelaes rates of 20-40% such as deafness, been one of the most frightening infections caus- convulsions, amputation and mental retardation. ing recurrent epidemics all over the world. Annually 500 thousand invasive meningococcal Meningococcal infection has a broad variance disease cases and nearly 50 thousand mortali- leading to asymptomatic carriage, occult bacte- ties are seen worldwide (4). Received: 02.05.2014 remia, sepsis, meningococcemia, fast-develop- The most important characteristic differenti- Accepted: 02.06.2014 ing meningococcemia characterized by tissue ating meningococcia from other bacteria causing

Correspondence loss (1). N. meningitides is one of the most com- bacterial meningitis is that it can lead to epidem- Address: mon causes of meningitis and sepsis in children ics. The only reservoir in meningococcal infec- Halil Özdemir, Konya and adults all over the world. In parallel to the tions is humans. N. meningitides is carried Eğitim ve Araştırma Hastanesi, Çocuk rise of pneumococcal conjugate and Haemophilus nearly in 10% people’s the upper respiratory Enfeksiyon Hastalıkları influenzae type b (Hib) vaccines to be included tracts and transmitted from human to human Birimi, Konya, Türkiye Phone: +90 532 493 52 43 in the national vaccine calendars, N. meningitidis through droplet spread. Meningococcal infec- E-mail: today is the most important cause of purulent tions are common usually in children under two [email protected] meningitis. In a multi-centered study done by years old in developing countries and over ten ©Copyright 2014 by Pediatric Infectious Diseases Society - Ceyhan et al. in Turkey, it was found that menin- years olds in industrialized countries (2, 5, 6). Available online at www.jpediatrinf.org gococcus was on the top of the list with 56.5% in Some people are under greater risk for invasive DOI:10.5152/ced.2014.1765 childhood acute bacterial meningitis (2). meningococcal diseases. The most important In the United States of America (USA), factor is age and the disease is more prevalent 1400-3000 new cases diagnosed with invasive in infants under one year old and adolescent and meningococcal diseases are reported annually young adults aged 15-24. The peak incidence of (3). Morbidity and mortality of invasive meningo- the endemic disease is under 1 and 35-40% of Özdemir and Çiftçi. J Pediatr Inf 2014; 8: 178-86 Meningococcal Vaccines 179 the disease in children under 5 is seen in children under in 1997 and 2000 that serogroup C (27.8%) and sero- 1 (7, 8). Other factors generating predisposition for group Y (53%) were respectively the common ones (19- meningococcal diseases are living in over-crowded envi- 21). Similarly, while it was found that the most common ronments (such as boarding schools and military), pover- one was serogroup B (35.2%) in carriage in two studies ty, smoking and exposure to smoking, having viral respira- done in Manisa in 2001 and 2002, serogroup W135 was tory infections especially influenza, winter months and the most common with 35.2% in 2005 in Istanbul (22, 23). moving to a new social environment (9). Furthermore, First studies regarding the patients were done in Ankara sensitivity to meningococcal infections is defined whether and the most common serogroup was B with 32% in first there are IgG type antibodies developing against capsule studies (between 1974 and 1981), followed by serogroup polysaccharide. Complements also have an important role A (20%) and C (16%) (24). In the second study (1987), on in bactericidal activity. Therefore, people with the lack of the other hand, it was reported that majority of the isolates bactericidal antibody or lack ofhereditary terminal comple- were serogroup C (25). Given the results of a multi-cen- ment activity (C5-C9) and people with anatomic/functional tered meningitis surveillance study initiated by Ceyhan et asplenia, or lack of hereditary properdin or factor D have a al. in 2005, they found that N. meningitides was the in the higher risk ofmeningococcal disease respectively. The risk first place among the pediatric bacterial meningitis agents in people with the lack of properdin or lack of terminal between 2005 and 2012, and of the isolates in the 2005- complement is 250 and 600 times greater (10-12). 2006 period, 42.7% were serogroup W135 and 31.1% Thirteen serogroups have been defined leading to serogroup B; in the 2007-2008 period, serogroup B was meningococcal diseases and the groups causing the most on the top of the list (35.1%), followed by serogroup W135 frequently diseases are A, B, C, Y, W135 and X. Serogroups (17.6%); the dominant serogroup in 2009-2010 period may differ with regards to geographical regions and age was again W135 (56.1%), followed by serogroup A groups (13, 14). While meningococcal infections are spo- (36.6%), and in the 2012-2012 period, serogroup W135 radically seen in developed countries, firstly group A and (56.5%) was again in the first place. It wasproved by this then W135-associated epidemics have long been known study once again that the increase in genotyping and in meningitis zone in Africa (from Senegal to Ethiopia in W135 stemmed from the transfer of the strains responsi- Sub-Saharan Africa) (2, 15, 16). Apart from that, sero- ble for the epidemic in Saudi Arabia to Turkeyvia the group C-related epidemics have occurred especially Turkish pilgrims (2, 18, 26). among university students in England and North America (15). There occurred a Serogroup W135 epidemic during B. Meningococcal Vaccines pilgrimage between 2000 and 2002 in Saudi Arabia and spread to other Muslim countries (2). Given the latest Polysaccharide vaccines have been developed tofight serogroup distributions commonly seen in different regions against meningococcal diseases and then since both the of the world are examined, while serogroup B and C are efficiency of these vaccines was insufficient and they the factors of meningococcal infections in the continents were not be used in children under two, meningococcal of Europe and America, serogroup B in Japan and conjugate vaccines have been developed. Since polysac- Australia and serogroup A in China and Africa are the charide vaccines are not T-cell-dependent, they do not dominant groups. Serogroup Y, one of the rare serogroups generate immunological memory and are not effective in in recent years in North America and W135 are increas- children under two. Therefore, booster dose should be ingly isolated more frequently in Muslim countries includ- administered at intervals. In conjugated vaccines, poly- ing Turkey sending pilgrims to Saudi Arabia. In fact, in a saccharide antibody was bound to a carrier protein and study done in the USA, it was found that while the rate of converted into a T-cell and eventually it was enabled to be infections caused by serogroup Y in 1988 rose from 2% to effective in infants and allowed the patient to be immune for 36% in 2007 (17). a long time. Furthermore, nasopharyngeal carriage was Given the studies done with meningococcal sero- decreased through conjugated vaccines and their contribu- groups in Turkey, it is seen that initially studies regarding tion was observed to contribute to herd immunity. Since nasopharyngeal meningococcal carriage in healthy peo- serogroup B has had immune tolerance towards polysac- ple and then in the later years, studies serotyping in peo- charide in recent years, serogroup B vaccines have come ple who had invasive meningococcal diseases were car- into use with a non-capsular approach (17, 27). ried out. It is observed that in the carriage studies locally carried out in various centers, the dominant serogroup I. Polysaccharide vaccines: The first polysaccharide has changed over the years (18). In a study done in vaccine ever was licensed in the USA in 1974. Until today, Ankara in 1996, while serogroup B was the most common one-valent (A and C), 2 valent (A/C) and for valent (A/C/Y/ with 47.5%, it was found in two different studies in Istanbul W135) have come into use. Currently, quadrivalent vac- Özdemir and Çiftçi. 180 Meningococcal Vaccines J Pediatr Inf 2014; 8: 178-86 cines are in use; one is the Menomune® vaccine in use in meningococcal vaccine has yet been added to the routine the USA and the other one is Mencevax® licensed in vaccine calendar in Turkey. Europe. Since the capsule polysaccharides inmeningo- coccai are the T-cell-independent antibodies, they only 1. Serogroup C conjugate vaccine (Menjugate®): It stimulate mature B lymphocytes. Therefore, they fail to was included for the first time in the routine vaccine pro- generate the expected memory response in the case of gram in England in an attempt to control the epidemic and encountering once again the T-cell-dependent memory 76% remission was enabled in the prevalence rate of the response, long-term permanent antibodies and the same vaccine in adolescents. It was revealed that the effectivity antibody again. The protective immunity reaches the level of the vaccine was 97% in adolescents and 92% if school of 85-100% following the two weeks after vaccination. age children and adolescents were considered together. However, the antibody levels in children drop rapidly. It Since carriage was reduced by 66% and the disease was proved that immunity against especially serogroup prevalence in unvaccinated people reduced by 67%, it Ccould drop in recurrences. The immune response gener- was thought herd immunity could be enabled (34). ated by these vaccines in children under two year olds is weak and therefore, cannot be used before two years ago. 2. Serogroup A/C/W135/Y conjugate vaccines: The protectiveness of polysaccharide vaccines in children There have so far been 3 kinds of quadrivalent (A/C/Y/ under 5 years oldlasts for 1-3 years and in adolescents W135) conjugated vaccines licensed to be administered and adults for 3-5 years.Therefore, booster doses are to infants, children and adults and they are available in needed.Additionally, these vaccines do not reduce car- Turkey as well. riage and fail to generate herd immunity. The undesirable side effects are rare and the most common side effects a) MenACWY-DT conjugate vaccine (Menactra®): are local pains, irritability, headaches and exhaustion. Menactra®, the first conjugated quadrivalent vaccine in Fever was reported in 2-5% of the adolescents. Today, the world, includes 4 meningococcal polysaccharides conjugated vaccines are used instead of polysaccharide with each one covalently bound to diphtheria toxoid pro- vaccines and the polysaccharide vaccinesare recom- tein. It does not include adjuvant orprophylactics, and is mended only for people over the age of 55 who has administered intramuscularly (35). It was licensed in the meningococcal vaccine indication (28, 29). USA in 2005 to be administered to 11-55 adolescent and adult age groups in order to prevent meningococcal dis- II. Conjugated Vaccines: The infants under 2 years eases caused by serogroup A, C, Y and W135. are the one of the age groups in which invasive meningo- Subsequently, age indication was firstly expanded to 2 coccal infections are the most common. The ineffectivity years and it was approved for 9-23 months old infants by of polysaccharide vaccines in these infants has acceler- the FDA (Food and Drug Administration). It is recom- ated the development of meningococcal vaccines (30). mended as a one dose for children above two years old, The first meningococcal vaccine was the one-valent sero- and two doses for infants aged 9-23 months with at least group C vaccine and firstly went into use in England in 3 month intervals (32, 33). 1999 (31). Subsequently, four valent vaccines composed In pediatric studies done related to Menactra®, it was of serogroup A, C, Y and W135 vaccines were developed found that antibody levels gradually decreased, and espe- (31, 32). Besides, different from the four valent vaccine, cially the antibody levels of more than half of the 2 year- two valent (serogroup C and Y) vaccines were developed old childrenvaccinated one-dose dropped. It was also as well (31). Afterwards, serogroup C vaccine (Menitorix®) revealed that the antibody titers in adolescents did not conjugated with Hib was licensed in the USA (33). At a drop; the antibody response in those given booster shot result of the research carried out by the World Health was higher than those in the serogroups shot for the first Organization (WHO) and Program for Appropriate time except those in serogroup A (36, 37). There is no Technology in Health (PATH), conjugated meningococcal potential problem in using Menactra® together with other A vaccine (MenAfriVac®) was developed to be used in the vaccines (measles-mumps-rubella vaccines, varicella, countries in the African meningitis zone. The vaccine was hepatitis A, 7-valent conjugated pneumococcus) with used for the first time in Burkina Faso in 2010, and in Mali regards to efficiency and reliability. Despite the decrease and Niger in 2011. Finally, Hib conjugated meningococcal in the antibody responses only against 3 of the 7 sero- serogroup C and Y vaccines were licensed (31, 33). The types in the 7-valent conjugated pneumococus vaccine as conjugated vaccines in use today are one-valent sero- a result of the combined use, the fact that the rate of chil- group C, one-valent serogroup A and due to the difference dren with protective level of antibody titres was over 98% of protein they are conjugated with, 3 different quadriva- does not make this decline clinically significant. Even lent (A/C/Y/W135) conjugated vaccines are used. No though the side effects (fever and local reactions) are Özdemir and Çiftçi. J Pediatr Inf 2014; 8: 178-86 Meningococcal Vaccines 181 more commonly observed, they are within acceptable to be used for in children under one year old and above limits. Moreover, after combined administration with other and in adults. It is administered intramuscularly as a single vaccines, no change was observed in the frequency of dose to all approved age groups. Currently, the only quad- side effects (35). rivalent conjugated vaccine to be used in 12-23 month-old Despite a decline in the prevalence of invasive menin- infants in Europe is Nimenrix® (28). gococcal diseases following the use of Menactra® in the Different from the two quadrivalent meningococcal USA, it was seen that the diseases peak around the age conjugate vaccines, a new spacer molecule was used in of 18 continued. Therefore, while the Advisory Committee A and C conjugation in Nimenrix®; the purpose of this was on Immunization (ACIP) in the USA recommended the to increase the immunological response to these sero- routine administration of quadrivalent conjugated menin- groups. It is because in the other studies done with the gococcal vaccine to adolescents aged between 11 and other two quadrivalent conjugated vaccines, it was found 18, they decided that one booster dose be shot to adoles- that antibody response related with serogroup A was cents vaccinated before 16 years old (38). lower than other serogroups (42). In a study in which Nimenrix® and Menactra® were compared, it was found b) MenACWY-CRM conjugate vaccine (Menveo®): that the percentage of cases whose protective antibody Menveo® was obtained by binding the C/W135 sero- titres were 1:4 and 1:8 for serogroup A, Y and W135 was groups to CRM197 mutant diphtheria toxoide (non-toxic higher than those vaccinated with Nimenrix®. However, purified protein obtained from corynebacterium diphthe- the effect of this difference on clinical protection is ria) of capsule polysaccharides.It does not contain adju- unknown (43). All the studies proved that the vaccine was vant orprophylactics, and is administered intramuscularly well-tolerated in all age groups and that it had similar side (39). It was licensed as one dose for people aged between effect profile with immunogenetical, other polysaccharide 11 and 55 in the USA and Europe in 2010 and the age and meningococcal conjugate vaccines. Similarly, as it group was rearranged as 2-55 in 2011. Subsequently, was the case with other conjugated vaccines, no interac- European Medicines Agency (EMA) approved its use for tion was observed in its combined use together with other those above 2 years old (with no upper age limit) in 2012; childhood vaccines (30). and the FDA in the USA approved the use of vaccine for infants in August 2013 basing their decision on the immu- 3. Serogroup A conjugate vaccine (MenAfriVac®): nogenicity and reliance study involving 8700 infants. A serogroup-bound meningococcal epidemics are Accordingly, Menveo® was recommended 4 doses in 2, 4, extremely common in African meningitis zone and epi- 6 and 12 months during early infancy and 2 doses in 7th demic-related mortality occurs more here compared to and 12th months in the late infancy period (33, 38, 39). other parts of the world. Since quadrivalent meningococ- In studies in which Menveo® and Menactra® were cal conjugate vaccines were more expensive, a serogroup compared, while no difference emerged with regards to A polysaccharide/ tetanus toxoid-protein conjugated vac- immunogenicity and side effects between the two vaccine developed through “Meningitis Vaccine Project” by cines in children aged 2-5 and 5-10, and in adults, it was WHO-PATH was started to be administered as a single found that the antibody levels of over 1:8 obtained in ado- dose to everyone aged 1-29 in December 2010 as part of lescents for the serogroups A, W135 and Y vaccines were a mass vaccination campaigns in Burkina Faso, Mali and higher than those vaccinated with Menveo®. However, it is Niger. According to the data obtained in Burkina Faso not known whether this difference is important with within this project, it was proved that serogroup A conju- regards to clinical protection. No problem was found in gate vaccine decreased the serogroup A-related menin- combining Menveo® together with other vaccines (diphthe- gococcal disease nearly 100%, eliminated the serogroup ria, tetanus, acellular pertussis, Hib, inactive polio, hepati- A epidemics on regional basis, caused decline in carriage tis B); in fact, when it was used in combination with the and improved herd immunity (2, 44). other vaccine, 7-valent conjugated pneumococcus vaccine in which CRM197 was used as a carriage protein, no 4. Hib-meningococcal serogroup C-Y conjugate interaction occurred Similar symptoms to Menactra®were vaccine (MenHibrix®): It is a combined vaccine that observed with regards to side effects (30, 40). includes three different (Hib, meningococcal serogroup C and Y) capsule polysaccharides and uses tetanus toxoid c) MenACWY-TTconjugate vaccine (Nimenrix®): for conjugation. It was approved by the FDA in June 2012 The carriage protein of Nimenrix®, a quadrivalent menin- to be used in infants aged 6 weeks and 18 months in gococcal conjugate vaccine inclusive of polysaccharide order to be protected from invasive Hib and serogroup C serogroups A, C, W135 and Yis tetanus toxoide (41). The and Y-related meningococcal infections. ACIP recom- use of this vaccine was approved by EMA in April in 2012 mended MenHibrix® for children with an increased risk Özdemir and Çiftçi. 182 Meningococcal Vaccines J Pediatr Inf 2014; 8: 178-86 factor in this age group. The vaccine is recommended in ling to the regions where the disease is hyperendemic for six weeks the earliest and the last dose at 18 months old. work/visit are recommended the conjugated meningococ- Besides, it was reported that when the vaccine was cal vaccine. Besides, the microbiology laboratory person- administered together with other childhood diseases in 2, nel dealing with meningococcal isolates are also recom- 4, 6, 12-15 months, there was a decline in its immunoge- mended the vaccine (33, 38). nicity (33). Lastly, regarding the booster dose of the children whose polysaccharide or meningococcal conjugate vac- C. The Use of Meningococcal Vaccines cination is complete, but who continue to pose a risk (Indications) interms of meningococcal disease, the following booster dose vaccination recommendation is made; to children When the recommendations by ACIP in the USA aged 2-6, 3 years later after the first vaccination; to chil- regarding the use of meningococcal vaccines are consid- dren and adolescents aged 7-10, 5 years after the first ered, there are fundamentally three groups targeted to be vaccination. Those administered two doses of primer vac- vaccinated. The first group includes those recommended cination should be shot a booster dose after 5 years. to be vaccinated routinely; the second group is those with Besides, as long as the risk continues, booster doses the risk factor of invasive meningococcal disease or those should be repeated every five years (28, 33, 38). travelling to the regions where the disease is hyperen- Table 1 illustrates the countries that have included demic and the last group is the health personnel (33). meningococcal conjugate vaccines into their national vac- While Menomune®, the polysaccharide vaccine, is the cination calendars, the target group of children and vac- licensed vaccine in the USA, quadrivalent (A/C/Y/W135) cination schemas (33, 45-48). conjugated meningococcal vaccines are Menactra® and Menveo®. Nimenrix® has a license in Europe (28). D. Serogroup B Meningococcal Vaccines Advisory Committee on Immunization (ACIP) recommends the meningococcal vaccine to be routinely admin- Since polysaccharide capsule of Serogroup Bhas a istered to the adolescents aged 11-18. Since the biggest great similarity with the polysaccharide epitopes of neural age group in which invasive meningococcal disease is cell adhesive molecule glycoproteinsin human nerve tis- most common in the USA is the adolescents, it is recom- sues, it has an immune tolerance to serogroup B capsule. mended that the first dose is routinely administered at If the structure of polysaccharide in serogroup B capsule 11-12 and the second dose at 16. In case the first dose is is changed in order to eliminate immune tolerance, this not administered at 11-12, the first dose is recommended time the risk of triggering autoimmunity in humans occurs. at 13-15 and the second dose at 16-18; those who are Therefore, the use of external structure of capsules due to given the first dose at 16 or over, are not recommended a their antigenic characteristics was considered; and simi- booster dose. Besides, the university students who were larly, the development of vaccines in which outer mem- not vaccinated at the 11-18 period and will stay at the uni- brane vesicles (OMV) and outer membrane proteins were versity dormitory are recommended a single dose (33, 38). used were considered as well (28). Advisory Committee on Immunization (ACIP) recommends the vaccine for those with a risk of invasive menin- I. OMV Vaccines: Strain-specific OMV vaccines were gococcal disease from 9 month on (those lacking persis- developed in order to control serogroup B clonal epidem- tent complement component, those with anatomic or func- ics and were used to stop the spread of serogroup B tional asplenia, soldiers-military personnel, HIV-infected epidemics extending all the way to Cuba, Norway, France, people, those wishing to minimize the risk of their meningo- Brazil, Chile and New Zealand. In conclusion, protection coccal disease or controlling meningococcal epidemics or rates varying between 57% and 94% were obtained. those travelling to the regions where the disease is hyper- However, the most important limiting handicaps of OMV endemic. Besides, since children with asplenia have inva- vaccines are that they generate strain-specific protection sivepneumococcus infection risk, Menactra®, conjugated and that they fail to generate cross-protection against meningococcal vaccine which includes diphtheria toxin other strains especially in infants (28, 31, 49). also available in the conjugated meningococcal vaccine should not be administered to children under 2 years old in II. Quadrivalent Serogroup B Vaccine (Bexsero®): order for the immune response not to degenerate against In an attempt to develop non-strain-specific serogroup B the pneumococcus vaccine (33). vaccine by specifying the protected proteins expressed The health personnel are not recommended the rou- on the meningococcus surface, some genomic studies tine administration of meningococcal vaccine. Those with termed as “reverse vaccinology” were carried out. As a the risks mentioned above or the health personnel travel- result, (in addition to the OMV and the inclusive porin A Özdemir and Çiftçi. J Pediatr Inf 2014; 8: 178-86 Meningococcal Vaccines 183

Table 1. Countries that added meningococcal conjugate vaccine in their routine vaccine calendar Countries Conjugated serogroup C vaccine Conjugated serogroup ACWY vaccine The USA • 11-12 years first dose and 16 years second dose • If the first dose shot at 13-15 second dose at 16-18 • >16 years one dose • One dose to students aged between 19-24 staying in dormitory Canada • In frequently seen regions, 3 doses with one-month • At 12 years one dose regardless of the previous interval beginning from 2nd month vaccination history • All infants and children aged 1-11, one dose (12th month on the calendar) Austria • 12th month one dose • 12 years one dose Belgium • 15th month one dose Southern Cyprus • 12th month one dose France • Between 1-24 years one dose Germany • Between 11 months-17 year one dose Greece • In the 2nd, 4th and 6th months 3 doses • Between 11-18 years one dose Island • In the 6th and 8th months 2 doses Ireland • In the 4th, 6th and 13th months 3 doses Italy • Between 13-15 months one dose • Between 11-18 years one dose if not vaccinated before Liechtenstein • Between 12-14 months one dose • Between 11-15 years one dose if not vaccinated before Luxembourg • In the 13th month one dose Holland • In the 14th month one dose Portugal • In the 12th month one dose Spain • In the 2nd month, 12th month and 12 years 3 doses in total England* • In the 3rd month, 12th month and 14-15. Years 3 doses in total Australia** • In the 12th month one dose Saudi Arabia • <6 months and <2 years: 2 doses with at least 3-month intervals • 2-5 years: One dose The United • At 11-12 years first dose and at 16-18 years second dose Arab Emirates *The vaccine shot in the 12th month Hib-MenC combined vaccine **The vaccine administered Hib-MenC combined vaccine obtained from the epidemic strain in New Zealand), a vac- by MATS; in order to do this, it is primarily crucial to cine that included three major antigens (factor H-bound strengthen the meningococcus surveillance. However, if protein, recombinant neisseryal adezin A andneisseryal this is not possible, the data of the neighboring countries heparin-bound antigen) was developed. The serogroup B can be used for coverage. It is also promising that there strains coverage of the vaccine was investigated in differ- are data available suggesting that this vaccine also gener- ent countries by the Meningococcal Antigen Typing ates cross-protection against other serogroups apart from System (MATS) test which could be implemented in a the serogroup B. The vaccine was administered to all age limited number of reference laboratories in the world. groups beginning from two-month-old infants and studies Based on these analyses, the coverage rate of Bexsero revealed that it was well tolerated and immunogenetical. vaccine varies between 66% and 91%. It is possible to The vaccine was approved in January, 2013 by EMA to be collect the strains in our country and get them analyzed used in Europe, and was recommended to be included Özdemir and Çiftçi. 184 Meningococcal Vaccines J Pediatr Inf 2014; 8: 178-86 into the national vaccine calendar in England in March Conflict of Interest: No conflict of interest was declared by the 2014. Its usage;three doses with one-month interval authors. between shots in infants aged 2-6 monthsand one boost- Financial Disclosure: The authors declared that this study has er dose between 12-23 months; two doses with at least received no financial support. two-month intervals in infants aged 6-11 months and one booster dose at the age of 2 with at least two-month inter- References vals between the primer series and the booster dose; two doses with at least two-month intervals in infants aged 1. Özen M, Aslan N. Meningokok tarihçesi. 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