With the exception of a few geographically confined outbreaks, the overall incidence of IMD has decreased between the late 1990s and 2006–2007 in the USA and most European countries 
. This is mainly due to the decrease of serogroup C IMD following the introduction of serogroup C vaccination. Overall IMD incidence in Quebec presented an increasing trend during the same period and a certain stabilisation during 2007–2011. Although this new level (1/100,000) is lower than that observed in the pre-vaccination period, it is 2 times higher than the incidence in other Canadian provinces (0.47/100,000 in 2008) and in the USA (0.28/100,000 in 2009) and is comparable to the incidence in Europe (overall 0.92/100,000 in 2009) 
. However, the IMD incidence in Quebec remains lower than in Ireland (3.4/100,000 in 2009) and the UK (2.0/100,000 in 2009) 
Following the 2001 mass immunization campaign and the introduction of a routine one-dose monovalent C conjugate vaccine program for 12-month-old children in 2002, serogroup C IMD has been virtually eliminated with only a few cases in older patients. Meanwhile, serogroup B incidence has been steadily increasing since the historical low in 1998–2000. In the last three years, serogroup B has been responsible for 88% of all IMD cases reported to laboratory surveillance and 61% of all IMD deaths. Only a few cases due to serogroups C, Y and W-135 have been reported and serogroup A was absent. This means that the great majority of IMD cases and related deaths in Quebec are not vaccine preventable using currently available vaccines.
Among serogroup B IMD, 2/3 of cases are now caused by ST-269cc. The proportion of this clonal complex among serogroup B IMD isolates and its incidence, which is paralleling the serogroup B IMD incidence, has been continually increasing since 2003 and is estimated to be accounting now for more than half of overall IMD incidence in Quebec. In other Canadian provinces, ST-269cc is less common. For example, in the neighbouring province of Ontario, only 20 (10.4%) of the 193 invasive serogroup B isolates collected from 2001 to 2010 belonged to ST-269cc. In provinces other than Quebec and Ontario, of the 46 serogroup B isolates recovered from IMD cases in 2006 to 2009, only 7 (15.2%) belonged to ST-269cc (Public Health Ontario and NML, unpublished data).
ST-269cc was first reported in 1975 in England, and since then it has been identified in the USA, France, Belgium and Japan 
. Although localized ST-269cc outbreaks 
and some increases in the number and proportion of ST-269cc were observed over time 
, reported increases have not been as dramatic as in Quebec in terms of rapidity and magnitude, neither has ST-269cc become a predominant clone. Overall prevalence of this strain in other parts of the world remains low, with the highest proportion of ST-269cc (36%) among all IMD having been reported in England and Wales between 2006 and 2010 
. Another particularity of Quebec ST-269cc epidemiology is that its population is highly homogenous, with a great majority (92%) of the meningococci in ST-269cc belonging to a single sequence type (ST-269) 
. This is different from other provinces of Canada and other parts of the world, where the ST-269cc population is more heterogenous 
. We can not exclude that epidemiological changes in Quebec are due to natural cyclical patterns of meningococcal disease. However, the increase in ST-269cc incidence, ST-269cc predominance among serogroup B IMD cases, its homogeneity and specific age distribution could suggest that the ST-269cc may however represent an emerging clonal complex of meningococci.
Previous reports show that a limited number of clonal complexes have been responsible for the majority of IMD reported during the 20th
century. As an example, serogroup B ST-11cc (ET-37) caused an epidemic in the US Army in the 1960s 
; a new variant member of the ST-11cc (ET-15, serogroup C) caused an increase in IMD in Canada in 1986 
, was later associated with outbreaks in the USA 
then spread throughout Europe 
, leading a number of countries to introduce serogroup C conjugate vaccines into routine immunization programs. Variants of the ST-32cc (ET-5), usually expressing serogroup B capsules, have been responsible for epidemics in Norway and Spain in the 1970s, followed by increases in IMD incidence and outbreaks in other European countries 
. Members of the ST41/44cc displaced the ST-32cc as the major cause of serogroup B IMD in Europe during the 1990s 
. Although the ST41/44cc was associated with an increase in serogroup B IMD in the Netherlands starting in 1980 
, it has not been associated with large outbreaks in other European countries. However, a particular variant of the ST41/44cc was responsible for a long-lasting epidemic of IMD in New Zealand, where it represented more than 70% of serogroup B isolates in 1995 
The genetic and antigenic differences of meningococcal isolates, diversity in their pathogenicity, phenotypic expression, as well as interstrain competition, mediated by immune selection, may explain some differences in sporadic, endemic, or epidemic occurrence of meningococcal disease 
. However, at this point meningococcal disease epidemiology remains highly unpredictable. Other factors, such as host (age, low level of serum bactericidal antibody, ethnicity, genetic polymorphisms, deficiencies in innate immune system components) and environmental (overcrowding, behavioural risk factors, low socioeconomic status) have been shown to be associated with risk of IMD 
. Complex interplay between the pathogen, the host and environmental factors most probably contribute to spatiotemporal variations in disease incidence and severity.
In Quebec, changes in serogroup B age distribution with incidence increase first seen in 15–24-year-olds, followed by the younger and older age groups, corresponded to ST-269cc spread. We hypothesize that this clone was first introduced in adolescent and young adults and then spread to other age groups, analogous to the pattern observed in epidemic settings. First cases were detected in three adjacent regions and remained clustered thereafter. IMD incidences in these three regions, as well as CFR in two of them, were consistently higher than in the rest of the province. Causes of this clustering remain unknown. Deprivation indexes in these regions are comparable to other parts of the province and it is unlikely that ethnicity or overcrowding played a major role. This is different from the New Zealand epidemic, which affected mainly Maori and Pacific populations and was also associated with household crowding 
. We can not, however, exclude that other variables, such as genetic factors shown to determine human susceptibility to meningococcal infection and its outcome 
, have played a role. In the three most affected regions of Quebec, the population is genetically more homogenous compared to the rest of the province. At least one of the three regions (Saguenay-Lac-St-Jean) is known for an increased proportion of genetically inherited diseases 
Although members of ST-269cc have been reported to be more likely associated with disease than with carriage 
, to our knowledge, no data exist as to higher CFR associated with this particular clonal complex. Our results show an increase in the incidence associated with ST-269cc, but not a higher CFR associated with serogroup B (or ST-269cc). This is consistent with data from England and Wales, where serogroup B (with around a third belonging to ST-269cc) presented a CFR close to that observed in our study (5.2%) 
. It is possible that higher transmissibility, not pathogenicity, explains predominance of a limited number of STs in meningococcal populations 
Limitations of our study include the absence of an unique identifier between the two sources of data and missing information on clinical data and sequelae among cases reported to the notifiable disease registry. This precludes us from presenting clinical data and outcomes in this analysis. A study aiming to validate notifiable disease registry data with clinical files data in Quebec is ongoing. However, we think data on deaths are valid since this outcome is generally well reported, and there is excellent correspondence between deaths reported to the notifiable disease registry and to the provincial death registry. The increase in overall and serogroup B-specific IMD incidence based on laboratory surveillance data during the last years may be partially explained by a potential ascertainment bias due to an increasing number of PCR-confirmed cases. However, we believe this has not impacted on the overall incidence based on notifiable disease registry data since it is unlikely that reporting of clinical cases by physicians has changed.
In conclusion, important changes in the epidemiology of IMD have been observed in the province of Quebec during the last two decades. Serogroup C meningococci virtually disappeared since the implementation of a universal childhood immunization program. During the last years, most cases have been due to the serogroup B ST-269cc. Although overall IMD incidence somewhat increased in recent years, it remains relatively low, with important variations across regions. Different options for the use of future protein-based serogroup B meningococcal vaccines may be considered. They might be included in the routine immunization program, or as a targeted intervention in regions/populations at higher risk. A routine immunization program is not likely to be economically attractive, given the relatively low current level of incidence. However, the high level of public concern about meningococcal disease and its sequelaes may outweigh economical considerations. Recent data show that probability of long-term sequelaes after serogroup B IMD may be more important than previously estimated 
. Incorporation of these parameters into cost-effectiveness modelling may change current estimates. Furthermore, given historical dynamics of IMD epidemiology, it is unpredictable whether low disease incidence will persist and what potential regional or global impact emerging strains may have. It is not fully understood whether new multicomponent vaccines against serogroup B meningococci will protect against particular strains circulating in different regions, and how long the protection will last. In addition, it is not known what impact the new vaccine will have on the dynamic of nasopharyngeal carriage and consequently on herd protection. Acceptability, feasibility and cost-effectiveness studies coupled with ongoing strengthened clinical and molecular surveillance of IMD should be assessed when prioritizing, recommending, and evaluating meningococcal disease prevention and control strategies.