Transmissibility and pathogenicity of the emerging meningococcal serogroup W sequence type-11 complex South American strain: a mathematical modeling study

The meningococcus (Neisseria meningitidis) is a bacterium that frequently colonizes the human nasopharynx, particularly that of adolescents and young adults [1]. Although colonization is typically asymptomatic and harmless to the host, the meningococcus can move from the nasopharynx to cause severe invasive diseases, such as bacteremia and meningitis [2]. The burden of invasive meningococcal disease (IMD) varies substantially worldwide, with the highest incidence rates observed in the so-called African meningitis belt, a region stretching from Senegal to Ethiopia that recurrently experiences large epidemics [3]. In contrast, the burden of IMD is generally low in high-income countries (e.g., annual incidence rate of 0.3–3/100,000 during 2004–2014 in Europe [4] and of 0.26/100,000 during 2006–2015 in the USA [5]), but the disease remains a public health concern because of its high lethality (typically 5–10%) and of its frequent long-term sequelae in survivors [6‐8].

Although the N. meningitidis species is antigenically and genetically diverse, only six serogroups (A, B, C, W, X, and Y) cause the vast majority of IMD [9]. The genetic characterization of disease isolates using molecular typing methods has also demonstrated the predominance of a small number of clonal complexes (cc)—called hyper-invasive lineages—which can be associated with several serogroups [9, 10]. The epidemiology of IMDs caused by different serogroups and by different ccs displays substantial spatial heterogeneity worldwide [9]. Locally, temporal variations can also be pronounced and result in changes in the population structure of meningococci associated with disease [11]. Hence, close epidemiological surveillance has been essential to implement vaccination strategies, such as the introduction of the conjugate vaccine against the meningococcal serogroup C in 1999 in the UK [12].

Recent changes in the epidemiology of meningococcal serogroup W (MenW) provide another case in point [13]. Historically an infrequent cause of IMD, a large outbreak among Hajj pilgrims in 2000 led to an increase of MenW disease (in individuals returning from the Hajj or linked to those who had attended) in the early 2000s in different parts of the world, including Europe [14] and the USA [15]. Genomic analyses demonstrated the emergence of a new strain belonging to cc11—the MenW:cc11 Anglo-French Hajj strain [16]—that subsequently became a major cause of disease in the African belt, and elsewhere [17‐19]. From the mid-2000s, an increasing incidence of MenW disease was also reported in a number of South American countries, starting with Brazil [20], followed by Argentina [21] and Chile [22]. A genetic comparison of the South American isolates with other MenW disease isolates revealed the emergence of a new strain also belonging to cc11, but distinct from the Hajj strain [16]. That strain subsequently spread worldwide and has caused increasing endemic disease in Europe [23, 24], in the USA [25], and in Australia [26]. In England, the South American strain and its descendants, collectively called the MenW:cc11 South American strain (MenW:cc11/SA) strain, caused a precipitous rise of MenW disease from 2009 [24, 27]. In response, an emergency program of vaccination with the MenACWY quadrivalent conjugate vaccine was implemented in adolescents from August 2015 [28]. Other countries that experienced comparable trends in MenW disease, such as the Netherlands, have also rolled out reactive MenACWY vaccination programs [13].

Because of its ability to spread and to cause severe disease, the MenW:cc11/SA strain is deemed highly transmissible and hyper-invasive [16, 29]. Quantitative estimates, however, are currently lacking, but are needed to anticipate changes in the epidemiology of MenW and to adapt vaccination strategies. Here, we analyzed the epidemiology of MenW in England and in France, both countries that recently witnessed an upsurge of cases caused by MenW:cc11/SA. Using mathematical transmission models, fitted to age-specific incidence data, we aimed to estimate the transmissibility (that is, the ability to transmit carriage from host to host) and the invasiveness (i.e., the risk of disease given carriage) of MenW:cc11/SA.

In this study, we aimed to quantify the transmissibility and the pathogenicity of MenW:cc11/SA, a new strain that has recently caused important shifts in meningococcal epidemiology. To do so, we developed a mathematical model of MenW transmission, carriage, and disease that represented the joint epidemiological dynamics of non-MenW:cc11 and of MenW:cc11/SA strains. Based on detailed incidence data in England, where a marked year-on-year increase of MenW:cc11/SA disease was observed during 2010/2011–2014/2015, we estimated that MenW:cc11/SA strains were 20% more transmissible and 5–20 times more invasive than other MenW strains not belonging to cc11. We also showed that the model parametrized in England correctly reproduced the early increase of MenW:cc11/SA disease in France. Finally, we found that, in both countries, the emergence of MenW:cc11/SA carriage likely started long before the emergence of MenW:cc11/SA disease.

Since its emergence in Latin America, the MenW:cc11/SA strain has spread extensively and has caused increasing endemic disease in many parts of the world [24‐26]. Due to its ability to spread, in addition to cause outbreaks and severe disease, it has been hypothesized that the strain was highly transmissible and invasive [29]. Our analysis in England—a country that has conducted rigorous surveillance of meningococcal disease for decades—is consistent with this view and provides precise estimates of MenW:cc11/SA transmissibility and invasiveness. The absence of comparable analyses in other regions, however, limits the comparison with previous studies. Hence, challenge experimental studies in animal models [46] or replicates of our epidemiological analysis in other populations will be useful to assess the validity of our estimates.

The rapidly changing epidemiology of MenW disease in England has been documented in previous studies [24, 27, 28]. After a transient increase in the early 2000s, associated with an outbreak among Hajj pilgrims returning from Saudi Arabia [47], the incidence of MenW disease stabilized at a low annual rate of ≈ 0.05/100,000 [24]. From 2009/2010, however, MenW disease increased steadily and was associated with atypical clinical symptoms and high lethality [48]. Our results confirm that this increase was almost entirely due to the expansion of MenW:cc11/SA, whose incidence almost doubled every year until 2014/2015. The alarming increase in MenW disease prompted the decision to introduce the MenACWY vaccine to immunize adolescents aged 13–18 years in England, with the additional aim of indirectly protecting the wider population through decreased carriage and resultant induction of herd protection [28, 49]. According to national estimates, the vaccine coverage for the school-based program that targeted 13–17 yo was high in every birth cohort, in the range 70–85% during 2015/2016–2017/2018 [50]. In contrast, the vaccine coverage for the general-practitioner–based program that targeted school leavers aged ≥ 18 was lower, reaching only 35–40% by March 2018 [51]. Despite this modest coverage, an early report estimated a 69 [18, 88]% decrease of MenW cases from September 2015 to August 2016 in the first cohort of school leavers targeted by the vaccine [52]. The trends observed in age groups that were not offered MenACWY vaccination also suggested indirect effects of this vaccine [52]. Nevertheless, the effect of the 4CMenB vaccine—which may also confer protection against MenW [53]—offered in infants and toddlers could not be ruled out. Extending the model presented here to incorporate vaccination with MenACWY and with 4CMenB may be useful to refine those vaccine impact estimates and to quantify vaccine effectiveness from the observed incidence data [35].

As in England, the epidemiology of MenW disease has changed substantially since 2000 in France. An increase of MenW disease associated with the Hajj strain was also observed in the early 2000s, but quickly receded and MenW caused few cases during 2006–2011 [23, 31]. Unlike in England, however, new cases of the Hajj strain were reported from 2012, but the increase was transient and mostly associated with recent travel to sub-Saharan countries [54, 55]. Since 2012, the MenW:cc11/SA strain has caused increasing disease and appears to have spread endemically, and sometimes epidemically [23, 56]. Genomic analyses of disease isolates identified both the original UK and the UK 2013 strains, though the latter strain became predominant from 2015 [23]. Our results suggest that, as in England before the vaccines’ roll-out in 2015, MenW:cc11/SA could further spread and cause disease in the years to come. Such trends may undermine the current meningococcal immunization program, which, since January 2018, consists of mandatory vaccination of infants with the conjugate MenC vaccine [57]. Therefore, we propose that mathematical transmission models—such as those developed here or in previous studies [35, 36]—may help forecast the impact of alternative vaccination strategies in France.

An intriguing result of our analyses in France was that the emergence of MenW:cc11/SA carriage may have predated the emergence of MenW:cc11/SA disease by several months. A sensitivity analysis also showed that such a scenario provided an equally good fit to the data in England, although the estimate of MenW:cc11/SA invasiveness was, in this case, lower (Additional file 1: Table S1). Furthermore, our simulation study confirmed the possibility of prolonged and silent transmission of MenW:cc11/SA carriage. These results are consistent with a “tip-of-the-iceberg” phenomenon, which has been described for other infectious diseases that cause infection (or carriage) much more frequently than disease [58]. An important practical consequence is that the absence of MenW:cc11/SA disease does not necessarily imply the absence of MenW:cc11/SA carriage, which may, in fact, already be widespread before the first case report. In a context of international spread and of multi-focal emergence of MenW:cc11/SA, these results may have implications for epidemic preparedness.

Several caveats of our analysis are worth noting. First, we parametrized our model based on the results of a meta-analysis that assessed the overall prevalence of meningococcal carriage [1] and of a clinical trial of meningococcal vaccines in university students in England [43]. Ideally, estimates of MenW carriage prevalence in every age group would be needed to more accurately parametrize our model. Specific data on MenW:cc11/SA carriage would also be needed to verify our model-based predictions of carriage prevalence. Second, it has been proposed that the genetic differences defining the UK 2013 strain—which emerged in 2013 in England—might make it more transmissible and more invasive than the original UK strain [24]. Because of the limited amount of data in England, however, we were not able to examine such differences. Nevertheless, the fact our model’s fit to data did not appreciably worsen after 2013 suggests that such differences may have been modest in England. However, analyzing the data in other countries—such as the Netherlands [24]—where the increase of MenW disease was predominantly caused by the UK 2013 strain may shed more light on this question. Third, the lesser model fit to the most recent MenW:cc11/SA disease data in France suggests that the predictive accuracy of our model might be limited to 5–6 years. Considering the simplicity of our model, however, this forecast horizon is sizable and may still allow to predict the medium-term impact of control interventions (e.g., vaccination) in countries where MenW:cc11/SA started to emerge. Finally, we acknowledge the potential presence of unmeasured confounding factors that may also have been associated with the increase of MenW:cc11/SA in England and in France.

In conclusion, our study provides the first estimates of the transmissibility and of the pathogenicity of MenW:cc11/SA. Such estimates may be useful to anticipate changes in the epidemiology of MenW and to adapt vaccination strategies. Our results also point to silent, prolonged transmission of MenW:cc11/SA carriage, with potentially important implications for epidemic preparedness.