Meningococcal Disease: Shifting Epidemiology and Genetic Mechanisms That May Contribute to Serogroup C Virulence
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- MacNeil, J.R., Thomas, J.D. & Cohn, A.C. Curr Infect Dis Rep (2011) 13: 374. doi:10.1007/s11908-011-0195-7
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During the past decade, monovalent serogroup C and quadrivalent (serogroups A, C, W135, Y) meningococcal vaccination programs have been introduced in multiple industrialized countries. Many of these programs have been successful in reducing the burden of disease due to vaccine-preventable serogroups of Neisseria meningitidis in target age groups. As a result, disease burden in these countries has decreased and is primarily serogroup B, which is not vaccine preventable. Despite the success of these programs, meningococcal disease continues to occur and there is always concern that serogroup C organisms will adapt their virulence mechanisms to escape pressure from vaccination. This review highlights the current epidemiology of meningococcal disease in Europe and United States, as well as genetic mechanisms that may affect virulence of serogroup C strains and effectiveness of new vaccines.
KeywordsNeisseria meningitidisMeningitisVaccineVirulenceEpidemiologyGeneticsSerogroup CSerogroup BMonovalent vaccineQuadrivalent vaccineSerogroup C meningococcal conjugate vaccinationMenCVaccination programImmunization
While meningococcal disease is relatively infrequent in the industrialized world, it remains a devastating infectious disease that often strikes previously healthy persons of all ages. About 10–15% of infected persons die, and 11–19% of survivors have sequelae (eg, neurologic disability, limb loss, and hearing loss) . Serogroup C meningococcal disease causes a higher frequency and more severe sequelae (skin scarring, limb loss, renal problems) among survivors when compared to serogroup B meningococcal disease [2, 3]. The case-fatality ratio (CFR) for serogroup C meningococcal disease in the United States is 14–15% compared to 6–11% for serogroup B meningococcal disease; however, the CFR varies by age and syndrome [4, 5••]. In the United Kingdom, the CFR due to serogroup C infection before serogroup C meningococcal (MenC) vaccination among those younger than 20 years was 12.4% [6••]. Serogroup C clones with CFRs of 18.2% and 21.1% were reported in Norway in 2006 .
During the past decade, vaccination with both monovalent MenC and quadrivalent (serogroups A, C, W135, Y) meningococcal conjugate vaccines has been introduced in the United Kingdom and a number of other European countries , the United States , and Canada . The vaccination programs implemented in these countries differ greatly, and some countries have successfully reduced the burden of serogroup C disease more than 99% [5••, 9, 10]. However, Neisseria meningitidis has a natural ability to take up DNA from the surrounding environment (ie, transformability), and thereby can alter its virulence factors. There is concern that serogroup C organisms will adapt their virulence mechanisms to escape pressure from vaccination. Recent reports demonstrate a broadening understanding of N. meningitidis virulence mechanisms, and describe more virulent and/or transmissible serogroup C strains .
Epidemiology of Serogroup C Meningococcal Disease
With the introduction of MenC vaccination programs in Europe, reductions in the incidence of meningococcal disease, particularly disease due to serogroup C, have been observed in multiple countries. Currently serogroup B is responsible for up to 90% of cases in some European countries ; however, the proportion of disease caused by serogroups B and C varies by country [8, 10, 12].
The epidemiology of meningococcal disease in the United Kingdom has been well reported in the literature. In the 1990s, there was an increase in the incidence of a “hypervirulent” serogroup C strain (sequence type [ST]-11) that was associated with severe disease . A nationwide MenC vaccination program implemented in the United Kingdom has been highly successful in reducing overall disease incidence, and serogroup C meningococcal disease in particular [6••]. Surveillance data demonstrated a marked and rapid reduction in serogroup C disease, which previously was responsible for 30–40% of cases in the United Kingdom, in close temporal association with the introduction of the vaccine into each identified age cohort. Remarkably, with only continued vaccination of infants, serogroup C disease rates in the United Kingdom remain low over 10 years after the large-scale vaccination campaign, suggesting a sustained interruption in transmission. The success of the program led to the subsequent introduction of meningococcal conjugate vaccines into routine immunization schedules in many European countries and in programs in other parts of the world.
In contrast to the United Kingdom, the United States introduced quadrivalent meningococcal conjugate vaccine (MCV4) in 2005 with a program targeting adolescents. This program has been shown to have impacted rates of serogroups C and Y meningococcal disease among 11–19-year-old people in the United States , but there does not appear to be significant indirect effects from herd immunity 5 years after introduction. Rates of meningococcal disease in the United States currently are at a nadir that began before the introduction of MCV4. Decreases in incidence have not been observed in unvaccinated age cohorts, and rates of serogroup B disease have fallen in parallel with the vaccine serogroups during this time. These facts make it highly unlikely that the current nadir is due to vaccination. Historically, serogroup C was an important cause of outbreaks in the United States ; however, only about 2% of cases in the United States are outbreak related. While serogroup C outbreaks continue to occur, recent outbreaks have included age groups not currently recommended for vaccination (Centers for Disease Control and Prevention, unpublished data). There is evidence of waning vaccine immunity, and a booster dose recently has been recommended in the United States .
In several European countries where MenC vaccination programs are selective, voluntary, or not being used, serogroup C still causes a substantial proportion of disease compared to countries with routine vaccination programs . A recent report describes emergence of a new serogroup C clone in France (which does not have a MenC vaccination program) that had a CFR of 22% compared to 15% for other French serogroup C isolates. This clone was responsible for 5 of 9 serogroup C meningococcal disease clusters during 2007 through 2008, and demonstrated an apparent increased infection severity in humans, causing extensive hemorrhagic rash .
N. meningitidis is a commensal bacterium of the human nasopharynx (ie, asymptomatic carriage), which is an important site for interaction among normal flora that may result in genetic recombination events. The prevalence of meningococcal carriage is highly variable. In industrialized countries, carriage is generally observed in 10% of the population overall, rising from 2% in children under 4 years to a peak of 24.5–32% among 15–24-year-old teenagers and adults, then declining with increasing age [6••, 7]. However, in recent carriage studies in the United States, prevalence of carriage has been lower . Carriage prevalence does not predict either the incidence of disease or the occurrence or severity of outbreaks. For most people, carriage is an immunizing event, and the carrier develops protective antibodies against the organism [17–20]. In a minority of carriers, N. meningitidis penetrates the nasopharyngeal mucosa, reaches the bloodstream, and causes systemic disease .
Genetic Mechanisms That May Contribute to Increased Virulence of Serogroup C Strains
Summary of recently reported genetic mechanisms involving Neisseria meningitidis serogroup C virulence factors
Geographic location of studied example
Capsular polysaccharide biosynthesis (syn or sia) ± capsule-transport (ctr) operons
United States; Portugal; New Zealand
Transformation with DNA from:
Commensal N. spp.
≥70 virulence genes, DNA gyrase (gyrA)
Various; United States
IS element activity
ctr-syn/sia intergenic region
Spain; United Kingdom
Recombination involving repetitive elements
Widespread throughout N. spp. genomes: DUSs, Correia elements, dRS3 elements, others
Capsule switching, first described by Swartley et al. , is an important diversity-promoting mechanism among N. meningitidis. The capsule is currently the target of most meningococcal vaccines, and the ability of the organism to switch it is a cause for concern. In a recent study of 1160 invasive isolates from the United States collected from 2000 to 2005 , there was considerable capsular switching observed. Without vaccine pressure, serogroup C isolates were the most frequent results of these events (12.9% of serogroup Cs, compared to 1.5% of serogroup Bs and 0.9% of serogroup Ys): 97.2% of the serogroup C isolates demonstrating capsular switching were of STs usually associated with serogroup B, suggesting that these isolates had undergone capsule switching from B to C. A serogroup C-to-B capsular switch occurred in Portugal sometime between October 2002 and December 2006, raising concern that selective pressure from MenC vaccination, which was introduced in January 2006, would encourage similar events . A report from New Zealand described a serogroup C-to-W135 switch moving the entire capsule locus from a carriage-associated ST-22 W135 clone to create an invasive ST-11 W135 strain , which, along with other recent studies [28–30], supports the longstanding hypothesis that carried N. meningitidis and nonpathogenic commensal Neisseria species are sources of DNA for disease-causing meningococci.
IS and repetitive elements in the meningococcal genome play a significant role in recombination and the control of gene expression. Uria et al. [31••] recently described the identification of three invasive Spanish N. meningitidis isolates that harbored an IS1301 in the intergenic region (IGR) between the capsule-transport and biosynthesis operons (IS1301-IGR) [31••]. As measured in vitro, this insertion resulted in increased capsule expression and resistance to human serum bactericidal antibodies generated by MenC vaccine. These isolates were from patients who had not received MenC vaccine, and IS1301-IGR was not found in a follow-up study of 33 United Kingdom serogroup C vaccine failure isolates . However, these findings imply that, theoretically, MenC vaccine could be less effective against an IS1301-IGR serogroup C isolate.
Recombination involving the porA gene may be another route to the generation of more virulent serogroup C strains, as was hypothesized for a serogroup C clone that emerged in Australia at the turn of this century . Mutation of porA can allow meningococcal evasion of bactericidal antibodies [34–36]. Clones of serosubtypes (ie, based on porA sequencing) P1.5,2 and P1.5 caused the hypervirulent disease seen in France from 2000 to 2005 . However, it is unclear whether the clone observed in France arose anew via recombination or by physical transfer from other parts of the world, as has been seen before .
MenC vaccines have been used for several years in Europe, where there is no evidence that virulent meningococci have adapted to vaccine pressure. We also can be reassured based on experience with Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae conjugate vaccines; clinically relevant serotype replacement has not been observed with widespread Hib vaccine use, while serotype replacement in S. pneumoniae has been observed in some populations and geographic areas, but has not been widespread [38, 39].
Implications for Next-generation Serogroup B Vaccines
The rapid adaptability of N. meningitidis in response to selective pressure has implications for the efficacy of future vaccines. New vaccines in development are designed to target major serogroup B outer membrane proteins, including factor H binding protein (FHbp, LP2086) alone  or in combination with Neisserial heparin binding antigen A (NhbA [also named GNA2132]), Neisseria adhesion A (NadA) , and outer membrane vesicles. These outer membrane proteins also are found in invasive and carried meningococci of other serogroups and among other Neisseria species [42–50]. Therefore, these new vaccines may be effective against N. meningitidis other than invasive serogroup B [51, 52]. In a recent study, a single base pair deletion in FHbp was noted for 9 of 116 serogroup C strains examined . This single base pair deletion led to a frameshift mutation, predicted truncation of the FHbp protein, and resulted in decreased expression of FHbp . This brings to light a potential mechanism for escape of serogroup C strains from an FHbp-based vaccine.
Despite the fact that there currently is no capsule-based vaccine-related selective pressure on the serogroup B population in the United Kingdom, insertions similar to the IS1301-IGR insertion found in Spanish serogroup C isolates [31••] were found in 14% of United Kingdom invasive serogroup B isolates studied . Fortunately, in contrast with the IS1301-IGR found in Spanish serogroup C isolates, the polymorphic IS1301-IGR mutations found in serogroup B isolates did not alter capsule expression or resistance to bactericidal antibodies and complement-mediated lysis. Nonetheless, this recent example again calls to mind the potential effects of the flexible meningococcal genome.
Vaccination programs have been highly successful at reducing the burden of serogroup C meningococcal disease in many countries worldwide, and serogroup B now causes most disease in those countries. However, serogroup C continues to demonstrate a high level of virulence, and multiple mechanisms exist whereby the meningococcus could adapt and evade vaccine pressure. After several years of widespread vaccination, there still is no evidence of serogroup C developing evasion mechanisms against vaccine-induced immunity; however, continued monitoring of the epidemiology of serogroup C meningococcal disease through laboratory-based surveillance is critical.
Both Jessica R. MacNeil and Dr. Jennifer D. Thomas contributed equally to the completion of this article.
The authors thank Dr. Leonard Mayer for helpful discussions and Dr. Nancy Messonnier for her careful review of this article.
No potential conflicts of interest relevant to this article were reported.