Scholarly article on topic 'Epidemiological Profile of Meningococcal Disease in the United States'

Epidemiological Profile of Meningococcal Disease in the United States Academic research paper on "Veterinary science"

Share paper
Academic journal
Clinical Infectious Diseases
OECD Field of science

Academic research paper on topic "Epidemiological Profile of Meningococcal Disease in the United States"


Epidemiological Profile of Meningococcal Disease in the United States

Lee H. Harrison

Infectious Diseases Epidemiology Research Unit, Division of Infectious Diseases, University of Pittsburgh Graduate School of Public Health and School of Medicine, Pittsburgh, Pennsylvania

Neisseria meningitidis is a leading cause of bacterial meningitis and other serious infections worldwide. The epidemiological profile of N. meningitidis is highly changeable, with great differences in disease incidence and serogroup distribution. Six serogroups (namely serogroups A, B, C, W-135, X, and Y) are responsible for most cases of meningococcal disease worldwide; the epidemiological profile of disease caused by each serogroup is unique. No vaccine is available for endemic disease caused by serogroup B strains. Two tetravalent (A/C/Y/ W-135) meningococcal vaccines are licensed in the United States: a purified polysaccharide product and a polysaccharide-protein conjugate vaccine. The conjugate vaccine is recommended for all adolescents, although vaccine coverage remains low, and other groups at high risk of infection. A comprehensive program to prevent invasive meningococcal disease in the United States will require vaccination of infants; several conjugate vaccines for infants may become available in the near future. Broadly protective vaccines for endemic serogroup B disease are also needed.

Neisseria meningitidis remains a major cause of bacterial meningitis and other invasive bacterial infections worldwide [1—4]. A remarkable characteristic of meningococcal epidemiology is that it is highly fluid, with major fluctuations in the incidence of endemic disease and the occurrence of outbreaks and epidemics. In addition, meningococcal serogroup distribution is highly regional and cyclical.

The purpose of this review is to discuss the current epidemiological profile of meningococcal disease and the vaccines that are presently available in the United States. Recent experiences with meningococcal vaccines in the United Kingdom and New Zealand will also be reviewed, because they illustrate the potential public health impact of meningococcal conjugate and

The opinions expressed in this review are solely those of the author. Dr. Harrison reports that the content of this paper overlaps with the content of other reviews that he has written, either as the sole author [2] or with other authors [1, 3, 4].

Reprints or correspondence: Lee H. Harrison, Infectious Diseases Epidemiology Research Unit, 521 Parran Hall, 130 Desoto St, University of Pittsburgh, Pittsburgh, PA 15261 ( Clinical Infectious Diseases 2010;50:S37-S44

© 2010 by the Infectious Diseases Society of America. All rights reserved.


DOI: 10.1086/648963

outer membrane protein-based serogroup B vaccines, respectively.


Virulent N. meningitidis strains have a polysaccharide capsule, which allows the organism to cause invasive diseases, such as bacteremia and meningitis. Unencap-sulated strains, which are frequently found in the pharynx of asymptomatic carriers, have only rarely been determined to cause invasive infections [5, 6]. Of the 13 different polysaccharide capsular types, only 6 frequently cause disease globally (A, B, C, W-135, X, and Y), although substantial rates of serogroup X disease are restricted to parts of sub-Saharan Africa [1].

Serogroup A N. meningitidis occurs primarily in the "meningitis belt" of sub-Saharan Africa and has been responsible for the largest and most devastating me-ningococcal epidemics [7, 8]. Serogroup A meningo-coccal disease also occurs in other parts of the world, such as China and Russia, but is currently extremely rare in the United States, despite the documented introduction of virulent serogroup A strains in this country [9]. Serogroup B strains cause a substantial proportion of meningococcal disease endemic in many

parts of the world, including the United States, as well as prolonged epidemics [10, 11]. Serogroup C, which is also a prominent serogroup in many regions of the world, has occasionally caused epidemics and frequently causes outbreaks [12]. Serogroup Y strains cause a high proportion of cases in the United States and other countries in the Americas [13, 14]. Although not generally considered to be one of the major meningococcal serogroups, serogroup X strains have been reported to cause a substantial amount of meningococcal disease in some countries in Africa, such as Niger, Togo, and western Kenya [15-17]. The reasons for the distinct serogroup distribution in different regions of the world are unknown, but possible mechanisms include differences in population immunity and environmental factors. A summary of the global distribution of meningococcal serogroups is shown in Figure 1.


Several mechanisms are used to change the characteristics (eg, antigenic structure or resistance to antibiotics) of meningococcus. Many of these changes occur through horizontal gene transfer, which permits the organism to obtain large DNA sequences from other meningococcal strains or other species [18]. N. meningitidis also uses multiple other mechanisms to achieve antigenic variation [19-26]. One such mechanism is gene conversion, which involves autologous recombination. For example, PilE is a prominent component of the N. meningitidis pilus that is encoded by pilE. Contiguous to pilE are 8 truncated pseudogenes that are able to undergo recombination with pilE,

which allows for generation of major antigenic variability without the acquisition of foreign DNA.

Capsular switching is a genetic mechanism that allows N. meningitidis to change its capsular phenotype. Outbreaks of N. meningitidis infection can be started or sustained using this mechanism, which permits immunologic escape from immunity to the original serogroup [27-30]. Capsular switching occurs through horizontal gene transfer and is generally defined as strains that belong to the same genetic lineage (as determined, for example, by multilocus sequence typing) but have a different polysaccharide capsule. Capsular switching presumably occurs when a person is cocolonized in the pharynx with ^2 meningococcal strains [31, 32]. For example, the boyfriend of a young girl who died of serogroup B meningococcal disease had pharyngeal colonization with serogroup C strain that was otherwise genetically indistinguishable [29]. A significant percentage of meningococcal strains that cause disease in the United States apparently have arisen through the mechanism of capsular switching [33].

Capsular switching appeared to be responsible for an outbreak of serogroup W-135 disease during the 2000 Hajj in Mecca, Saudi Arabia. Subsequent to this outbreak, the epidemic strain spread globally and caused an epidemic in Burkina Faso [34, 35]. Capsular switching was also observed in the 1990s during an outbreak of serogroup B disease in Oregon, with some serogroup C strains found to be otherwise genetically indistinguishable from the serogroup B outbreak strain [10, 27].

A key concern is that, with mass vaccination using vaccines that do not include protection against all of the major menin-

Figure 1. Worldwide distribution of major meningococcal serogroups [1]. Reprinted from Vaccine 27(Suppl 2), Harrison LH, Trotter CL, Ramsay ME, Global Epidemiology of Meningococcal Disease, B51-B63, Copyright 2009, with permission from Elsevier.

gococcal serogroups, there could be an increase in the incidence of meningococcal disease caused by strains not included in the vaccine. This could occur through the mechanisms of capsular switching or capsular replacement. Serotype replacement has been observed since the routine use of pediatric pneumococcal conjugate vaccine began in the United States in 2000 [36, 37]. However, meningococcal serogroup replacement has not been observed in the United Kingdom since the introduction of routine vaccination with serogroup C conjugate vaccines [38]. Serogroup C carriage is relatively uncommon, even in the face of a substantial incidence of serogroup C meningococcal disease; it remains to be seen whether serogroup replacement will occur with the use of meningococcal vaccines that cover a higher proportion of carriage strains.

Increases in the incidence of meningococcal disease have also been associated with changes in noncapsular outer membrane proteins. This observation has implications for outer-membrane protein-based vaccines for the prevention of serogroup B meningococcal disease. In Maryland, an increase in the incidence of serogroup C and serogroup Y meningococcal disease occurred in association with a substantial antigenic shift in several outer membrane proteins [14]. For serogroup C, horizontal gene transfer led to major antigenic changes in FetA, and the porA gene was entirely deleted from some strains. For serogroup Y, major antigenic changes were caused by horizontal gene transfer involving 3 outer membrane protein genes.


There are numerous known risk factors for meningococcal disease; incidence varies greatly by age, with infants having the highest risk of disease (Figure 2) [13]. A low level of serum bactericidal antibody is among the most important host factors associated with risk of infection [40, 41]. Low socioeconomic status and minority ethnicity have also been found to be as-

sociated with increased risk [4, 13, 42, 43]. Conditions associated with immune compromise, such as functional or anatomic asplenia, human immunodeficiency virus infection, and genetic polymorphisms and deficiencies in components of the innate immune system, have been associated with increased risk of meningococcal disease [44-52].

Environmental factors associated with the risk of both invasive disease and carriage include recent or concurrent upper respiratory infection, such as influenza [53-58]. In the meningitis belt of sub-Saharan Africa, epidemics commence during the dry season and end at the onset of the rainy season [59]. Population crowding has long been known to be associated with increased risk of meningococcal disease [60]. More recently, behavioral risk factors, such as passive and active smoking, pub and bar patronage, kissing, and living in a university dormitory, have been shown to be associated with risk of me-ningococcal carriage and disease in a variety of studies [6171].


The Active Bacterial Core surveillance (ABCs) network, a population-based surveillance system for invasive meningococcal disease and other serious bacterial pathogens, has provided invaluable information about the epidemiological profile ofme-ningococcal disease in the United States [72]. Because active surveillance methods are used, ABCs is highly sensitive for culture-positive N. meningitidis disease and infection caused by other bacterial pathogens. In 2009, ~40 million persons (~13% of the US population) lived in an area with ABCs for menin-gococcal disease.

Since World War II, the annual incidence of meningococcal disease has varied from 0.5 to 1.5 cases per 100,000 population. During the past 3 decades, the incidence has increased and decreased in multiyear cycles (Figure 3) [3, 73]. The most recent

Figure 2. Mean annual incidence of invasive meningococcal disease, 1997-2007, by age group [39].

Figure 3. Incidence of invasive meningococcal disease, by year, in the United States, 1976-2006 [73].

peak in incidence occurred during the mid-1990s. Subsequently, there was a decrease to ~0.35 cases per 100,000 population in 2007, caused by decreases in the 3 most common serogroups in the United States: B, C, and Y. Of interest, the current nadir in incidence began before the introduction of tetravalent meningococcal conjugate vaccine (MCV4) and has been more sustained than in previous years. In addition, MCV4 does not contain a serogroup B component and, therefore, had no influence on the reduction in the incidence of serogroup B disease. The factors responsible for this substantial decrease in the overall rate of meningococcal disease are unknown but could include population immunity to the strains currently circulating in the United States, changes in the prevalence of behavioral risk factors, and unknown variables.

Meningococcal serogroup distribution varies over time. For example, serogroup Y accounted for only 2% of meningococcal infections during 1989-1991 [42]. By the mid-1990s, the incidence of serogroup Y disease increased and serogroup Y strains accounted for one-third of meningococcal infections [13]. The increase in the incidence of serogroup Y disease in Maryland occurred primarily in children <15 years of age and in adults >25 years of age [74]. The incidence of serogroup C meningococcal disease also increased and subsequently decreased during the 1990s. Serogroup W-135 disease, which currently accounts for a small percentage of cases, was previously more common [13, 75, 76]. On the basis of ABCs data, the serogroup distribution in the United States in 2007 was sero-group B (25% of cases), serogroup C (30%), and serogroup Y (37%), with 9% of cases caused by serogroup W-135, other serogroups, and nongroupable strains [77]. The proportion of serogroup B isolates is higher in Oregon, as is the incidence of serogroup B disease, because of an ongoing outbreak involving a serogroup B sequence type-32 complex/enzyme type-5 complex clone [10].

As the incidence in meningococcal disease increased in the United States during the 1990s, the number of outbreaks of N. meningitidis infection also increased. From mid-1994 through mid-2002, 76 outbreaks in the community, specifically in colleges, primary and secondary schools, and nursing homes, were identified throughout the United States [12, 78-81]. The majority of the outbreaks were caused by serogroup C strains.


Two tetravalent (A/C/Y/W-135) meningococcal vaccines are licensed in the United States; one of these is a purified polysac-charide product, and the other is a polysaccharide-protein conjugate vaccine (MCV4) with diphtheria toxoid as the protein carrier [82]. MCV4 was licensed in 2005 and is recommended for all US adolescents. In 2007, despite this universal recommendation, only 33% of persons aged 13 years had received MCV4, as determined by the National Immunization Survey [83]. MCV4 is also recommended for college freshmen living in dormitories, travelers to areas where meningococcal disease is hyperendemic or epidemic, microbiologists working with live N. meningitidis, military recruits, and persons with immuno-logical deficits, such as terminal complement deficiency and functional or anatomic asplenia [82].

The current focus on adolescents is a laudable step toward prevention of meningococcal disease in the United States, although a comprehensive program will require vaccination of infants, the group with the highest risk [84, 85]. Several me-ningococcal conjugate vaccines that are immunogenic in infants may soon be licensed in the United States; these include a second tetravalent (A/C/Y/W-135) polysaccharide-protein conjugate vaccine that uses CRM197 as the protein carrier [86-88] and a combination Haemophilus influenzae serotype B and se-rogroup C/Y meningococcal conjugate vaccine with each poly-saccharide component conjugated to tetanus toxoid [89]. Outer membrane protein-based vaccines for the prevention of endemic serogroup B disease are also in development for use in the United States and worldwide [90, 91], although these vaccines will probably not be available for several more years. The addition of protection against serogroup B meningococcal disease is crucial because of the importance of disease caused by this serogroup in many countries [1].


Because insufficient time has elapsed since the beginning of routine use of MCV4 and because of the low vaccine coverage rates among adolescents, it is not possible to draw conclusions about the eventual impact of routine meningococcal immunization in the United States [83]. However, several recent ex-

periences from abroad provide valuable information about this issue. In 1999, the United Kingdom was the first country to introduce serogroup C meningococcal conjugate vaccines to control the growing burden of serogroup C disease. This program has been highly successful in reducing the incidence of serogroup C meningococcal disease in vaccinated persons [92, 93]. In addition, serogroup C meningococcal pharyngeal carriage has been reduced, leading to a reduction in the incidence of serogroup C meningococcal disease in the unvaccinated population as a result of the herd immunity effect [94, 95]. The reduction in the incidence of serogroup C disease resulted in a substantial decrease in the overall incidence of meningo-coccal disease [96]. The success of this program led to the subsequent introduction of meningococcal conjugate vaccines into routine immunization programs in many European countries and in programs in other parts of the world [9799]. With the success of the immunization campaign in the United Kingdom, ~90% of cases of invasive meningococcal disease in that country are now caused by serogroup B strains.


In the United States and many other parts of the world, a substantial proportion of meningococcal disease is caused by serogroup B N. meningitidis, which is antigenically highly variable in settings where it is endemic. Unfortunately, no licensed vaccine exists that covers all serogroup B strains. However, epidemics of serogroup B disease are caused by single clones, which has allowed for the development of tailor-made sero-group B vaccines. The incidence of meningococcal disease in New Zealand increased from ~1.6 cases per 100,000 population in 1990 to a peak of 17.4 cases per 100,000 population in 2001. This was the result primarily of the emergence of a sequence type 41/44 clonal complex/lineage 3 serogroup B clone, which accounted for 85% of cases by 2000 [11, 100]. The highest rates of disease occurred among young children, and a disproportionate number of cases occurred in Pacific Islander and Maori children [11].

This epidemic led to the development and introduction of an outer membrane vesicle vaccine against the epidemic strain [101]. The vaccine was initially introduced in mid-2004 in areas of North Island, where the incidence of disease was high, and was further introduced across the country over a period of 2 years. The incidence of meningococcal disease decreased to 2.6 cases per 100,000 population by 2007, and the estimated effectiveness of the vaccine was 80% in fully immunized children aged 6 months to <5 years [102]. However, no data are available on the impact, if any, of this vaccine on meningococcal carriage among persons who were vaccinated or on the incidence of meningococcal disease among unvaccinated persons.

In summary, the epidemiological profile of meningococcal

disease in the United States is highly dynamic and constantly changing. The introduction of MCV4 into the routine immunization schedule for adolescents is a promising first step, but additional work is needed. First, efforts must be made to increase vaccine coverage with MCV4 and with the other vaccines that are now recommended for adolescents. Second, conjugate vaccines for infants, which are likely to be available soon, are required. Finally, broadly protective vaccines that prevent both endemic and epidemic serogroup B disease are needed.


Potential conflicts of interest. L.H.H. has received research funding from Sanofi Pasteur and consulting fees and speaking honoraria from Sanofi Pasteur, Novartis, Merck, Wyeth, and GlaxoSmithKline.

Financial support. National Institute of Allergy and Infectious Diseases (K24 AI52788 to L.H.H.).

Supplement sponsorship. This article was published as part of a supplement entitled "Immunization to Prevent Meningococcal Disease: Yesterday, Today, and Tomorrow," which was sponsored by DIME and funded through an educational grant from Novartis Vaccines.


1. Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine 2009; 27(Suppl 2):B51-B63.

2. Harrison LH. Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev 2006; 19:142-164.

3. Granoff DM, Harrison LH, Borrow R. Meningococcal vaccines. In: Plotkin S, Orenstein WA, Offit PA, eds. Vaccines. 5th ed. Philadelphia: Saunders Elsevier, 2008:399-434.

4. Harrison LH, Broome CV. The epidemiology of meningococcal meningitis in the US civilian population. In: Vedros NA, ed. Evolution of meningococcal disease. Vol. 1. Boca Raton, FL: CRC Press, 1987: 27-45.

5. Vogel U, Claus H, von Muller L, Bunjes D, Elias J, Frosch M. Bac-teremia in an immunocompromised patient caused by a commensal Neisseria meningitidis strain harboring the capsule null locus (cnl). J Clin Microbiol 2004;42:2898-2901.

6. Hoang LM, Thomas E, Tyler S, et al. Rapid and fatal meningococcal disease due to a strain of Neisseria meningitidis containing the capsule null locus. Clin Infect Dis 2005; 40:e38-e42.

7. Greenwood B. Manson Lecture. Meningococcal meningitis in Africa. Trans R Soc Trop Med Hyg 1999;93:341-353.

8. Roberts L. Hitting early, epidemic meningitis ravages Nigeria and Niger. Science 2009;324:20-21.

9. Moore PS, Harrison LH, Telzak EE, Ajello GW, Broome CV. Group A meningococcal carriage in travelers returning from Saudi Arabia. JAMA 1988; 260:2686-2689.

10. Diermayer M, Hedberg K, Hoesly F, et al. Epidemic serogroup B meningococcal disease in Oregon: the evolving epidemiology of the ET-5 strain. JAMA 1999;281:1493-1497.

11. Baker MG, Martin DR, Kieft CE, Lennon D. A 10-year serogroup B meningococcal disease epidemic in New Zealand: descriptive epidemiology, 1991-2000. J Paediatr Child Health 2001; 37:S13-S19.

12. Brooks R, Woods CW, Benjamin DK Jr, Rosenstein NE. Increased case-fatality rate associated with outbreaks of Neisseria meningitidis infection, compared with sporadic meningococcal disease, in the United States, 1994-2002. Clin Infect Dis 2006; 43:49-54.

13. Rosenstein NE, Perkins BA, Stephens DS, et al. The changing epidemiology of meningococcal disease in the United States, 1992-1996. J Infect Dis 1999; 180:1894-1901.

14. Harrison LH, Jolley KA, Shutt KA, et al. Antigenic shift and increased incidence of meningococcal disease. J Infect Dis 2006; 193:1266-1274.

15. Boisier P, Nicolas P, Djibo S, et al. Meningococcal meningitis: unprecedented incidence of serogroup X-related cases in 2006 in Niger. Clin Infect Dis 2007; 44:657-663.

16. Njanpop Lafourcade BM, Tamekloe TA, Snou O, et al. Serogroup X meningococcal meningitis in Togo during 2007 and 2008. In: International Pathogenic Neisseria Conference (Rotterdam, Netherlands). 7-12 September 2008. Abstract P140.

17. Mutonga DM, Pimentel G, Muindi J, et al. Epidemiology and risk factors for serogroup X meningococcal meningitis during an outbreak in western Kenya, 2005-2006. Am J Trop Med Hyg 2009; 80: 619-624.

18. Wu HM, Harcourt BH, Hatcher CP, et al. Emergence of ciprofloxacin-resistant Neisseria meningitidis in North America. N Engl J Med 2009; 360:886-892.

19. Andrews TD, Gojobori T. Strong positive selection and recombination drive the antigenic variation of the PilE protein of the human pathogen Neisseria meningitidis. Genetics 2004; 166:25-32.

20. Howell-Adams B, Seifert HS. Molecular models accounting for the gene conversion reactions mediating gonococcal pilin antigenic variation. Mol Microbiol 2000;37:1146-1158.

21. Saunders NJ, Jeffries AC, Peden JF, et al. Repeat-associated phase variable genes in the complete genome sequence of Neisseria meningitidis strain MC58. Mol Microbiol 2000;37:207-215.

22. Claus H, Borrow R, Achtman M, et al. Genetics of capsule O-acet-ylation in serogroup C, W-135 and Y meningococci. Mol Microbiol 2004;51:227-239.

23. Stephens DS, Swartley JS, Kathariou S, Morse SA. Insertion of Tn916 in Neisseria meningitidis resulting in loss of group B capsular poly-saccharide. Infect Immun 1991;59:4097-4102.

24. Dolan-Livengood JM, Miller YK, Martin LE, Urwin R, Stephens DS. Genetic basis for nongroupable Neisseria meningitidis. J Infect Dis 2003; 187:1616-1628.

25. Uria MJ, Zhang Q, Li Y, et al. A generic mechanism in Neisseria meningitidis for enhanced resistance against bactericidal antibodies. J Exp Med 2008;205:1423-1434.

26. Marsh JW, Conley AM, Harrison LH. IS1301 insertion in opaD of an emergent Neisseria meningitidis ET-15 clone. In: International Pathogenic Neisseria Conference (Rotterdam, The Netherlands). 7-12 September 2008. Abstract P239.

27. Swartley JS, Marfin AA, Edupuganti S, et al. Capsule switching of Neisseria meningitidis. Proc Natl Acad Sci U S A 1997; 94:271-276.

28. Aguilera JF, Perrocheau A, Meffre C, Hahne S. Outbreak of serogroup W135 meningococcal disease after the Hajj pilgrimage, Europe, 2000. Emerg Infect Dis 2002; 8:761-767.

29. Vogel U, Claus H, Frosch M. Rapid serogroup switching in Neisseria meningitidis. N Engl J Med 2000;342:219-220.

30. Kertesz DA, Coulthart MB, Ryan JA, Johnson WM, Ashton FE. Se-rogroup B, electrophoretic type 15 Neisseria meningitidis in Canada. J Infect Dis 1998; 177:1754-1757.

31. Maiden MC, Malorny B, Achtman M. A global gene pool in the neisseriae. Mol Microbiol 1996;21:1297-1298.

32. Linz B, Schenker M, Zhu P, Achtman M. Frequent interspecific genetic exchange between commensal Neisseriae and Neisseria meningitidis. Mol Microbiol 2000;36:1049-1058.

33. Harrison LH, Shutt KA, Marsh JW, et al. Evidence of capsular switching in invasive Neisseria meningitidis isolates in the pre-meningococcal conjugate vaccine era, United States, 2000-2005. In: International Pathogenic Neisseria Conference (Rotterdam, The Netherlands). 7-12 September 2008. Abstract O51.

34. Mayer LW, Reeves MW, Al-Hamdan N, et al. Outbreak of W135 meningococcal disease in 2000: not emergence of a new W135 strain but clonal expansion within the electophoretic type-37 complex. J Infect Dis 2002; 185:1596-1605.

35. Zombre S, Hacen MM, Ouango G, et al. The outbreak of meningitis due to Neisseria meningitidis W135 in 2003 in Burkina Faso and the national response: main lessons learnt. Vaccine 2007; 25(Suppl 1): A69-A71.

36. Hicks LA, Harrison LH, Flannery B, et al. Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998-2004. J Infect Dis 2007; 196:1346-1354.

37. Hsu HE, Shutt KA, Moore MR, et al. Effect of pneumococcal conjugate vaccine on pneumococcal meningitis. N Engl J Med 2009; 360: 244-256.

38. Trotter CL, Ramsay ME, Gray S, Fox A, Kaczmarski E. No evidence for capsule replacement following mass immunisation with menin-gococcal serogroup C conjugate vaccines in England and Wales. Lancet Infect Dis 2006;6:616-617; author reply 617-618.

39. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance surveillance reports. Available at: abcs/survreports.htm. Accessed 17 December 2009.

40. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 1969; 129:1307-1326.

41. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. II. Development of natural immunity. J Exp Med 1969; 129:1327-1348.

42. Jackson LA, Wenger JD. Laboratory-based surveillance for menin-gococcal disease in selected areas, United States, 1989-1991. MMWR CDC Surveill Summ 1993;42:21-30.

43. Jones IR, Urwin G, Feldman RA, Banatvala N. Social deprivation and bacterial meningitis in north east Thames region: three year study using small area statistics. BMJ 1997;314:794-795.

44. Platonov AE, Vershinina IV, Kuijper EJ, Borrow R, Kayhty H. Long term effects of vaccination of patients deficient in a late complement component with a tetravalent meningococcal polysaccharide vaccine. Vaccine 2003;21:4437-4447.

45. Stephens DS, Hajjeh RA, Baughman WS, Harvey RC, Wenger JD, Farley MM. Sporadic meningococcal disease in adults: results of a 5-year population-based study. Ann Intern Med 1995; 123:937-940.

46. Holmes FF, Weyandt T, Glazier J, Cuppage FE, Moral LA, Lindsey NJ. Fulminant meningococcemia after splenectomy. JAMA 1981; 246: 1119-1120.

47. Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev 1991;4:359-395.

48. Francke EL, Neu HC. Postsplenectomy infection. Surg Clin North Am 1981;61:135-155.

49. Salimans MM, Bax WA, Stegeman F, van Deuren M, Bartelink AK, van Dijk H. Association between familial deficiencyofmannose-bind-ing lectin and mutations in the corresponding gene and promoter region. Clin Diagn Lab Immunol 2004; 11:806-807.

50. Kuipers S, Aerts PC, Cluysenaer OJ, et al. A case of familial menin-gococcal disease due to deficiency in mannose-binding lectin (MBL). Adv Exp Med Biol 2003;531:351-355.

51. Emonts M, Hazelzet JA, de Groot R, Hermans PW. Host genetic determinants of Neisseria meningitidis infections. Lancet Infect Dis 2003; 3:565-577.

52. Smirnova I, Mann N, Dols A, et al. Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci U S A 2003; 100:6075-6080.

53. Olcen P, Kjellander J, Danielsson D and Lindquist BL. Epidemiology of Neisseria meningitidis: prevalence and symptoms from the upper respiratory tract in family members to patients with meningococcal disease. Scand J Infect Dis 1981; 13:105-109.

54. Young LS, LaForce FM, Head JJ, Feeley JC, Bennett JV. A simultaneous outbreak of meningococcal and influenza infections. N Engl J Med 1972; 287:5-9.

55. Harrison LH, Armstrong CW, Jenkins SR, et al. A cluster of menin-gococcal disease on a school bus following epidemic influenza. Arch Intern Med 1991; 151:1005-1009.

56. Moore PS, Hierholzer J, DeWitt W, et al. Respiratory viruses and mycoplasma as cofactors for epidemic group A meningococcal meningitis. JAMA 1990;264:1271-1275.

57. Krasinski K, Nelson JD, Butler S, Luby JP, Kusmiesz H. Possible association of mycoplasma and viral respiratory infections with bacterial meningitis. Am J Epidemiol 1987; 125:499-508.

58. Cartwright KA, Jones DM, Smith AJ, Stuart JM, Kaczmarski EB, Palmer SR. Influenza A and meningococcal disease. Lancet 1991; 338: 554-557.

59. Greenwood BM, Bradley AK, Cleland PG, et al. An epidemic of me-ningococcal infection at Zaria, Northern Nigeria. 1. General epide-miological features. Trans R Soc Trop Med Hyg 1979; 73:557-562.

60. Brundage JF, Zollinger WD. Evolution of meningococcal disease epidemiology in the US army. In: Vedros NA, ed. Evolution of menin-gococcal disease. Vol. I. Boca Raton, FL: CRC Press, 1987:5-25.

61. Tappero JW, Reporter R, Wenger JD, et al. Meningococcal disease in Los Angeles County, California, and among men in the county jails. N Engl J Med 1996;335:833-840.

62. Imrey PB, Jackson LA, Ludwinski PH, et al. Outbreak of serogroup C meningococcal disease associated with campus bar patronage. Am J Epidemiol 1996; 143:624-630.

63. Imrey PB, Jackson LA, Ludwinski PH, et al. Meningococcal carriage, alcohol consumption, and campus bar patronage in a serogroup C meningococcal disease outbreak. J Clin Microbiol 1995; 33: 3133-3137.

64. Fischer M, Hedberg K, Cardosi P, et al. Tobacco smoke as a risk factor for meningococcal disease. Pediatr Infect Dis J 1997; 16:979-983.

65. Cookson ST, Corrales JL, Lotero JO, et al. Disco fever: epidemic meningococcal disease in northeastern Argentina associated with disco patronage. J Infect Dis 1998; 178:266-269.

66. Froeschle JE. Meningococcal disease in college students. Clin Infect Dis 1999;29:215-216.

67. Harrison LH, Dwyer DM, Maples CT, Billmann L. Risk of menin-gococcal infection in college students. JAMA 1999;281:1906-1910.

68. Bruce MG, Rosenstein NE, Capparella JM, Shutt KA, Perkins BA, Collins M. Risk factors for meningococcal disease in college students. JAMA 2001;286:688-693.

69. MacLennan J, Kafatos G, Neal K, et al. Social behavior and menin-gococcal carriage in British teenagers. Emerg Infect Dis 2006; 12: 950-957.

70. Neal KR, Nguyen-Van-Tam JS, Jeffrey N, et al. Changing carriage rate of Neisseria meningitidis among university students during the first week of term: cross sectional study. BMJ 2000; 320:846-849.

71. Harrison LH, Kreiner CJ, Shutt KA, et al. Risk factors for menin-gococcal disease in students in grades 9-12. Pediatr Infect Dis J 2008;27:193-199.

72. Schuchat A, Hilger T, Zell E, et al. Active bacterial core surveillance of the emerging infections program network. Emerg Infect Dis 2001;7: 92-99.

73. McNabb SJ, Jajosky RA, Hall-Baker PA, et al. Summary of notifiable diseases—United States, 2006. MMWR Morb Mortal Wkly Rep 2008;55:1-92.

74. McEllistrem MC, Kolano JA, Pass MA, et al. Correlating epidemio-logic trends with the genotypes causing meningococcal disease, Maryland. Emerg Infect Dis 2004; 10:451-456.

75. Band JD, Chamberland ME, Platt T, Weaver RE, Thornsberry C, Fraser DW. Trends in meningococcal disease in the United States, 1975-1980. J Infect Dis 1983; 148:754-758.

76. Galaid EI, Cherubin CE, Marr JS, Schaefler S, Barone J, Lee W. Me-ningococcal disease in New York City, 1973 to 1978: recognition of groups Y and W-135 as frequent pathogens. JAMA 1980;244: 2167-2171.

77. Centers for Disease Control and Prevention. Available at: http:// Accessed 17 December 2009.

78. Jackson LA, Schuchat A, Reeves MW, Wenger JD. Serogroup C meningococcal outbreaks in the United States: an emerging threat. JAMA 1995; 273:383-389.

79. Zangwill KM, Schuchat A, Riedo FX, et al. School-based clusters of meningococcal disease in the United States: descriptive epidemiology and a case-control analysis. JAMA 1997; 277:389-395.

80. Finn R, Groves C, Coe M, Pass M, Harrison LH. Cluster of serogroup C meningococcal disease associated with attendance at a party. South Med J 2001;94:1192-1194.

81. Whalen CM, Hockin JC, Ryan A, Ashton F. The changing epidemiology of invasive meningococcal disease in Canada, 1985 through 1992: emergence of a virulent clone of Neisseria meningitidis. JAMA 1995; 273:390-394.

82. Bilukha OO, Rosenstein N. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54:1-21.

83. Vaccination coverage among adolescents aged 13-17 years—United States, 2007. MMWR Morb Mortal Wkly Rep 2008;57:1100-1103.

84. Harrison LH, Pass MA, Mendelsohn AB, et al. Invasive meningo-coccal disease in adolescents and young adults. JAMA 2001;286: 694-699.

85. Lingappa JR, Rosenstein N, Zell ER, Shutt KA, Schuchat A, Perkins BA. Surveillance for meningococcal disease and strategies for use of conjugate meningococcal vaccines in the United States. Vaccine 2001; 19:4566-4575.

86. Snape MD, Perrett KP, Ford KJ, et al. Immunogenicity ofa tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial. JAMA 2008;299:173-184.

87. Harrison LH. A multivalent conjugate vaccine for prevention of meningococcal disease in infants. JAMA 2008;299:217-219.

88. Jackson LA, Baxter R, Reisinger K, et al.; V59P13 Study Group. Phase III comparison of an investigational quadrivalent meningococcal conjugate vaccine with the licensed meningococcal ACWY conjugate vaccine in adolescents. Clin Infect Dis 2009; 49:e1-e10.

89. Nolan T, Lambert S, Roberton D, et al. A novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus-toxoid conjugate vaccine is immunogenic and induces immune memory when co-administered with DTPa-HBV-IPV and conjugate pneumococcal vaccines in infants. Vaccine 2007;25: 8487-8499.

90. Giuliani MM, Adu-Bobie J, Comanducci M, et al. A universal vaccine for serogroup B meningococcus. Proc Natl Acad Sci U S A 2006; 103: 10834-10839.

91. Fletcher LD, Bernfield L, Barniak V, et al. Vaccine potential of the Neisseria meningitidis 2086 lipoprotein. Infect Immun 2004; 72: 2088-2100.

92. Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 2004; 364:365-367.

93. Trotter CL, Ramsay ME, Kaczmarski EB. Meningococcal serogroup C conjugate vaccination in England and Wales: coverage and initial impact of the campaign. Commun Dis Public Health 2002;5: 220-225.

94. Maiden MC, Stuart JM. Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination. Lancet 2002;359:1829-1831.

95. Maiden MC, Ibarz-Pavon AB, Urwin R, et al. Impact of meningo-coccal serogroup C conjugate vaccines on carriage and herd immunity. J Infect Dis 2008; 197:737-743.

96. Gray SJ, Trotter CL, Ramsay ME, et al. Epidemiology of meningococcal disease in England and Wales 1993/94 to 2003/04: contribution and experiences of the Meningococcal Reference Unit. J Med Micro-biol 2006; 55:887-896.

97. Trotter CL, Ramsay ME. Vaccination against meningococcal disease in Europe: review and recommendations for the use of conjugate vaccines. FEMS Microbiol Rev 2007;31:101-107.

98. Tapsall J. Annual report of the Australian Meningococcal Surveillance Programme, 2007. Commun Dis Intell 2008; 32:299-307.

99. De Wals P. Meningococcal C vaccines: the Canadian experience. Pe-diatr Infect Dis J 2004; 23:S280-S284.

100. O'Hallahan J, Lennon D, Oster P, et al. From secondary prevention to primary prevention: a unique strategy that gives hope to a country ravaged by meningococcal disease. Vaccine 2005; 23:21972201.

101. Oster P, Lennon D, O'Hallahan J, Mulholland K, Reid S, Martin D. MeNZB: a safe and highly immunogenic tailor-made vaccine against the New Zealand Neisseria meningitidis serogroup B disease epidemic strain. Vaccine 2005;23:2191-2196.

102. Galloway Y, Stehr-Green P, McNicholas A, O'Hallahan J. Use of an observational cohort study to estimate the effectiveness of the New Zealand group B meningococcal vaccine in children aged under 5 years. Int J Epidemiol 2009;38:413-418.