Healio
Healio
Issue: December 2017
ByMatthew E. Levison, MD, FACP
ByDonald Kaye, MD, MACP
December 19, 2017
11 min read
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Meningococcal infection: Worldwide evolution

Issue: December 2017
ByMatthew E. Levison, MD, FACP
ByDonald Kaye, MD, MACP
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Neisseria meningitidis is a gram-negative diplococcus, which like all gram-negative bacteria, possesses a lipopolysaccharide-like component in its outer cell membrane. Almost all invasive isolates of N. meningitidis also express capsular polysaccharide. Based on the antigenic specificity of its capsular polysaccharide, meningococci are divided into 13 groups (A-E; H, I, K and L; and W-Z). However, most meningococcal infections worldwide are caused by only six of these 13 serogroups — A, B, C, W, X and Y.

Multilocus sequence typing, derived from the analysis of seven housekeeping genes, groups isolates into sequence types and sets of related sequence types called clonal complexes. Pathogenic strains have been found to belong to a few genetically defined clonal complexes (eg, hypervirulent ST-11 clonal complex of serogroup C), which have spread worldwide. Invasive meningococcal disease (IMD) may occur as sporadic cases or outbreaks (ie, multiple cases of the same serogroup in a population over a short period), which are either localized within an institution or spread across the community.

Matthew E. Levison
Donald Kaye

The clinical presentation of IMD is variable. Patients usually present with meningitis, meningococcal sepsis (meningococcemia) or some combination of the two. Meningococcemia can range from a mild condition to a devastating, rapidly evolving illness with purpura fulminans, gangrene of digits and limbs, disseminated intravascular coagulation, multiorgan failure, and shock, ending in death in a few hours. The diversity in spectrum and severity of IMD is likely a consequence of both the virulence of the particular strain and the state of the patient’s immune defenses against the invading strain. Of prime importance is the complement system for recognizing and eliminating the invasive pathogen upon its entering the bloodstream by means of direct killing and/or stimulation of phagocytosis. Deficiencies in components of the alternative, lectin and terminal complement pathways are known to increase risk for invasive meningococcal disease.

Rapid and accurate serogroup identification of N. meningitidis isolates is very important to monitor the changing epidemiology of the disease and to develop prevention strategies. Serogroup identification has historically been based on the slide agglutination assay using serogroup-specific antisera. However, PCR has more recently been used to determine the serogroup of clinical isolates.

The polysaccharide capsule is a major virulence determinant, and for serogroups A, C, W and Y, it forms the basis of polysaccharide vaccines used to prevent IMD. Serogroup A, C, W and Y polysaccharides all elicit an immune response, which allows for the development of successful quadrivalent vaccines. The capsular polysaccharide conjugate vaccines are preferred over vaccines that contain the capsular polysaccharide alone, because the conjugate vaccines induce a higher and more sustained immune response; they reduce the nasopharyngeal carriage of the bacteria and thus its transmission to close contacts, such as family members who would otherwise have been exposed to IMD. Conjugate vaccines are particularly effective in protecting children aged younger than 2 years who do not respond to the conventional polysaccharide vaccines. There are several polysaccharide conjugate vaccines available: a monovalent meningococcal A conjugate vaccine, a monovalent C conjugate vaccine, and quadrivalent A, C, Y and W conjugate vaccines. Among the conjugate vaccines, only quadrivalent formulations are available in the United States.

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For serogroup B, polysaccharide vaccines cannot be developed due to the poor immunogenicity of serogroup B capsular polysaccharide and its antigenic mimicry with polysaccharide in human tissues. The B vaccines instead use meningococcal constituent outer membrane proteins.

The immunity induced by meningococcal polysaccharide vaccines is specific to the type of capsular polysaccharide that the vaccine contains, offering no cross-protection against infection due to other meningococcal polysaccharide groups. However, because the surface protein antigens in the serogroup B meningococcal vaccines may also be present and expressed in meningococci belonging to non-B serogroups, serogroup B vaccines potentially could offer some level of protection against non-B serogroups. Preliminary studies of an in vitro bactericidal assay against serogroup C, W and Y meningococci found that sera from individuals immunized with one of the B serogroup vaccines was bactericidal against these non-B serogroup strains.

Nevertheless, the CDC currently recommends that serogroup B meningococcal vaccines be used to prevent meningococcal disease caused by serogroup B and that meningococcal conjugate vaccines be used to prevent disease due to serogroups A, C, W and Y. For protection against the five serogroups of meningococcus (A, B, C, W and Y), receipt of both a quadrivalent polysaccharide vaccine and a serogroup B vaccine is thought to be necessary. At present, no vaccine is available that offers protection against serogroup X.

Over the past several decades, there have been changes in the epidemiology of meningococcal disease that have important implications for vaccination and other prevention strategies. Following large-scale vaccine programs that used the monovalent serogroup A or C conjugate vaccines in Africa, the United Kingdom, Australia and elsewhere, meningitis due to the respective serogroup began disappearing, only to be replaced by other meningococcal serogroups, although at lower rates.

Africa

The African meningitis belt (AMB) is a region of sub-Saharan Africa where meningococcal meningitis is hyperendemic, with outbreaks occurring every year and major epidemics occurring every 5 to 12 years in which attack rates reach 1,000 cases per 100,000 population. The AMB extends from the Atlantic coast in the west to the Red Sea in the east and includes 26 countries. Meningococcal meningitis in this region is seasonal, occurring from December to March, when dry, dust-laden Harmattan winds blow from the Sahara Desert over West Africa into the Gulf of Guinea. The winds, which may lower visibility and cause the relative humidity to drop under 10%, can possibly damage the mucous membranes of the respiratory system, increasing nasopharyngeal carriage of meningococci. Also, temperatures fall at night at this time of year, which can cause crowding in enclosed, poorly ventilated spaces that facilitates person-to-person spread of respiratory pathogens.

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Historically, meningitis in the AMB was primarily due to N. meningitidis serogroup A. This serogroup accounted for 90% of meningococcal disease cases and most large epidemics, although serogroups W and X occasionally did cause some outbreaks of IMD. In the 7 years before 2010, serogroup A of the ST-5 clonal complex was identified as the predominant disease-causing strain.

Starting in 2010, a monovalent meningococcal serogroup A conjugate vaccine was progressively made available through large-scale vaccination campaigns for individuals aged 1 to 29 years in 16 of the 26 countries of the AMB. As of June 2015, WHO reported more than 220 million people had received meningococcal A conjugate vaccine in 15 countries of the AMB.

After serogroup A vaccine introduction in 2010, the incidence rate of serogroup A meningitis fell dramatically — more than 10-fold in vaccination areas. During the 2014 epidemic season, 19 African countries reported the lowest numbers of meningitis cases since the implementation of enhanced surveillance in 2004.

Despite the disappearance of serogroup A, epidemics of IMD still occur, now primarily due to serogroups C and W, as well as X in some countries. The serogroup C outbreak, caused by a unique clone (multilocus sequence type ST10217, clonal complex unassigned), started in 2013 in Nigeria and Niger, and has continued every year since then, with subsequent expansion into surrounding countries.

In 2000, a large outbreak caused by serogroup W meningococci was reported among hajj pilgrims in Mecca. Since then, epidemics caused by serogroup W meningococci derived from the Mecca strain have occurred in the AMB. Most W isolates belong to clonal complex 11 (CC11), which seems to have emerged through capsule switching from virulent serogroup C meningococci. (Hyperinvasive meningococcal isolates belonging to CC11 can express C, W or, less frequently, B or Y capsule polysaccharides, presumably through capsule switching.)

United Kingdom

The U.K. is the first country to introduce a national immunization program with a conjugate vaccine. Meningococcal monovalent serogroup C conjugate vaccine was offered to infants at the end of 1999 following a rapid rise in cases during the 1990s caused by a single serogroup C clone, belonging to the ST-11 complex, that was associated with a high case-fatality rate. Because meningococci are carried in the nasopharynx, particularly among adolescents and young adults, and because the conjugate vaccines prevent acquisition of nasopharyngeal colonization, thereby interrupting transmission of serogroup C, the conjugate C vaccine was also offered to all adolescents aged 15 to 17 years.

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Subsequently, IMD due to serogroup C almost disappeared, with a reduction of more than 98% in target age groups and of more than 90% in unvaccinated age groups, and the effect has been sustained, providing evidence of the strong effect of the vaccine.

Serogroup B is now responsible for almost all cases of IMD in the U.K., especially in children and young adults, but its incidence has been declining in all age groups — from 1,614 cases in the 2000-2001 season to 418 cases in 2014-2015, despite no serogroup B vaccine having been offered at the time. However, a routine infant immunization program with a serogroup B vaccine was started in 2015.

Since 2009, the incidence of serogroup W IMD has been increasing across all regions and age groups in England and Wales, often with atypical clinical presentations — from 19 cases in the 2008-2009 season to 176 in 2014-2015 — accounting for a quarter of all laboratory-confirmed meningococcal cases that year. The emergent serogroup W strain was derived by capsular switching from the highly virulent CC11 that was responsible for the U.K. serogroup C outbreak in the 1990s and is genetically identical to serogroup W strains currently causing large national outbreaks in South America. In response to the emergence of serogroup W CC11 in the U.K., Public Health England has recommended that individuals aged 14 to 18 years be vaccinated with the quadrivalent conjugate ACWY vaccine, replacing routine serogroup C conjugate vaccine in this age group, who are more likely to carry meningococcal bacteria in their nasopharynx than any other age group.

Australia

A similar situation is apparently occurring in Australia following the introduction of the conjugate meningococcal monovalent C vaccine in 2003, with a single dose at 12 months of age, along with a catch-up for individuals aged younger than 20 years. Since 2003, there has been a significant (93%) and sustained reduction in serogroup C meningococcal cases, from 162 (41% of cases) in 2002 to 1.2% of cases in 2016, accompanied by an increase in the relative proportion of serogroup B, from 51% of cases in 2002 to 83% of cases in 2012. The number of laboratory-confirmed IMD cases in 2012 was the lowest since laboratory surveillance data have been reported.

Before 2013, most IMD cases in Australia had been caused by serogroups B and C. However, since 2013, the incidence and the relative proportion of serogroup W have steadily increased. By 2016, serogroup W, rather than B, had become the predominant serogroup, increasing from 3% in 2012 (7/223 cases) to 19% (34/182 cases) in 2015, and to 45% (109/244 cases) in 2016, surpassing serogroup B (92 cases, 38%). The state of Victoria has been the most heavily affected, with 50% (17/34 cases) of national cases of serogroup W in 2015 occurring there. The case-fatality rate for serogroup W was 21% — 2.3 times higher than for all other IMD serogroups combined. The majority of Australian serogroup W isolates cluster within CC11, similar to the U.K. isolates.

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A smaller increase in serogroup Y disease has occurred in the last few years, from 12 cases (7.4% of those with an identified serogroup) in 2014 to 40 cases (16.4%) in 2016.

Eculizumab

Soliris (eculizumab, Alexion Pharmaceuticals) is a humanized monoclonal antibody that was reported to be the most expensive drug in the world in 2010, costing $409,500 a year in the U.S. Eculizumab binds to the complement protein C5, inhibiting its cleavage to C5a and C5b. This prevents circulation of the C5a peptide and generation of the terminal complement complex C5b-9. It is used to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

From 2008 to 2016, IMD occurred in 16 eculizumab recipients in the U.S., resulting in a 1,000- to 2,000-fold increased risk for meningococcal disease. IMD occurred despite some of the recipients having received a meningococcal vaccine before receipt of eculizumab. This is likely attributable to the fact that IMD in 11 cases was caused by nongroupable (ie, nonencapsulated) N. meningitidis. Nonencapsulated meningococci can cause disease in vaccinated people because there is no protective immunity induced by the capsular polysaccharide-based meningococcal vaccines against nonencapsulated strains. However, nonencapsulated strains rarely cause disease in immunocompetent individuals.

Meningococcal vaccination is recommended at least 2 weeks before receiving eculizumab, unless the risks of delaying eculizumab therapy outweigh the risk of developing a meningococcal infection, in which case the meningococcal vaccine should be administered as soon as possible. Both a conjugate ACWY meningococcal vaccine and a serogroup B meningococcal vaccine are recommended for people receiving eculizumab, although the vaccinations may not prevent all meningococcal infections, especially those caused by nongroupable N. meningitidis. Consequently, prophylaxis with antimicrobial drugs is recommended for the duration of eculizumab treatment, which will mean a lifelong course of antimicrobial drugs for many eculizumab recipients.

Urogenital infections

Urogenital infections due to N. meningitidis have been reported sporadically in the past, but in 2015, a marked increase in the incidence of meningococcal urethritis was noted in heterosexual men at two U.S. sexual health clinics in Columbus, Ohio, and Oakland County, Michigan, as well as in Atlanta and Indianapolis. Oral sex was reported by almost all patients. The urethral isolates were nongroupable (nonencapsulated) CC11 that formed a unique clade, with a common molecular fingerprint and characterized by anaerobic growth, which is usually rare in meningococci but is found in gonococci. Anaerobic growth was thought to allow gonococci to survive in the urethra and rectum, leading to the clinical manifestation of urethritis/proctitis and facilitating direct sexual transmission.

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A similar situation occurred in men who have sex with men (MSM). Outbreaks of IMD due to serogroup C meningococci have been reported in MSM in the U.S. and Europe during the past several years due to a hyperinvasive meningococcal lineage (CC11). Meningococci isolated from patients with IMD and from patients with urethritis/proctitis in Germany and France were found to have the same genotype, and all isolates were able to grow anaerobically, unlike meningococcal isolates unrelated to the MSM outbreak. However, invasive isolates from MSM, but not urethritis isolates, expressed a protein that binds human factor H, a complement regulatory protein, which favors survival in the bloodstream.

A diagnosis of urethritis is often based on Gram staining or nucleic acid amplification tests (NAATs). However, Gram staining cannot differentiate N. meningitidis from N. gonorrhoeae, and NAATs detect only N. gonorrhoeae. If the Gram stain shows intracellular gram-negative diplococci and the NAAT is negative for N. gonorrhoeae, presumptively the urethritis is due to N. meningitidis. In the U.S., the CDC recommends that meningococcal and gonococcal urethritis be treated the same way (a single 250-mg dose of intramuscular ceftriaxone plus a single 1-g oral dose of azithromycin). If only NAAT is performed, as is now a common practice, the CDC recommends that patients be treated with the drug regimen effective against both gonorrhea and chlamydia (see earlier), which will also cover meningococci; however, the diagnosis of meningococcal urethritis will be missed, and the disease will be underreported.

In conclusion, we have effective vaccines against IMD. However, the experience has been that, for whatever reason, when vaccines are used that are effective only against the circulating serogroup, that serogroup is replaced by others, albeit in decreased numbers.

  • For more information:
  • Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.
  • Matthew E. Levison, MD, FACP, is a ProMED-mail associate editor and bacterial disease moderator, professor of public health, Drexel University School of Public Health, and adjunct professor of medicine and former chief of the division of infectious diseases, Drexel University College of Medicine.

Disclosures: Kaye and Levison report no relevant financial disclosures.

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