Review

The current situation of meningococcal disease in Latin America and recommendations for a new case definition from the Global Meningococcal Initiative
Expert Rev. Vaccines Early online, 113

Marco Aurlio P Sfadi*, Luz Elena Espinosa de los Monteros, Eduardo Luis Lpez, Xavier Sez-Llorens, Ana Paula Lemos, Sarbelio Moreno-Espinosa, Silvia Gonzlez Ayala, Juan Pablo Torres, Jos Cassio de Moraes and Julio Alberto Vzquez
FCM da Santa Casa de So Paulo, Alameda dos Indigenas, 228, ZIP 04059 060, So Paulo, Brazil *Author for correspondence: Tel.: +55 11 99842584; +55 11 55947579 Fax: +55 11 55947579 masafadi@uol.com.br

The Global Meningococcal Initiative (GMI) is an international group of scientists and clinicians with expertise in meningococcal disease (MD). It promotes MD prevention through education and research. Given geographic differences in disease epidemiology, prevention strategies (e.g., vaccination) should be country-specific to ensure local needs are met. However, regional policies/ recommendations and standardized disease diagnostic criteria should be implemented to improve surveillance and control strategies, and allow for more robust data comparisons. Consequently, the GMI convened a meeting with Latin American representatives to discuss the burden of MD and vaccination practices/policies, and consider if the global GMI recommendations could be tailored. The group determined that as robust, uniform epidemiologic data are required to make informed health-policy decisions, it would be useful to first summarize the regional situation herein (including disease surveillance, case definitions, epidemiology, vaccination and outbreak control strategies) and then determine a consensus-based meningococcal case definition for use throughout the region.
Keywords: case definition control epidemiology Global Meningococcal Initiative Latin America management meningococcal disease PCR surveillance vaccination

Meningococcal disease (MD) is a serious, rapidly developing and potentially fatal infection. The causative bacterium for endemic and epidemic MD is Neisseria meningitidis [1] . Invasive disease is characterized by one or more clinical syndromes including bacteremia, sepsis or meningitis, the latter being the most common presentation. Pneumonia, conjunctivitis, a rthritis, pericarditis and myocarditis are less common manifestations of N. meningitidis infection. In general, the highest incidence rates of MD are observed in children <1 year of age, both across the globe and in Latin America [2,3] . Additionally, in some areas of the world, other high incidence peaks are observed among adolescents (16 through 21 years of age [47]) (but this is not seen in all countries [810]) and older
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adults, that is, those aged 65 years [11] . Indeed, MD affects people of all ages, from the very young to the elderly across the globe, as well as in Latin America. However, the proportion of cases caused by each serogroup varies according to age group. Serogroup B N. meningitidis tends to be more prevalent among infants and young children, while serogroup Y affects more older individuals [3,12] . In general, six meningococcal serogroups (A,B, C, W-135, X and Y) are the etiological agents for nearly all clinical cases of MD [13] . However, the quality and the reliability of the information on MD are not uniform across the world. The reasons for this include, but are not limited to, differences in surveillance practices (or lack thereof ), use of different diagnostic
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methods and protocols and application of different meningococcal case definitions. Vaccination is considered the best strategy for MD prevention [14] . There are available meningococcal conjugate vaccines against serogroups A, C, W-135 and Y [11] . Vaccines composed of outer membrane vesicles (OMV) against serogroup B are also available and have proved to be efficacious to control specific outbreaks or epidemics. However, their modest immunogenicity in young children, short duration of protection and narrow strain specificity are limiting factors for their usefulness [15] . Recently, new serogroup B vaccines developed by reverse vaccinology or recombinant technology have shown high immunogenicity in children and adolescents in Phase II/III studies [1618] , and one such vaccine has already obtained marketing authorization and is approved for use in Europe [101] . These vaccines are expected to be available globally in the next few years. The Global Meningococcal Initiative (GMI), founded in 2009, is led by a group of international scientists and clinicians with expertise in meningococcal immunology, microbiology, epidemiology, public health and vaccination. Its purpose is to promote MD prevention worldwide through education, research, international cooperation and vaccination. The GMI has proposed several recommendations to reduce the worldwide burden of MD [2] (Table 1) . Because of geographic and temporal variations in disease, the GMI convened a roundtable meeting with 11 experts from sevenLatin American countries (Argentina, Brazil, Chile, Dominican Republic, Mexico, Panama and Uruguay). As the epidemiology of MD in Latin America recently had been reviewed [3,19] , the meetings primary objective was to tailor the global GMI recommendations to the region. Additionally, as robust, uniform epidemiologic data are required to make informed health policy decisions that result in the introduction and expanded use of lifesaving meningococcal vaccines, a consensus-based meningococcal case definition for use throughout Latin America was proposed.
Surveillance & disease diagnosis

In Latin America, MD surveillance is largely passive, with heterogeneous reporting confounding inter-country epidemiologic

comparisons. Moreover, concern exists over how representative the collected information is in terms of disease epidemiology, with a potential underestimation of the true burden of MD in the majority of the countries in the region, which can negatively impact data quality and hamper evidence-based health policy. However, since 2010, countries qualifying for Global Alliance for Vaccines and Immunization (GAVI) support in partnership with the Family and Community Health (FCH/IM) unit at the Pan American Health Organization (PAHO) have been strengthening existing surveillance and actively monitoring etiologic agents of meningitis and pneumonia, particularly in children <5 years of age [102,103] . In 1993, PAHO and WHO implemented a Latin American laboratory-based passive surveillance program, named SIREVA, initially for cases of invasive Streptococcus pneumoniae infection. This network was extended in 1999 to cases of Haemophilus influenzae and in 2000 to cases of N. meningitidis. Currently, SIREVAII performs a systematic analysis of isolates recovered by the epidemiological survey network from countries in the Latin American and Caribbean region. The Instituto de Salud Carlos III, in Spain, is the international reference center, and the Adolfo Lutz Institute in So Paulo, Brazil, is the regional reference laboratory responsible for N. meningitidis characterization and other tests [20] . Laboratory-based diagnosis of suspected cases of MD in Latin America occurs almost exclusively via culture, in the absence of a standardized strategy based on nucleic acid amplification techniques and meningococcal genotype studies. However, previous antibiotic use is a risk factor for culture negativity [21] , contributing to disease underreporting. Several countries in Latin America have regions with limited access to laboratory equipment and facilities, affecting the quality of the sample processing. Moreover, some hospitals cannot spare the funds to transport samples, further contributing to MD underreporting. The Pan American Health and Education Foundation (PAHEF) Surveillance Study seeks to improve the surveillance and characterization of MD in Latin America and the Caribbean [104] . One of the first steps in improving surveillance is the standardization of case definitions for the disease.

Table 1. Global Meningococcal Initiative recommendations for reducing the global burden of meningococcal disease.
Country-specific approaches to vaccine prevention are needed because of geographic and temporal variations in disease epidemiology Country-specific meningococcal policy should be based on local epidemiology and economic considerations Continued funding of the introduction of MenAfriVacTM is an important global and regional public health priority The MVP model should be considered when developing other products with markets that are primarily or exclusively in developing countries Travelers to high-risk areas should be vaccinated against MD Vaccines against all clinically relevant meningococcal serogroups (A, B, C, W-135, X and Y) should be developed Conjugate vaccines should replace polysaccharide vaccines wherever possible, but polysaccharide vaccines are still recommended where conjugate vaccines are not available Laboratory-based surveillance for MD should be strengthened (or initiated) to determine the true burden of disease
MD: Meningococcal disease; MVP: Meningitis Vaccine Project. Reproduced with permission from [2]. Copyright (2011), with permission from Elsevier.

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Present situation of meningococcal disease in Latin America

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Table 2. Meningococcal meningitis and meningococcemia case definitions in a number of Latin American countries.
Argentina Probable: person with compatible disease and purpura fulminans or antigen detection in CSF Suspected: acute onset with high fever, meningeal syndrome, petechial or purpuric exanthem Confirmed: person with compatible disease and isolation of Neisseria meningitidis from a normally sterile site or detection of N. meningitidis antigen in blood, CSF or other normally sterile site Clinical: >1 year of age: fever, severe headache, vomiting, stiff neck, signs of meningeal irritation, seizures and/or red spots on the body; <1 year of age: irritability, persistent crying or bulging fontanelle Confirmed: isolation of N. meningitidis from blood, CSF or skin lesion or detection of N. meningitidis antigen in blood or CSF or detection of intracellular Gram-negative diplococci or detection of bacterial DNA by RT-PCR or epidemiologic link with a laboratory-confirmed case or disease compatible with meningococcemia with petechial rash Suspected: >1 year of age: fever (>38C) and headache and vomiting and one of the following: stiff neck, altered consciousness, Kernig or Brudzinski sign or petechial or purpuric rash; <1 year of age: fever accompanied by bulging fontanelle, vomiting, drowsiness, irritability, seizures (with or without petechial rash) Confirmed: isolation of N. meningitidis from normally sterile site or detection of N. meningitidis DNA in blood or CSF by RT-PCR OR epidemiologic link with a laboratory-confirmed case Suspected: fever (>38C) and two of the following: bulging fontanelle, stiff neck, Kernig or Brudzinski sign, back pain, photophobia, encephalic irritability, disorientation, confusion, drowsiness, somnolence, stupor, coma, apathy, aggression, slurred speech, cranial nerve attack, seizure or cloudy CSF Confirmed: positive culture or epidemiologic link with a laboratory-confirmed case Meningococcal meningitis: any illness with sudden onset of fever and one of the following: stiff neck, altered consciousness, other meningeal sign or petechial or purpuric rash Meningococcemia: sudden febrile episode with some kind of hemorrhagic rash and negative IgM against dengue Confirmed: positive culture or detection of Gram-negative diplococci in CSF or blood Suspected: a case that meets the clinical case definition (an illness with sudden onset of fever (>38.5C rectal or >38.0C axillary) and one of the following: neck stiffness, altered consciousness, other meningeal sign or petechial or purpuric rash. For patients <1 year of age, suspect meningitis when fever accompanied by bulging fontanelle) Probable: a suspected case as defined above and turbid CSF (with or without positive Gram stain) or occurring during an ongoing epidemic and with an epidemiologic link to a confirmed case Confirmed: a suspected or probable case with laboratory confirmation (either detection of bacterial antigen(s) in CSF or positive culture)

Brazil

Chile

Mexico

Panama

PAHO

In some hospitals, buffy coat smears are tested, particularly in patients with suspected meningococcemia and known previous antibiotic use. CSF: Cerebrospinal fluid; PAHO: Pan American Health Organization.

Despite the existence of a PAHO-recommended case definition for MD in the region, the countries of Latin America employ different case definitions, complicating intercountry comparisons (Table 2) . The attendees of the GMI Latin America Roundtable Meeting regarded the restrictive case definition criteria for MD in some countries, such as Mexico, as one of the potential determinants for the exceedingly low rates consistently reported in these countries. Evidence in support of this assumption is the recent results of a prospective, active hospital-based surveillance performed along the US border, showing rates of MD in infants several times higher than those reported in Mexico [22] and also the increase in the number of cases detected after the implementation of multiplex PCR in Mexico City [23] .
Epidemiology

As the epidemiology of MD in Latin America has been thoroughly and recently reviewed [3,19] , only a brief overview will be provided here. In Latin America, the incidence of MD varies from <0.1 cases per 100,000 in countries including Mexico, Paraguay, Peru and Bolivia to almost two cases per 100,000 in Brazil. Although current estimates suggest that Brazil, together with the countries from the southern cone (Uruguay, Argentina
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and Chile), bear the highest burden of MD in Latin America, this rate may be the result of ascertainment bias. These countries, relative to others in the region, have a more robust surveillance system in place for MD and established laboratory infrastructure. In Brazil, for example, access to molecular diagnostics is available in sentinel sites in the state of So Paulo. In fact, the introduction of multiplex real-time PCR (RT-PCR) assay testing for S. pneumoniae, N. meningitidis and H. influenzae type B in sentinel hospitals in So Paulo provided an increase in the diagnostic yield for bacterial meningitis by 52, 85 and 20%, respectively, over culture-based methods [21] . In 2010, only a single isolate of N. meningitidis was reported to SIREVA from four Latin American countries: Costa Rica (serogroup Y), Ecuador (serogroup C), Nicaragua (serogroup B) and Peru (serogroup W-135 [103]), another likely illustration of ascertainment bias. However, although RT-PCR is the ideal, conventional PCR systems may be somewhat advantageous in some situations due to lower cost and ease of implementation [24] or in areas where RT-PCR facilities are not available. Among the countries where information on incidence rates of MD is available, the highest burden of disease is consistently reported in infants and children younger than 5 years of age.
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100 90 80 70

Percentage (%)

60 50 40 30 20 10 0

B C W-135 Y

1)

8)

3)

6)

9)

7)

8)

62

24

27

15

57

(n

(n

(n

(n

(n

(n

(n

(n

(n

(n

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ub

am

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ay

ex i

il

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ag

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Pa n

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Figure 1. Meningococcal serogroup distribution of isolates sent to SIREVA II in 2011 for analysis by a number of Latin American countries. Adapted from [103] .

However, during epidemics and outbreaks (the majority of them associated with serogroup C and reported in Brazil, but also an outbreak of serogroup B in Argentina in 19931994), an increase in the incidence rates in adolescents and young adults is observed. Regarding serogroup distribution, serogroups B and C have been responsible for the majority of cases reported in the region for the past two decades, although this may be biased as the vast majority of data come from Brazil. Serogroup B has been the prevalent cause of disease in Chile, Uruguay and Colombia, although a decreasing trend in the incidence rates of serogroup B has been observed in Latin America in recent years [19] . Serogroup Y has also been predominant in Colombia for several years. Serogroup W-135 has emerged in Argentina and Chile, with the prevalence of this serogroup increasing from no cases in 2001 to 34% of total cases in 2011 and 55% of all cases identified by December 2012 within Chile, with an increase in the case fatality rates from 1015% (expected for the disease) to 26% in 2012 [105,106] and from 2% of cases with confirmed serogroup in 2000 to 50% in 2010 within Argentina [25] . Clusters of MD cases resulting from serogroup W-135 have also been reported in Brazil. The emergence of serogroup W-135 in Latin America is related to the hypervirulent Hajj clone W-135:P1.5,2:ST-11 (ST-11/ET-37
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om

in

Country (number of isolates)

ic

an

clonal complex), which emerged and has spread internationally since 2000 [26] . In Brazil, from 2002 onward, a significant increase in the proportion of cases attributed to serogroup C, associated with the ST-103 complex, has been observed and, currently, serogroup C is the most frequent serogroup causing MD in Brazil [26] . Serogroup C is also the predominant cause of disease in Mexico, Central America and the Caribbean. In the Andean region, limited information is available, although serogroups B and Y appear to be predominant in Colombia. Serogroup A has virtually disappeared from Latin America (Figure 1, based on the data from the 2011 SIREVA II report [20,103]). Before implementing meningococcal vaccination strategies in the region, it is of paramount importance to have better information on representative carriage prevalence studies. This will have important implications in future vaccination strategies, optimizing the indirect effects provided by meningococcal C conjugate vaccines and also by other meningococcal vaccines with potential to induce indirect protection. Carriage prevalence studies proved to be crucial to understanding the dynamics of carriage and disease and also the potential effect of control programs, such as vaccination, on the
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Ve n

ez

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in

la

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25

Present situation of meningococcal disease in Latin America

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transmission of meningococci. European and North American studies showed that age was a key factor influencing meningococcal carriage rates. In these studies, carriage rates were low in young children, increasing in teenagers and reaching a peak in older adolescents and young adults, and then declining in adulthood [27] . However, it is important to acknowledge that very limited published data describing carriage prevalence of N. meningitidis in Latin America are currently available.
Vaccination

Table 3. Meningococcal vaccine availability in the public and/or private markets in a number of Latin American countries.
Polysaccharide
Argentina Bolivia Brazil Chile Colombia Costa Rica Cuba Dominican Republic ACWY AC

Conjugate
C, ACWY ACWY C, Hib-C, ACWY C, ACWY ACWY ACWY

Other
BC BC BC BC

Polysaccharide, conjugate and OMV-based Ecuador AC vaccines are available in Latin America Guatemala ACWY (Table 3) . Conjugate vaccines offer a numMexico C ber of advantages over polysaccharide AC ACWY formulations. The conjugation of polysac- Panama AC charides with carrier proteins alters the Paraguay nature of the anti-polysaccharide response Peru ACWY to a T-dependent response, inducing the Venezuela C production of high levels of antibodies AC: Polysaccharide vaccine against Neisseria meningitidis serogroups A and C; ACWY: Polysaccharide or (even in infants), higher antibody avid- conjugate vaccine against N. meningitidis serogroups A, C, W-135 and Y; C: Conjugate vaccine against ity and increased serum bactericidal N.meningitidis serogroup C; Hib-C: Conjugate vaccine against N. meningitidis serogroup C and Haemophilus influenzae type B; BC: N. meningitidis serogroup B outer membrane vesicles (OMV) plus a activity. The formation of populations serogroup C polysaccharide vaccine. of memory B lymphocytes, of long duration, provides an excellent anamnestic response (booster effect) has been routinely administered to infants at 3 and 5 months on re-exposure. Furthermore, these vaccines have the ability to of age, as part of the national immunization schedule. In 2008, reduce n asopharyngeal colonization by serogroup C N. menin- Cuba reported a low incidence of MD (0.1/100,000 inhabitants), gitidis, reducing the number of carriers among the vaccinated and, but only a few isolates were sent to SIREVA II for analysis [29] . therefore, the spread of the disease in the population (indirect Most cases of MD that have occurred in Cuba since the availimmunity or herd protection [1]). ability of the OMV vaccine have been caused by ST-33 strains, Meningococcal C conjugate vaccines and quadrivalent A, C, with the same phenotype (B:4:P1.19,15) as the strain included in W-135 and Y meningococcal conjugate vaccines are available in VA-MENGOC-BC [29] . the private sector in Argentina, Brazil, Bolivia, Chile, Colombia, In response to an increase in the amount of disease attributable Costa Rica, Guatemala, Panama and Peru. In Argentina, quad- to serogroup C, Brazil began to routinely immunize infants (two rivalent meningococcal conjugate vaccines are available (with- doses at 3 and 5 months plus a booster dose at 1215 months) out cost) to individuals at high risk of disease. In response to and toddlers (one dose between 12 and 23 months) with a meninan increase in the number of serogroup W-135 cases in Chile gococcal C conjugate vaccine in September 2010 [12] . Coverage during 2012 (incidence rates of serogroup W-135 disease were for the two primary doses was >90% in late 2011, and a popapproximately three-times higher in 2012 compared with 2011), ulation-based analysis showed a 30% decrease in MD rates in an immunization program in children aged between 9 months this cohort, a significant early reduction relative to prevaccine and 5 years old, with quadrivalent meningococcal conjugate vac- disease incidence [26] . Mathematical modeling has shown the cines, has recently been implemented [107] . These vaccines are also routine immunization of Brazilian infants against serogroup C available to control outbreaks and epidemics. to be cost effective [30] , but no catch-up campaign of older age Meningococcal vaccine use and scheduling vary by country. groups was done due to cost and resourcing constraints [12] . As a However, Cuba and Brazil are the only countries in Latin America consequence, only the burden of MD borne by those <2 years of with universal MD vaccine recommendations. In fact, Cuba was age is anticipated to be impacted in the immediate period after the first country in the Americas to implement mass vaccination vaccine introduction. against MD, specifically against serogroup B [28] . Cuba introduced a locally produced serogroup B OMV plus a serogroup C Outbreak management polysaccharide vaccine (VA-MENGOC-BC) in a catch-up cam- In most situations, the number of cases of MD during an outbreak paign targeting individuals aged 3 months to 24 years in 1990. is not substantial, emphasizing the importance of a well-estabThe program achieved 95% coverage. Since 1991, this vaccine lished surveillance system, with quality information on baseline
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patterns of disease that can identify whether the occurrence of cases represents an outbreak. PAHO defines an epidemic/outbreak as occurring or likely to occur in areas considered hyperendemic when an average of 15cases per 100,000 per week occur over 2 consecutive weeks. Once epidemic disease is detected in a given area, a lower value (e.g., five cases/100,000 per week) may be used as a threshold in contiguous areas. In non-hyperendemic areas, the occurrence of an epidemic can be defined when a three to fourfold increase in disease incidence relative to previous years or a doubling in the number of cases from 1 week to the next over 3 weeks is observed [108] (however, other thresholds have been proposed [31]). In general, outbreaks are difficult to declare in countries with scant information on endemic disease, underscoring the need for improvements in case reporting and laboratory capabilities. Outbreak preparedness and responses vary from one Latin American country to the next and are dependent on local disease epidemiology and policies (Figure 2) . However, containment efforts that have been employed in the region include augmented disease monitoring; chemoprophylaxis of close contacts (such as, household contacts; other close contacts, especially children (school contacts, people who have eaten or slept with the patient at least 4h a day within a radius of 1 m in the 7 days preceding illness onset); health workers in contact with the patients oral secretions (e.g., mouth-to-mouth resuscitation)) and reactive vaccination to the population age groups with higher risk of disease. In Brazil, recent serogroup C MD outbreaks are typically contained via chemoprophylaxis of close contacts and reactive vaccination of high-risk groups if the attack rate exceeds 10cases/100,000 population over a 3-month period (three or more confirmed or probable primary cases of MD of the same serogroup). The population at risk is used as the denominator in calculations of the disease attack rate. The population at risk is usually defined on the basis of organizational affiliation or community of residence. Outbreaks can be classified as organization-based (common affiliation but no close contact with each other, e.g., a school or a university) or community-based (persons residing in the same area who are not close contacts of each other and who do not share a common affiliation). Given the poor immunogenicity of polysaccharide vaccines in infants and young children, meningococcal C conjugate vaccines are administered to those <2 years of age, while meningococcal A/C polysaccharide formulations are given to those 2 years of age [3] . Although reactive meningococcal A/C polysaccharide vaccination prevented new cases of disease among vaccinated workers during an organization-based outbreak at a food-processing facility in Midwestern Brazil, it did not prevent the surrounding community from experiencing an attack rate of 12 cases per 100,000 [32] . Reactive vaccination has also failed to control serogroup A meningococcal epidemics in the African Meningitis Belt [33,34] . Reactive vaccination has met with limited success because it is difficult to determine when sporadic disease incidence becomes an outbreak, especially in countries without routine disease surveillance. Second, there may be delays in acquiring and/or shortages in vaccine supply and manpower to initiate any proposed reactive
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immunization strategy [34] . Mathematical modeling of MD in the African Meningitis Belt has shown that preventative vaccination in these settings is more cost effective than reactive i mmunization, avoiding more cases of disease and costing less per case [35] .
GMI recommendations
Surveillance

As inadequate surveillance and heterogeneous reporting severely hamper evidence-based immunization policy, the GMI encourages the supplementation of culture with standardized nucleic acid amplification techniques for disease confirmation and implementation of molecular genotype characterization techniques as a routine in national and regional reference laboratories; the introduction of quality controls, so that data from different laboratories can be harmonized; consistent and universal use of standardized diagnostic protocols, such as those set forth by SIREVA II or PAHO; the forging of partnerships between resource-rich and resource-constrained regions to improve laboratory capacity (and the quality and quantity of the epidemiologic data available) and the implementation of active population- and laboratory-based surveillance for invasive MD in determined sites to assist in early outbreak detection and estimation of age-specific incidence rates and serogroup distribution. PAHO recognizes the utility of laboratory diagnostics in analyzing clinical samples [109] , considering culture positivity and cerebrospinal fluid (CSF) antigen detection as acceptable confirmatory evidence of meningococcal infection [108] . However, given the potential for antibiotic-induced culture negativity and for prolonged transport times to compromise sample integrity, the GMI also endorses the use of PCR, at least at the National Reference Laboratory (NRL), but ideally at designated regional reference laboratories. PCR techniques have demonstrated a high impact on the diagnosis of MD [36] . However, the GMI understand that low-income countries may not have the resources to implement PCR techniques and therefore may need to continue with the PAHO confirmed case definition as it stands unless of course financial support can be identified. The GMI acknowledges that if a case definition does not include a requirement for laboratory confirmation, it would be difficult for Latin American hospitals to justify the costs of such tests. To this end, there was unanimous agreement among the meeting attendees to amend the existing PAHO case definition for confirmed MD to include molecular diagnostic techniques, like PCR, if available (RT-RCR if possible) (Table 4) . RT-PCR is associated with high sensitivity and specificity for N. meningitidis [3740] , especially relative to culture-based detection methods [38,39,41] . Even when the organisms are nonviable after antibiotic treatment, PCR can still detect N. meningitidis DNA [21] . As mentioned, laboratory infrastructure is limited in many parts of the region. Although some countries have NRLs, they are not intended to serve as central processing/diagnostic facilities, but rather to lend guidance to smaller institutions, train staff and oversee quality control. Having multiple laboratories coordinated by a NRL would alleviate resource constraints and promote the generation of more robust, uniform epidemiologic data. Data generated at satellite laboratories can then be sent to the NRL for
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Mexico Dominican Republic Cuba Dominican Republic

Cuba

Mexico Antibiotic prophylaxis Polysaccharide MenC Trinidad (< 2 years of age)

and Tobago Venezuela Jamaica Haiti Belize Honduras

None
Guatemala Trinidad and Tobago Venezuela

Guatemala El Salvador

Jamaica Belize Honduras Haiti

Nicaragua

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Antibiotic prophylaxis El Salvador Nicaragua (chloramphenicol, ceftriaxone) Costa Rica Panama Conjugate MenC (< 2 years of age) Targeted vaccination (conjugate MenC) Antibiotic prophylaxis school closure
Colombia Brazil Peru Brazil Bolivia

Costa Rica

Panama

None

Colombia

Peru

Antibiotics and vaccines stockpiled

Bolivia Paraguay

Paraguay

Antibiotics prophylaxis Targeted vaccination

Uruguay Argentina Chile Argentina Uruguay

Antibiotics and vaccines stockpiled

Chile

None Antibiotic prophylaxis (rifampin) Targeted vaccination

Present situation of meningococcal disease in Latin America

Figure 2.Outbreak preparedness and response in a number of Latin American countries.

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collation. To minimize costs, equipment and manpower dedicated to the monitoring of other infectious organisms could be coopted for MD surveillance. Multiplexed versions of RT-PCR that simultaneously target N. meningitidis, S. pneumoniae and H. influenzae have been developed [41] . Another solution lies in the forging of partnerships between resource-rich and resource-constrained countries. Such relationships are not without precedent in the region: the Instituto Nacional de Salud (Bogot, Colombia), the Instituto Adolfo Lutz (So Paulo, Brazil) and other regional NRLs participate in an international quality assurance program with the Instituto de Salud Carlos III in Madrid, Spain [3,8,10] . In an effort to reduce bias and to gain a more accurate understanding of the burden of MD in Latin America, the GMI recommends that >50% of a countrys suspected clinical cases be sent for central processing and that samples derive from different areas (i.e., urban and rural locales) and different hospital types (e.g., pediatric and general) to be representative. In many Latin American countries, the proportion of clinical samples being sent to NRLs is unacceptably low. For example, in Colombia, only 27% of the total samples of meningococcal isolates recorded nationally were analyzed at the NRL [8,10] . The corresponding values for isolates received at the NRLs in Argentina, Brazil, Chile and Costa Rica were 45, 25, 65 and 40%, respectively [10] . Moreover, in Argentina, pediatric hospitals are known to be overrepresented at the NRL, biasing data toward children [10,25] .
Outbreak prevention

The GMI and local representatives unanimously supported the replacement of polysaccharide vaccines with conjugate formulations, wherever possible. Because infants and young children bear the highest burden of MD in a number of Latin American countries [103] , use of vaccines that stimulate adequate immune responses are desired. Meningococcal C conjugate vaccines have proved to be immunogenic in children <2 years of age [1] . Incontrast to conjugate vaccines, serogroup C polysaccharide vaccines lack satisfactory immunogenicity in infants and are associated with hyporesponsiveness, a phenomenon by which immune responses are blunted upon revaccination [1,42,43] . Conjugate vaccines may overcome at least partially the refractoriness associated with repeat administration of polysaccharide formulations [44] . Moreover, in countries where serogroup C conjugate vaccines were introduced in large catch-up programs, including adolescents and young adults, they contributed to the development of herd immunity [45,46] , a phenomenon whereby unvaccinated individuals are at a reduced risk of disease because those who have been vaccinated are less likely to carry and transmit N. meningitidis [1] . Although herd immunity has only been demonstrated in a population immunized with meningococcal C conjugate vaccine [46] , this vaccination benefit is believed to extend to conjugate formulations targeting other meningococcal serogroups. In light of the recent demonstration of waning antibody titers a few years after being vaccinated [4752] , revaccination is necessary with conjugate vaccines, especially in places where herd immunity effects were not observed after vaccination.
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As government decisions on vaccine policy are based (in part) on disease prevalence, robust epidemiologic data are needed. Disease perception and vaccine safety, cost and availability also play a role in such decisions. The GMI stresses that proposed vaccination policies against MD be country-specific and based on local disease dynamics and health priorities. Although an understanding of disease burden makes the implementation of immunization policy easier, vaccines have been introduced in Latin America using international data, such as those directed against rotavirus (Brazil) and human papillomavirus (HPV, Panama); pressure from academic societies and the press also played an important role in the availability of HPV vaccines to Panamanians. While robust epidemiologic data are always desirable, prophylactic strategies should be implemented prior to large numbers of fatalities. Recently, an increase in the number of cases of MD caused by serogroup W-135 in Chile led to a massive vaccination campaign in the country for children between 9 months and 5 years of age with the quadrivalent conjugate vaccine [107] . Although more than 80% of the cases were concentrated in the country's metropolitan region, the impact of this national campaign will be seen in the coming months. As vaccine costs are a concern in Latin America as in other parts of the world novel financing arrangements should be considered. For example, technology transfer agreements have been used to introduce vaccines against rotavirus [110] , yellow fever [53] , serogroup C MD [12] , pneumococcal disease in Brazil [53,54] and an influenza vaccine in Argentina with an Argentinean private laboratory drug producer, called Synergium Biotech, which represents a joint effort between Novartis, ELEA and Biogenesis Bag. However, technology transfer requires that countries have the facilities and resources (human and technological) to manufacture vaccines. A provision allowing for the exportation of regionally produced vaccines to neighboring countries that lack manufacturing capabilities would further expand access to life-saving vaccines. The PAHO Revolving Fund, which purchases vaccines in bulk through the consolidation of orders from countries in the region, represents another innovative financial arrangement. A revolving fund facilitated the introduction of rotavirus vaccine to 12 Latin American and Caribbean countries [55] . A third option lies in Advanced Market Commitments (AMC), which use donor funds, from nonprofit organizations, companies or countries, to supplement the costs associated with a certain amount of vaccine for a prespecified period of time. Such an arrangement resulted in US$1.5 billion being committed to incentivize manufacturers to supply pneumococcal vaccines that met specific criteria needed in developing countries at a lower price, and this allowed Nicaragua and other countries to receive these vaccines in 20102011 [111] .
Expert commentary

MD remains an important health concern in Latin America, where high morbidity and mortality rates are still reported in many countries. Additionally, few countries have established surveillance programs, and the information gathered is not standardized. As accurate epidemiologic insight (i.e., disease burden, serogroup distribution and better characterization of the carrier
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Present situation of meningococcal disease in Latin America

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Finally, although the authors report herein the challenges faced by Latin America and a case definition specific for the region, it should be remembered that the key conSuspected [108] clusions and general recommendations can be extrapolated to all other regions of the An illness with sudden onset of fever (>38.5C rectal or >38.0C axillary) and one of the following: neck stiffness, altered consciousness, other meningeal sign or petechial or world. Control efforts, for example, should purpuric rash always focus on educating physicians and regulators on the importance of the disease, For patients <1 year of age, MD should be suspected when fever is accompanied by bulging fontanelle its diagnosis, improving meningococcal surveillance and the need for uniform, qualConfirmed ( one of the following) ity data, and this should be a key aspect for Detection of bacterial antigen(s) in CSF or consideration globally (indeed, a separate Positive bacterial culture or GMI meeting held in India identified simiDetection of bacterial DNA by PCR, where available lar key conclusions as noted herein for the CSF: Cerebrospinal fluid; GMI: Global Meningococcal Initiative; MD: meningococcal disease; Latin American region)[56] . Additionally, PAHO:PanAmerican Health Organization. other regions should consider developing a uniform meningococcal case definition state in local population) will permit health and political officials relevant to their needs to improve surveillance and facilitate data to strategize and invest appropriately in the prevention of MD, it comparisons in that region. is paramount that such data are gathered and in a uniform fashion. This sentiment is echoed by PAHO: In order to justify the Five-year view incorporation of anti-meningococcal vaccines already available, MD will continue to be mostly endemic in Latin America, with or to advocate for a new cost-effective formulation for countries periodic occurrences of outbreaks and epidemics in future years. in the Region, it is a priority to implement sensitive surveillance It is possible that the recently observed increase of serogroup systems and the systematic compilation of reliable laboratory W-135 disease in Southern Brazil, Argentina and Chile (which data [103] . Taking into consideration the available data for the was linked to the hypervirulent Hajj clone W-135:P1.5,2:ST-11 region presented herein, the GMI thus proposed the following (ST-11/ET-37 clonal complex), that emerged in 2000 and has recommendations so as to gain a more accurate epidemiologic since spread internationally) will gain in importance and be insight of MD in Latin America and subsequently assist health observed in other Latin American countries. It is also likely that and political officials in the prevention of MD: incorporation the increase in serogroup C disease reported in Brazil, associated of molecular diagnostic techniques, like PCR/RT-PCR, into with the ST-103 complex, where it currently represents 80% of routine surveillance and expanded use of Gram staining, rapid cases, will also gain in importance and become widespread in the testing and culture; establishment of well-equipped sentinel and Latin American countries. reference laboratories with properly trained personnel and adopAlthough progress has already been made in improving and tion of a single case definition for the region, with a provision coordinating the surveillance of invasive disease in the region, for confirmatory diagnosis via PCR (where available). Such data with the implementation of a laboratory surveillance network would then inform and guide public health authorities for the (SIREVA), there is a clear need to improve and establish more implementation of vaccination programs. Additionally, although uniform quality surveillance across the region and standardthe replacement of polysaccharide vaccines with conjugate formu- ized case definitions. The establishment of sentinel-based active lations wherever possible was unanimously recommended by surveillance incorporating population-based data, the adoption the GMI, differences in disease epidemiology and health priorities of a universal case definition together with an expanded use of require immunization strategies to be tailored to and integrated molecular-based diagnostic techniques into routine surveillance within each countrys existing infrastructure. of invasive disease will be crucial for a better understanding of It should be remembered, however, that individual country the true MD epidemiology in the region. financial and resource aspects will greatly impact the uptake of the The authors anticipate increased use of the meningococcal mulrecommendations discussed herein. Indeed, due to the perceived tivalent conjugate vaccines in the Latin American region, replaclow incidence of MD in some Latin American countries, decision ing the use of polysaccharide vaccines in the near future. In parand policy makers may determine other healthcare concerns more ticular, they believe these vaccines will be used for the control of worthy of resourcing. However, given the importance of bacterial outbreaks/epidemics, high-risk groups, travelers or even in routine invasive disease as a whole, and that the surveillance of MD can immunization programs where the disease is hyperendemic. Over be included within the same systems, the authors are hopeful that the next 5 years, it is also expected that currently investigation decision makers will continue to see the importance of improved recombinant protein vaccines will be licensed. surveillance systems and invest and form alliances with other With this in mind, the authors have developed a new case defisupportive organizations appropriately. nition for MD, specific for the unique Latin American situation. Table 4. GMI-proposed universal case definition for meningococcal disease in Latin America (PAHO case definition plus, where available, confirmatory diagnosis by PCR).
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Adoption of this revised universal case definition over the next few years may: Improve surveillance in the region; Provide us with a better understanding of the true burden of disease in Latin America; Allow cross comparisons of epidemiological data; Improve evidence-based immunization policies; Enable vaccine and control strategies to be better tailored to regions needs, thereby markedly reducing the burden and impact of disease. Within the next 5 years, the authors also anticipate that enhanced surveillance and indeed surveillance networks in the Latin American region, combining laboratory and clinical reporting, will be further developed at all levels and enable better systematic gathering and collating of country and regional data. They also hope that mandatory reporting of the disease will be implemented in all Latin American countries in the coming years. To anticipate the potential coverage of the new recombinant protein-based Men B vaccines, baseline information on molecular and phenotypic characterization of the diverse invasive strains is needed. Together, this will provide us with a better understanding of the epidemiology of MD and may allow for the monitoring of the effectiveness and long-term impact of the new recombinant protein-based vaccines (once introduced in national immunization programs). The effect of recombinant protein Men B vaccines on carriage, yet not clearly defined, is likely to be an important factor in assessing their potential impact and costeffectiveness across all age groups. These improved, and more encompassing, surveillance networks are likely to be formed by a number of strategic alliances, and to include passive and active sentinel surveillance methods. Additionally, once these newer vaccines are introduced the authors feel that in all likelihood PAHO will expand their surveillance recommendations, ensuring that Key issues

individual countries and the Latin American region gather data using agreed standards and definitions. Such recommendations may include gathering of strain data, case numbers, among others, as well as vaccine-specific aspects such as vaccine failures, examination of defined correlates of protection and adverse event monitoring.
Acknowledgements

The authors thank Lee H Harrison, Jose Brea and Gonzalo Giambruno for their participation in and contributions to the success of the GMI Latin America Regional Roundtable Meeting.
Financial & competing interests disclosure

The authors are all members of The Global Meningococcal Initiative (GMI), which is funded by an unrestricted educational grant from Sanofi Pasteur. However, while the GMI is funded by an unrestricted educational grant from Sanofi Pasteur, the group is not led in any way by the company; GMI members determine meeting agenda items and lead the discussions and outputs. Sanofi Pasteur representatives may attend the meetings but in the role of observers and do not influence the findings of the group. MAP Sfadi has received consultation and lecture fees from Baxter, GlaxoSmithKline (GSK), MSD, Novartis, Sanofi Pasteur and Wyeth. JA Vzquez has received grants to support research projects from Novartis, Sanofi Pasteur, Pfizer, Baxter and GSK. He has also received fees for acting as an advisor or speaker for Novartis, Sanofi Pasteur, Pfizer, GSK and Baxter. LE Espinosa de los Monteros has received grants to support research projects from Sanofi Pasteur. AP Lemos has received lecture fees from Sanofi Pasteur and Novartis. EL Lpez has received consultation and lecture fees from Sanofi Pasteur, Pfizer, Merck and GSK. S Gonzlez Ayala has received fees for acting as an advisor or speaker for Pfizer, GSK and Novartis. X Sez-Llorens has received consultation and lecture fees from GSK, Sanofi Pasteur and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Medical writing support was provided by Shelley Lindley, PhD of PAREXEL. PAREXEL was funded by Sanofi Pasteur.

The Global Meningococcal Initiative (GMI) is an international group of scientists and clinicians with expertise in meningococcal immunology, epidemiology, public health and vaccination that aims to promote meningococcal disease (MD) prevention worldwide. GMI representatives from seven Latin American countries discussed the burden of MD and vaccination practices/policies in the region. MD burden in Latin America was concluded to be largely underestimated. Serogroups B and C are dominant in the region, however, we have seen a recent emergence of serogroups W-135 and Y in several countries. Control efforts should focus on educating physicians and regulators on the importance of the disease, its diagnosis, improving meningococcal surveillance in the region and the need for uniform, quality data. To improve surveillance in the region, and facilitate data comparisons, a uniform meningococcal case definition supplementing Pan American Health Organization (PAHO) criteria with diagnosis by PCR (where available) is proposed herein.

References
Papers of special note have been highlighted as: of interest of considerable interest
1 2

Fifth Edition. WB Saunders, Philadelphia, PA, USA, 399434 (2008). Harrison LH, Pelton SI, Wilder-Smith A etal. The Global Meningococcal Initiative: recommendations for reducing the global burden of meningococcal disease. Vaccine 29(18), 33633371 (2011).

Granoff DM, Harrison LH, Borrow R. Meningococcal vaccines. In: Vaccines. Plotkin SA, Orenstein WA, Offit PA (Eds).

Sfadi MA, Cintra OA. Epidemiology of meningococcal disease in Latin America: current situation and opportunities for prevention. Neurol. Res. 32(3), 263271 (2010). Bilukha OO, Rosenstein N; National Center for Infectious Diseases, Centers for

doi: 10.1586/14760584.2013.814879

Expert Rev. Vaccines

Present situation of meningococcal disease in Latin America

Review

Disease Control and Prevention (CDC). Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Recomm. Rep. 54(RR-7), 121 (2005).
5

14

Stephens DS. Conquering the meningo coccus. FEMS Microbiol. Rev. 31(1), 314 (2007). Panatto D, Amicizia D, Lai PL, Gasparini R. Neisseria meningitidis B vaccines. Expert Rev. Vaccines 10(9), 13371351 (2011). Gossger N, Snape MD, Yu LM etal .; European MenB Vaccine Study Group. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: arandomized controlled trial. JAMA 307(6), 573582 (2012). Richmond PC, Marshall HS, Nissen MD etal.; 2001 Study Investigators. Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, Phase 2 trial. Lancet Infect. Dis. 12(8), 597607 (2012). Santolaya ME, ORyan ML, Valenzuela MT etal.; V72P10 Meningococcal B Adolescent Vaccine Study group. Immunogenicity and tolerability of a multi component meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a Phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet 379(9816), 617624 (2012). Sfadi MA, Gonzlez-Ayala S, Jkel A, Wieffer H, Moreno C, Vyse A. The epidemiology of meningococcal disease in Latin America 1945-2010: an unpredictable and changing landscape. Epidemiol. Infect. 112 (2012). Detailed recent review of the epidemiology of meningococcal disease (MD). Ibarz-Pavn AB, Lemos AP, Gorla MC, Regueira M, Gabastou JM; SIREVA Working Group II. Laboratory-based surveillance of Neisseria meningitidis isolates from disease cases in Latin American and Caribbean countries, SIREVA II 2006-2010. PLoS ONE 7(8), e44102 (2012).
22

of culture negative bacterial meningitis in So Paulo, Brazil. PLoS ONE 6(6), e20675 (2011). Chacon-Cruz E, Sugerman DE, Ginsberg MM etal. Surveillance for invasive meningococcal disease in children, US-Mexico border, 2005-2008. Emerging Infect. Dis. 17(3), 543546 (2011). Espinosa de los Monteros LE, JimenezRojas LV, Matias San Juan NA, GomezBarreto D. Grupo Mexicano de Trabajo en Enfermedad Meningococcica. Unusual increase in meningococcal disease associated with serogroup C in Mexico City. 7th World Congress on Pediatric Infectious Diseases (WSPID), 1619 November 2011. Pai R, Gertz RE, Beall B. Sequential multiplex PCR approach for determining capsular serotypes of Streptococcus pneumoniae isolates. J. Clin. Microbiol. 44(1), 124131 (2006). Efron AM, Sorhouet C, Salcedo C, Abad R, Regueira M, Vzquez JA. W135 invasive meningococcal strains spreading in South America: significant increase in incidence rate in Argentina. J. Clin. Microbiol. 47(6), 19791980 (2009). Safadi MA, Liphaus B, Okay MIG, Yu ALF, Ribeiro AF, Carvalhanas TRMP. Early impact of meningococcal C conjugate vaccination program on disease trends in Sao Paulo, Brazil. Presented at: European Society for Paediatrics Infectious Diseases, Thessaloniki, Greece, 812 May 2012. Caugant DA, Maiden MC. Meningococcal carriage and diseasepopulation biology and evolution. Vaccine 27(Suppl. 2), B64B70 (2009). Sierra GV, Campa HC, Varcacel NM etal . Vaccine against group B Neisseria meningitidis : protection trial and mass vaccination results in Cuba. NIPH Ann. 14(2), 195207; discussion 208 (1991). Climent Y, Yero D, Martinez I etal . Clonal distribution of disease-associated and healthy carrier isolates of Neisseria meningitidis between 1983 and 2005 in Cuba. J. Clin. Microbiol. 48(3), 802810 (2010). Paper evaluates the effect of the introduction of a vaccine against MD in Cuba on serogroups, and the frequency and diversity of hypervirulent clonal complexes. de Soarez PC, Sartori AM, de Andrade Lagoa Nbrega L, Itria A, Novaes HM. Cost-effectiveness analysis of a universal infant immunization program with

15

National Advisory Committee on Immunization. An update on the invasive meningococcal disease and meningococcal vaccine conjugate recommendations. An Advisory Committee Statement (ACS). Can. Commun. Dis. Rep. 35(ACS-3), 140 (2009). Cohn AC, MacNeil JR, Harrison LH etal. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998-2007: implications for prevention of meningococcal disease. Clin. Infect. Dis. 50(2), 184191 (2010). Cordeiro SM, Neves AB, Ribeiro CT etal. Hospital-based surveillance of meningococcal meningitis in Salvador, Brazil. Trans. R. Soc. Trop. Med. Hyg. 101(11), 11471153 (2007). Ins Agudelo C, Sanabria OM, Ovalle MV. Serogroup Y meningococcal disease, Colombia. Emerging Infect. Dis. 14(6), 990991 (2008). Nieto-Guevara J, Luciani K, MontesdeocaMelan A, Mateos-Durn M. Epidemiology of meningococcal disease in the Panamanian pediatric population, 1998-2008. J.Infect. Dev. Ctries. 5(5), 318323 (2011). Abad R, Agudelo CI, Brandileone MC etal. Molecular characterization of invasive serogroup Y Neisseria meningitidis strains isolated in the Latin America region. J.Infect. 59(2), 104114 (2009). Reports the analysis of serogroup Y isolates received at the National Reference Laboratories of Argentina, Brazil, Chile, Colombia and Costa Rica during 20002006. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm. Rep. 62(RR-2), 122 (2013). Sfadi MA, McIntosh ED. Epidemiology and prevention of meningococcal disease: acritical appraisal of vaccine policies. Expert Rev. Vaccines 10(12), 17171730 (2011). Review evaluating vaccine policies across different regions of the world to set the stage for future policy decisions. Kimmel SR. Prevention of meningococcal disease. Am. Fam. Physician 72(10), 20492056 (2005).

16

23

17

24

25

18

26

10

19

27

28

11

20

29

12

Paper from the SIREVA II working group showing the highly variable serogroup distribution among Latin American and Caribbean countries.
21

13

Sacchi CT, Fukasawa LO, Gonalves MG etal.; So Paulo RT-PCR Surveillance Project Team. Incorporation of real-time PCR into routine public health surveillance

30

www.expert-reviews.com

doi: 10.1586/14760584.2013.814879

Review

Sfadi, Espinosa de los Monteros, Lpez et al.

meningococcal C conjugate vaccine in Brazil. Value Health 14(8), 10191027 (2011).

31

41

Kaninda AV, Belanger F, Lewis R etal. Effectiveness of incidence thresholds for detection and control of meningococcal meningitis epidemics in northern Togo. Int. J. Epidemiol. 29(5), 933940 (2000). Iser BP, Lima HC, de Moraes C etal. Outbreak of Neisseria meningitidis C in workers at a large food-processing plant in Brazil: challenges of controlling disease spread to the larger community. Epidemiol. Infect. 140(5), 906915 (2012). Marc LaForce F, Ravenscroft N, Djingarey M, Viviani S. Epidemic meningitis due to Group A Neisseria meningitidis in the African meningitis belt: a persistent problem with an imminent solution. Vaccine 27(Suppl. 2), B13B19 (2009). Saliou P, Debois H. Which vaccination strategies for African meningococcal meningitis?. Bull. Soc. Pathol. Exot. 95(5), 326330 (2002). Parent du Chatelet I, Gessner BD, da SA. Comparison of cost-effectiveness of preventive and reactive mass immunization campaigns against meningococcal meningitis in West Africa: a theoretical modeling analysis. Vaccine 19(2526), 34203431 (2001). Drew RJ, Maoldomhnaigh C, Gavin PJ, O Sullivan N, Butler KM, Cafferkey M. The impact of meningococcal polymerase chain reaction testing on laboratory confirmation of invasive meningococcal disease. Pediatr. Infect. Dis. J. 31(3), 316318 (2012). Dolan Thomas J, Hatcher CP, Satterfield DA etal. sodC-based real-time PCR for detection of Neisseria meningitidis. PLoS ONE 6(5), e19361 (2011). Van Gastel E, Bruynseels P, Verstrepen W, Mertens A. Evaluation of a real-time polymerase chain reaction assay for the diagnosis of pneumococcal and meningococcal meningitis in a tertiary care hospital. Eur. J. Clin. Microbiol. Infect. Dis. 26(9), 651653 (2007). Bryant PA, Li HY, Zaia A etal. Prospective study of a real-time PCR that is highly sensitive, specific, and clinically useful for diagnosis of meningococcal disease in children. J. Clin. Microbiol. 42(7), 29192925 (2004). Wang X, Theodore MJ, Mair R etal. Clinical validation of multiplex real-time PCR assays for detection of bacterial meningitis pathogens. J. Clin. Microbiol. 50(3), 702708 (2012).
44 42

Corless CE, Guiver M, Borrow R, Edwards-Jones V, Fox AJ, Kaczmarski EB. Simultaneous detection of Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae in suspected cases of meningitis and septicemia using real-time PCR. J. Clin. Microbiol. 39(4), 15531558 (2001). Granoff DM, Gupta RK, Belshe RB, Anderson EL. Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination. J. Infect. Dis. 178(3), 870874 (1998). MacDonald NE, Halperin SA, Law BJ, Forrest B, Danzig LE, Granoff DM. Induction of immunologic memory by conjugated vs plain meningococcal C polysaccharide vaccine in toddlers: arandomized controlled trial. JAMA 280(19), 16851689 (1998). Al Mazrou Y, Khalil M, Bravo C etal. Meningococcal conjugate vs meningococcal polysaccharide vaccine in Saudi Arabia adolescents previously vaccinated with multiple doses of meningococcal polysaccharide vaccine. Presented at: European Meningococcal Disease Society (EMGM) Congress. Manchester, UK, 1719 June 2009. Gray SJ, Trotter CL, Ramsay ME etal. Epidemiology of meningococcal disease in England and Wales 1993/94 to 2003/04: contribution and experiences of the Meningococcal Reference Unit. J. Med. Microbiol. 55(Pt 7), 887896 (2006). Trotter CL, Maiden MC. Meningococcal vaccines and herd immunity: lessons learned from serogroup C conjugate vaccination programs. Expert Rev. Vaccines 8(7), 851861 (2009). Review evaluating the effect of meningococcal vaccines on herd immunity and the consequences of this on the design and evaluation of new vaccines. Perrett KP, Winter AP, Kibwana E etal . Antibody persistence after serogroup C meningococcal conjugate immunization of United Kingdom primary-school children in 19992000 and response to a booster: aPhase 4 clinical trial. Clin. Infect. Dis. 50(12), 16011610 (2010). Espn Ros I, Garca-Fulgueras A, Navarro Alonso JA etal. Seroconversion and duration of immunity after vaccination against group C meningococcal infection in young children. Vaccine 18(24), 26562660 (2000). Granoff DM, Morgan A, Welsch JA. Persistence of group C anticapsular antibodies two to three years after immunization with an investigational

quadrivalent Neisseria meningitidisdiphtheria toxoid conjugate vaccine. Pediatr. Infect. Dis. J. 24(2), 132136 (2005).
50

32

Khatami A, Snape MD, Davis E etal. Persistence of the immune response at 5years of age following infant immunisation with investigational quadrivalent MenACWY conjugate vaccine formulations. Vaccine 30(18), 28312838 (2012). Borrow R, Goldblatt D, Andrews N etal. Antibody persistence and immunological memory at age 4 years after meningococcal group C conjugate vaccination in children in the United Kingdom. J. Infect. Dis. 186(9), 13531357 (2002). Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 364(9431), 365367 (2004). Neto RB, Jayaraman K. Brazil and India access pharma vaccine know-how. Nat. Biotechnol. 27(12), 10631064 (2009). Milstien JB, Gaul P, Kaddar M. Access to vaccine technologies in developing countries: Brazil and India. Vaccine 25(44), 76107619 (2007). de Oliveira LH, Danovaro-Holliday MC, Sanwogou NJ, Ruiz-Matus C, Tambini G, Andrus JK. Progress in the introduction of the rotavirus vaccine in Latin America and the Caribbean: four years of accumulated experience. Pediatr. Infect. Dis. J. 30(Suppl. 1), S61S66 (2011). John TJ, Gupta S, Chitkara AJ, Dutta AK, Borrow R. An overview of meningococcal disease in India: knowledge gaps and potential solutions. Vaccine 31(25), 27312737 (2013). Ulloa-Gutierrez R, Mio G, Odio C, Avila-Aguero ML, Brea J. Vaccine-preventable diseases and their impact on Latin American children. Expert Rev. Vaccines 10(12), 16711673 (2011).

51

43

33

52

34

53

35

54

45

55

36

46

56

37

57

38

47

Websites
101

39

48

European Medicines Agency (EMA). Bexsero [authorisation details]. 2013. www.ema.europa.eu/ema/index. jsp?curl=pages/medicines/human/ medicines/002333/human_med_001614. jsp&mid=WC0b01ac058001d124 Pan American Health Organization. Surveillance of Bacterial Pneumonia and Meningitis in Children Aged Under 5 Years Field Guide. Pan American Health Organization (2010). http://new.paho.org/hq/dmdocuments/
Expert Rev. Vaccines

102

40

49

doi: 10.1586/14760584.2013.814879

Present situation of meningococcal disease in Latin America

Review

2010/FieldGuide_BacPneumoMening_ 1stEd_e.pdf
103

http://epi.minsal.cl/epi/html/bolets/ reportes/Meningitis/W135_SE482012.pdf
106

109

Pan American Health Organization. Informe Regional de SIREVA II, 2011. Pan American Health Organization (2011). http://new.paho.org/hq/index. php?option=com_content&task=view&id =5461&Itemid=3953 Pan American Health and Education Foundation. About PAHEF. Pan American Health and Education Foundation (2012). www.pahef.org/en/aboutus/15-about-us/8about-us-.html Ministerio de Salud Gobierno de Chile. Situacin enfermedad meningoccica por serogrupo W-135 (del 1/1/12 al 1/12/12). Ministerio de Salud Gobierno de Chile (2012).

Ministerio de Salud Gobierno de Chile. (2012). http://epi.minsal.cl/epi/html/bolets/ reportes/Meningitis/meningitis.pdf Ministerio de Salud Gobierno de Chile. Plan de accin W135 (2012). www.gob.cl/informa/2012/11/11/gobiernoconstituye-grupo-de-trabajo-plan-deaccion-contra-w135-y-anuncia-la-llegadade-expertos-int.htm Pan American Health Organization. Case Definitions: Meningococcal Disease. Pan American Health Organization (2001). www.1.paho.org/english/dd/ais/ eb_v22n4.pdf
110

107

Pan American Health Organization. Epidemiological Alert: Meningococcal Meningitis (Cerebrospinal fever). Pan American Health Organization (2012). http://new.paho.org/hq/index. php?option=com_content&view=article&i d=6690&Itemid=259&lang=en National Institutes of Health. Rotavirus Vaccine: NIH Office of Technology Transfer. National Institutes of Health (NIH) (2012). www.ott.nih.gov/pdfs/CaseStudy13.pdf Medical News Today. Options for Making New Vaccines Affordable. Medical News Today (2012). www.medicalnewstoday.com/releases/ 227912.php

104

108

111

105

www.expert-reviews.com

doi: 10.1586/14760584.2013.814879