Global Epidemiology of Vaccine-preventable Bacterial Meningitis : The Pediatric Infectious Disease Journal

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ESPID Reports and Reviews

Global Epidemiology of Vaccine-preventable Bacterial Meningitis

Syrogiannopoulos, George A. MD; Michoula, Aspasia N. MD; Grivea, Ioanna N. MD

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The Pediatric Infectious Disease Journal: December 2022 - Volume 41 - Issue 12 - p e525-e529
doi: 10.1097/INF.0000000000003629
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Acute bacterial meningitis is characterized by infection and inflammation within the subarachnoid space and causes significant morbidity and mortality globally, particularly in infants.1–3 Its incidence and prevalence vary by geographical region and over time.4,5 The African meningitis belt, involving the Sub-Saharan region with 26 countries and stretching from Senegal to Ethiopia, presents the highest meningitis incidence, with an estimated 80,000 suspected cases resulting in more than 4000 deaths in 2009, for example.2

Systematic reviews of studies on bacterial meningitis, which included low-, middle- and high-income countries, reported variable case fatality rates ranging from 5% to 30% of cases, which were attributed mainly to the large variation in presentation to medical services, access to healthcare and medical resources.6,7 Furthermore, survivors of bacterial meningitis may develop a number of sequelae such as hearing loss, developmental delay and poor school performance, depending on the patient’s age and the infecting organism.6,7

A meta-analysis of 61 evaluable studies published during 2012 to 2017 evaluated the prevalence of bacterial meningitis in various geographical regions and age groups. It showed that the most common etiologic agents of bacterial meningitis were Neisseria meningitidis and Streptococcus pneumoniae with weighted means for frequency across geographical regions and age groups ranging from 3.2% to 47.0% and 9.6% to 75.2%, respectively. The weighted means for frequency of Haemophilus influenzae in geographic regions, stratified by age, ranged from 0.2% to 15.5%.2 Clinical diagnosis of meningitis can be difficult, particularly in young infants who do not present the classical signs/symptoms of the disease.8 In most patients, etiologic diagnosis is not available due to combination of factors including prior administration of antimicrobial treatment, unavailability of existing diagnostic tests in some centers and technical difficulties in the diagnosis of certain pathogens.8,9

Polysaccharide vaccines offering protection against pneumococcal, meningococcal or H. influenzae type b disease have been available for more than 4 decades.10,11 However, their widespread use has been hindered by a number of disadvantages: (1) poor antibody response in children below 2 years of age, (2) rapid waning of protective antibodies in young children, (3) absence of immunologic memory at reexposure, (4) inability to overcome immune hyporesponsiveness to the next dose and (5) minimal or no effect on naso- or oropharyngeal carriage, which prohibits the development of herd protection.12,13 These limitations have been overcome by the development of polysaccharide conjugate vaccines, in which a carrier protein is covalently linked to a microbial capsule polysaccharide.11

Conjugate vaccines that target specific serogroups or serotypes of the most prevalent bacteria have contributed to a lower burden of bacterial meningitis in the United States,14 the United Kingdom15 and other countries globally.3,16

Recently, protein-based vaccines against the serogroup B meningococcal (MenB) disease have been added to our armamentarium against meningitis.

H. INFLUENZAE TYPE b

H. influenzae can be distinguished into 6 serotypes (a–e) based on their unique polysaccharide capsule or can be nonencapsulated. Before routine vaccination, serotype b was a major cause of bacterial meningitis, especially in young children. In the United States, before vaccine availability, the annual incidence of H. influenzae type b (Hib) meningitis in children aged 0–4 years was 50–60/100,000. This incidence, for unidentified reasons, was greater than twice that of the prevaccination weighted average for Europe (23 cases/100,000), as well as for large parts of South America, Asia and Oceania (20 cases/100,000).17,18

Routine use of Hib conjugate vaccines given at 18 months of age was introduced initially in the United States in 1987 and subsequently established at 2 months of age in 1991, with most industrialized countries following in the 1990s. Only few vaccines in the history of vaccination have achieved such dramatic decrease in the incidence of their target diseases over such a short period as the Hib conjugate vaccines.17 The impressive decrease of “all-age incidence” of Hib meningitis—more than 97% between 1986 and 2007—illustrates the profound population-wide effect of Hib conjugate vaccines in the United States.19

The decline in the incidence of Hib meningitis following the implementation of the Hib conjugate vaccines in the National Immunization Program (NIP) of European countries was also large and swift.3,18

Various conjugate vaccine schedules are used globally, such as 2 primary doses + 1 booster, 3 primary doses with no booster and 3 primary doses + 1 booster; the initial primary dose can be administered at 6 or 8 weeks of age.18 Hib conjugate vaccines have been widely implemented in developed countries and are increasingly used in limited-resource countries. Large and sustained reductions in Hib meningitis have been observed in many immunization programs supported by the Global Alliance for Vaccines and Immunization in Africa where Hib vaccination was introduced using a 3 + 0 vaccine schedule.18,20 The results of 2 meta-analyses do not favor any particular vaccine schedule.21,22

By the end of 2020, the Hib vaccine had been implemented in 192 World Health Organization Member States. Global coverage with 3 doses of the Hib vaccine is estimated at 70%. Nevertheless, many children remain unimmunized or partially immunized, especially in low-income countries. Therefore, efforts to further decrease the burden of invasive Hib disease remain a high priority.18

Childhood Hib immunization provides direct and indirect protection, that is, reduced pharyngeal Hib colonization in vaccinated children leading to reduced transmission to others in the community.3,20 However, children are not the only reservoir for Hib, and rare cases continue to occur even in highly immunized populations, mainly in adults and the elderly.3

Currently in industrialized countries, there are few cases due to other H. influenzae, most commonly due to isolates that belong to serotypes a or f, or are nontypeable (nonencapsulated).3,19,20

N. MENINGITIDIS

Invasive meningococcal disease (IMD) represents a severe infection that primarily affects infants and young children, with a smaller peak in adolescents and young adults. Its main clinical presentations are meningitis (almost half of the cases), sepsis, or a combination of the two. Data on disease burden often refer to the total IMD cases without distinguishing meningitis cases from those without meningeal inflammation. The epidemiology of N. meningitidis serogroups is unpredictable and differs geographically and temporally.23

Conjugate Vaccines

Serogroup C meningococcal (MenC) disease has been the second vaccine-preventable disease that was targeted with a conjugate vaccine. It was introduced in many NIPs after 1999. Its implementation in the United Kingdom in that year was supported by an intense catchup campaign targeting all children under the age of 19 years (subsequently extended to 24 years).10 Herd protection, including reduction in MenC cases in adults and the elderly, occurred promptly following the introduction of MenC vaccination, as did an impressive decrease in the incidence of MenC infection among both immunized and nonvaccinated individuals, with total cases declining from approximately 1000 cases in 1999 to 28 cases in 2006.10 It is likely that herd protection was accelerated due to the eradication of MenC carriage by vaccination of adolescents and young adults who are the main nasopharyngeal carriers of N. meningitidis.

Early outbreaks of serogroup W meningococcal (MenW) disease were observed following Hajj pilgrimages in 2000 and 2001.24 Although cases and outbreaks decreased in subsequent years because of mandatory vaccination for pilgrims traveling to the Hajj, they have been increasingly responsible for local epidemics and caused large outbreaks nationally in South Africa, the United Kingdom, Australia and Chile, among other countries.24 Recently, in the Netherlands, MenW cases also increased, with 52% of MenW meningitis episodes diagnosed during 2015 to 2019 among preschool- and school-aged children.3

In the African meningitis belt during epidemics, mainly caused by serogroup A meningococcal (MenA) disease but also by other serogroups, the incidence was as high as 1% of inhabitants. A MenA conjugate vaccine with capsular polysaccharide (PsA) covalently linked to tetanus toxoid (TT) (PsA-TT, MenAfriVac) was developed by the Serum Institute of India (SII), and massive vaccination campaigns were introduced in the African meningitis belt in late 2010 for individuals aged 1 to 29 years in different phases. PsA-TT implementation led to dramatic reductions in the incidence rates of suspected meningitis (57%), epidemic risk (59%) and confirmed MenA infection (>99% reductions in fully immunized individuals) in 9 countries through 2015.25 An affordable, pentavalent MenACWYX conjugate vaccine is planned to be available and licensed in the coming years aiming to achieve optimal protection against MenC, MenW and serogroup X outbreaks in Africa.25

Adolescents and young adults represent an age group of particular interest in meningococcal transmission and prevention. Meningococcal carriage acquisition peaks in middle and late adolescence and in early adulthood, thus establishing this age group as the second highest IMD risk after infants and young children; adolescents are the most vulnerable group during meningococcal outbreaks. Adolescent survivors of IMD are also at higher risk of major long-term sequelae.11 The MenACWY conjugate vaccines have proven to be effective in preventing IMD due to these 4 serogroups through direct protection of vaccinated individuals and prevention of carriage acquisition leading to indirect (herd) protection. These protective effects have led many countries to include MenACWY conjugate vaccine for adolescents in their NIPs.11 Furthermore, the NIPs of certain countries with increased number of MenW cases have switched from the monovalent MenC conjugate vaccine to the quadrivalent MenACWY vaccine in young children.

After the implementation of the MenC conjugate vaccine, MenB has been the main pathogen responsible for IMD in Europe and North America and one of the most prevalent serogroups in Latin America.26 The incidence is higher in the second half of the first year of life.

Protein-based Vaccines

Two protein-based MenB vaccines are available, 4CMenB and MenB-FHbp. 4CMenB is licensed for use in infants from 2 months of age in the European Union and for 10- to 25-year-olds in the United States. MenB-FHbp is licensed for administration to individuals aged ≥10 years. 4CMenB was initially incorporated into the publicly funded UK NIP. When compared with the prevaccine period, a 50% decrease in MenB cases was observed in vaccine-eligible children within the first year of the program, irrespective of the infants’ vaccination status or predicted MenB strain coverage.27 After 3 years, vaccine effectiveness against MenB infection was 52.7% for infants immunized with 2 primary doses and 59.1% for those who had received 2 primary doses plus 1 (booster) dose at 1 year of age.28

In the Italian regions of Tuscany and Veneto, 4CMenB also prevented MenB IMD. There was a rapid decrease of MenB cases among vaccinated children (total reduction of 94% in Tuscany and 90% in Veneto). The decrease was evident in the first year after the immunization program began.29

Unlike capsular polysaccharides, the protein and outer membrane vesicle antigens of MenB vaccines vary antigenically among the circulating strains that express them.25,30 In a study of Australian adolescents, the 4CMenB vaccine showed no noticeable effect on the carriage of disease-causing meningococci, including MenB.30

The MenB-FHbp vaccine is licensed as a 2-dose schedule with a 6-month interval. In the setting of a MenB outbreak, a 3-dose vaccine series is recommended: at 0, 1–2 and 6 months. MenB-FHbp and 4CMenB have been used to control college/university outbreaks in the United States. The 2 protein-based MenB vaccines do not affect meningococcal carriage or prevent MenB carriage acquisition and, therefore, only provide direct protection for vaccinated persons.30–32 During outbreaks, high immunization coverage to protect vaccinated individuals and chemoprophylaxis for close contacts is recommended.25,31,32

Studies are ongoing to assess the duration of protection provided by MenB protein-based vaccines.27,28 Starting on February 1, 2019, the South Australian government announced a funded 4CMenB immunization program to provide direct protection for infants, children (1–3 years), adolescents and young people (17- to 20-year-olds).33

A pentavalent vaccine against serogroups ABCWY is under development. It contains polysaccharide-protein conjugate components in combination with MenB protein-antigen ones.34

S. PNEUMONIAE

S. pneumoniae has been a major pathogen of acute bacterial meningitis across all age groups in the United States, with the highest incidence in children <2 years of age.35

A pneumococcal conjugate vaccine (PCV), a 7-valent one (PCV7; capsular antigens of S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F and 23F), was first added to the United States infant immunization schedule in 200036,37 and resulted in a 62% reduction in the incidence of pneumococcal meningitis among children aged <2 years during 2006 to 2007 compared with 1998 to 1999.38

Subsequently, 2 second-generation PCVs became available, the 10-valent conjugate vaccine (PCV10; ie, PCV7 + serotypes 1, 5 and 7F) in 2009 and the 13-valent conjugate vaccine (PCV13; ie, PCV7 + serotypes 1, 3, 5, 6A, 7F and 19A) in 2010, which were introduced in different countries. These 2 vaccines have since replaced the PCV7 vaccine with PCV13, becoming the most used second-generation PCVs.39

In England and Wales, a significant effect on S. pneumoniae meningitis was noted after PCV7/PCV13 implementation in children aged <5 years. PCV7 introduction and its replacement with PCV13 led to a reduction of pneumococcal meningitis incidence from 4.08 cases/100,000 person-years in the pre-PCV7 period to 3.10/100,000 person-years in the pre-PCV13 period and further to 1.22/100,000 person-years in the post-PCV13 period.15

A recent global surveillance reported that in sites where PCV10 or PCV13 has been implemented with a primary series uptake of above 70% for approximately 7 years, there is a substantial reduction in invasive pneumococcal disease including meningitis as compared with the pre-PCV period. Indeed, before the pneumococcal immunization program, 62%–72% of meningitis cases were due to PCV10/13 serotypes among children aged <5 years, depending on vaccine formulation and region of implementation.40 Although the rates of pediatric pneumococcal meningitis have continued to decline since PCV10/13, hospital length of stay, morbidity and case fatality rates have remained among the highest of the major causes of bacterial meningitis.15

Three serotypes, that is, 19A, 6C and 3, have become of particular interest during the PCV10/13 period. Specifically, serotype 19A—a PCV13-only type, although rare (≤3%) at PCV13 sites—is responsible for almost a quarter of preschool-age cases and was found to be common among older children at PCV10 sites.40 The second most frequent serotype at PCV10 sites was serotype 6C among children <5 years (10.3%) and ≥5 years (approximately 10%). This serotype is postulated to be preventable by PCV13 via cross-protection from serotype 6A capsule, which is included in PCV13. Serotype 6C has been detected in 1.0% of children aged <5 years and in 2.2% of children aged ≥5 years. The proportion of serotype 3 cases in <5-year-olds was lower (7.4% and 4.0% at PCV10 and PCV13 sites, respectively) but higher at PCV10 sites (ranked 3rd) than at PCV13 sites (ranked 8th). Among ≥5-year-olds, serotype 3 remains one of the most common serotype at both PCV13 (13.1%) and PCV10 sites (13.9%).40

By the end of 2020, PCVs had been introduced in 151 World Health Organization Member States (3 countries without a country-wide immunization program were included).41 Recently, a PCV10 formulation from SII (Pneumosil) was licensed to target low- and middle-income countries due to its affordability. PCV10-SII contains most of the PCV10-GSK serotypes, except for serotypes 4 and 18C, which have been replaced by serotypes 6A and 19A.39

Three dosing schedules of PCVs, that is, 3 + 1, 2 + 1 and 3 + 0, have been shown to be effective in preventing pneumococcal disease, are approved and used globally. In general, all schedules have been shown to reduce vaccine-type pharyngeal carriage leading to herd protection, but the magnitude of each serotype reduction may differ depending on the schedule. In industrialized countries that include a booster (3 + 1 or 2 + 1), there has been an almost complete elimination of circulation of most vaccine serotypes.42,43 Conversely, in low-income countries, the use of a 3 + 0 schedule has resulted, despite good vaccine coverage, in a continued high residual carriage of PCV types,44 leading several African countries to switch to a 2 + 1 schedule. In these low-income settings, continued surveillance of pneumococcal meningitis and other IPD, as well as pneumococcal carriage, will provide important data on the role of the booster dose in controlling pneumococcal disease through herd protection. As of January 2020, the United Kingdom changed its infant vaccination schedule to 1 + 1; the effectiveness of this approach is currently being evaluated.39

Countries with established PCV programs have observed serotype replacement in both disease and carriage, which has eroded the total benefits of the vaccination program. Overall, however, a large number of cases of pneumococcal meningitis and other IPDs have been prevented by PCVs.

Currently, most pneumococcal meningitis cases in countries with established PCV programs are due to serotypes that will be included in next-generation PCVs: 15-valent (PCV15; ie, PCV13 serotypes + 22F and 33F), 20-valent (PCV20; ie, PCV13 serotypes + 8, 10A, 11A, 12F, 15B/C, 22F and 33F) and 24-valent (PCV24; ie, PCV20 serotypes + 2, 9N, 17F and 20) vaccines.39

PCV15 has been estimated to cover an additional 36% to the PCV10 coverage of cases of meningitis <5-year-olds compared with an additional 7% of cases at PCV13 sites. PCV20 and PCV24 are expected to cover an additional 49%–59% at PCV10 sites and an additional 43%–47% at PCV13 sites. PCV15 and PCV20 are expected to be licensed for pediatric use within the next 12 months.40

The current third-generation PCVs, however, do not include certain important serotypes, in particular, 24F, 23B and 23A, which cumulatively are responsible for 10%–12% of pneumococcal meningitis cases across PCV10 and PCV13 settings in different age groups.40 A novel 21-valent PCV (serotypes 3, 6A/C, 7F, 8, 9N, 10A, 11Α, 12F, 15Α, 15B/C, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F and 35B) is going to enter phase 3 studies in adults in 2022.45 In addition, 25- and 30-valent vaccines are currently under development.

To overcome the need of expanded serotype coverage and serotype replacement, a non–serotype-specific vaccine, that is, either a protein-based or a whole-cell pneumococcal vaccine, is the optimal solution.

CONCLUSIONS

During the past 3 decades, conjugate vaccines implemented in pediatric NIPs have greatly reduced the burden of meningitis globally. Due to herd protection, conjugate vaccines have also resulted in the decline of the incidence of meningitis in nonvaccinated populations, including older children and adults. The magnitude of each vaccine’s effect on the development of herd immunity may differ depending on the schedule. The effectiveness and duration of protection provided by MenB protein-based vaccines is ongoing. Taken together, these findings suggest that it is important to maintain careful surveillance and well-thought prevention strategies of the pathogens responsible for acute bacterial meningitis that is supported by robust global epidemiological studies. Data specific to each pathogen’s characteristics, geographical incidence rates and social development should be utilized to formulate and implement effective vaccination policies.

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Keywords:

bacterial meningitis; conjugate vaccines; protein-based vaccines; vaccine preventable disease

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