Vaccine-Preventable Bacterial Meningitis: A Persistent Threat

Acute bacterial meningitis is characterized by infection and inflammation within the subarachnoid space and causes significant morbidity and mortality worldwide, particularly in infants.1–3 Its incidence and prevalence vary by geographic region and over time. 4,5 The African meningitis belt, affecting the sub-Saharan region with 26 countries and extending from Senegal to Ethiopia, has the highest incidence of meningitis, with an estimated 80,000 suspected cases resulting in more than 4,000 deaths in 2009. , for example.2

Systematic reviews of studies on bacterial meningitis, including middle- and high-income countries, showed variable case fatality rates ranging from 5% to 30% of cases, which were reported primarily because of wide variation in presentation to services. doctors, access to health care, and medical resources.6,7 Additionally, survivors of bacterial meningitis may develop a number of sequelae, such as hearing loss, developmental delay, and poor school performance, depending on age. of the patient and the infectious organism.6,7

A meta-analysis of 61 evaluable studies published between 2012 and 2017 evaluated the prevalence of bacterial meningitis in various geographic regions and age groups. It showed that the most common etiological agents of bacterial meningitis were Neisseria meningitidis and Streptococcus pneumoniae with weighted mean frequencies in geographic regions and age groups ranging between 3.2% and 47.0% and between 9.6% and 75.0%. 2%, respectively.

Weighted means of Haemophilus influenzae frequency in geographic regions, stratified by age, ranged from 0.2% to 15.5%.2 Clinical diagnosis of meningitis can be difficult, especially in young infants who do not have the classic signs/symptoms of the disease. 8 In most patients, an etiological diagnosis is not available due to a combination of factors including prior administration of antimicrobial treatment, lack of availability of existing diagnostic tests in some centers, and technical difficulties in diagnosing certain diseases. pathogens.8, 9

Polysaccharide vaccines that offer protection against pneumococcus, meningococcus, or H. influenzae type b have been available for more than 4 decades.10,11 However, their widespread use has been hampered by a number of disadvantages: (1) low response of antibodies in children less than 2 years of age, (2)) rapid decline of protective antibodies in young children, (3) absence of immunological memory on rechallenge, (4) inability to overcome immune hyporesponsiveness to the next dose, and (5) ) minimal or no effect on nasopharyngeal or oropharyngeal transport, which prevents the development of collective protection.12,13 These limitations have been overcome by the development of polysaccharide conjugate vaccines, in which a polysaccharide of the microbial capsule.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 Kingdom, 15 and other countries globally.3, 16

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

H. influenzae can be distinguished into 6 serotypes (ae) based on its unique polysaccharide capsule or may be unencapsulated. Before routine vaccination, serotype b was a leading cause of bacterial meningitis, especially in young children.

In the United States, before the vaccine was available, the annual incidence of H. influenzae type b (Hib) meningitis in children 0 to 4 years of age was 50 to 60/100,000. This incidence, for unidentified reasons, was more than double the pre-vaccination weighted average for Europe (23 cases/100,000), as well as for much of South America, Asia, and Oceania (20 cases/100,000).17, 18

Routine use of Hib conjugate vaccines administered at 18 months of age was initially introduced in the United States in 1987 and was subsequently established at 2 months of age in 1991, followed by most industrialized countries in the 1990s. Only a few vaccines in history have achieved such a dramatic decline in the incidence of their target diseases over such a short period as Hib conjugate vaccines.17 The impressive decline in the "all-age incidence" of meningitis Hib: more than 97% between 1986 and 2007—illustrates the profound effect of Hib conjugate vaccines on the entire US population.19 

The decrease in the incidence of Hib meningitis following the implementation of Hib conjugate vaccines in the National Immunization Program (NIP) of European countries was also large and rapid. 3.18

Various schedules of conjugate vaccines are used globally, such as 2 primary doses plus 1 booster, 3 primary doses without booster, and 3 primary doses plus 1 booster; the initial primary dose can be administered at 6 to 8 weeks of age18 Hib conjugate vaccines have been widely implemented in developed countries and are increasingly used in resource-limited 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 vaccination schedule.18,20 The results of 2 meta-analyses do not favor any particular vaccination program.21,22

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

Childhood immunization against Hib provides direct and indirect protection , that is, it reduces pharyngeal colonization of Hib in vaccinated children to reduce transmission to other members of the community.3, 20 However, children are not the only reservoir of Hib, and rare cases continue to occur in highly immunized populations, especially 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 the aof serotypes, or that are nontypeable (nonencapsulated).3, 19, 20

Invasive meningococcal disease (IMD) represents a serious 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 both.

Data on disease burden often refer to total IMD cases without distinguishing cases of meningitis from those without meningeal inflammation. The epidemiology of N. meningitidis serogroups is unpredictable and differs geographically and temporally.23

Meningococcal disease serogroup C (MenC) has been the second vaccine-preventable disease to be attacked with a conjugate vaccine. It was introduced in many PINs after 1999. Its implementation in the United Kingdom in that year was supported by an intense update campaign aimed at all children under 19 years of age (later extended to 24 years of age).10

Herd protection, including reductions in MenC cases in adults and the elderly, occurred immediately after the introduction of MenC vaccination, as did an impressive decline in the incidence of MenC infection among vaccinated and unvaccinated individuals, with a total of cases which decreased from approximately 1000 cases in 1999 to 28 cases in 2006. It is likely that herd protection has accelerated due to the eradication of the MenC carrier state through vaccination of adolescents and young adults who are the main nasopharyngeal carriers of N. meningitidis.

The first outbreaks of meningococcal disease serogroup W (MenW) were observed after the Hajj pilgrimages in 2000 and 2001. 24 Although cases and outbreaks decreased in subsequent years due to mandatory vaccination of pilgrims traveling to the Hajj, they have have been increasingly responsible for local epidemics and have caused large national outbreaks in South Africa, the United Kingdom, Australia and Chile, among other countries.24

Recently in the Netherlands, MenW cases have also increased, with 52% of MenW meningitis episodes diagnosed between 2015 and 2019 among preschool and school-age children. 3 In the African meningitis belt during epidemics, caused mainly by meningococcal disease serogroup A (MenA), but also by other serogroups, the incidence reached 1% of the 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 mass vaccination campaigns were introduced in the African belt. meningitis at the end of 2010 for people aged 1 to 29 in different phases.

Implementation of PsA-TT 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 to 2015.25 An accessible pentavalent MenACWYX. The conjugate vaccine is planned to be available and licensed in the coming years with the goal of achieving optimal protection against MenC, MenW and serogroup X outbreaks in Africa.25

Adolescents and young adults represent an age group of particular interest in meningococcus transmission and prevention. Acquisition of meningococcal carriage peaks in middle and late adolescence and early adulthood, establishing this age group as the second highest risk for IMD after infants and young children; Adolescents are the most vulnerable group during meningococcal outbreaks. Adolescent survivors of IMD are also at increased risk for significant long-term sequelae.11

MenACWY conjugate vaccines have been shown to be effective in preventing IMD due to these 4 serogroups through direct protection of vaccinated individuals and prevention of acquisition of carriage leading to indirect protective (herd) transmission. These protective effects have led many countries to include the MenACWY conjugate vaccine for adolescents in their NIPs.11 Additionally, the NIPs of certain countries with a higher number of MenW cases have changed from the monovalent MenC conjugate vaccine to the quadrivalent MenACWY vaccine in Small 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 America26. The incidence is highest in the second half of the first year of life.

Two protein-based MenB vaccines are available, 4CMenB and MenB-FHbp. 4CMenB is authorized for use in infants 2 months of age and older in the European Union and for children 10 to 25 years of age in the United States. MenB-FHbp is authorized for administration to people ≥10 years of age. 4CMenB was initially incorporated into the publicly funded UK NIP.

Compared with the pre-vaccination period, a 50% decrease in MenB cases was observed in vaccine-eligible children during the first year of the program, regardless of infants’ vaccination status or expected strain coverage. MenB.27 After 3 years, vaccine efficacy against MenB infection was 52.7% in infants immunized with 2 primary doses and 59.1% in those who had received 2 primary doses plus 1 dose ( booster) at one year of age.28

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

Unlike capsular polysaccharides, the outer membrane protein and 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 no notable effect on the carriage of disease-causing meningococci, including MenB.30

The MenB-FHbp vaccine is licensed as a 2-dose schedule 6 months apart. In the context 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 university outbreaks in the United States.

The 2 protein-based MenB vaccines do not affect meningococcal carriage or prevent the acquisition of MenB carriage and therefore only provide direct protection to vaccinated individuals30–32. During outbreaks, high immunization coverage is recommended to protect vaccinated individuals and chemoprophylaxis for close contacts. 25, 31,32

Studies are underway to evaluate the duration of protection provided by vaccines based on the MenB protein.27,28 As of February 1, 2019, the South Australian government announced a 4CMenB immunization program funded to provide direct protection to babies, children 1-3 years old, adolescents and young people from 17 to 20 years old.33

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

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

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

Subsequently, 2 second-generation PCVs became available, the 10-valent conjugate vaccine (PCV10; i.e., PCV7 + serotypes 1, 5, and 7F) in 2009 and the 13-valent conjugate vaccine (PCV13; i.e., PCV7 + serotypes 1, 5, and 7F) in 2009. 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 widely used second-generation PCVs.39

In England and Wales, a significant effect on S. pneumoniae meningitis was observed after implementation of PCV7/PCV13 in children under 5 years of age. The introduction of PCV7 and its replacement by PCV13 led to a reduction in the incidence of pneumococcal meningitis from 4.08 cases/100,000 person-years in the period before PCV7 to 3.10/100,000 person-years in the period prior to PCV13 and subsequently to 1.22/100,000 person-years in the post-PCV period.13

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

Three serotypes, i.e., 19A, 6C, and 3, have become of particular interest during the PCV10/13 period. Specifically, serotype 19A, a unique type of PCV13, although rare (≤3%) at PCV13 sites, is responsible for almost a quarter of preschool cases and was found to be common among older children in the PCV10.40 sites

The second most common 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 through capsule cross-protection of serotype 6A, which is included in PCV13. Serotype 6C has been detected in 1.0% of children under 5 years of age and 2.2% of children ≥5 years of age.

The proportion of serotype 3 cases in children under 5 years of age was lower (7.4% and 4.0% in the PCV10 and PCV13 sites, respectively) but higher in the PCV10 sites (in third place) than in the PCV13 sites. (in the eighth). Among children ≥5 years, serotype 3 remains one of the most common serotypes at both the PCV13 (13.1%) and PCV10 (13.9%) sites.40

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

Three PCV dosing schedules, i.e., 3+1, 2+1, and 3+0, have been shown to be effective in preventing pneumococcal disease and are approved and used worldwide. In general, all schemes have been shown to reduce vaccine-type pharyngeal carriage, leading to herd protection, but the magnitude of the reduction for each serotype may differ depending on the scheme.

In industrialized countries that include a booster (3+1 or 2+1), there was almost complete elimination from circulation of most vaccine serotypes.42, 43 In contrast, in low-income countries, the use of a 3+0 schedule has resulted, despite good vaccination coverage, in a continued high number of residual carriers of PCV44 types that has led several African countries to switch to a 2+1 schedule. In these low-income settings, continued surveillance for pneumococcal meningitis and other IPD, as well as pneumococcus transmission, will provide important data on the role of booster dosing in controlling pneumococcal disease through herd protection. . As of January 2020, the UK changed its childhood 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 full benefits of the vaccination program. However, in general, PCVs have prevented a large number of cases of pneumococcal meningitis and other IPDs.

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

It has been estimated that PCV15 covers an additional 36% vaccine to PCV10 coverage of meningitis cases to overcome the need to expand serotype coverage and serotype replacement, the optimal solution is a non-serotype-specific vaccine, i.e. a protein-based or whole cell pneumococcal vaccine.

Countries with established PCV programs have observed serotype replacement in both disease and carrier status, resulting in the full benefits of the vaccination program. In general, however, a large number of cases of pneumococcal meningitis and other IPD have been prevented by PCVs.

Currently, the majority of pneumococcal meningitis cases in countries with established PCV programs are due to serotypes that will be included in next-generation PCVs: 15-valent (PCV15; i.e., PCV13 serotypes + 22F and 33F), 20-valent 39

PCV15 has been estimated to cover an additional 36% to PCV10 coverage of meningitis cases <5 years of age compared to 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

However, current third-generation PCVs do not include certain important serotypes, notably 24F, 23B, and 23A, which together are responsible for 10% to 12% of pneumococcal meningitis cases in PCV10 and PCV13 settings in different groups. old.40 The new 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) will enter Phase 3 studies in adults in 2022.45 Additionally, 25- and 30-valent vaccines are currently being developed.

To overcome the need for expanded coverage and serotype replacement, the optimal solution is a non-serotype-specific vaccine, i.e., a protein-based or whole-cell pneumococcal vaccine.

Over 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 decreased incidence of meningitis in unvaccinated 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 vaccines based on the MenB protein are ongoing.

Taken together, these findings suggest that it is important to maintain careful surveillance and well-thought-out prevention strategies of the pathogens responsible for acute bacterial meningitis that are supported by robust global epidemiological studies.

Specific data on each pathogen’s characteristics, geographic incidence rates, and social development should be used to formulate and implement effective vaccination policies.

Bacterial meningitis causes significant morbidity and mortality worldwide, especially in infants. In addition, those who survive may develop sequelae related to hearing loss, developmental delay, and poor school performance.

A large multicenter study showed that the most common etiological agents were Neisseria meningitidis and Streptococcus pneumoniae. Clinical diagnosis can be difficult, especially in infants who do not present classic signs or symptoms of the disease.

In most patients, it is not possible to reach an etiological diagnosis due to a combination of factors including prior administration of antibiotic treatment, lack of availability of diagnostic tests, and technical difficulties in diagnosing certain pathogens.

Polysaccharide vaccines that offer protection against pneumococcus, meningococcus, or H. influenzae type b have been available for decades. However, its widespread use was limited by certain disadvantages that have been overcome by the development of polysaccharide conjugate vaccines.