Changing patterns of invasive meningococcal disease and future immunization strategies

ABSTRACT

Invasive meningococcal disease (IMD) is a life-threatening disease caused by Neisseria meningitidis and has high mortality rates. Survivors often exhibit long-term sequelae and reduced life expectancy. Disease incidence is highest in infants and toddlers, with a resurgence of cases in adolescents and older adults (>50 years of age). Substantial heterogeneity exists in the recommendations of meningococcal vaccines included in National Immunization Programs (NIPs) across countries. Recommendations are usually based on infant/toddler immunization, with some countries recommending immunization only for toddlers. While existing recommendations have led to a reduced incidence of IMD in children <5 years of age, there has been an increase in cases among adolescents and older adults. Currently, older adults are not included in the recommendations. The higher healthcare burden and the economic costs associated with IMD in these age groups suggest that it is time to consider including adolescents and older adults in NIPs to protect against IMD caused by the five most prevalent serogroups. Currently, the lack of equity of access to vaccines in the immunization programs is a glaring gap in the betterment of public health, and a broader meningococcal strategy is recommended to provide optimal protection for all age groups.

Plain Language Summary

Invasive meningococcal diseases, which include meningitis, are rare and unpredictable, but may lead to very important/debilitating long-term sequelae, death, or reduced life expectancy. Vaccination is the best way to prevent them. Vaccination recommendations provided by national health agencies usually target infants (or toddlers), children, and adolescents. Older adults are only considered when they are at risk for invasive meningococcal diseases.

Here, we analyzed the vaccination strategies for invasive meningococcal disease in different countries to identify the gaps preventing access to vaccination.

We found that recommendations for invasive meningococcal disease vaccination vary markedly among countries. Vaccination programs target mainly infants and toddlers, and they successfully reduced the number of cases among them. However, we also observed that the disease now affects more adults. We also found that the lack of equitable access to vaccination prevents broader meningococcal protection for persons of any age.

With this analysis, we suggest improving the current meningococcal vaccination guidelines to also provide adolescents and healthy older adults with access to vaccines. Promoting equal access to vaccination for everyone could reduce the impact on the healthcare system and help reduce social disparity. In order to do so, we advise universal recommendation of meningococcal vaccines, which would provide clear guidance to health-care practitioners.

Invasive meningococcal disease (IMD) is caused by the bacterium Neisseria meningitidis. It is an unpredictable and serious disease with clinical presentations, such as meningitis and septicemia. ¹ Disease onset can be sudden, and IMD may be fatal within 24–48 hours after symptom development.² One in five survivors may suffer from long-term sequelae, including neurological disabilities, hearing loss, limb amputation, and other deficits.³ The bacterium N. meningitidis remains the predominant cause of invasive bacterial infections along with Streptococcus pneumoniae and Haemophilus influenzae.⁴ Twelve N. meningitidis serogroups have been identified, of which five are responsible for the majority of IMD cases (serogroups A, B, C, W, and Y).⁵ According to the 2016 Global Burden of Disease study, an estimated 2.8 million cases of meningitis were reported worldwide, causing almost 318,400 deaths.⁶

Evidence suggests that IMD affects all age groups.⁷ However, the disease burden is highest in infants, followed by children <5 years of age.⁷ The European Centre for Disease Prevention and Control (ECDC) reports that the age-specific rate of incidence in 30 European Union/European Economic Area (EU/EEA) countries peaks in infants <1 year of age (8.3/100,000 population), then between 1 and 4 years of age (2.4/100,000 population) and again between 15 and 24 years of age (0.9/100,000 population).⁷ Current global vaccination recommendations target these three specific age groups.⁸ While the recommendations have led to a substantial impact on IMD incidence in children and adolescents, a corresponding increase among older adults has been observed. In 2003, the median age of IMD patients in Canada was 16 years of age, which increased to 42 years of age in 2006.⁹ In Australia, the proportion of IMD cases among those >65 years of age increased from 4% to 6%, with a mortality rate of 32%.¹⁰ Evidence of increased IMD incidence in older adults is also seen across the United States (US),¹¹ and Brazil.¹² Meanwhile, in Europe, IMD incidence due to serogroups W and Y increased, while IMD cases due to the most prevalent serogroups, B and C, decreased.^13,14

The primary treatment for IMD is antibiotic therapy for the patient and antibiotic prophylaxis for their household and intimate contacts.¹⁵ While antibiotic prophylaxis may be effective, antimicrobial resistance to ciprofloxacin has been seen in N. meningitidis isolates from IMD cases and asymptomatic carriers worldwide, such as the US, France, India, Argentina, and China, among various other countries, thus leading to future concerns for public health.¹⁶

Vaccination is considered the best strategy for preventing IMD due to the rapid nature of disease progression.¹⁷ Based on serogroups, four types of meningococcal vaccines are available for use: polysaccharide-protein conjugated monovalent vaccines, which protect against serogroups A and C (MenA; MenC);¹⁸ meningococcal polysaccharide tetanus toxoid conjugate vaccines, which protect against serogroup A (MenAfriVac, Serum Institute of India Ltd. (SIIL), Pune, India);¹⁹ quadrivalent meningococcal conjugate vaccines, which protect against serogroups A, C, W, and Y (MenACWY); and the recombinant serogroup B meningococcal vaccines (MenB) which protect against serogroup B.³

Vaccination recommendations provided by the National Immunization Programs (NIPs) support infants (or toddlers), children, and adolescents. Older adults are only considered when at risk for IMD. In this commentary, we review the global IMD epidemiology, disease burden, available meningococcal vaccines, and the current recommendations for meningococcal vaccination. This evidence could identify gaps in existing strategies, recognize unmet needs, and address gaps to achieve access to protective meningococcal vaccines, especially for an older age group.

Methods

A targeted review of peer-reviewed articles related to IMD was performed to study epidemiology, disease burden, available vaccines, and current vaccination recommendations by different countries in Asia-Pacific, Europe, and the North and South America regions. Existing strategies were analyzed utilizing published data for epidemiology and serogroup prevalence. We also identified gaps in global vaccination programs and presented recommendations to maximize program efficiency to reduce IMD disease burden in key age groups.

Results

Inclusion of meningococcal vaccines in NIPs is constantly evolving in response to IMD epidemiology (based on predominant serogroup and age group at risk), ease of vaccine administration, potential to induce herd immunity, and cost-effectiveness.⁸ An overview of current meningococcal vaccines incorporated into the NIPs of selected countries and their recommended use in specific age groups has been described in Figure 1.

Figure 1.

Age-based primary schedule and catch-up recommendations for meningococcal immunization within National Immunization Programs in selected countries .

^aVaccines are recommended but not funded.

^bRegional catch-up vaccination programs for adolescents up to the third year of high school. This applies to children born on or after 1 June 2019.

^cNo MenB vaccine is currently in the NIP, but it is proposed for inclusion from 1 March 2023. Catch-up vaccination is proposed until 31 August 2025.

^dCatch-up vaccination for children who missed vaccination from 2 to 4 years of age. The MenAC vaccine is recommended for children up to 7 years of age.

APAC: Asia-Pacific; m: months; MenA: polysaccharide vaccine against meningococcal serogroup A; MenAC: polysaccharide vaccine against meningococcal serogroups A and C; MenACWY: conjugated quadrivalent vaccine against meningococcal serogroups A, C, W135, and Y; MenB: recombinant vaccine against meningococcal serogroup B; MenC: conjugated vaccine against meningococcal serogroup C; NIP: National Immunization Program; w: weeks; y: years.

Meningococcal vaccination and immunization recommendations in infants, toddlers, and adolescents

Current immunization landscape

The ECDC Surveillance Atlas of Infectious Diseases tool reported MenB as the leading serogroup for most IMD cases in infants, children 1–4 years of age, and adolescents 15–24 years of age in the EU from 2018 to 2020 (Figure 2).²⁰ A similar trend was also observed in the US in 2018–2019 (Figure 3).^11,21 While the majority of EU countries follow similar recommendations for infant and toddler immunization with MenB and MenC vaccines and for adolescents with MenACWY vaccines (Figure 1), overall vaccination recommendations differ among countries as these are influenced by local epidemiology.²² The age group most affected by IMD and the most prevalent serogroup in a specific region can also influence vaccination recommendations.²² Since the rate of IMD incidence has been highest among infants, most of the vaccination recommendations target infants and toddlers using MenB, MenC, or MenACWY vaccines. In the event of an epidemic or during the early phase of NIP implementation, certain countries may implement catch-up campaigns to increase protection in target populations.^23–25 A MenC or MenACWY booster dose in adolescents is frequently implemented to boost the waning MenC titers after infant vaccination.^25–32 As such, only few countries have targeted just the adolescent population in their NIPs,^33,34 while Chile, China, and Lithuania remain the only countries to have no vaccination guidelines for adolescents in their NIPs (Figure 1).

Figure 2.

Serogroup distribution of confirmed invasive meningococcal disease cases stratified by age in Europe, France and the United Kingdom, 2018–2020.

A: Meningococcal serogroup A; B: Meningococcal serogroup B; C: Meningococcal serogroup C; W: Meningococcal serogroup W; Y: Meningococcal serogroup Y. Data taken from European Centre for Disease Prevention and Control Surveillance Atlas of Infectious Diseases.²⁰ Data for 2020 for the United Kingdom are not available.

Figure 3.

Invasive meningococcal disease case numbers and serogroup distribution in the United States in 2018 and 2019 stratified by age.

B: Meningococcal serogroup B; C: Meningococcal serogroup C; IMD: Invasive meningococcal disease; W: Meningococcal serogroup W; Y: Meningococcal serogroup Y. Data as reported by the Centers for Disease Control and Prevention.^11,21

Notably, only a few countries have recommended the same meningococcal vaccine for immunization in infants (or toddlers) and adolescents. Argentina,³⁰ Australia,²⁵ Belgium,^35,36 Malta,²⁸ and the Netherlands³⁷ endorse MenACWY for vaccination in both age groups, while the Czech Republic^31,38 and some regions of Australia³⁹ and Canada^32,40 utilize MenB to immunize both age groups. Australia,^25,39 Austria,⁴¹ Canada,^32,40 the Czech Republic,^31,38 Ireland,²⁷ Italy,⁴² Malta,²⁸ Spain,²⁶ and the United Kingdom (UK),⁴³ use a combination of MenB vaccine for infant vaccination and MenACWY vaccine for adolescent immunization. Interestingly, Argentina,³⁰ the Czech Republic,^31,38 and Malta²⁸ are the only countries that have recommended the use of MenACWY for infant, toddler, and adolescent immunization (Figure 1).

What is missing?

There is overwhelming evidence of the efficacy of vaccines and their reduction in the incidence of serogroup-B-related IMD in infants.^2,17,18,44 The countries with the highest incidence of IMD in infants and children <5 years of age have meningococcal immunization strategies in place.⁵⁸ A growing number of countries have also introduced MenB vaccine for infants.⁸ Although countries like Belgium, the Netherlands, Greece, the US, Brazil, Argentina, Chile, and China have incorporated MenACWY in adolescent and/or infants (MenA or MenAC in the case of China), they have not yet introduced infant MenB vaccine in their NIPs (Figure 1). Similarly, the majority of the countries have not included MenB vaccine in their adolescent NIPs, even though this age group is at increased risk for serogroup B meningococcal disease.⁵⁸ This gap in infant and adolescent meningococcal vaccination strategy must be addressed since serogroup B remains a major cause of IMD in all age groups.⁷ The gap may be reduced by extending MenB infant and adolescent vaccination into countries, which have not yet included it in their NIPs. Further protection against the five prevalent serogroups causing IMD can be achieved by co-administration of MenB and MenACWY in both infants and adolescents.⁵⁹ Emerging evidence also suggests that a four-component vaccine against N. meningitidis meningococcal serogroup B (4CMenB) may provide some protection against other serogroups and against gonorrhea, which is an additional benefit for adolescents. Studies have shown that MenB vaccine may have 30–40% efficacy against N. gonorrhoeae infections.^60–65 A public-health-impact model of MenB vaccine on gonorrhea showed that with 50% or greater vaccination coverage, MenB vaccination can avert ~10% of gonorrhea cases over 10 years.⁶⁶ Another study that utilized a decision analysis model reported that 4CMenB could prevent approximately 83,000 gonorrhea infections (95% credible interval [CrI], 44,600–134,600) and 55 HIV infections (95% CrI, 2–129) per vaccinated birth cohort in the US.⁶⁷ Thus, co-administration of MenB and MenACWY vaccines among adolescents could have a significant health impact on reducing the burden of both IMD and gonorrhea.

Except China, none of the countries implemented meningococcal vaccination for infants and toddlers (6–18 months of age) with a booster dose for children (up to 7 years of age).^56,57 Typically, vaccination programs target the ages of peak incidence, but many countries that include meningococcal vaccines in their NIPs during infancy do not provide it during adolescence (11–25 years of age). Contrastingly, only Argentina,³⁰ Belgium,^35,36 the Czech Republic,^31,38 Malta,²⁸ and the Netherlands³⁷ were reported to have introduced MenACWY vaccination among toddlers and adolescents. Evidence suggests that vaccinating infants or toddlers with MenC and adolescents with MenACWY reduced the incidence of IMD in both age groups and offered wider protection.²³

Among all meningococcal serogroups, serogroup B is the most predominant strain in Europe and the US depending on age group (Figure 2, 3).^11,14 Despite the prevalence of serogroup B in the two regions and the higher incidence rates among adolescents, only the Czech Republic,^31,38 Austria,⁴¹ the US,⁴⁹ Canada,^32,40 and South Australia^25,39 recommend both MenB and MenACWY vaccines (or shared clinical decision, in the case of Canada and the US) for adolescents.

Meningococcal vaccination and immunization recommendations in older adults

Current vaccination landscape

The current immunization recommendations target infants and adolescents, reducing the incidence in those age groups. However, this has resulted in a greater incidence in older adults. The ECDC Surveillance Atlas of Infectious Diseases tool reported that the incidence of IMD cases in older adults (≥50 years of age) has been increasing over time (Figure 4). The data also highlight increasing mortality rates with a corresponding increase in age, as the highest case fatality rate (CFR) was observed in adults ≥50 years of age.¹⁵ Similar trends were observed in the US in 2019, where the CFR in patients aged 24–44 years of age was 5.2%, which increased to 14.1% in those aged 45–64 years of age, and to 10.5% in older adults ≥65 years of age.¹¹ Between 2006 and 2015, 11% of the total IMD cases in France were diagnosed in older adults ≥60 years of age (CFR 20%), which increased to 22% (CFR 23%) in 2019.⁶⁸ In the Czech Republic, IMD patients aged >65 years of age reported the highest CFR (24.7%).⁶⁹ Similarly, in the UK, the highest CFR (22%) was observed among patients ≥50 years of age.⁷⁰

Figure 4.

Invasive meningococcal disease case numbers and case fatality rates in Europe, France and the United Kingdom, 2011–2020, stratified by age.

EU/EAA: European Union/European Economic Area. Data taken from the European Centre for Disease Prevention and Control Surveillance Atlas of Infectious Diseases.²⁰ Data for 2020 for the United Kingdom are not available.

Hospitalization for older IMD patients is associated with a considerable healthcare burden, which increases with age.⁷¹ Apart from the initial hospitalization costs, sequelae management significantly raises health-care costs up to 1.5 times for a patient with one sequela, and 2.4 times in case of multiple sequelae, which accrues over the years.⁷¹ Evidence suggests that older adults are more susceptible to IMD, its associated sequelae, health-care costs, and mortality rates. However, none of the countries have included meningococcal vaccines for older adults in their NIPs (Figure 1), excluding individuals at-risk for IMD.⁴⁴

What is missing?

The highly dynamic serogroup prevalence, life-threatening nature of the disease, and its rapid progression suggest that infants, toddlers, adolescents, and older adults need to be vaccinated against IMD. However, none of the countries have IMD vaccination recommendations for older adults in their NIPs. Currently, the number of IMD cases is low, which may be due to the social distancing measures implemented because of the coronavirus pandemic.⁷² This could rebound as these measures are withdrawn. Without vaccination recommendations from public health agencies, the potential increase in the number of cases may put an additional burden on the public health systems already strained by the coronavirus pandemic.

Discussion

The following section highlights the key gaps in current meningococcal immunization recommendations and offers suggestions on bridging these gaps.

Improve vaccine equity among infants and adolescents

We found that an increasing number of countries have implemented MenB vaccination for infants and children <5 years of age due to the high rate of incidence in this specific age group (Figure 1). However, the rate of incidence also peaks in adolescence and old age, but the majority of countries have not yet introduced specific vaccination programs for these age groups. The need to improve vaccine equity within communities demonstrates a socio-economic disparity between those who can afford the protection of the vaccine and those that are at increased risk of contracting the disease.⁶⁸ Along with the inclusion of the vaccine in NIPs, improved vaccine uptake and increased disease awareness can help the effectiveness of these programs.

Remaining gap: absence of vaccination recommendations for healthy older adults

Focused meningococcal vaccination in infants and at-risk adults has greatly reduced the incidence of IMD in targeted age groups.⁷³ However, the incidence of IMDs in healthy adults ≥50 years of age shows an increasing and steady trend, particularly for the MenW and MenY serogroups.^13,14,20 Apart from the increased mortality rate in older adults during the acute phase of the disease, meningitis survivors often experience reduced life expectancy and a higher risk of post-discharge death.^74,75 Atypical symptoms of IMD have been reported in older adults, which makes diagnoses difficult, allowing the disease to progress without treatment.⁷⁶ The financial burden of hospitalization and treatment of IMD-related sequelae on the individual and society is substantial.^71,74 Vaccinating older adults ≥50 years of age irrespective of the risk factors can reduce the healthcare burden and mortality in this age group.

Crowded living conditions, as seen in nursing homes, are another risk factor for IMD. Closeness among the residents as well as intimate interactions could increase the risk of IMD transmission.⁷⁷ Meningococcal infection in older adults with reduced access to health care and diminished financial reserves could further burden the healthcare system.⁷¹

In a vaccine participation study, older adults chose to be vaccinated to safeguard their own health and that of their loved ones.⁷⁸ Based on this evidence, vaccine-specific interventions emphasizing the risk of the disease as well as the benefits of vaccination are likely to be successful.

Equity of access to vaccines

While MenC vaccine coverage in infants is progressing, MenB vaccine implementation in NIPs has been difficult due to cost constraints. Several countries now include MenB vaccines in their NIPs (Figure 1). Steps such as universal recommendation and reimbursement could provide clear guidance to health-care practitioners and improve vaccine access for the recommended age groups. In addition to this, the Centers for Disease Control and Prevention (CDC) has recently published a framework that describes how the CDC moves information from evidence to vaccine recommendations.⁷⁹ In this publication, the CDC describes how transparency coupled with a systematic, reliable, and action-oriented review of evidence can together enhance equitable access to vaccines. Frameworks such as this could be utilized by other public health agencies to improve their own processes for more equitable access to vaccines.

Expert recommendations

This analysis highlights the public health value and importance of expanding infant MenB vaccination in countries where it is not yet implemented and expanding adolescent MenB vaccination in countries that have MenB infant vaccination recommendations in place. This report also highlights the value of extending MenACWY vaccination in adolescents where they are not already included. Vaccinating the adolescent population boosts individual immunity from the previous infant MenC priming and provides broader protection against the most prevalent serogroups. Due to the similarity of the Neisseria strains, the MenB vaccine also confers protection against gonorrhea. Concomitant administration of MenB and MenACWY is a viable alternative. As a result, adolescents and young adults may be more likely to comply with vaccine schedules.

The authors recommend expanding the implementation of IMD vaccination in older adults regardless of the presence of concomitant risk factors for IMD, considering the increased incidence and mortality in this age group. Older adults are highly susceptible due to the quick progression of the disease, potential misdiagnosis due to the atypical symptoms, the presence of underlying health conditions, and limited financial resources. Updating current evidence-based recommendations to provide lifelong and equitable access to vaccines could lead toward life course immunization against IMD.

Funding Statement

GlaxoSmithKline Biologicals SA funded this report and all costs related to the development and publication of this manuscript.

Disclosure statement

Véronique Abitbol and Rafik Bekkat-Berkani are employed by GSK and hold shares in GSK. Muhamed-Kheir Taha reports grants/contracts from GSK, Pfizer, and Sanofi Pasteur for activities outside the presented work. Muhamed-Kheir Taha also reports a patent 630133 issued for activities outside the presented work. The authors declare no other financial or non-financial relationships and activities.

Contributors

All authors participated in the conception and design of the review article and interpretation of the relevant literature and were involved in writing the review article or revising it for intellectual content. All authors have approved the final version of the manuscript.

Trademark

MenAfriVac is a trademark of Serum Institute of India Ltd.

Previous congress activities

ESPID 2022, 9–13 May 2022, Athens, Greece, Virtual and on-site