Continuing Education Activity

Meningococcal disease is a leading cause of morbidity and mortality worldwide. This activity will describe how to deal with this disease as a serious problem. It will also illustrate the importance of meningococcal vaccination and how it enhances immunological memory and reduces nasopharyngeal carriers (who represent the primary source of meningococcal infections ), leading to herd immunity. Then, we will mention the risk factors, individuals at high risk, ways of vaccine administration, doses, indications, and contraindications.

Objectives:

• Describe the characteristics of Neisseria meningitides that causes meningitis.
• Summarize the at-risk populations for Meningococcal disease.
• Explain the differences between the two types of meningococcal vaccines.
• Review the importance of improving care coordination among interprofessional team members to improve the rate of meningococcal vaccination.

Indications

The bacterium meningococcus, recently called Neisseria meningitides, is an exclusively human-encapsulated Gram-negative diplococcus. It colonizes the human nasopharynx (termed nasopharyngeal carriage) and mostly affects children and young people with high mortalities. Rarely, invasive strains of N. meningitides may invade across the mucosal surface, entering the bloodstream and invading the blood-brain barrier, causing septicemia and meningitis, also called invasive meningococcal disease (IMD).[1][2][3] 

Issue of concern: In addition to meningitis and septicemia (meningococcemia), IMD is responsible for a spectrum of infections such as pneumonia, and more rarely, septic arthritis and pericarditis. It also may be associated with long-term sequelae and lifelong morbidity, including limb loss, neurologic impairment, allergic complications, hearing loss, and even death.[4][5] 

The onset of the disease is typically rapid and fulminant, as it may develop in 1 to 14 days after acquisition. The characteristic symptoms, however, manifest relatively late, making the infection tricky to diagnose on time. So the celerity of the disease and difficulty distinguishing it from other febrile infections can lead to the death of a previously healthy individual within hours. The disease mostly affects infants aged less than one year, but the incidence is likewise high in adolescents, so this age group mainly has the highest fatality rates. Even when given antibiotics, mortality due to IMD  reaches 10 to 20%, being highest in older adults, especially when accompanied by septicemia.[6][7][8][2] 

Transmission of the meningococcus occurs through droplets transmitted via close contact with a carrier of N. meningitides or an infected one. Studies calculate roughly that carriage crests in early-to-late adolescence, depending on the region, showing that persons of these ages are likely essential vectors of the disease. Meningococcal disease has an association with exposure to active or passive smoking, travelers to endemic regions (e.g., the meningitis belt in Africa, Hajj pilgrims), settings of increased exposure and close contact with a person carrying the organism such as crowding in military barracks and student residences, in addition to antecedent respiratory infections (e.g., Mycoplasma, influenza and other viruses), and finally dry or windy air conditions which are associated with a heightened risk for invasive disease due to mucosal damage and irritation.[2][4][6][9]

Usually, the humoral response is adequate to stop the spreading of the micro-organism and avert IMD; but, when the antibody response is not enough, bacteremia occurs, causing endothelial damage, increasing vascular permeability, and inducing a prothrombotic state. That is why the real meningococcal disease is a very unusual complication of bacterial colonization in healthy individuals.[10] Developing sporadic meningococcal disease more than once is rare but probable due to infection with other serogroups; however, this would be very suspicious for an underlying host immune defect.[11] Some several factors and conditions are known to increase the susceptibility for meningococcal disease. These can include specific age groups, medical conditions, or drugs that cause immunodeficiency, anatomical defects of the natural barriers of the CNS, and host genetic factors. All of which are described more elaborately in the following points:[9] 

1.  Extremes of age (<6 months and greater than or equal to 65 years), as well as some specific host genetic polymorphisms usually associated with invasive diseases.[6]
2. A defective complement system, be it early (including C3, properdin, or factor H and D) or late complement system (C5-C9). The late complement system plays the main role in the host defense against invasive bacterial meningitis, mainly meningococcus, which causes up to 85% of identified invasive bacterial infections in those patients. Attacks are usually observed in those with terminal complement deficiency as they are associated with a 1400- to a 10000-fold increase in meningococcal disease risk and propensity for recurrent infections (in up to 50% of patients) with a recurrence rate of 100-150 times higher than that in the general population.[6][12][13]
3. In some cases, the defect in immunity and complement system is not congenital but acquired. A multitude of causes, including inadequate production of complement components secondary to liver dysfunction, increased consumption of complement by an autoimmune disease such as lupus, increased excretion by protein-losing diseases. It can also occur secondary to drugs like eculizumab, which inhibit complement protein C5 leading to terminal complement cascade, or by receiving some medications like eculizumab (therapy for atypical hemolytic-uremic syndrome), which is a monoclonal antibody that binds e inhibition.[11]
4. Children with human immunodeficiency virus (HIV), partial T-cell defects (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome, ataxia-telangiectasia), and those with anatomic and functional asplenia (that are associated with impaired antibody production). Studies have shown those with low CD4 counts or AIDS or are at higher risk than the general population. Additionally, reports exist of outbreaks among HIV-infected people or men who have sex with men (MSM).[11]
5. Conditions associated with poor antibody responses (e.g., congenital or acquired antibody deficiencies such as those seen in hypogammaglobulinemia and glomerulonephritis) also pose a risk for invasive disease. These conditions can cause atypical presentations of invasive disease. Hence providers need a high degree of suspicion for this disease when dealing with these underlying conditions. Invasive meningococcal disease represents a serious but potentially preventable healthcare problem in both developed and developing countries; that makes it a formidable public health concern due to its rapid clinical onset, a predilection for causing high rates of permanent disability or death, and the inability to accurately forecast when an epidemic or sporadic case might occur.[11]

Mechanism of Action

Due to the significant burden worldwide and the serious nature of infections caused by N. meningitis, the pharmaceutical industry has developed vaccines. Providing vaccination is the best way to prevent the patient against this aggressive disease, leaving little time for intervention after the first manifestation of signs/symptoms.[2][13]

It is a known fact that the characteristics of the organism, host, and environment likely play a role in disease pathogenesis. Regarding the organism, N. meningitis, its capsular strains are more likely to cause invasive disease, as encapsulated bacterium whose pathogenic strains divide into serogroups based on its capsular polysaccharide (CPS) components, which represent the major virulence factor that allowing for evasion of opsonization as well as complement and phagocytic-mediated killing, which also represent the basis of currently licensed vaccines.[5][6] 

To date, worldwide, there are 12 known distinct meningococcal serogroups designated based on the composition of CPS polymers (A, B, C, E, H, I, K, L, W, X, Y, and Z), with serogroups A, B, C, W, Y, and X, being responsible for the majority of disease. These 12 serogroups differ immunologically due to characteristic differences in their polysaccharide capsule; serotype menW correlates with more severe clinical manifestations and higher fatality rates than the rest, with more estimated outbreaks and disease clusters worldwide. These polysaccharides form the basis of production for the current vaccines, except for serogroup X and B, for which no vaccine is available, and the MenB vaccine's basis is on its outer membrane polysaccharides, respectively.[3][6][7][14][15]

We know two types of meningococcal vaccines: (1) polysaccharide and (2) conjugated polysaccharide vaccines.[12]

Initially, vaccines were polysaccharide in nature, called plain polysaccharide vaccines, available as bivalent (groups A and C) forms, trivalent (groups A, C, and W) forms, or the quadrivalent (groups A, C, Y, and W) forms, which are generally safe and well-tolerated. However, since the conjugation of a bacterial CPS to a protein induces stronger antibody responses to the carbohydrate moiety than the corresponding plain CPS, and that the success of the Hib type B CPS conjugate vaccine in eliminating all Hib disease in countries that use this vaccine has provided strong evidence, the development of Men CPS-conjugated vaccines has emerged.[6][7][16]

Quadrivalent plain polysaccharide meningococcal vaccines do not provide an adequate immune response in the age group with the highest disease incidence, namely children under two years of age. However, the conjugation of a bacterial CPS makes the glycoconjugate vaccine MenACWY-CRM197 highly immunogenic for serogroups A, C, W-135, and Y across broad age groups, including infants beginning from 2 months of age due to the conversion of T-cell-independent plain CPS into a T-cell-dependent antigen. This response results in a more robust primary immune response, producing immunologic memory and boosting potential, compared with polysaccharide-only vaccines that rely on humoral responses; hence, the immune protection may be short-lived. In addition to the conjugated vaccine's ability to elicit immunologic memory, it reduces nasopharyngeal carriage. Hence, it interrupts the transmission and establishment of population protection, which also effectively protects children less than two years of age who may respond poorly to conventional polysaccharide vaccines.[6][7]

The commercially available conjugated vaccines are usually conjugated to a protein carrier and do not contain other adjuvants in their formula. There are three available quadrivalent conjugated vaccines in the global market, all of them contain the most common polysaccharides (A, C, W, and Y), but each uses a different protein carrier: MenACWY-TT conjugated to tetanus toxoid, MenACWY-DT conjugated to diphtheria toxoid, and MenACWY-CRM conjugated to the nontoxic mutant of diphtheria toxin. Maintaining a protective and effective immune response of these licensed vaccines requires booster doses and needles for administration. Nevertheless, some limitations hinder the effectiveness and availability of these vaccines, including the high cost of the chemical conjugation, the cold chain requirements (continuous refrigeration), and the preparation of every single dose. All of the above are limitations affecting the production and distribution of conjugate vaccines.[2][17]

Until recently, no effective serogroup B vaccine was available. Many studies have attempted to develop a protective MenB vaccine, but to date, they have not obtained satisfying results. Developing a MenB vaccine was very challenging, as the capsular MenB polysaccharide proteins resemble a human neural cell adhesion molecule, which increases the concern about autoimmunity. Moreover, to obtain a broadly effective vaccine, one must consider a high level of antigenic diversity/variability and escape mutants.[6][10]

The pharmaceutical industry has developed vaccines containing outer membrane vesicles (OMV) to overcome these issues. They have many areas of utilization, but the main limitation is their lack of broad protection against the wide global diversity/variability of serogroup B meningococcal strains.[6]

A new improvement occurred with the subsequent recent breakthroughs using "reverse vaccinology," which was successfully created based on conserved proteins. These new formulas provide broad MenB coverage that overcomes the main previous limitation, which may protect even against some non-serogroup B strains, but not all of them, as it may miss some serogroup B meningococcal strains.[6]

A new era of vaccinology and nanotechnology entered the field of meningococcal vaccines, which facilitate the development of novel meningococcal vaccine formulations that mimic conjugation effects by using albumin-based nanoparticles encapsulated into spherical shaped micro and nanoparticles that biologically mimics N. meningitis bacteria. This way of presenting the vaccine into the body makes the immune system deal with it as an invader but without causing disease. This spherical albumin-based nanoparticle capsule contains meningococcal CPS polymers in a biodegradable matrix that slowly releases antigens. Upon contact with antigen-presenting cells as dendritic cells and macrophages, the nanoparticles will induce phagocytosis and then trigger a respiratory burst that leads to reactive oxygen species (ROS) released in huge amounts. That not only triggers the oxidative killing of invading pathogens but also potentiates a second messenger that enhances adaptive immunity.[17]

The antigenicity of these nanoparticles is significantly higher when compared to the vaccine delivered in solution. It is also greatly potentiated when combined with some adjuvants such as alum or MF59 that become encapsulated in these nanoparticles. These alum and MF59 adjuvants have approval from the Federal and Drug Administration (FDA) for administration with licensed vaccines. There is a high potential for novel nanotechnology-based slow-release antigens to enhance antigen presentation, induce immune responses, and overcome the limitations of traditionally formulated vaccines. In addition to the low cost, its ability to be stored as a dry powder without the requirement of maintaining the cold-chain reaction facilitates storage and distribution, which in turn provides a suitable solution not only to low resource countries with endemic areas but also for vaccinations required for the annual Hajj season.[17]

Administration

Doses

Successful vaccines must promote immune responses that induce optimal adaptive immune responses. Effectiveness is usually measured based on immunogenicity, which is evaluated by serum bacterial activity (SBA) to determine the patient's level of protection and his need for a booster dose or not. Doses of each type of vaccine depend on the patient's age, personal status, and the type of vaccine used.[6][17]

Up to this moment, there is not any vaccine that provides lifelong immunity. Since these polysaccharide vaccines induce only 3 to 5 years of immunity among adults, conjugating these vaccines was supposed to provide a longer duration of immunity. Unfortunately, this would not occur after single-dose administration.[6]

For initial vaccination, the recommendation is to use a single dose of meningococcal vaccine in most adults and children (age greater than or equal to 24 months). Due to the low incidence of meningococcal disease in most of the world, indication for additional doses occurs in specific groups and conditions such as infants and toddlers (age greater than or equal to 24 months) and cases where underlying medical conditions and low immunity are present, as significantly low antibody titer is present after a single dose.[6]

According to the WHO recommendations, countries with high (greater than 10 cases per 100000) or intermediate (2 to 10 cases per 100000) endemicity have to conduct large-scale meningococcal vaccine programs and mass vaccination campaigns including young individuals (e.g., nine months to 18 years of age) with a favor for the use of conjugated vaccines for population protection. On the other hand, areas with low meningococcal incidence (less than 2 cases per 100000) are very challenging. Guidelines regarding these countries are usually available, but most recommend vaccines for defined "at-risk" groups based on age, immunity, and underlying precipitating conditions.[6]

It is worth knowing that malignant diseases are not associated with IMD, but the recommendations state to revaccinate any previously immunized children after hematopoietic stem cell transplant (HSCT).[13]

Vaccine Administration 

In general, plain and conjugate polysaccharide vaccines are given by injection, subcutaneously, and intramuscularly, respectively. Conjugated vaccines are usually injected in the deltoid muscle except in patients under 12 months, in whom the anterolateral thigh is a preferential site. It is Contraindications include administering the vaccine intravenously and mixing it with other vaccines in the same syringe. Coadministration with other routinely used vaccines is generally safe and effective with separate sites of injection taken into consideration.[6][15]

Most recently, investigations regarding the safety and immunogenicity of the intradermal administration of meningococcal vaccines are in progress. As the skin (dermis) contains a much higher density of antigen-presenting cells (dendritic cells) than in muscles and subcutaneous regions, that would be sufficient to achieve an effective protective immune response. Since the lymphatic skin system is extensively prepared and drained into several plexus systems, it makes the transportation of these presenting dendritic cells very efficient. Consequently, the patient will need a lower dose of the vaccine to have the same immunogenic response.[17][18]

Administration Errors

Unusually, administration errors could occur due to healthcare providers' unfamiliarity with the new vaccines and their requirements for appropriate use. These errors rarely cause a serious safety problem. Additional vaccine doses may be necessary as the patient may remain unprotected in some situations, potentially leading to a local adverse reaction, additional cost, and loss of trust of the health care provider.[19]

Adverse Effects

Many surveillance and clinical studies continue to take place to better comprehend the safety, immunogenicity, and vaccine adverse effects.

According to these trials and international reporting systems like the Vaccine Adverse Event Reporting System, the Centers for Disease Control and Prevention, and the Food and Drug Administration, no significant adverse reactions have been reported. Most adverse events were typically mild and related to injection site administration, like erythema, swelling, and tenderness. Post-vaccination headache, dizziness, and fever have also been reported but less frequently. Syncope has also been reported, especially in adolescents.[6][19]

In some studies, the administration of multiple vaccine doses didn't increase reactogenicity, but the incidence of fever (not the grade of fever itself) was higher when the vaccine was given concomitantly with another vaccine.[10]

Other studies demonstrate a temporal association between the vaccine administration and the occurrence of Bell palsy. However, there needs to be more clinical research to understand whether this is a coincidental finding secondary to, due to co-administered vaccination or previous medical history predisposing to Bell palsy.[5]

Contraindications

Contraindications

Like other vaccines, the contraindications to the meningococcal vaccine include individuals with severe allergic reactions to any component of the vaccine. Vaccines containing diphtheria or tetanus toxoids are contraindicated in patients known to have severe allergic reactions to vaccines containing these toxoids (ex. MenACWY-TT conjugated to tetanus toxoid, MenACWY-DT conjugated to diphtheria toxoid, and MenACWY-CRM conjugated to the nontoxic mutant of diphtheria toxin).[12]

Currently, available licensed vaccines have an inactivated antigen, making them safe in patients with immune deficiency, but the response to the meningococcal vaccine will be suboptimal so that additional doses may be necessary.[12]

The Vaccine Adverse Event Reporting System (VAERS) system in the U.S. does not report any significant safety concerns in the mother and the fetus. Although if there are no available extensive studies or trials to show the safety and reactogenicity in this specific group of community, vaccine administration in pregnant and lactating mothers is not a contraindication.[19]

Other Prevention Strategies Including Antibiotic Prophylaxis 

Recommendations strongly advocate administering prophylactic antibiotics for people in close contact with patients who have invasive diseases like meningococcal meningitis. Individuals including household members, college dormitories, or those at direct exposure to the patient's oral secretions (by kissing, sharing food, or drinking utensils) should receive prophylaxis within 7-days before symptoms appear. Antibiotic prophylaxis should be initiated instantly, optimally within 24 hours of exposure identification. Prophylactic antibiotic regimens may include oral ciprofloxacin, ceftriaxone, rifampin, or azithromycin. In which effectiveness is estimated as 90% to 95%.[6]

Enhancing Healthcare Team Outcomes

Vaccination providers, including PSs, nurse practitioners, and pharmacists, commonly encounter patients who do not have adequate immunization documentation. Providers should only accept dated and written records as evidence of vaccination. If records are unavailable, these patients should have serologic testing to determine immunity and start on their age-appropriate vaccination schedule. 

On administering a vaccine, the provider should chart it in detail and add it to the patient's health record so that future providers can see the full vaccine picture. This practice applies to clinicians, nurses, and pharmacists.

Providers should administer vaccines as close to the recommended intervals as possible. It is essential to know the indications, doses, mode of administration, and contraindications of the meningococcal vaccine.

Misperceptions by healthcare providers result in missed opportunities to administer recommended vaccinations and should be avoided. Unusually, administration errors could occur due to healthcare providers' unfamiliarity with the new vaccines and their requirements for appropriate use. These errors rarely cause a serious safety problem. Additional vaccine doses may be necessary as the patient may remain unprotected in some situations, potentially leading to a local adverse reaction, additional cost, and loss of trust of the health care provider. 

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References

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Disclosure: Rawan Daraghma declares no relevant financial relationships with ineligible companies.

Disclosure: Amit Sapra declares no relevant financial relationships with ineligible companies.