Prevention of Meningococcal Disease

Volume VIII, Number 4 | July/August 2005
Phil Chung, Pharm.D.

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Introduction

Bacterial meningitis is most commonly caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis (meningococcus), accounting for more than 80% of all cases.¹ Administration of conjugate vaccines against S. pneumoniae and H. influenzae have dramatically reduced the incidence of meningitis caused by these pathogens.² As a result, N. meningitidis is now the leading cause of bacterial meningitis in the United States.² In addition to causing meningitis, meningococcus is also the causative agent of sepsis (meningococcemia), bacteremia, respiratory infections, and focal infections, known collectively as meningococcal disease.^3,4 The Centers for Disease Control and Prevention (CDC) have previously recommended the use of a tetravalent polysaccharide vaccine (Menomune^®, Aventis Pasteur) for individuals at increased risk of contracting the disease and for control of meningococcal disease outbreaks.⁵ The recent approval of a new tetravalent conjugate vaccine (Menactra™, Aventis Pasteur) by the Food and Drug Administration (FDA) in January 2005 prompted the Advisory Committee on Immunization Practices (ACIP) to update its recommendations on prevention and control of meningococcal disease in May 2005.²

Bacteriology

N. meningitidis are gram-negative diplococci. These organisms produce a polysaccharide capsule which is the basis for serotype grouping and components of currently licensed vaccines.^3,4 Meningococci can be separated by seroagglutination into at least 13 serotypes including A, B, C, Y, L, and W-135.⁴ Meningococci serotypes A and C, for which vaccines are available, and serotype B, which is poorly immunogenic, are the most common causes of meningococcal disease.³ Serotype switching between meningococcal serotypes B and C, made possible through the exchange of genetic material responsible for capsule production, has been demonstrated.⁴ With the widespread use of serotype-specific meningococcal vaccines (serotypes A, C, Y, and W-135 but not serotype B), capsule switching may become an important cause of virulence worldwide.⁴

Humans are the only natural reservoir for meningococci which are transmitted to the nasopharyngeal surface through direct contact with secretions or aerosolized secretions from asymptomatic carriers or patients with meningococcal disease.^2-4 Once transmitted onto the nasopharyngeal surface, meningococci can overcome host mucosal defenses through unknown mechanisms and attach to non-ciliated cells in the airway where they proliferate.^3,4

Approximately 5 to 10% of individuals are asymptomatic carriers of N. meningitidis. In most individuals, carriage of the organisms elicits protective immunity.^3,4 However, in a small number of individuals, N. meningitidis penetrates through the mucosal surface and gains entry into the bloodstream, causing meningococcal disease which can include meningitis.³

Epidemiology

Meningococcal disease occurs throughout the year, but the highest incidence is usually observed during winter and spring.⁶ According to published statistics, a total of 1,756 cases of meningococcal disease were reported to the CDC in 2003.⁷ The estimated number of cases of meningococcal disease has remained relatively constant at 1,400-2,800 cases annually in the United States.² This number translates to an attack rate of 0.5-1.1/100,000 people.² Between 1991 and 2000, the incidence of meningococcal disease was highest among infants <1 year of age (9.2/100,000).² The rate of meningococcal disease was also higher among those 11 to 19 years old (1.2/100,000) compared to the general population.² For those <1 year of age, more than 50% of their meningococcal disease was caused by serotype B for which no commercially licensed vaccine is available.⁶ However, for those ≥11 years old, the most common causes of meningococcal disease were serotypes C, Y, or W-135.²

Several studies have specifically examined the incidence and risk of meningococcal disease in college students in the United States.^8-10 These studies suggest that the incidence of meningococcal disease among college students (0.7-1.7/100,000) and age-matched individuals in the general population (1.4/100,000) is comparable.^8-10 However, college students living in dormitories were more likely to have meningococcal disease compared to those who were not, with the rates of meningococcal disease highest among freshmen living in dormitories (5.1/100,000).^9,10 Based on these available data, ACIP and the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) concluded that college students, especially those living in dormitories, are at increased risk for meningococcal disease compared to the general population.^2,11

Additional risk factors for acquiring meningococcal disease include functional or anatomical asplenia, deficiencies in terminal complement pathway, antecedent viral infection, household crowding, chronic underlying illness, and active or passive smoking.^2,3

Despite the availability of numerous effective antimicrobial agents, the fatality rate associated with meningococcal disease remains high at 10 to 14%.² Survivors of meningococcal disease often suffer from a number of morbidities including limb amputation, hearing loss, and other neurologic disabilities.²

Clinical Manifestations

A number of clinical signs and symptoms are associated with meningococcal disease. Presentation of the disease can vary and ranges from fever, bacteremia, and sepsis with death occurring within hours after presentation of initial symptoms.⁴ Symptoms associated with meningococcal meningitis, which occurs in approximately 50% of infected patients, are similar to those caused by other bacterial pathogens (e.g., sudden onset of headache, stiff neck, and fever accompanied by nausea, vomiting, and photophobia).³ Infants usually present with more nonspecific symptoms and stiffness of the neck is usually absent.³ Meningococcemia occurs in 5% to 20% of patients.³ These patients can present with abrupt onset of fever and petechial rash of 1 to 2 mm in diameter on the trunk and lower extremities and is often associated with hypotension, acute adrenal hemorrhage, and multiorgan failure.^3,4 Meningococcal disease can be manifested as pneumonia in another 5 to 15% of patients.³ Other syndromes associated with meningococcal disease may include arthritis, conjunctivitis, otitis media, urethritis, and pericarditis.³

Treatment for Meningococcal Disease

The availability of antibiotics for treatment of meningococcal disease dramatically reduces mortality due to N. meningitidis. Because of the risks of severe morbidities and death, antimicrobial therapy should be initiated promptly once meningococcal disease is suspected.³ Empiric antimicrobial therapy should be directed at the most likely pathogens based on the patient’s age and local epidemiologic and susceptibility data. In the case of meningococcal meningitis, empiric antibiotic therapy using aminoglycosides, ampicillin, cefotaxime, ceftriaxone, and/or vancomycin should be initiated prior to obtaining culture and sensitivity results (Table 1).^1,12,13 If the causative organism is confirmed to be N. meningitidis, directed antimicrobial therapy should be initiated. Sensitivity of meningococci to penicillin remains high in the United States; therefore, penicillin should be the treatment of choice.^3,4 Acceptable alternatives to penicillin include cefotaxime and ceftriaxone; chloramphenicol can be used in patients with severe anaphylaxis to penicillins.^1,3,13 Therapy for meningococcal meningitis should be continued for a total of 7 to 14 days based on clinical response and other comorbidities.⁴ The use of corticosteroids in pediatric patients as adjunctive therapy has been shown to decrease neurological sequelae in H. influenzae meningitis.¹³ However, the benefit of steroid use in meningococcal meningitis is less well-defined.¹³ Table 2 lists the dosages of antimicrobial agents effective in meningococcal disease.

Table 1. Choice of empiric therapy for suspected bacterial meningitis¹³

* Common pathogens include Escherichia coli, Klebsiella spp., Enterobacter spp.
† Use should be based on local incidence of penicillin-resistant S. pneumoniae and until susceptibility to ceftriaxone or cefotaxime is known.

Table 2. Antibiotic dosages for treatment of meningococcal disease^4,13

* Restricted for use in infants <6 months of age for therapeutic or empiric treatment of sepsis or meningitis at The Cleveland Clinic Foundation.
† Doses higher than 1 g q24h are restricted to treatment of endocarditis and meningitis at The Cleveland Clinic Foundation.

Chemoprophylaxis against Meningococcal Disease

Chemoprophylaxis is the primary method to prevent transmission of meningococcal disease from infected individuals to close contacts.² Close contacts are defined as household members, child-care center contacts, and anyone exposed to the patient’s oral secretions.² The attack rate for these close contacts is estimated to be 4 cases/1,000 persons exposed, which is more than 500 times that of the general population.² Since the risk of contracting secondary disease is greatest immediately after onset of symptoms in the index case, chemoprophylaxis should be given within 24 hours after identification of the index case.² Administration of chemoprophylaxis is probably of limited value if 14 or more days have elapsed after onset of symptoms in the index case.² The CDC recommended antibiotics and dosing regimens for chemoprophylaxis are listed in Table 3.

Table 3. Recommendations for chemoprophylaxis against meningococcal disease

* Not usually recommended for persons <18 years or in pregnant and lactating women due to cartilage damage in immature laboratory animals.
† Not recommended for pregnant women due to teratogenicity in laboratory animals.

Immunoprophylaxis against Meningococcal Disease

While chemoprophylaxis is an efficacious and immediate measure for post-exposure prophylaxis and for prevention of meningococcal disease caused by N. meningitidis serotype B, immunoprophylaxis is more appropriate for reducing future risk of contracting meningococcal disease. Two vaccines for prevention of meningococcal disease are currently available in the United States. Both of these vaccines are approved for active immunization against invasive meningococcal disease caused by N. meningitidis serotypes A, C, Y and W-135. However, these vaccines differ in composition, route of administration, target patient populations, and use in combination with other vaccines.

Meningococcal tetravalent polysaccharide vaccine: The meningococcal polysaccharide vaccine for serotypes A, C, Y, and W-135 (Menomune^®) contains 50 mcg of polysaccharide antigens from each of the four N. meningitidis serotypes per dose. The vaccine is approved for use in individuals ≥2 years old. It is also approved for use in infants ≥3 months old as short-term protection against N. meningitidis serotype A.¹⁴

Menomune^® is administered subcutaneously as a single injection of 0.5 ml.¹⁴ Repeated administration 3 months after the initial dose is recommended in children between 3-18 months of age for short-term protection against N. meningitidis serotype A (Table 4).² In addition, revaccination may be indicated in children who were first vaccinated at <4 years of age.¹⁴ These children should be considered for revaccination 2 or 3 years after initial vaccination especially if they remain at high risk for infection (e.g., residence in hyperendemic areas).¹⁴ The vaccine should not be given in combination with whole-cell pertussis or whole-cell typhoid vaccines due to combined endotoxin content which may increase the frequency and severity of adverse events.^14,15 Other vaccines can be given concomitantly at separate sites using separate syringes.¹⁵ Severe reactions to the vaccine are rare; the incidence of systemic reactions such as urticaria, wheezing, and rash is reported to be 0-0.1/100,000 vaccine doses.² Adverse reactions are usually mild and transient consisting of local reactions including pain, tenderness, and/or erythema at the injection site lasting ≤2 days, and transient fever in ≤2% of young children.^2,14

Table 4. Recommendations for meningococcal vaccination in previously unvaccinated persons²

* Groups at increased risk include college freshman living in dormitories, travels to areas where N. meningitidis is hyperendemic or epidemic, microbiologists routinely exposed to isolates of N. meningitidis, certain populations experiencing outbreaks of meningococcal disease, military recruits, persons with terminal complement deficiencies, and persons with functional or anatomical asplenia.
† Two doses of meningococcal polysaccharide vaccine (Menomune^®) given 3 months apart can be given to children 3-18 months of age to elicit short-term protection against N. meningitidis serotype A disease. A single dose should be considered in infants 19-23 months of age.
‡ Meningococcal conjugate vaccine.

The efficacies of meningococcal vaccines containing serotype A and C polysaccharides are well established. Efficacy, defined by an increase in bactericidal titers or the number of infections prevented, ≥85% has been observed in school-aged children and adults who received the serotype A and C vaccine. Serotype Y and W-135 polysaccharides have been shown to produce bactericidal antibodies in children >2 years of age and adults. Appropriate antibody response was also observed in high-risk populations with altered impaired immunologic functions, such as individuals with asplenia or terminal complement deficiencies, after vaccination with the tetravalent polysaccharide meningococcal vaccine.²

Antibodies against serotype A and C polysaccharides decline substantially in both children and adults following vaccination.² Antibody levels remain detectable in adults for up to 10 years while those in infants and children decrease markedly within 3 years after a single dose.² Even though clinical efficacy after a single dose of vaccine is likely to persist for 3 years or more among school-aged children and adults, clinical protection against N. meningitidis serotype A in children <5 years of age might decline substantially during the same period.²

Meningococcal Tetravalent Conjugate Vaccine

Meningococcal tetravalent conjugate vaccine for serotypes A, C, Y, and W-135 (Menactra™) contains 4 mcg of capsular polysaccharides from N. meningitidis serotypes A, C, Y, and W-135 conjugated to 48 mcg of diphtheria toxoid per dose. Menactra™ is approved for use in adolescents and adults 11-55 years of age.¹⁶

Menactra™ is administered as a single intramuscular injection of 0.5 ml.¹⁶ Although Menactra™ is conjugated to diphtheria toxoid, it is not indicated for immunization against diphtheria. A specific guideline for booster vaccination is not available at this time even though booster vaccination has been studied in one controlled trial. The incidence of serious adverse events (1.3%) was comparable between Menactra™ and Menomune^®. The most commonly reported adverse reactions were local pain, headache, and fatigue. Local reactions (e.g., swelling, induration, and pain at injection site) were more frequent after Menactra™ compared to Menomune^® with the exception of redness at the injection site for adults.¹⁶

Menactra™ was developed in response to several limitations associated with Menomune^®. Bacterial capsular polysaccharides such as those found in Menomune^® elicit a T-cell-independent immune response that is neither long-lasting nor characterized by an anamnestic response. Antibody response elicited by serotype A polysaccharide declines rapidly in both children and adults after vaccination whereas serotype C polysaccharide is poorly immunogenic in children ≤2 years of age. In addition, Menomune^® does not cause sustained reduction in nasal carriage of N. meningitidis to provide herd immunity. Furthermore, repeated vaccination of serotype A and C polysaccharides may reduce the immunologic response to these antigens.² Conjugation of meningococcal capsular polysaccharides to diphtheria toxoid, which contains T-cell epitopes, changes the immune response toward these antigens from T-cell independent to T-cell dependent. This strategy is similar to that used in conjugated vaccines for H. influenzae type b and S. pneumoniae to elicit a substantial primary response and strong immunologic memory. In addition, modification of the meningococcal capsular antigens should reduce asymptomatic carriage of N. meningitidis.²

The efficacy of Menactra™ was assessed in two comparative, randomized, active-controlled clinical trials in adolescents (11-18 years old) and adults (18-55 years old). Study subjects received a single vaccination of Menactra™ or Menomune^®. Proportions of study participants able to achieve the primary immunologic measure of a 4-fold or greater rise in serotype-specific anti-capsular bactericidal antibody were compared between vaccine groups. In the study involving adolescents, the proportion of participants able to achieve the primary immunologic measure 28 days after vaccination was similar between Menactra™ (81.8 to 96.7%) and Menomune^® (80.1 to 95.3%) for all four serotypes.^2,16-18 In adult vaccinees, although seroconversion rates for all four serotypes were higher for the Menomune^® group (79.4 to 94.4%) compared to the Menactra™ group (73.5 to 89.4%) 28 days after vaccination, criteria for indicating noninferiority (i.e., 10% margin and a one-sided Type I error rate of 0.05) were still achieved. Seroconversion rates were highest for serotype W-135 and lowest for serotype Y for both groups in both studies.^2,16-18

In another study aimed to assess persistence of antibodies and response to booster vaccine, Menactra™ was given to subjects who received Menactra™ or Menomune^® and age-matched vaccine-naïve subjects. Subjects vaccinated with Menactra™ 3 years prior to the booster vaccine had a higher geometric mean titer of serum bactericidal activity using baby rabbit complement (rSBA GMT) compared to those vaccinated with Menomune^®. After revaccination with Menactra™, higher rSBA GMT was observed in subjects initially given Menactra™ compared to vaccine-naïve subjects 8 and 28 days after vaccination with the exception of serotype A. Menactra™-primed subjects also had higher rSBA GMT compared to Menomune^®-primed subjects after revaccination with Menactra™.^2,16-18

Two other studies compared the immunologic response of Menactra™ given alone and concomitantly or sequentially with tetanus and diphtheria toxoid (Td) or typhoid Vi polysaccharide vaccines. No difference in overall immunologic response was observed when Menactra™ was given alone, concomitantly with Td or typhoid Vi polysaccharide vaccine, or sequentially with Td. In addition, Menactra™ did not affect the immunogenicity of the other vaccines.^2,16,17

The results of these studies suggest that Menactra™ is as safe and effective as Menomune^® in increasing serum bactericidal titers against N. meningitidis serotypes A, C, Y, and W-135. In addition, vaccination with Menactra™ may confer longer immunity against N. meningitidis compared to Menomune^® as suggested by the higher antibody titers 3 years after vaccination with Menactra™.

Recommendations for Meningococcal Vaccination: With the recent approval of Menactra™, ACIP recommends routine vaccination of individuals 11-12 years of age at the pre-adolescent healthcare visit using Menactra™. For adolescents not previously vaccinated with Menactra™, ACIP recommends vaccination prior to high school entry. Routine vaccination using Menactra™ in all adolescents starting at 11 years of age is the goal by 2008. Routine vaccination against meningococcal disease is also recommended for individuals at higher risk of acquiring the disease (e.g., freshmen living in dormitories or individuals with functional or anatomical asplenia). Beginning July 1, 2005, the Ohio Revised Code prohibits colleges or universities from allowing students to live in on-campus housing unless each student discloses whether he has been vaccinated against meningococcal disease, as well as hepatitis B.¹⁹ Menactra™ is preferred for persons 11-55 years old. Menomune^® should be used in children 2-10 years old and adults >55 years old. Table 4 summarizes recommendations from the ACIP for meningococcal vaccination.¹⁶ The average wholesale price for a single dose of the Menactra™ and Menomune^® are $102.50 and $107.63, respectively.²⁰

Conclusion

The newly approved meningococcal tetravalent conjugate vaccine (Menactra™) has been shown to be safe and effective in preventing meningococcal disease in persons 11-55 years old. This vaccine has comparable seroconversion rates to the meningococcal tetravalent polysaccharide vaccine (Menomune^®). In addition, the immunologic response elicited by Menactra™ appears to last longer than that induced by Menomune^®. The recent addition of Menactra™ to the Formulary of The Cleveland Clinic Foundation reflects the change in current vaccination strategies against meningococcal disease recommended by the ACIP.

Addendum

As of October 4, 2005, five cases of Guillain-Barre Syndrome (GBS) associated with the administration of meningococcal conjugate vaccine (Menactra®) have been reported to the Vaccine Adverse Event Reporting System (VAERS). These cases occurred between June 10, 2005, and July 25, 2005, in five individuals 17 to 18 years of age who had received vaccine from one of four different lots. In one of these cases, the involved individual had a previous history of GBS after receiving childhood vaccinations at ages 2 and 5 years. Symptoms in these cases included weakness of extremities, loss of deep tendon reflex, facial weakness, headache, neck and back pain. All five individuals were initially hospitalized and treated with intravenous immunoglobulin (IVIG) and/or plasmapheresis. These individuals recovered after treatment without further complications. The FDA and CDC are actively investigating the situation and alerting heath care professionals.²¹

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References

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