Meningococcal Immunization Update: A New Conjugate Vaccine

With the significant decline in disease caused by Haemophilus influenzae type b and Streptococcus pneumoniae achieved through vaccination, Neisseria meningitidis has moved to the forefront. Its emergence as the most important cause of bacterial meningitis challenges the pediatrician to prevent and control this terrible disease. Meningococcal disease can be easily misdiagnosed. It may present with different clinical manifestations, and its signs and symptoms may mimic those of common viral illnesses, such as influenza. The onset and progression of meningococcal disease are rapid. Although the rate of disease is highest in infants, morbidity and mortality rates for this disease are highest in adolescents and young adults, despite the existence of effective therapies.¹

Here I discuss the expanding role of meningococcal vaccine and the potential advantages of the new conjugate formulation.

INCIDENCE AND CAUSES

An estimated 2500 to 3000 cases of invasive meningococcal disease are reported each year in the United States.² Rates of meningococcal disease decline after infancy and then increase during adolescence and early adulthood (Figure 1).¹ Recently, the total number of cases among adolescents and young adults has been on the rise in this country. Certain groups of adolescents and young adults--particularly first-year college students living in dormitories--are at increased risk for meningococcal disease.³

In the United States, N meningitidis serogroups B and C are the most important causes of meningococcal disease, although serogroup Y increasingly has been implicated as a cause of meningococcal infection, especially in adults aged 30 and older (Figure 2).¹ Serogroup Y is now responsible for about one third of all cases. Among persons aged 2 to 22 years, two thirds of meningococcal disease is attributable to serogroups C, Y, and W-135, whereas among infants, about half of all cases are caused by serogroup B. Disease caused by serogroup A is rare in this country.

ROLE OF MENINGOCOCCAL VACCINE

Although a safe and effective meningococcal polysaccharide vaccine that targets 4 of the most common N meningitidis serogroups (A, C, Y, W-135) has been available for more than 20 years in the United States, it has been underused. The polysaccharide vaccine has proved to be a reliable tool for preventing illness during outbreaks. Recently, it has played an expanded role for college students and for others who live communally.⁴ A serogroup B vaccine is not available because the group B polysaccharide cross-reacts with human brain glycoproteins and, therefore, has the potential to induce autoimmune antibodies.

Table 1 lists properties that have contributed to the limited use of the meningococcal polysaccharide vaccine. Key among these are the lack of a T-cell-dependent immune response and immune memory. Protection against meningococcal disease afforded by the polysaccharide vaccine is short-lived, and there is no booster effect. Furthermore, no reduction in nasopharyngeal carriage of N meningitidis has been documented; thus, there is no induction of herd immunity. Revaccination with meningococcal polysaccharide vaccine may diminish antibody responses to subsequent doses.^5,6 Finally, the polysaccharide vaccine is licensed only for use in children 2 years and older.

QUADRIVALENT MENINGOCOCCAL CONJUGATE VACCINE

The conjugate technology used to develop H influenzae and S pneumoniae vaccines has been effectively applied to the meningococcal serogroups. The resulting quadrivalent meningococcal glycoconjugate vaccine includes 4 µg each of A, C, Y, and W-135, covalently conjugated to 48 µg of diphtheria toxoid (Table 2). After extensive clinical evaluation in the United States, the vaccine was licensed by the FDA in January 2005 for children and adults aged 11 to 55 years.

The meningococcal conjugate vaccine overcomes the shortcomings of the polysaccharide formulation. Potential advantages include both B-cell-dependent and T-cell-dependent immune responses, induction of immunologic memory and booster effects, long-term protection, reduction of nasopharyngeal carriage of N meningitidis, and production of herd immunity. Meningococcal conjugate vaccines can also overcome the immunologic hyporesponsiveness associated with the polysaccharide vaccine.⁷

EFFICACY AND SAFETY

Large US studies have compared the meningococcal polysaccharide and conjugate vaccines in children aged 2 to 10 years, in children and adolescents aged 11 to 18 years, and in adults up to age 55 years.

In comparative trials, children who received the conjugate vaccine consistently had 4-fold increases in antibody titers and significantly higher overall antibody titers 28 days after vaccination than children who received the polysaccharide vaccine.⁸ Notably, the children who received the conjugate vaccine also had a better persistence of response for all meningococcal serogroups 6 months after vaccination. An application to the FDA for licensure of the meningococcal conjugate vaccine for children aged 2 to 10 years was submitted in March 2005.

In adolescents who received the conjugate vaccine, seroconversion rates exceeded 98% for all 4 meningococcal serogroups after vaccination (Figure 3). High levels of anti-meningococcal antibody were noted in adolescents who received the conjugate vaccine concomitantly with tetanus and diphtheria toxoids (Td) or 1 month later (thereby demonstrating the acceptability of concomitant administration, if desired). For meningococcal serogroups C, Y, and W-135, more adolescents achieved a 4-fold or greater increase in the antibody titer 1 month after vaccination when Td and the meningococcal conjugate vaccine were given together, and the booster response to tetanus and diphtheria antigens was optimum.

A strong safety profile emerged from clinical studies of the meningococcal conjugate vaccine in all groups studied.^8,9 Overall, systemic reactions associated with the polysaccharide and conjugate vaccines were similar in all groups and were generally mild and of short duration (Table 3).

There were more frequent reports of local reactions in recipients of the meningococcal conjugate vaccine than in recipients of the polysaccharide vaccine. The most common complaint was mild pain of short duration at the injection site. The rate of local reactions reported with the meningococcal conjugate vaccine was comparable to that of the Td vaccine.

EXPANDING ROLE OF MENINGOCOCCAL CONJUGATE VACCINE

With the licensure of the quadrivalent meningococcal conjugate vaccine, the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics Committee on Infectious Diseases (the Red Book Committee) have recently issued their recommendations. This new vaccine was added to the immunization schedule for use in all adolescents (universal use). The targeted groups for administration include children aged 11 to 12 years, adolescents aged 14 to 15 years (those about to enter high school), and young adults about to enter college.

The recommendations for universal use of this vaccine were based, in part, on a meningococcal conjugate C vaccination program in the United Kingdom. In that program, those considered at highest risk--adolescents aged 15 to 17 years--were targeted first, followed by infants. Vaccine was offered to all other children younger than 18 years in a catch-up campaign.¹⁰

During the first 2 years of the UK immunization program (1999 to 2001), an overall reduction of 86.7% was observed in the incidence of serogroup C invasive disease in the targeted age groups, along with a decline in deaths from 67 to 5.¹¹ In the unvaccinated population, the attack rate for invasive meningococ- cal serogroup C disease was reduced by 67%, which confirmed that vaccination produced a herd-immunity effect.¹²

Because meningococcal disease and its sequelae are of such consequence and of great concern to parents, having the new meningococcal conjugate vaccine to help prevent this disease is a most welcome development. The recommendations of the ACIP and the Red Book Committee for universal use in adolescents will help guide us in offering this important new vaccine to our patients.

References:

REFERENCES:

1. Rosenstein NE, Perkins BA, Stephens DS, et al. The changing epidemiology of meningococcal disease in the United States, 1992-1996.

J Infect Dis.

1999;180:1894-1901.
2. Rosenstein NE, Perkins BA. Update on

Hae- mophilus influenzae

serotype b and meningococcal vaccines.

Pediatr Clin North Am.

2000;47:337-352.
3. Bruce MG, Rosenstein NE, Capparella JM, et al. Risk factors for meningococcal disease in college students.

JAMA

. 2001;286:688-693.
4. American Academy of Pediatrics. Committee on Infectious Diseases. Meningococcal disease prevention and control strategies for practice-based physicians (addendum: recommendations for college students).

Pediatrics

. 2000;106:1500-1504.
5. Granoff DM, Gupta RK, Belshe RB, Anderson EL. Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination.

J Infect Dis.

1998;178:870-874.
6. MacLennan J, Obaro S, Deeks J, et al. Immunologic memory 5 years after meningococcal A/C conjugate vaccination in infancy.

J Infect Dis

. 2001;183:97-104.
7. Richmond P, Kaczmarski E, Borrow R, et al. Meningococcal C polysaccharide vaccine induces immunologic hyporesponsiveness in adults that is overcome by meningococcal C conjugate vaccine.

J Infect Dis

. 2000;181:761-764.
8. Pichichero M, Casey J, Blatter M, et al. Comparative trial of the safety and immunogenicity of quadrivalent (A, C, Y, W-135) meningococcal polysaccharide-diphtheria conjugate vaccine versus quadrivalent polysaccharide vaccine in two- to ten-year-old children.

Pediatr Infect Dis J.

2005;24:57-62.
9. Keyserling H, Papa T, Bybel M. Age related immune response to meningococcal vaccines. In: 21st Annual Conference on Pediatric Infectious Diseases. May 3-6, 2003, Seattle. Alexandria, Va: Pediatric Infectious Diseases Society; 2003. Abstract 6.
10. Miller E, Salisbury D, Ramsay M. Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story.

Vaccine

. 2001;20: S58-S67.
11. Balmer P, Borrow R, Miller E. Impact of meningococcal C conjugate vaccine in the UK.

J Med Microbiol

. 2002;51:717-722.
12. Ramsay ME, Andrews NJ, Trotter CL, et al. Herd immunity from meningococcal serogroup C conjugate vaccination in England: database analysis.

BMJ

. 2003;326:365-366.