CDC Releases New Recommendations for Meningococcal Vaccine
Abstract & Commentary
Synopsis: The Advisory Committee on Immunization Practices (ACIP) to the Centers for Disease Control (CDC) earlier this year for the first time recommended routine immunization of children 11-12 years of age. Also, in January, Aventis Pasteur received FDA approval to market a quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine.
Source: Centers for Disease Control Advisory Committee on Immunization Practices. February 10, 2005. www.cdc.gov/nip/vaccine/meningitis/mcv4/mcv4_acip.htm
On February 10, 2005, the CDC’s Advisory Committee on Immunization Practices recommended routine meningococcal immunization of all children between ages 11 and 12, with catch up immunization targeted to teens entering high school and college freshmen living in dormitories. On January 14, 2005, the FDA’s Center for Biologics Evaluation and Research (CBER) approved Aventis Pasteur’s new meningococcal quadrivalent (Groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine (Menactra) for active immunization of adolescents and adults 11-55 years of age. Controlled, comparative trials of Menactra vs the gold standard quadrivalent polysaccharide vaccine (Menomune) showed equivalent levels of efficacy as assessed by seroconversion in adolescents 11-18 years of age and in adults 18-55 years old.
Comment by Dean Winslow, MD, FACP
Invasive disease due to Neisseria meningitidis remains a major cause of morbidity and mortality in both the developed and the developing world. Despite effective bactericidal antibiotics and modern supportive care given in our ICUs, the mortality rate has remained about 10%.1-3 Case fatality rates due to fulminant meningococcal sepsis, approach 40%1, and about 10-20% of survivors are left with serious sequelae.1 Five (serogroups A, B, C, Y, and W-135) of the 13 serogroups of Neisseria meningitidis account for the majority of cases of invasive disease/bacteremia. Meningococcal disease is seen in patients of all ages, with peaks in children less than 1 year of age (mainly due to Group B strains) and in early adolescence and early adulthood. From 1989 to 2002, cases due to serogroup Y have increased from 2 to 29%, Serogroup B cases have decreased from 46 to 24%, and serogroup C from 45 to 34% in the United States.4 While uncommon in the United States, serogroup A is the predominant cause of epidemic meningoccal disease in Africa and Asia.1 Serogroup W-135 was the cause of a recent outbreak of meningoccal disease in Islamic pilgrims returning from the Hajj in Saudi Arabia5, and is the likely serogroup responsible for an ongoing epidemic in North Darfur, Sudan.6
Prior to the licensure of Menactra, several different monovalent and quadrivalent meningococcal polysaccharide vaccines had been available. These polysaccharide vaccines generally produced high rates of seroconversion in older children and healthy adults, as demonstrated by development of serum bactericidal antibody titers, and showed clinical efficacy in the setting of outbreaks, generally against serogroups A and C. Unfortunately, the humoral immune response tends to be short-lived, and the immune response in young children is generally suboptimal. Menactra consists of polysaccharides extracted from N. meningitidis cells, which are purified and then covalently linked to diphtheria toxoid. In theory, as with immunization with Haemophilus influenzae type B (HiB), where thepolysaccharide is covalently linked to a protein carrier such as a nontoxic diphtheria toxin or tetanus toxoid, the immunogen is converted from a T-cell independent to a T cell dependent antigen. This is felt to be the mechanism responsible for the greater immunogenicity of HiB conjugate vs simple PRP polysaccharide vaccine in young children.7
Aventis Pasteur conducted 2 randomized, controlled clinical trials of Menactra vs the active control, Menomune. These studies used as a surrogate marker for clinical efficacy, the percentage of patients by serogroup who achieved antibody titers which rose by greater than or equal to 4-fold from baseline by serum bactericidal assay using baby rabbit complement (SBA-BR). In these 2 studies of patients 11-18 and 18-55 years of age,8 SBA titers to all 4 of the vaccine serogroups were equivalent between the Menactra and Menomune arms. In adolescents, adverse effects of redness, swelling, induration, pain, headache, fatigue, malaise, arthralgia, anorexia, chills, and fever were statistically more common in the Menactra group. In adults, only swelling, induration, pain, arthralgia, chills, and fever were more common in the Menactra group.
From the data presented in the 2 clinical trials, it does not appear that for the population studied in the 2 pharma-sponsored clinical trials, that Menactra shows any advantage in either efficacy or tolerability over the older polysaccharide meningococcal vaccine. However, according to the manufacturer of Menactra, preliminary data from ongoing clinical trials suggest that individuals immunized with the new conjugate vaccine, maintain bactericidal antibody titers much longer than with the polysaccharide vaccine. In addition, Aventis Pasteur filed a supplemental BLA with CBER in February which demonstrates efficacy of Menactra in patients from 2-12 years of age, and improves on the approximately 58% SBA seroconversion rate with serogroup C and 72% rate with serogroup A in children who were administered Menomune in earlier trials.9
Prior to the FDAs action in January and the CDCs recommendations in February, meningococcal vaccination had been recommended for only select groups of individuals felt to be at especially high risk for meningococcal disease, including patients deficient in late complement components or those with asplenia, laboratory workers who frequently handled meningococci, travelers to endemic areas, and military recruits. The previously available unconjugated quadrivalent polysaccharide vaccine was officially labeled as indicated in only these indications. The new CDC recommendations represent a significant departure from these earlier, more limited populations targeted for immunization to prevent invasive meningococcal disease. It is hoped and anticipated that by targeting preadolescents and adolescents, much of the invasive disease occurring shortly after enteringhigh school or university may be eliminated. Meanwhile, the poor immunogenic properties of serogroup B Neisseria meningitidis remain a barrier to eliminating this large cause of endemic invasive meningococcal disease, especially in children less than 2 years of age.10 While the licensure of Menactra represents a small advance, clearly more research needs to be done on meningococcal vaccines to further reduce the scourge of this disease.
References
- Rosenstein, NE, et al. Meningococcal Disease. N Engl J Med. 2001;344:1378-1388.
- World Health Organization (WHO). Group A and C Meningococcal Vaccines. Wkly Epidemiol Rec. 1999;74:297-303.
- Sorensen HT, et al. Outcome of Pre-hospital Treatment of Meningococcal Disease. J Clin Epidemiol. 1998;51:717-721.
- CDC. Active Bacterial Core Surveillance (ABC’s) Report. Emerging Infections Program Network, Neisseria meningitidis. www.cdc.gov/ncidod/dbmd/abcs/survreports.htm
- Decosas, J, et al. Chronicle of an Outbreak Foretold: Meningococcal Meningitis W135 in Burkina Faso. Lancet. 2002;2:763-765.
- WHO Outbreak Reports. Meningococcal Disease in Sudan. www.who.int/csr/don/2005_04_06a/en/
- Greenburg, DP, et al. Enhanced Antibody Responses in Infants Given Different Sequences of Heterogenous Haemophilus influenzae Type B Conjugate Vaccines. J Pediatr. 1995;126:206-211.
- Package Insert. Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine Menactra-TM. Aventis Pasteur.
- Gilmet, G. (personal communication). April 5, 2005
- Wyle, FA, et al. Immunologic Response of Man to Group B Meningococcal Polysaccharide Vaccines. J Infect Dis. 1972;126:514-522.
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