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PRIORITY PRESS - 88th Canadian Paediatric Society Annual Conference

Québec City, Québec / June 15-18, 2011

Québec City - Five serogroups cause the majority of clinical meningococcal disease worldwide; 4 of these are preventable through both monovalent and quadrivalent vaccination. Meningococcal disease researchers have long sought to create a vaccine against the last remaining serogroup, which has proven to be an overwhelming challenge. Novel technology has now made possible the development of a candidate vaccine against serogroup B disease. Studies to date show the vaccine invokes robust immunological responses against 4 specific antigens contained in the vaccine across a variety of age groups, including infants, the group at highest risk for serogroup B meningococcal disease. With an acceptable safety profile, physicians are poised to more adequately manage meningococcal disease caused by all 5 serogroups, an important step forward in child and adolescent health.

Medical Editor: Dr. Julie Frère, Montréal, Québec

According to investigators, Neisseria meningitidis is most prevalent in late winter/early spring. The highest incidence is in children under the age of 1 year with a second peak in adolescence. The organism has many serogroups but only 5 cause the majority of clinical disease worldwide—A, B, C, Y and W-135, as noted by Julie Bettinger, PhD, Assistant Professor of Paediatrics, Vaccine Evaluation Centre, University of British Columbia, Vancouver. In Canada, serogroups A and W-135 are largely travel-associated while serogroups B and C disease have been the major cause of meningococcal disease in the Americas and in Europe. In the 1990s, public health authorities in the US detected a significant increase in serogroup Y disease; however, “we did not see a similar increase here in Canada,” Dr. Bettinger told CPS delegates.

Meningococcal Disease by the Numbers

In Canada, the incidence of meningococcal disease in 2006 was low at 0.42 cases/100,000, but 54% of all meningococcal disease across Canada was caused by serogroup B at that time. “This does vary by province,” Dr. Bettinger noted, “especially in Québec, where over 80% of the disease is caused by serogroup B.” In fact, Québec public health officials reported at the European Society of Paediatric Infectious Diseases (ESPID) in June 2011 that over the past 3 years, 97% of all meningococcal disease seen in residents between 0 and 19 years of age was caused by serogroup B. “It is very important to look at the local epidemiology,” Dr. Bettinger observed.

In contrast, serogroup C now accounts for less than 20% of meningococcal disease in Canada, a reflection of the decrease in serogroup C disease following the initiation of the conjugate C (MenC) immunization program in Québec in 2001 and in select provinces starting in 2002. Herd immunity from widespread conjugate MenC immunization in infants likely has extended to unvaccinated adults, further contributing to the decline in serogroup C disease in the country. Serogroup Y accounts for about 17% in Canada and W-135 accounts for most of the rest.

Serogroup B disease still disproportionately affects children <1 year but it is also highly prevalent in children between 1 and 4 years of age. There is also a second peak in serogroup B disease in adolescents between the ages of 15 and 19 and young adults between 20 and 24 years of age, as Dr. Bettinger pointed out. The overall case-fatality rate for all serogroups is 12%; interestingly, “as people age, they have a greater risk of dying of the infection,” Dr. Bettinger noted.

Case-fatality rates do vary by serogroup, at 13% for serogroup C, 2.5% for serogroup Y and 5% for W-135. Indeed, it was due in large part to the burden of disease associated with serogroup C that the immunization programs were implemented in Canada.

Three monovalent vaccines are available in Canada to protect against serogroup C disease and 2 quadrivalent vaccines protect against serogroups A, C, Y and W-135: the MENACWY-D vaccine (Menactra) is licensed for subjects between 2 and 55 years of age, and the MENACWY-CRM vaccine (Menveo) is also licensed for use in subjects between the ages of 2 and 55. Currently in Canada, there is no vaccine approved to protect against serogroup B disease.

Vaccine Against Serogroup B Disease Elusive

The reason why researchers have been unable to develop a vaccine against the most prevalent serogroup causing meningococcal disease in Canada is because the group B polysaccharide capsule contains auto-antigens and is therefore poorly immunogenic. “Outer membrane vesicle (OMV) vaccines have been made against N. meningitidis,” noted Dr. Marc Lebel, Associate Professor of Paediatrics, CHU-Sainte Justine, Université de Montréal, Québec, “but they are tailor-made to specific B clones for a specific epidemic and they are not effective in other outbreaks.”

First described in 2000, the technique of “reverse vaccinology” was used to identify a large number of genes from the N. meningitidis genome that encode for surface antigens. Out of an initially large number of antigens, 3 were selected as being the most immunogenic: Neisserial adhesin A (NadA), factor-H-binding protein (fHBP) and Neisserial heparin-binding antigen (NHBA). A specific OMV against a hypervirulent outbreak strain of meningococcal disease in New Zealand was added to the candidate vaccine to provide additional protection and immunogenicity. This vaccine, the 4CMenB vaccine, has now been extensively evaluated in clinical trials of infants, toddlers and adolescents (and even some adult laboratory workers at high risk for meningococcal B disease).

Vaccine Efficacy and Reactogenicity

The efficacy of the 4CMenB vaccine, especially in young infants at highest risk for serogroup B disease, has been extremely promising to date. Noting that an antibody titre =1:5 is a marker of protection against serogroup B disease, Dr. Lebel reviewed results from a phase III study in infants who received the vaccine at 2, 4, 6 and 12 months. Post-primary series, the vaccine was 100% seroprotective against both the fHBP and the NadA antigens, and 84% seroprotective against PorA 1.4, the OMV component of the vaccine.

Antibody titres to the various vaccine antigens do wane after 6 months, as Dr. Lebel told CPS delegates. Following a booster dose at 12 months, the 4CMenB vaccine was between 95% and 100% seroprotective against vaccine antigens, Dr. Lebel observed. The vaccine is equally effective in older infants between the ages of 6 and 8 months. In a separate 3-dose study in older infants, the vaccine achieved 100% seroprotective levels 2 months’ post-dose against 2 key antigens and was 95% effective against the PorA 1.4 antigen. Following the third dose at 12 months, seroprotective levels achieved against antigens contained in the vaccine were equally robust in the same cohort.

The vaccine does cause local reactions and is associated with more tenderness and erythema than comparator vaccines. “The 4CMenB is also associated with more fever (38.5° C or higher) than routine vaccines,” Dr. Lebel indicated, occurring in up to 40% of infants who receive the vaccine. However, “the fever follows a very specific pattern,” he added, peaking about 6 hours after a dose but declining by day 2. Fever is absent by the third day. Dr. Lebel also noted that in the observer-blinded part of the infant study, when neither investigators nor parents knew if the infant had received the 4CMenB vaccine, the rate of medically attended fevers was about twice that following the 4CMenB vaccine than for comparator routine vaccines. On the other hand, during the open-label part of the study when parents did know if their child had received the 4CMenB vaccine, rates of medically attended fevers were similar between 4CMenB recipients and comparator vaccines.

Prophylactic acetaminophen also significantly attenuates fever rates in infants, as Prymula et al. reported at ESPID 2011. For the study, 2 groups of infants received routine childhood vaccines plus the 4CMenB vaccine but 1 group received prophylactic acetaminophen 10 to 15 mg/kg, with 1 dose given prior to vaccination and 2 further doses separated by 4 to 6 hours given after vaccination. Only 1% of children who received prophylactic acetaminophen developed fever =39.5° C after any dose of the 4CMenB vaccine, Dr. Lebel reported.

In the booster dose study, reactogenicity of the 4CMenB vaccine was also compared to that caused by the measles-mumps-rubella-varicella vaccine (MMRV), the most reactogenic of paediatric vaccines. Although the pattern of fever varies between the 2 vaccines—fever with the 4CMenB vaccine occurring shortly after vaccination and that with the MMRV occurring about 8 days later—reactogenicity profiles were similar and neither systemic reactions nor immunogenicity was affected by concomitant administration of the 2 vaccines.

“Systemic reactogenicity is increased when the 4CMenB vaccine is given with routine childhood vaccines,” Dr. Lebel stated, “and the possibility of a child developing fever after the 4CMenB vaccine should be communicated to parents in the event of routine implementation if increased systemic reactogenicity is to be an accepted component in the control of this serious infection.”

Summary

Serogroup B meningococcal disease now accounts for the lion’s share of meningococcal disease in Canada today. A novel candidate vaccine against serogroup B disease, the 4CMenB vaccine, has been shown to be highly immunogenic, the first vaccine against meningococcal disease that can be used in infants where the risk of disease is highest. With an acceptable safety profile, the new 4CMenB vaccine has the potential to protect recipients against the last remaining serogroup causing meningococcal disease and close the chapter in the control of this serious vaccine-preventable infection.