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PRIORITY PRESS - Primary Care Today

Toronto, Ontario / May 5-7, 2011

Meningococcal disease is never an infection physicians can take lightly. “Meningococcal disease is extremely rare and very few of us will have seen a case,” Dr. Marina Salvadori, Associate Professor of Pediatrics, University of Western Ontario, London, told delegates here. “But it is truly one of the most dramatic presentations you’ll ever see and it is one of those times when you feel hopeless as a physician.” Even in state-of-the-art tertiary care centres, mortality rates from bacteremia caused by Neisseria meningitidis are as high as 40 to 50%. In patients who survive the infection, up to 20% have devastating sequelae including deafness, amputation and neurological impairment.

As Dr. Salvadori explained, N. meningitidis is a bacteria covered by a polysaccharide coating and it is this coating that defines the serogroup or type of bacteria that emerges. “There are lots of types,” she noted, “but only a few are important.” These are serogroups A, B, C, W-135 and Y. “Meningococcal C is by far the most lethal type,” Dr. Salvadori noted.

Fortunately, due to the success of the meningococcal C vaccination program, invasive meningococcal disease (IMD) caused by serogroup C has been dramatically attenuated to the point where serogroup B is now a much more important cause of IMD than any other serogroup. (Serogroup A disease is primarily of concern for travellers to places such as the sub-Sahara while disease caused by serogroups W-135 and Y is relatively limited in Canada and its incidence has remained stable over time.)

According to a 2009 statement from the National Advisory Committee on Immunization (NACI), rates of serogroup B disease are “particularly high” in infants and children <4 years of age, but disease can occur at any age. Indeed, in 2006, 54% of all IMD in Canada was caused by serogroup B, with incidence rates ranging from about 33% in some provinces to as high as 100% in others (CCDR 2009; 36:ACS-3). In the same year, serogroup B caused 82% of all IMD in infants under the age of 1 year and 72% of all IMD in children 1 to 4, while in adolescents between the ages of 15 and 19, the same serogroup caused 68% of all IMD. Again in 2006, there were “appreciable numbers of cases” in both Ontario and Quebec, Dr. Salvadori noted; due to the sparse population in the Northwest Territories, rates of IMD from serogroup B are also “extremely high,” she added.

“Now that we have meningococcal C disease under control with our national programs, serogroup B is the number one cause of IMD in Canada with the highest incidence rates in infants and in adolescence,” Dr. Salvadori emphasized. “While it affects each province slightly differently, serogroup B disease remains a demonstrable and serious problem in every province and territory in Canada and we need a solution to this problem.”

Pathogenesis of Serogroup B Disease

As Dr. Ron Gold, Professor of Pediatrics, Hospital for Sick Children, Toronto, Ontario, explained to delegates, the antigenic structure of the B polysaccharide capsule is identical to a glycoprotein on the surface of fetal neuroblasts in the brain. “This means that the developing immune system is exposed to the antigen and becomes tolerant to it, so the immune system does not recognize the group B polysaccharide as foreign and we don’t make antibody responses to group B,” he stated. The outer membrane vesicle (OMV) does contain important non-polysaccharide antigens that will induce bactericidal antibody responses.

Yet genes that give rise to surface antigens on the B capsule have high mutation rates. Even if people do make antibodies to the major antigens contained on the surface of serogroup B, “antigens keep changing so a single serotype vaccine can’t be used for routine vaccination against serogroup B,” Dr. Gold noted. Vaccine researcher Rino Rappuoli, PhD, Siena, Italy, used a technique referred to as “reverse vaccinology” to examine the bacterium’s genetic makeup and eventually identified 3 novel antigens that proved to be immunogenic in a candidate vaccine: factor-H-binding protein (fHbp) that prevents activation of alternative complement pathway; Neisserial adhesin A (NadA) that enables the organism to attach to and probably invade the mucosal cell and the respiratory tract; and Neisserial heparin-binding antigen (NHBA) that has a similar effect to fHbp.

The fourth immunologically active component in the vaccine is the OMV which was developed to control a MenB epidemic in New Zealand. The OMV serves to induce specific protective bacterial antibodies against the known hypervirulent subtype (PorA 1.4). It also potentiates the immune response to the 3 antigens contained in the 4CMenB vaccine.

Confirmed Dr. Gold, “These proteins are very important in the pathogenesis of meningococcal disease and if you can make antibodies to them, you not only kill the bacteria but you [also] inhibit its ability to cause disease if it gets into the bloodstream. Having multiple antigens in a vaccine gives you the ability to cover many more different strains of serogroup B and reduces the risk of a mutation producing a strain that the vaccine does not cover.”

Study Findings

These three antigens, together with the OMV, have been incorporated into the new multicomponent meningococcal serogroup B vaccine, 4CMenB. To date, it has been evaluated in 1584 adolescents and adults from 11 to 55 years of age and in 4846 infants between the ages of 2 and 12 months.

Dr. Gold reported on primary immunogenicity data based on serum bactericidal antibody (SBA) titres against 4 different serogroup B antigens 30 days after the third vaccination (i.e. following the 3-dose primary series of a 4-dose regimen). Findings showed that 100%, 100%, 84% and 84% of infants who received the 4CMenB vaccine (along with routine infant vaccines) mounted a protective antibody response against all 4 serogroup B antigens (fHbp, NadA, PorA 1.4 and NHBA).

Dr. Gold cited another study of 54 laboratory workers at increased risk for IMD. Findings showed that those who received the new serogroup B vaccine at baseline and again at 2 and 6 months (followed by a single dose of the MenACWY-CRM [Menveo] quadrivalent vaccine 1 month later) had evidence of bactericidal immune responses after each dose of the new vaccine, as assessed by serum bactericidal assay using human complement (Kimura et al. Clin Vaccine Immunol 2011:18(3):483-6). Vaccinated lab workers also demonstrated hSBA titres =8 against serogroups A, C, W-135 and Y. The data in adults appear to support a 2-dose immunization schedule.

Overall efficacy data using the 4CMenB vaccine in adolescents and adults indicate that 83% of them achieved protective antibody responses to current serogroup B strains. “Local reactions with the 4CMenB vaccine are about the same as they are with routine infant vaccines,” Dr. Gold told delegates.

Fever does occur more often with the new vaccine than with routine vaccination, he noted. However, even when told to anticipate fever, parents involved in the 4CMenB clinical trials were not more likely to seek medical attention than with routine vaccination. Dr. Gold stated that acetaminophen prophylaxis is not routinely recommended to prevent it.

Summary

“As family practitioners, we are inundated with an ‘alphabet soup’ of meningitis,” observed session moderator Dr. Vivien Brown, University of Toronto and McMaster University, Hamilton, Ontario. But she added, “What is really important is the epidemiology of meningococcal B disease which now accounts for about half of all the bacterial meningitis we see.” As they need to do for all vaccines, physicians must educate themselves about the efficacy of the vaccine and understand the safety data. Dr. Brown stressed that parents seek out pediatricians to ask about vaccine efficacy and safety and whether they as pediatricians would recommend them. “We have to speak to patients, answer their questions and then tell them what we recommend because it is our recommendation that is going to get the child immunized or not.”