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PRIORITY PRESS - 9th Canadian Immunization Conference (CIC)

Quebec City, Quebec / December 5-8, 2010

IMPACT (Immunization Monitoring Program, ACTive) surveillance data presented here at the CIC by Dr. Julie Bettinger, Assistant Professor, Vaccine Evaluation Centre, and Child and Family Research Institute, University of British Columbia (UBC), Vancouver, showed that serogroup B represented 53% of all cases of invasive meningococcal disease (IMD) reported by the 12 participating centres between January 2002 and December 2009. During that interval, there were 665 hospital admissions for IMD in the IMPACT centres, approximately half of them occurring in patients under the age of 20.

However, as Dr. Bettinger pointed out, the distribution of serogroup B disease varies by province and age, causing approximately 80% of IMD in infants and between 50 to 60% in 10- to 19-year-olds. Canada launched its mass immunization program with the monovalent meningococcal C vaccine (MenC) first in Quebec in 2001, followed by other infant programs in select provinces starting in 2002.

As a result of these programs, serogroup C disease accounts for only about 20% of IMD now in Canada, while serogroup Y is responsible for about 13% and W-135 even less, the latter two serogroups primarily being travel-associated, as Dr. Bettinger observed. “Provinces that initiated MenC vaccination early saw a decline in serogroup C incidence while provinces that launched later had not seen a decline by 2006,” she added.

Unlike pneumococcal disease where the preponderance of disease is now caused by serotypes not contained in the 7-valent pneumococcal vaccine, serogroup B remained relatively stable in provinces with both early and late MenC immunization programs. There is no evidence of serogroup replacement to date, although continued monitoring is necessary. “We also need to monitor immunity as immunity against meningococcal disease may be waning in children,” Dr. Bettinger told delegates, although the duration of protection against serogroup C disease is not yet known.

Most provinces and territories give one dose of the MenC vaccine at the age of 12 months although some provinces give 2 infant doses. Children who did not receive the vaccine in infancy are offered the vaccine via a catch-up program in adolescence.

Quadrivalent Meningococcal Vaccines

There are currently 2 quadrivalent meningococcal vaccines, both of which contain saccharides derived from serogroup capsules A, C, W-135 and Y. The MenACWY-D (Menactra) was the first to be licensed and was followed recently by MenACWY-CRM (Menveo). The MenACWY-CRM uses a different carrier protein than the MenACWY-D vaccine (the CRM197, a nontoxic mutant of diphtheria toxin vs. the diphtheria toxoid carrier protein used in the MenACWY-D vaccine).

Approval of the second quadrivalent meningococcal vaccine was based on a series of separate studies, as reviewed here at the CIC by Dr. Scott Halperin, Director, Canadian Center for Vaccinology, and Professor of Pediatrics, Dalhousie University, Halifax, Nova Scotia. In a series of comparisons between the then-investigational quadrivalent vaccine and the licensed quadrivalent vaccine, investigators first reported overall seroresponse rates in adolescents.

One month post-vaccination, seroresponse rates were statistically significantly higher for serotypes A, W-135 and Y with the MenACWY-CRM vaccine than with the MenACWY-D vaccine; seroresponse rates to serogroup C were virtually identical at approximately 74% for each vaccine. Persistence of protective antibody levels (hSBA titres =1:8) at 2 years’ post-vaccination in the same group of adolescents was also statistically higher for serogroups A, W-135 and Y with the MenACWY-CRM vaccine than the MenACWY-D counterpart, with equal results seen against serogroup C disease.

In 2- to 10-year-olds, non-inferiority criteria were demonstrated for all 4 serogroups following MenACWY-CRM vaccination and statistical superiority was demonstrated for groups C, W-135 and Y compared with the MenACWY-D vaccine.

Dr. Halperin also recently reported (Eur J Clin Microbiol Infect Dis 2010;29:259-67) that the MenACWY-CRM vaccine was well-tolerated and immunogenic in infants 6 months of age and primed for an enhanced response at 12 months of age.

MenACWY-CRM also had a similar adverse-event profile and immunogenicity against serogroup C to the monovalent MenC vaccine in infants 6 to 18 months of age who received either 2 doses of the MenACWY-CRM vaccine at 6 and 12 months; 1 dose of the same vaccine at 12 months; or the MenC vaccine at 12 months, followed by the MenACWY-CRM vaccine at 18 months.

“The monovalent conjugate C vaccine is licensed for infants but to potentially have a vaccine that is able to prevent disease from 4 out of the 5 serogroups would be fantastic. When that vaccine gets licensed [for infants and children <2], it will be great as there is a great need for a vaccine in these young children,” commented Dr. Bettinger.

Serogroup B Disease

Given the burden of serogroup B disease, especially in the very young, an effective vaccine against what is the predominant cause of meningococcal disease in certain age groups would be a major breakthrough. As explained by vaccine researcher Rino Rappuoli, PhD, Siena, Italy, N. meningitidis is a bacterium surrounded by a capsular polysaccharide each with a distinct chemical composition; depending on the chemical composition of the polysaccharide units, different serogroups emerge. When it comes to serogroup B, however, the meningococcal B capsule is a “self”-antigen and therefore cannot be used as a target for vaccination, Dr. Rappuoli noted.

In 1995, genomic research pioneer Dr. Craig Venter, then head of The Institute for Genomic Research in Rockville, Maryland, sequenced the first bacterial genome from Haemophilus influenzae. This pivotal breakthrough provided important insights that allowed the same group to sequence the meningococcal B genome in 2000. “Sequencing bacterial genomes provided the possibility to look not only at the few targets available to conventional technologies, but also to the entire repertoire of targets present in genome,” Dr. Rappuoli explained in an earlier interview.

By examining the bacterium’s genetic makeup in a process called “reverse vaccinology,” Dr. Rappuoli and colleagues were able to identify promising novel antigens that might prove immunogenic in candidate vaccines.

After many years, they narrowed multiple candidates antigens down to 3 novel proteins that had proven to be highly immunogenic in preclinical work; factor-H-binding protein (FHbp) variant 1; Neisseria adhesine A (NadA); and Neisseria heparin-binding antigen (NHBA). These 3 recombinant protein antigens were combined with an outer membrane vesicle from New Zealand hypervirulent strain 98/254 to form the new meningococcal B vaccine, 4CMenB.

This new vaccine has now been evaluated in a number of age groups, including infants as young as 2 months old. Primary immunogenicity data based on hSBA titres against 3 different serogroup B strains 30 days after the final vaccination showed that 100%, 100% and 84% of infants who received the 4CMenB vaccine together with routine infant vaccines had hSBA titres =1:5, seroprotective against the serogroup B strains.

The tolerability of the new multi-component 4CMenB vaccine has also been acceptable, as reported here by Esposito et al. in a related poster (P.006). Serious adverse events were observed in 8% of 4CMenB infants receiving the vaccine concomitantly with other routine vaccines. This compared with 6% for infants receiving the MenC vaccine plus routine infant vaccines and 8% for infants receiving routine vaccines only. Reported reactogenicity also followed a predictable pattern (with an observed fever peak at 6 hours and a markedly decreased rate on day 2 post-vaccination); few infants discontinued the trial due to reactogenicity outcomes.

“Serogroup B is the one serogroup that we have not been able to prevent and it causes a huge burden of disease in children,” Dr. Bettinger confirmed when asked to comment on the new 4CMenB vaccine. “This vaccine could potentially have a very big impact on meningococcal disease which is why I think it is so exciting.”