Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 17th International Pathogenic Neisseria Conference

Banff, Alberta / September 11-16, 2010

Invasive meningococcal disease is rare but potentially fatal and is often associated with significant clinical sequelae. Distribution of the five major serogroups which cause invasive meningococcal disease—A, B, C, W-135 and Y—is highly dynamic and region-specific. “There are also dramatic differences in disease incidence around the world,” observed Dr. Lee Harrison, Professor of Medicine and Epidemiology, University of Pittsburgh, Pennsylvania, here at the IPNC, although incidence rates are very low in developed countries: 0.42 per 100,000 in Canada, for example, and 0.34 per 100,000 in the US, in 2006.

Two quadrivalent conjugate meningococcal vaccines active against A, C, W-135 and Y serogroups are now available in Canada, MenACWY-D (Menactra) and MenACWY-CRM (Menveo).

As presented here at the IPNC, in a study designed to demonstrate non-inferiority of MenACWY-CRM to MenACWY-D in young children, Dr. Scott Halperin, Professor of Pediatrics, Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, and colleagues randomized a total of 2820 children between the ages of 2 and 10 years to receive either vaccine. Children were stratified by age: the 2- to 5-year-olds (n=1700) received either 2 doses of MenACWY-CRM or one dose of either vaccine; children between the ages of 6 and 10 years (n=1120) received a single dose of either vaccine. Seroresponse was defined as a serum bactericidal assay using human complement (hSBA) of =8 in each of the 2 age groups 28 days after receiving a single dose of either vaccine.

At study end, MenACWY-CRM met statistical superiority criteria vs. MenACWY-D for serogroups W-135 and Y and was non-inferior for serogroup C in both age groups. For serogroup A, non-inferiority criteria were not met; the serogroup A seroresponse rates for MenACWY-CRM and MenACWY-D, respectively, were 72% (95% CI, 68-75%) and 77% (95% CI, 73-80%) in 2- to 5-year-olds, and 77% (73-80%) and 83% (79-86%) in 6- to 10-year-olds. When the 2 age groups were combined (2- to 10-year-old children), MenACWY-CRM was non-inferior to MenACWY-D for all 4 serogroups, and statistically superior for serogroups C, W-135 and Y. Reactions to both vaccines were largely mild and self-limited (Figure 1).

Figure 1.

“If you do give a second shot [of MenACWY-CRM] to children, you do get higher antibody levels but the antibody levels achieved with a single shot were as good as or better than with MenACWY-D which is given as a single shot,” Dr. Halperin noted in an interview during the scientific sessions.

Serogroup B Disease

In Canada, serogroup B causes about 60% of all meningococcal disease; broken down into different age groups, serogroup B causes approximately 80% of the disease in infants and between 50 and 60% of the disease in 10- to 19-year-olds. Thus, the majority of invasive meningococcal disease in Canada is now caused by serogroup B, as data from IMPACT 2006-2009 confirm. A vaccine that protects infants in particular from serogroup B infection could be considered a major breakthrough in vaccine technology. One potential meningococcal B vaccine candidate, rLP2086, contains antigenic components from subfamilies A and B of meningococcal factor-H-binding protein (fHbp).

As presented here at the IPNC by Dr. Peter Richmond, University of Western Australia, Perth, results from 3 clinical trials evaluating rLP2086 showed that over 90% of adolescents and about 75% of adults achieved hSBA titres =4 for subfamily A and about 86% and 70%, respectively, against subfamily B. After a third dose, approximately 94% of adults achieved hSBA titres =4 for both subfamilies. “No significant safety concerns were identified,” Dr. Richmond told delegates, “and these data support further development of rLP2086 vaccine.”

A second meningococcal B candidate vaccine is a multi-component vaccine—4CMenB—that contains 3 recombinant protein antigens: fHbp variant 1; Neisseria adhesion A (NadA); Neisseria heparin-binding antigen (NHBA); and an outer membrane vesicle from New Zealand hypervirulent strain 98/254. As explained by several speakers here, the meningococcal B capsule is a self-antigen and thus cannot be used as a vaccine target. Through the novel process of “reverse vaccinology” (a genomic approach to vaccine discovery), researchers identified these antigens that now serve as vaccine targets in the 4CMenB vaccine. All 535 meningococcal B isolates analyzed by Dr. Jamie Findlow, Health Protection Agency, Manchester, UK, and colleagues who presented here were found to possess alleles for NHBA; 18% also had NadA alleles, 20% of isolates had the vaccine PorA protein (P1.4) and 70% harboured fHbp variant 1 proteins contained in the 4CMenB vaccine. The researchers noted that this would suggest the 4CMenB candidate vaccine has the potential to protect against a significant proportion of MenB disease in the UK.

As presented here at the IPNC by Vesikari and colleagues, 3630 infants were randomized to 1 of 3 lots of the 4CMenB vaccine along with routine infant vaccines, given at 2, 4 and 6 months of age. The primary immunogenicity assessment was based on hSBA titres against 3 different serogroup B strains 30 days after the final vaccination. “All 3 lots of investigational 4CMenB produced highly consistent immune responses,” the authors reported.

In the primary analysis, 100%, 100% and 84% of infants who received 1 of the 3 lots of the 4CMenB vaccine had hSBA titres =5 against all serogroup B strains. “When given with routine immunizations, the 4CMenB induced immune responses that met the primary pre-defined non-inferiority criteria for seroresponse for all antigens except polio 2 when compared to routine administration alone,” investigators noted. The tolerability of the new multi-component 4CMenB vaccine was also “acceptable,” as reported here by Esposito and colleagues in a related poster. 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 meningococcal C vaccine plus routine infant vaccines and 8% for infants receiving routine vaccines only. Reported reactogenicity also followed a predictable pattern, with an observed peak at 6 hours and a markedly decreased rate on day 2 post-vaccination; few infants discontinued the trial due to reactogenicity outcomes.

Protecting Laboratory Workers at Increased Risk

As observed here at the IPNC by Dull and colleagues, laboratory staff workers exposed to meningococci are at increased risk for invasive disease and the meningococcal vaccine is frequently recommended for such individuals.

In the first study of its kind, 54 laboratory workers received 3 doses of the 4CMenB vaccine at baseline, 2 and 6 months, followed by a single dose of MenACWY-CRM 1 month later. Immunogenicity was again assessed by analyzing hSBA titres.

Results showed that bactericidal immune responses were evident after each dose of the 4CMenB vaccine as reflected by geometric mean titres, as well as the percentage of participants with hSBA titres = 4 or =8 or with a fourfold rise in hSBA titres over baseline.“Responses were also strongly evident after 2 doses of the 4CMenB vaccine and responses after the third dose were not markedly higher than after 2 doses,” investigators reported. They added that 1 month after vaccination, most quadrivalent vaccine recipients also had hSBA titres =8 against serogroups A, C, W-135 and Y. Both vaccines were well tolerated, although reactogenicity rates were lower after the quadrivalent vaccine than after the 4CMenB vaccine.

Commenting on these early findings, Dr. Julie Bettinger, Assistant Professor of Pediatrics, University of British Columbia, Vancouver, characterized the prospect of a potential vaccine against serogroup B disease as “fantastic.”

“Being able to control all 5 serogroups has been the ‘Holy Grail’ of meningococcal research,” she confirmed in an interview during the scientific sessions. “The fact that we are on the cusp of having a vaccine to prevent B disease is very exciting.”