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 - 27th Annual Meeting of the European Society for Pediatric Infectious Diseases

Brussels, Belgium / June 9-13, 2009

Meningococcal infection is a major cause of invasive disease and meningitis worldwide. Almost all countries suffer from endemic meningococcal disease, but its epidemiology changes over time and varies depending on geographic location, season and age. Meningococcal disease is endemic in Canada, where the incidence peaked at around 1.6 per 100,000 population in 1992, but by 2005 had decreased to 0.56 per 100,000 population (Harrison et al. Vaccine 2009;27(suppl 2):B51-B63). The incidence is highest in infants aged <1 year (8.7 cases per 100,000) and children 1 to 4 years of age (2.3 per 100,000). Until adolescence, the rates of incidence decline before peaking again in 15- to 19-year-olds (1.9 per 100,000) (CCDR 2009;36(ACS-3):1-40).

Five serogroups (A, B, C, W135 and Y) account for the majority of cases globally while serogroups B and C cause the highest burden of disease. There has been a significant decline in the incidence of serogroup C disease in many countries, including Canada, following the implementation of vaccination programs using conjugate vaccines. Serogroups A and W135 are also rare in developed countries but the incidence of serogroup Y disease has recently increased in North America.

Meningococcal Conjugate Vaccines

Reviewing the development of vaccines, Prof. Andrew J. Pollard, Professor of Paediatric Infection and Immunity, and Director, Oxford Vaccine Group, University of Oxford, UK, noted that quadrivalent meningococcal ACWY (MenACWY) conjugate vaccines offer the possibility of broadening protection. To date, only one MenACWY conjugate vaccine (MenACWY-D), with diphtheria carrier protein, is available for use in Canada in those aged 2 to 55 years.

Two novel MenACWY conjugate vaccines are currently in development: MenACWY-CRM, with CRM-197, a naturally occurring nontoxic mutant of diphtheria toxin as carrier protein; and MenACWY-TT, conjugated to tetanus toxoid. Both have shown immunogenicity at all ages from early infancy in clinical trials. In a phase III study in adolescents, Prof. Pollard noted that only one direct comparison of two conjugate vaccines, the MenACWY-CRM vaccine, was found to generate a stronger immune response than the licensed conjugate vaccine for all four serogroups (Jackson et al. CID 2009;49:e1-e10). The decision to implement these vaccines is likely to be based on disease epidemiology and cost, although consideration of future disease threats should be included, Prof. Pollard suggested. Various approaches to implementation can be considered, including replacement of MenC by MenACWY or as a booster dose. Additionally, high-risk groups, such as travellers, may benefit from the conjugate MenACWY vaccines rather than plain polysaccharide vaccines. Arrival of these vaccines provides broader control of meningococcal disease, Prof. Pollard noted, but he stressed that a MenB vaccine is urgently needed for complete control.

New Data on MenACWY-CRM

The investigational MenACWY-CRM vaccine has been shown to be immunogenic in a two- or three-dose primary schedule in young infants. However, a decline in protective antibody was observed by 12 months of age, despite the induction of immunological memory, suggesting the value of a booster dose at 12 months of age (Perrett et al. Pediatr Infect Dis J 2009; 28(3):186-93). Prof. Pollard’s group previously showed that the long-term protection by maintenance of antibodies after protein-polysaccharide conjugate vaccine appeared to depend on effective production of memory B-cells/plasma during priming (Blanchard Rohner et al. J Immunol 2008;180(4):2165-73). They also studied the memory B-cell response in 216 healthy children who had been immunized with MenACWY-CRM at 2, 4 and 12 months of age. At 5 months of age, after two priming vaccine doses, only a small proportion of children had detectable meningococcal-specific memory B-cells, whereas after boosting, >50% of children had detectable meningococcal memory B-cells and 95% had carrier-specific memory B-cells. There was a significant difference between memory B-cell response to priming and boosting with vaccine for all antigens (P<0.0001 between 5 and 13 months), but there was no correlation between memory B-cell response to priming and boosting. No influence of the maternal antibody present at 2 months of age was observed on the memory B-cell response at 5 months of age. Researchers concluded that the decline in antibody after polysaccharide conjugate vaccination in early infancy might relate to the low frequency of memory B-cells induced in some infants during priming. Their data support the importance of a booster dose of vaccine at 12 months of age.

An Argentinian study discussed here at ESPID reported that MenACWY-CRM is well tolerated and significantly more immunogenic in children aged 2 to 10 years. The phase III, multicentre, double-blind study randomized 1500 healthy children to receive either MenACWY-CRM or the currently available unconjugated quadrivalent polysaccharide vaccine. Both vaccines were well tolerated and most reactions were mild to moderate in severity.

Dr. Silvia González Ayala, Servicio de Infectología, Hospital de Niños “Sor María Ludovica,” La Plata, reported that one month following vaccination, the percentage of those with human complement serum bactericidal activity (hSBA) seroresponse in the MenACWY-CRM group was significantly higher vs. the unconjugated vaccine group for serogroups A (93% vs. 53%), C (82% vs. 52%), W (74% vs. 46%) and Y (82% vs. 63%). Percentages of individuals with hSBA <u>></u>1:8 at one month after vaccination were significantly higher in the MenACWY-CRM group for serogroups A (95% vs. 55%), C (88% vs. 70%), W (99% vs. 73%) and Y (89% vs. 66%). At six months’ post-vaccination, bactericidal antibody persistence was evident for all MenACWY-CRM serogroups, but significantly more subjects in the MenACWY-CRM group maintained an hSBA titre <u>></u>1:8 against serogroups C, W and Y. Baseline hSBA geometric mean titres (GMTs) were significantly increased in both groups at one month, but significantly higher in the MenACWY-CRM group for all four serogroups (P<u><</u>0.004). At six months, hSBA GMTs had decreased in both vaccine groups but remained higher for serogroups C, W and Y in the MenACWY-CRM group.

Novel rMenB Vaccine

The majority of meningococcal infections in developed countries is caused by the meningococcal B strain and research for a universal vaccine against endemic polyclonal serogroup B meningococcal disease is ongoing.

As they told delegates here, Prof. Pollard and the Oxford Vaccine Group have been testing investigational recombinant MenB (rMenB) vaccines developed with and without the outer membrane vesicle (OMV) antigen. They had previously reported that after an early infant (2, 4, 6 and 12 months of age) or a late infant (6, 8 and 12 months of age) course of rMenB+OMV vaccine, <u>></u>93% of infants had hSBA titres <u>></u>1:4 against three menB strains (44/76-SL, NZ98/254 and 5/99) expressing the vaccine antigens (Snape et al. 16th IPNC, September 7-12, 2008, Rotterdam, The Netherlands). They have further evaluated the efficacy of the vaccine in protecting against an extended panel of additional MenB strains in two phase II studies. In an open-label, controlled study, 147 healthy infants were randomized to receive either rMenB or rMenB+OMV at 2, 4, 6 and 12 months of age or a single vaccination of rMenB+OMV at 12 months.

In the other single-blind study, 60 healthy infants were randomized to receive rMenB or rMenB+OMV at 6, 8 and 12 months of age. Immunization with rMenB+OMV generated hSBA titres of <u>></u>1:4 in <u>></u>70% of participants for five strains bearing homologous or closely related antigens by the early infant schedule and <u>></u>70% of participants for six strains tested following the late infant schedule. Immunization with rMenB alone generated hSBA titres of <u>></u>1:4 in <u>></u>70% of participants for only three strains tested. These studies confirmed the potential for improved vaccine prevention of meningococcal disease with rMenB+OMV, Prof. Pollard told delegates. The rMenB+OMV vaccine is currently in phase III clinical trials.