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 - 48th Annual Meeting of the Infectious Diseases Society of America

Vancouver, British Columbia / October 21-24, 2010

Although the annual incidence of invasive meningococcal disease (IMD) in Canada is low at 0.42 cases per 100,000 population, the disease is prone to epidemic outbreaks, during which this figure increases markedly. The overall case fatality rate in the US is approximately 12%. Furthermore, the sequelae of IMD can be severe and permanent. “Meningococcal disease is the most fearsome infection that we ever deal with,” stated Dr. Scott Halperin, Professor of Pediatrics, Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, speaking here at IDSA, “and eliminating it would be a bonus, not only to all the patients who get it but also to the physicians who have to take care of it.”

Dr. Julie Bettinger, Assistant Professor of Pediatrics, University of British Columbia, Vancouver, explained that most IMD is caused by 1 of 5 serotypes of the gram-negative diplococcus Neisseria meningitidis. Of these, type B is most prevalent (54%), followed by type C (20%) and Y (13%). Cases of types A (responsible for extensive disease in Africa) and W-135 are generally travel-related. The distribution of the serotypes within Canada is highly variable. For example, the proportion of cases due to type B is as high as 100% in Manitoba and the Northwest Territories, and as low as 33% in British Columbia and Nova Scotia. The age distribution of IMD is bimodal, with peaks in children less than 1 year old and in adolescents. Mortality increases with age, so that adolescents are at particularly high risk. UK experience presented by Dr. Edward Kaczmarski, Head, Health Protection Agency, Meningococcal Reference Unit, Manchester, UK, confirmed the bimodal increase in both incidence and deaths in infants and adolescents there in the 1990s.

Serogroup C Epidemics

Epidemics in Canada are mainly due to serogroup C, the incidence of which is cyclical in nature. Type C is associated with a high rate of sequelae, which include amputations, deafness and renal dysfunction. “We see the most severe disease from serogroup C,” noted Dr. Bettinger. “About 71% of cases with serogroup C disease require ICU care.” The 2001 Canadian mass immunization campaign against the type C outbreak appears to be highly successful and there seems to have been a herd immunity effect, in which disease incidence among adults who were not immunized also declined. However, Dr. Bettinger cautioned that, as type C is cyclical in nature, it is difficult to separate the immunization effect from the natural history of the organism.

Meningococcal Carriage

Carriage of N. meningitidis is widespread, and is an important component in the transmission of the disease. Between 10 and 20% of people carry the organism in the nasopharynx. It is not known exactly why carriage of the organism occasionally progresses to disease. “If it goes from the nasopharynx and enters the bloodstream, that’s bad news for both the patient and for the meningococcus,” commented Dr. Kaczmarski, “because it’s essentially an end point when that happens, because what the organism really wants to do is to transfer from one person to another.” He showed data that indicated a reduction in serogroup C carriage to one-third of its original level in the year following a meningococcal C conjugate vaccine program in the UK in 1999. The incidence of carriage dropped from 0.45% to 0.15% (n=14,064 in 1999, n=16,583 in 2000). A comparison of the drop in group C disease in adolescents with the continued increase in group B cases during 2000 and 2001 suggests that the reduction was due to the vaccination program rather than to a cyclical change in the distribution of the organism. Although group B disease persists in the UK, “serogroup C has fallen off to vanishingly small numbers” since the initiation of the program, noted Dr. Kaczmarski. A herd effect was seen immediately following the onset of the vaccination program, with a 65% reduction in disease in unvaccinated 15- to 17-year-olds. This effect has persisted to the present.

Serogroup titre rates tend to decline with time, and Dr. Kaczmarski pointed to data from Greece (Sakou et al. Vaccine 2009;27:4408-11) that suggest immunity may be preserved for longer periods in individuals who are vaccinated as adolescents, compared to those treated in infancy. He suggested that revaccination of adolescents might confer lifetime immunity.

Vaccines

A combined quadrivalent polysaccharide vaccine is effective against serogroups A, C, Y and W-135. However, it does not provoke a strong immune response in children under the age of about 5, it does not stimulate immunological memory and it may induce tolerance for the target organism, explained Dr. Halperin. It may be used in Canada in older patients and when conjugated vaccine is not available.

MenACWY-D (Menactra) is a quadrivalent vaccine in which the polysaccharide is conjugated with diphtheria toxoid in order to stimulate a T-cell-dependent response, which induces immunological memory, leading to prolonged protection. Conjugated vaccines also produce a good response in infants and reduce carriage, which results in herd immunity. MenACWY-D was approved based on non-inferiority comparisons with the combined quadrivalent polysaccharide vaccine. In turn, non-inferiority to MenACWY-D has been demonstrated by the conjugated quadrivalent vaccine MenACWY-CRM (Menveo), which is conjugated with cross-reactive material (CRM).

Dr. Halperin reviewed data from a phase III non-inferiority comparison study looking at adolescents. MenACWY-CRM demonstrated non-inferiority to MenACWY-D in all 4 serogroups in adolescent patients, and additionally provided a significantly higher response in groups A, W-135 and Y. Superiority in maintaining human serum bactericidal activity (hSBA) titres against these serogroups at or above 8 persisted at 2 years. The safety profile of the 2 vaccines was similar. Data comparing MenACWY-CRM to MenACWY-D in patients aged 2 to 10 years old was also reviewed. Eligible 2- to 5-year-olds received 1 or 2 doses of MenACWY-CRM or 1 dose of MenACWY-D while 6- to 10-year-olds received 1 dose of either vaccine. For the combined 2- to10-year-old cohort, non-inferiority criteria were demonstrated for all 4 groups following MenACWY-CRM vaccination and statistical superiority was demonstrated for groups C, W-135 and Y compared with the MenACWY-D vaccine.

The effectiveness of MenACWY-CRM in infants as young as 2 months old, has been evaluated in a large (n=4545) pivotal phase III study conducted in the US and Latin America. Dr. Nicola Klein, Kaiser Permanente Vaccine Study Center, Oakland, California, presented the US data from this trial, which investigated the immune response and tolerability of a 4-dose series, administered at 2, 4, 6 and 12 months of age. The study met its efficacy end point, with 94%, 98%, 100% and 100% of patients achieving hSBA titres of 8 or more after the 12-month dose for the A, C, W-135 and Y serogroups, respectively. A second primary end point showed that the 4-dose series produces titres more than twice as high as those produced by a single dose at 12 months. In this trial, tolerability of MenACWY-CRM was similar when compared to routine vaccinations alone. “The 4-dose series of MenACWY-CRM vaccinations was highly immunogenic in infants,” concluded Dr. Klein, adding, “The 3-dose infant series was also highly immunogenic. For 3 of the 4 serotypes, over 90% had titres greater than 8, while for type A it was 67%.”

Serogroup B

No vaccine is currently available against type B disease.The creation of a group B meningococcal vaccine presents considerable difficulties, stated researcher Dr. Rino Rappuoli, Siena, Italy. The polysaccharide capsule of this group consists of elements that closely resemble components of our own glycoproteins, he explained; thus a conjugate made with these polysaccharides would either elicit no response or possibly generate autoimmunity. However, gene-sequencing technology has made it possible to identify and synthesize bacterial surface proteins that would be vaccine candidates. From these, 4 components have been incorporated into a vaccine known as 4CMenB. Phase III trials of this vaccine in infants and adolescents have produced very encouraging results. Over 1800 strains of serotype B have been tested, and protection is estimated at 70 to 90%, depending on patient age and geographic region. The vaccine also has a good safety profile. “We have a vaccine that we know we can give safely to children,” Dr. Rappuoli told IDSA delegates. He expects the vaccine to be approved in Europe next year.