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MEDI-NEWS - Based on PLOS ONE. November 2012, Volume 7, Issue 11.

October 2013

Significant changes in the epidemiology of invasive meningococcal disease (IMD) have been observed in the province of Quebec during the last two decades. As in many other developed countries, most IMD in Quebec was once caused by serogroup C Neisseria meningitidis. Following the implementation of a universal vaccination program against serogroup C disease, serogroup C disease has now been virtually eradicated. Today, the great majority of IMD in Quebec is caused by serogroup B N. meningitidis and two-thirds of it is caused by a certain clonal complex of serogroup B, ST-269cc. A candidate vaccine, the 4CMenB vaccine, has been shown to be highly effective against serogroup B strains and importantly, against the major clonal complex causing IMD in Quebec. Given that serogroup B is now responsible in Quebec for the great majority of IMD and all IMD in children under the age of 1 year, a vaccine that has the potential to prevent almost all IMD in children under the age of 18 deserves urgent attention.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

In the province of Quebec, outbreaks of IMD caused by serogroup C occurred in the early 1990s as well as in 2001. Following the introduction of a mass immunization campaign in which a polysaccharide vaccine was initially introduced followed by a monovalent serogroup C conjugate vaccine several years later, serogroup C IMD has virtually disappeared in the province, with only 4 cases being reported during the last 3 years, all in adult patients. Indeed, as reported by de Wals and colleagues (Pediatr Infect Dis J 2011;30: 566–569) the incidence of meningococcal C disease dropped markedly following the introduction of the mass immunization campaign not only in highly vaccinated cohorts but also in poorly vaccinated and nonvaccinated birth cohorts. Among serogroup B isolates circulating in Canada in the 1990s, no particular clone or strain predominated.

In Quebec, however, one particular strain, ST-269, was identified as the strain responsible for a cluster of serogroup B IMD episodes which occurred in 2004 and 2005 in two adjacent regions. Since then, the percent of serogroup B isolates belonging to the ST-269 clonal complex (ST-269cc) has been increasing to the point where now, two-thirds of serogroup B IMD in Quebec is caused by ST-269cc. The highest infection rates from this clonal complex occur in infants under the age of 1 year.

In an effort to better match N. meningitidis vaccines for IMD prevention in the province, Dr. Rodica Gilca, Institut national de santé publique du Québec, Quebec City, Quebec and multi-centre colleagues (PLOS One. Published online), analyzed the epidemiology of IMD in Quebec 10 years prior to and 10 years after the introduction of serogroup C vaccination programs. From January 1997 through to December 2011, a total of 1028 IMD cases were reported to the province’s notifiable disease registry and 945 IMD cases to the laboratory surveillance. Of the 945 IMD cases identified by laboratory surveillance between 1997 to 2011, 68% were due to serogroup B strains while 20% were due to serogroup C. Only 8% and 3% were due to serogroups Y and W-135, respectively, the authors add.

Indeed, “in the last three years, serogroup B has been responsible for 88% of all IMD cases reported to laboratory surveillance and 61% of all IMD deaths,” the authors write. Breaking this down by age, almost half at 47% of IMD cases were in young children and adolescents, the highest incidence consistently being observed in ≤1-year olds. Numerically, serogroup B was responsible for all (35/35) laboratory-confirmed IMD in infants under 1 year of age; for 94% (102/108) in those between 1 to 24 years of age; for 76% (34/45) in 25 to 64-year-olds, and for 58% (11/19) in those 65 years of age and older.

Surveillance results also confirm that only a few cases of IMD due to serogroup Y and W-135 and no cases of serogroup A IMD have been reported in the province over the past 3 years.

4CMenB Vaccine

Currently, a vaccine that contains 3 proteins identified on the surface of many meningococcal strains (factor H-binding protein (fHbp) Neisserial adhesin A (NadA) and Neisseria heparin-binding antigen (NHBA) plus outer membrane vesicles from a New Zealand outbreak strain—the 4CMenB vaccine—has been evaluated in 5850 infants and toddlers and 1712 adolescents and adults across 13 different clinical studies. As reported by Vesikari et al. (Lancet 2013;381:825-35), 100% of infants achieved an hSBA titre of ≥5 against fHbp and NadA 1 month after receiving
3 doses of the 4CMenB vaccine, while 84% achieved the same hSBA titre against NHBA and the New Zealand outer-membrane vesicle strain. Antibody responses waned by the age of 12 months, as investigators noted.

Following a booster dose given alone or concomitantly with the measles-mumps-rubella-varicella (MMRV) vaccine, a booster response was observed against all test strains, resulting in hSBA protective titres of ≥5 against all 4 vaccine antigens in 95% to 100% of recipients. In adolescents between 11 and 17 years of age, Santolaya et al. (Lancet 2012;379:617-24) reported that 2 doses of the same vaccine produced protective antibody responses to all components of the vaccine in virtually all recipients.

Again, no clinically relevant immunological interference was seen when the 4CMenB was given concomitantly with other routine vaccines. Fever does occur more often when the 4CMenB vaccine is given concomitantly with other routine infant vaccines. However, the observed fever is of a mild to moderate intensity (38 to 39 degrees Celsius); is predictable (peaking by 6 hours post-immunization) and self-limiting (gone by 24 hours post-immunization). The transient increase in temperature following concomitant administration of the 4CMenB vaccine with other routine infant vaccines can also be limited with the prophylaxic use of acetaminophen without affecting response to individual antigens. Findings from the overall clinical development program indicate that the 4CMenB vaccine is both safe and effective in infants and adolescents and that it clearly has the potential to protect the most vulnerable cohorts in the population from the most common cause of IMD in Quebec today.

Common Circulating Serogroups

The potential for the 4CMenB vaccine to protect against the most common circulating serogroup B strains across the country is estimated to be high, particularly against the most common serogroup B strains currently circulating in Quebec. In a collaborative effort between the Canadian Immunization Monitoring Program Active (IMPACT), the National Microbiology Laboratory, the UK Health Protection Agency and Novartis Vaccines, Bettinger et al. (Vaccine 2013.03.063) characterized 157 isolates by the Meningococcal Antigen Typing System (MATS). Isolates were also sequenced for fHbp, NadA and NHBA.

Bettinger and colleagues found that the 4CMenB vaccine would provide protection against approximately two-thirds of the 157 isolates characterized by MATS. MATS also predicted that the vaccine would provide coverage against 2 prevalent strains of invasive Men B, ST-269 and ST-154, at 95% and 100%, respectively. Currently, the ST-269cc is responsible for two-thirds of serogroup B IMD in Quebec. “Using a conservative predictor for coverage, 4CMenB appears to provide good strain coverage… for the most prevalent recent ccs,” investigators write, “and overall, across all age groups, the majority of isolates are predicted to be covered by the 4CMenB vaccine.”

Of note, they add, the 4CMenB vaccine appears to provide coverage across a wide diversity of endemic strains and is not limited to protecting against one or two subtypes. At least 40% of isolates were covered by 2 or more vaccine antigens, with fHbp and NHBA contributing the most to vaccine coverage, as they also point out. 4CMenB antigens are also found in non-MenB isolates:  thus, protection against these other serogroups may be an added bonus, particularly in individuals not immunized with meningococcal conjugate vaccines.

The authors concluded that over two-thirds of recent IMD cases caused by serogroup B were potentially preventable with this vaccine. In a recent article (Vaccine 2013 August 14. Published Article in Press) Frosi et al. analyzed a panel of MenB strains from the UK and Wales. Investigators determined that MATS is a conservative predictor of strain coverage by 4CMenB in infants and adolescents.

They also concluded that a significant proportion of isolates MATS predicted the vaccine would not cover were in fact killed by pooled 4CMenB immune sera. 

 MATS also predicted that the vaccine would provide 82% coverage within the 2 most prevalent clonal complexes. These clonal complexes include ST-269 and ST-240, which the vaccine was predicted to cover by between 95 and 100%.

Questions and Answers

Question and Answers with Dr. Rodica Gilca, Institut national de santé publique du Québec, Québec City, Québec.

Q: Now that healthcare providers (HCPs) will better understand the current epidemiology of IMD in Quebec, how do you suggest they counsel parents about IMD vaccination?

A: Serogroup B is currently the leading cause of IMD in Quebec. Although the overall disease burden is low, its severity and sequelaes are a matter of high public concern. Knowledge, attitudes and beliefs studies show that personal knowledge and perception of disease as an important health problem is only one of the factors influencing vaccine acceptance by HCPs. Since intention to recommend new vaccines is shaped by many other elements, such as vaccine efficacy, safety, cost, immunization schedule, etc., it is difficult to predict how one particular factor will impact on the HCPs’ decision-making.

Q: Given the current epidemiology of men B disease in Quebec, would you expect a similar impact on men B disease upon introduction of the 4CMenB vaccine as was seen on men C disease with the introduction of the men C vaccine?

A: It has been shown that 4CMenB vaccine has the potential to protect against an important proportion of Canadian IMD Men B strains.  Its impact on current epidemiology of serogroup B IMD in Quebec depends on the choice of the immunization schedule to be implemented, how the vaccine will protect against particular strains circulating in different regions, how long the protection will last, and vaccine potential to provide herd protection and thus reduce disease in age groups where the vaccine will not be recommended. 

Based on “The Changing Epidemiology of Meningococcal Disease in Quebec, Canada, 1991–2011: Potential Implications of Emergence of New Strains.” Rodica Gilca et al. PLOS ONE November 2012, Volume 7, Issue 11.