Canada Communicable Disease Report

Final Report of Outcomes from the National Consensus Conference for Vaccine-Preventable Diseases in Canada

June 2005

Disease Summaries

Invasive meningococcal disease

Background

The purpose of this session was to review current evidence and recommendations for national goals to control of invasive meningococcal disease (IMD) in Canada, focusing on Neisseria meningitidis (N. meningitidis) serogroup C, one of the leading causes of bacterial meningitis in Canada. Below are highlights of presentations on IMD incidence and immunization programs in Canada and other countries.

Disease incidence in Canada:

(Kerri Watkins, MHSc)

The annual incidence of IMD in Canada was approximately 305 cases per year between 1985 and 2003, with outbreaks occurring during the periods from 1989 to 1993 and 1999 to 2001. Preliminary data from 2002 to 2003 show a larger decrease in IMD incidence in the provinces which first implemented meningococcal C conjugate (Men C-C) vaccines immunization programs relative to other jurisdictions in Canada; however, it was noted that the 2002 rates in the early implementer provinces were higher and in 2003 decreased only to levels reported in other provinces. There is an added challenge of identifying disease trends given the unpredictability of IMD epidemiology; adding that the federal government is working with provinces and territories to strengthen IMD surveillance, focusing on under-reporting and data quality.

National Microbiology Laboratory (NML):

(Dr. Raymond Tsang)

Immunization programs may contribute to induce changes in N. meningitidis circulating strains. Data collected in Quebec following mass immunization campaigns after a serogroup C IMD outbreak in 2001 showed a decrease in the number of serogroup C cases; however, by 2004, a cluster of serogroup B cases had been identified. Subsequent DNA analysis revealed that a unique clone of serogroup B meningococcus had emerged to cause an outbreak dating back to 2003. Evidence of capsule switching involving C:2a:P1.1,7 meningococci changing to B:2a:P1.1,7 was also found, suggesting that one strain may switch to another naturally or under pressure from increasing immunization rates. Dr. Tsang concluded by asking participants to consider whether reduced circulation of the C strain had created an opportunity for a B clone to proliferate and whether the change in bacterial community structure was related to the 2001 serogroup C outbreak and the subsequent mass immunization campaign.

Immunization in Canada:

(Dr. Philippe De Wals)

Currently all Canadian provinces administer Men C-C vaccines, with most offering primary programs consisting of one dose at 12 months of age. Current evidence shows that, regardless of a vaccine recipient's age, one dose of vaccine is sufficient to prime immune capacity for at least 5 years. Two to three doses are required for children < 12 months of age, although the benefit of the second and third doses is modest.

NACI recommends routine immunization of infants at 2, 4 and 6 months of age, with infants between 4 to 11 months of age who have not previously received Men C-C vaccine to be immunized with two doses given at least 4 weeks apart. A single dose of the vaccine is recommended for immunization of children 1 to 4 years of age and for adolescents and young adults, given the increased risk of IMD in these age groups.

Seeking the optimal Men C-C immunization schedule, the efficacy of selected provincial programs over an 8-year period was examined. Using a simulation model, assuming 96% coverage in the first year after primary immunization or booster dose, it was shown that staging multiple doses over several years conferred greater benefit than administering all doses during infancy. The most effective schedule was 12 months, 12 years, and 18 years which was found to be only marginally more effective than 12 months and 12 years. From a cost-effectiveness standpoint, a one-dose strategy was preferable to both a three-dose strategy and mass immunization campaigns. Ultimately a two-dose regimen, given at 12 months and 12 years, emerged as the optimal strategy.

Dr. De Wals concluded by challenging participants to consider the optimal age for initiating primary immunization; the optimal number of doses for primary immunization; and at what age catch-up immunization and/or booster doses should be given. Issues impacting the resolution of these questions included the unpredictable epidemiology of IMD, uncertainty around the long-term effectiveness of conjugate vaccine, and the rate at which immunity wanes suggesting that control strategies must remain flexible to enable responsiveness to new developments.

Immunization in other countries:

(Dr. Eric Bertherat, WHO)

The experience of selected countries with Men C-C immunization was reviewed, focusing on the United Kingdom (UK). A marked increase in the incidence of IMD in the UK in the late 1990s led to the initiation of a mass Men C-C immunization campaign in 1999. Other countries followed suit (e.g., Ireland, Spain, Belgium, the Netherlands, Australia and Iceland), adopting a variety of routine and catch-up immunization schedules. Evidence in the UK demonstrated high short-term protection and a reduction in both carriage and incidence of IMD, as well as good herd immunity levels obtained through catch-up. However, in Spain, serogroup switching from serogroup C to B occurred following mass immunization. The duration of immunity, in both the UK and Spain, rapidly fell-off among infants vaccinated at an early age, raising questions about booster timing. Dr. Bertherat noted that, while the effectiveness of the Men C-C vaccine has been demonstrated, its impact is less clear given the natural cycles of IMD. To improve understanding, increased surveillance is required.

Discussion

Participants identified the following issues concerning the development of national goals and recommendations for the control of IMD in Canada, recognizing that no national goals have been established since the implementation of Men C-C immunization programs. The discussion guide used by participants is attached in Appendix B.

Strain switching: The linkage between strain switching and vaccination programs was considered. In some cases, IMD carriers carry both B and C strains, allowing for switching. High mutation rates have also been observed. Referencing the 2001 IMD outbreak in Quebec, Dr. De Wals asserted that mass campaigns do not create the foundation for subsequent epidemics. Dr. Tsang clarified that most of the B strain cases identified following the 2001 Quebec outbreak were in adolescents, suggesting an invasive clone.

Duration of immunity: Participants questioned the high rate of post-immunization fall-off in the UK, comparing the infant dosage ages of 2, 3 and 4 months to the Canadian standard of 2, 4 and 6 months. Dr. De Wals noted that, in Quebec, with immunization at ≥ 12 months of age, protection decreased following immunization, but to a lesser extent than in the UK.

Immunization registries: Participants agreed on the potential role of immunization registries in strengthening IMD epidemiological analysis, acknowledging the need to address issues related to consistency and quality of data with entries being made by hundreds of physician and public health offices. However, registries are of limited use in assessing immunization coverage, due to a lack of denominator information.

Education campaigns: It was determined that, given the current public demand for Men C-C vaccines, there is limited need for professional or public education campaigns. However, the importance of alerting decision-makers and funding bodies to disease reduction targets was noted, prompting the suggestion that a "report card" be developed on the establishment and achievement of targets.

Quadrivalent vaccine: Participants discussed the pending approval of the quadrivalent conjugate vaccine Menactra™ (serotypes A, C, Y and W-135) in Canada. Questions were raised about how the vaccine will be used and the age groups for which it will be licensed. Also considered was the prospect of replacing the monovalent vaccine currently used in adolescent programs with the quadrivalent conjugate vaccine, with the cost of the new vaccine cited as a likely issue. The potential need for an incremental cost-benefit analysis was also noted.

Surveillance: The next steps of the recommendations will require the standardization of data elements to improve surveillance; due to the cyclical nature of this disease, a baseline using the average incidence for the period from 1995-2001 was recommended. Surveillance will also need to be enhanced to capture IMD cases, including information on age-specific disease incidence, hospitalization and mortality. Priority should be given to developing and implementing standard data elements and data collection methods. Other areas to be addressed include the completeness of provincial/territorial laboratory data on N. meningitidis isolates; the collection of serotype data to support target-setting and outcome evaluation; the measurement of long-term disease sequelae; and the inclusion of clinical information with specimens submitted to the national laboratory.

Setting goals and recommendations

Goal

Reduce illness and death due to N. meningitidis serogroup C through immunization. (Proposed by CIC)

Disease incidence

Recommendation 1

Prevent N. meningitidis serogroup C outbreaks in those < 25 years by 2012.

Rationale: An age-specific target is appropriate; outbreaks tend to occur among adolescents and adults in their early 20's. Targeting persons up to 25 years of age might prompt provinces/territories to expand the age range of immunization programs, including catch-up programs, beyond the 15 to 19 age group currently targeted by NACI.

The proposed timeline of 2010 was debated in plenary session. Concern was expressed that a significant number of cohorts would have to be immunized to achieve the desired outcome, which could necessitate mass immunization campaigns. Alternate timelines of 2012 and 2015 were suggested, with 2012 ultimately being selected.

Subsequent to proposed age and timing changes, plenary participants considered replacing "prevent" with "eliminate" or "eradicate". The original wording was retained as the group agreed that there will continue to be un-immunized persons and outbreaks.

Recommendation 2

Achieve a sustained reduction of 90% in the incidence of N. meningitidis serogroup C in children < 5 years of age by 2010.

Rationale: The reduction target is attainable, given current immunization programs, and appropriate, given that children < 5 years of age constitute a high-risk group.

Discussion: It was suggested that immunization at 2, 4 and 6 months of age may not be necessary to achieve the proposed recommendation; rather, a comprehensive program targeting young children and adolescents should be sufficient when considering the effect of herd immunity.

Recommendation 3

Achieve a sustained reduction of 95% in the incidence of N. meningitidis serogroup C in adolescents 12 to 19 years of age by 2010.

Rationale: Two age groups were considered for targeting adolescents; 12 to 19 versus 15 to 19 years of age. The more comprehensive age group was recommended for the following reasons; the herd immunity impact would be greater, the age at which persons begin engaging in higher risk social activity is closer to 12 years of age than 15; and IMD incidence starts rising at 10 years of age.

Recommendation 4

Achieve a sustained reduction of 70% in the incidence of N. meningitidis serogroup C by 2010.

Rationale: The proposed target can be achieved indirectly through implementing recommendations 1, 2, and 3. While there are currently no programs targeting older Canadians, the effect of herd immunity may contribute to this reduction.

Immunization coverage

Recommendation 5

Achieve and maintain age-appropriate immunization coverage with meningococcal C conjugate vaccine in 100% of N. meningitidis serogroup C close contacts* of cases by 2010. (* as defined by NACI)

Rationale: An age generic immunization coverage target was recommended because close contacts of serogroup C IMD cases of all ages, as defined by NACI, constitute a high-risk group.

Recommendation 6

Achieve and maintain age-appropriate immunization coverage with meningococcal C conjugate vaccine in 95% of high-risk groups* for N. meningitidis serogroup C disease. (*as defined by NACI)

Rationale: Building on recommendation 5, it was considered essential to achieve maximum immunization coverage among all high risk groups, as defined by NACI.

Recommendation 7

Achieve and maintain age-appropriate immunization coverage with meningococcal C conjugate vaccine in 97% of children by their 2^nd birthday by 2010.

Rationale: The recommended target is necessary to prevent fatal disease outcomes in children and to achieve established disease reduction targets.

Recommendation 8

Achieve and maintain age-appropriate immunization coverage with meningococcal C conjugate vaccine in 90% of adolescents by their 17^th birthday by 2012.

Rationale: The proposed target is measurable and encourages immunization prior to the end of secondary school. The coverage level is lower than that for children ≤ 2 years of age, as older age groups are more difficult to access. Further, there is public demand, by parents, for their children to receive Men C-C vaccine.

Discussion: In plenary session, it was proposed to extend the time frame from 2010 to 2012 as the additional time would be needed to accommodate the limitations and variations of current immunization programs.

In jurisdictions where age at the end of secondary school may be < 17 years of age, it was recommended that immunization programs target children < 17 years of age.

An interim target for assessing program implementation progress was recommended to respond to the intense public demand for Men C-C immunization programs for school-age cohorts.

Other mortality

Mortality targets for children < 5 years of age and adolescents 15 to 19 years of age were considered however, due to the variability of programs currently delivered across all the jurisdictions, no mortality reduction targets were set at this time.

Recommendation 9

Enhance epidemiological^{Footnote **}, clinical and laboratory^{Footnote ***} surveillance of invasive meningococcal C disease.

Rationale: Enhanced surveillance is required to improve data quality and track N. meningitidis serogroup trends. Access to immunization histories is also needed to enable provinces and territories to assess immunization rates.

Recommendation 10 (Statement)

Provinces and territories should evaluate N. meningitidis serogroup C immunization programs including, but not limited to, immunization coverage, vaccine effectiveness, vaccine safety and epidemiological changes.

Rationale: Evaluation is needed to measure outcomes and determine the need and nature of revisions to existing immunization schedules, programs and targets.

Vote

Participants achieved consensus on the following recommendations for IMD control, with extensive discussion ensuing and second votes being held (see Votes 1 and 2) on recommendations 1 and 8. No overarching goal was presented for consideration at the conference; however, a goal was proposed later and approved by CIC.