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Canada Communicable Disease Report

Volume 33 • ACS-11
November 2007

An Advisory Committee Statement (ACS)

National Advisory Committee on Immunization (NACI)†, † †

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Meningococcal C conjugate vaccination recommendations for infants

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

The National Advisory Committee on Immunization (NACI) made recommendations on the use of meningococcal C conjugate vaccine for infants (i.e. children < 1 year of age), children from 1 to 4 years of age, adolescents and young adults(1). The vaccine should be considered for children ≥ 5 years of age who have not reached adolescence. In the 2005 updated statement on meningococcal C conjugate vaccines (2), NACI recommended a three-dose schedule for young infants using Menjugate® (Novartis Vaccines) or Meningitec™ (Wyeth Canada). The first dose was to be given at no earlier than 2 months of age and the other doses separated by at least 1 month; at least one dose in the primary series was to be given after 5 months of age. For infants aged 4 to 11 months, a two-dose schedule was recommended for Menjugate® and Meningitec™ with the doses given at least 1 month apart. In the 2005 statement, the recommended schedule for NeisVac-C® (GlaxoSmithKline) was changed to two doses, the first being given no earlier than 2 months of age and the second at least 2 months later. NACI recommended that one dose of the primary series be given after 5 months of age. Children ≥ 1 year of age require only one dose for all three meningococcal C conjugate products.

Increasingly, evidence has raised concerns regarding the duration of protection following infant meningococcal C conjugate vaccination. The following will provide an overview of the epidemiology of meningococcal disease in infants, the immunogenicity and effectiveness data related to infant meningococcal C conjugate vaccinations, and the current vaccination practices for infants and toddlers in Canada. On the basis of these data, revised recommendations for infant and toddler vaccinations are made in order to increase the long-term effectiveness of meningococcal C conjugate vaccines.

It should be noted that the epidemiology of meningococcal disease changes over time, and the understanding of the effectiveness of meningococcal vaccines is an evolving area. Future modifications to NACI recommendations may be required as additional information becomes available.

Background

The carrier protein for NeisVac-C® is tetanus toxoid, and the carrier protein for Menjugate® and Meningitec™ is CRM197, a non-toxic mutant of diphtheria toxin isolated from culture of Corynebacterium diphtheriae. Aside from having a different carrier protein, NeisVac-C® also differs from Menjugate® and Meningitec™ in that it is made from an O-acetyl negative capsule whereas Menjugate® and Meningitec™ are produced from strains that contain O-acetyl groups in their polysaccharide capsule. Some isolates of meningococcal C lack the O-acetyl group in their capsule, and Menjugate® and Meningitec™ may have impaired activity against these strains(3). A detailed comparison of meningococcal vaccines currently available in Canada can be found in the NACI statement on conjugate meningococcal vaccine for serogroups A, C, Y and W135(4).

Since the 2005 NACI statement, changes to the infant schedules have been approved by Health Canada for NeisVac-C® and Meningitec™. The timing of the two doses of NeisVac-C® was changed in December 2006 so that for infants 2 to 12 months of age at least one of the two doses is given when the infant is > 5 months. A booster dose is recommended for infants who completed their primary series before the age of 5 months. It is suggested that the booster be given within the second year of life, approximately 1 year after the last dose of the primary series(5). The infant schedule for Meningitec™ was changed as of May 2007 to two doses, the first dose to be given no earlier than 2 months of age, with an interval of at least 2 months between doses, followed by a booster dose given preferably at about 12 months of age(6).

Epidemiology of invasive meningococcal disease in infants

The average annual incidence rate for all forms of invasive meningococcal disease (IMD) has been highest among children < 1 year of age (9.2 per 100,000 for the years 1995-2004). Of the 2,437 cases of IMD reported between 1995 and 2004, infants < 1 year of age accounted for 13% of cases (mean 32 cases per year). Serogroup B accounts for most of the burden of disease in this age group with a mean of 22.5 cases reported per year (range 12 to 41). The rate of IMD due to serogroup B was 6.40 per 100,000 among infants < 1 year old. Serogroup C accounts for fewer cases in this age group. Between 1995 and 2004, the average number of serogroup C meningococcal cases per year in Canada in children < 1 year of age was 3.2 (range 1 to 8), which results in a rate of 0.90 per 100,000 (Unpublished data, Public Health Agency of Canada, 2007).

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Immunogenicity data

Meningococcal C conjugate vaccines were approved for use on the basis of short-term immunogenicity data and safety data(5). Immunogenicity data with respect to vaccination of infants demonstrate that infants produce a good initial immune response to meningococcal C conjugate vaccine and that this response is demonstrable even after two doses of vaccine. However, several studies show that the immune response falls within 1 year of vaccination, but that an additional dose given at ≥ 1 year of age produces a strong booster response(7-10).

A Canadian study assessed 175 infants randomly assigned to receive Menjugate® at 2, 4, 6 and 15 months concurrently with DTaP-IPV-HIb (Pentacel®, Aventis Pasteur) (7). Two months after the second dose of Menjugate®, 99% (95% confidence interval [CI] 96% to 100%) of recipients had achieved a protective bactericidal antibody level for serogroup C (defined as ≥ 1:8). A titre of ≥ 1:8 is the putative immune correlate of short-term protection for serogroup C disease(8). One month after the third dose, 100% (95% CI, 98% to 100%) of recipients had achieved this protective level. At 15 months of age, before the booster dose was given, only 74% (95% CI, 66% to 81%) of recipients had maintained the protective level against serogroup C. One month following the booster dose, 100% (95% CI, 98% to 100%) again had protective levels. Geometric mean titres (GMTs) were as follows: 140 at 2 months after the second dose; 232 at 1 month after the third dose; 20 at 15 months of age before the booster dose; and 1,344 at 1 month after the booster dose.

A study from the United Kingdom (UK) administered two lots of vaccine similar to Menjugate® along with a quadrivalent vaccine containing diphtheria and tetanus toxoids and whole cell pertussis reconstituted with Haemophilus Influenzae type b (Hib) tetanus conjugate at 2, 3 and 4 months of age; oral polio vaccine (OPV) was also administered(8). A total of 120 subjects received either of the two lots of the meningococcal C conjugate vaccine. One month after the first dose, 56% of infants had a bactericidal antibody level of ≥ 1:8; 1 month after the second dose, 98% of recipients achieved this level, and 1 month after the third dose 100% of infants had achieved protection. At 12 months of age more than 75% of children still had a titre of ≥ 1:8. The GMTs were as follows (depending on the lot of meningococcal C conjugate vaccine received): 13 and 8.2 one month after the first dose, 302 and 220 one month after the second dose, 629 and 420 one month after the third dose, and 24 and 16 at 12 months of age. An additional dose of either meningococcal C conjugate vaccine or polysaccharide meningococcal vaccine was given at 12 months of age. The meningococcal C conjugate vaccine booster resulted in 100% of recipients achieving a titre of ≥ 1:8 one month after vaccination, while the polysaccharide vaccine resulted in 97% of recipients achieving that titre. GMTs were much higher after the meningococcal C conjugate vaccine booster than the polysaccharide vaccine (2,448 compared with 789). Control children did not receive meningococcal vaccine as infants and received only one dose of meningococcal C conjugate vaccine at 12 months of age. Among the control children, only 66% achieved protective antibody levels 1 month after their single meningococcal C conjugate vaccine, and their GMT was only 15.

A product similar to Meningitec™ was administered in another study from the UK along with a quadrivalent vaccine containing diphtheria and tetanus toxoids and pertussis reconstituted with Hib-CRM197 conjugate at 2, 3 and 4 months of age; OPV was also administered(9). Subjects received either a 2 μg or 10 μg formulation. The results are presented for the 10 µg formulation, as this is the concentration used in the current Meningitec™ product. A total of 57 subjects received the 10 μg formulation of the meningococcal C conjugate vaccine. Four weeks after the first dose, 68% of infants had a bactericidal antibody level of ≥ 1:8; 4 weeks after the second dose, 98% of recipients had achieved this level, and 4 weeks after the third dose 98% of infants had achieved protection. At 14 months of age 53% of children still had a titre of 1:8 or higher. The GMTs were as follows: 30.3 measured 4 weeks after the first dose, 766.3 measured 4 weeks after the second dose, 1,011 measured 4 weeks after the third dose and 13.5 at 14 months of age. At 15 to 20 months of age approximately half the children received a dose of polysaccharide vaccine containing 10 μg of each of meningococcal A and C polysaccharides. This resulted in 19 of 20 recipients (95%) achieving a titre of ≥ 1:8 one month after vaccination, with a GMT of 256. The other half of the infants in this study received the meningococcal A and C polysaccharide at 4 years of age(12). Prior to vaccination at 4 years of age, only three of 25 participants (12%) who had received the 10 μg formulation had a bactericidal antibody level of ≥ 1:8. One month after the administration of the polysaccharide vaccine, 21 of 22 (95%) had titres ≥ 1:8, with a GMT of 931.6.

NeisVac-C® may produce a more robust immune response than Menjugate® or Meningitec™. A UK study that enrolled 226 children between the ages of 12 and 18 months compared the immunogenicity of Menjugate®, Meningitec™ and Neis-Vac-C® using an O-acetyl positive strain of Neisseria meningitidis(13). NeisVac-C® appears to induce higher GMTs than Menjugate® or Meningitec™, and these titres remained higher over time. The GMTs at 4 to 6 weeks after vaccination were 123 for Menjugate®, 141 for Meningitec™ and 564 for NeisVac-C®. Before revaccination 6 months later with a low-dose polysaccharide vaccine challenge, GMT had fallen in all groups but remained higher for NeisVac-C® (19 for Menjugate®, 51 for Meningitec™ and 166 for Neis-Vac-C™). Furthermore, the percentage of individuals having a bactericidal titre of ≥ 1:8 was higher for NeisVac-C® (57% for Menjugate®, 75% for Meningitec™ and 86% for Neis Vac-C®). After the polysaccharide challenge, all three vaccine groups had very high percentages of children with titres ≥ 1:8, but the GMTs were highest for NeisVac-C® (1,318 for Menjugate®, 979 for Meningitec™ and 5,272 for NeisVac-C®). Good response from NeisVac-C® is observed to both O-acetyl negative and O-acetyl positive strains(14).

Another study in the UK assessed the immunogenicity of a one-, two- or three-dose schedule of NeisVac-C® in infants ≥ 11 weeks of age at enrollment(10). NeisVac-C® was administered concurrently with a vaccine containing diphtheria and tetanus toxoid, whole cell pertussis and H. influenzae type b (ACT-HibDTwP, Pasteur Merieux); OPV was also administered. Immunogenicity was assessed using three different strains of N. meningitidis, two of which were O-acetyl positive and one of which was O-acetyl negative. Of the 194 infants randomly assigned to the one-dose arm of the study, who received their vaccine at 2 months of age, ≥ 98.4% of subjects whose blood had been drawn at 1 month after vaccination had a bactericidal level of ≥ 1:8, depending on the strain used in the assay. One month after completing the primary series, protection was achieved in ≥ 98.9% of the 201 infants randomly assigned to receive NeisVac-C® at 2 and 4 months of age and ≥ 98.8% of the 191 infants randomly assigned to receive vaccine at 2, 3 and 4 months of age. The GMTs one month after completion of the vaccination schedule were higher in the groups that received two and three doses of vaccine compared with the group that received only one dose (460, 1,325 and 1,405 for one, two and three doses, respectively, for one O-acetyl positive strain of N. meningitidis). A low-dose polysaccharide vaccine challenge was administered at 13 to 14 months of age. Before the challenge, the group that had received only one dose of NeisVac-C® had a lower percentage of children with a titre of ≥ 1:8 than the group that had received two and three doses (43.8%, 59.9% and 70.2%, for one, two and three doses, respectively, for one O-acetyl positive strain of N. meningitidis). However, all three groups had a very high proportion of participants who achieved a titre of ≥ 1:8 one month after the polysaccharide vaccine challenge as well as very high GMTs, the one-dose group having the highest GMTs (6,377, 3,556 and 2,946 for one, two and three doses, respectively, for one O-acetyl positive strain of N. meningitidis).

The concurrent administration of NeisVac-C® with DTaP/Hib (Infanrix-Hib®, GlaxoSmithKline) was assessed in a further UK study involving 106 infants at 2, 3 and 4 months of age(15); OPV was also administered at each visit. One month after the first dose, 92% of infants had a protective bactericidal level for serogroup C of ≥ 1:8, which increased to 100% 1 month after the second and third doses. The GMTs 1 month after the first, second and third doses were 491, 1,052 and 1,024, respectively. The third dose did not appear to have contributed to the immune response using this schedule.

A recent Cochrane Collaboration review of meningococcal C conjugate vaccines concluded that most studies used three doses of meningococcal C conjugate vaccine in infancy but that two doses may be adequate, as most infants achieve protective titres after two doses, particularly with the tetanus toxoid conjugate vaccine. The reviewers also concluded that two doses of meningococcal C conjugate vaccine generated high antibody titres in children 12 to 18 months of age, and the majority were protected after one dose, particularly with the tetanus toxoid conjugate vaccine(16).

Several of the above studies have demonstrated immune memory for meningococcal C conjugate vaccines, as indicated by increases in titres when challenged with polysaccharide or meningococcal C conjugate vaccines(7-10,12,13). However, it is not known whether immune memory is sufficient to protect against IMD, which has a short incubation period (range 2 to 10 days, commonly 3 to 4 days (17)). It may be that, because of the short incubation period, circulating antibodies are required for protection.

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Effectiveness data

Because IMD is rare, the sample size required to do efficacy studies makes such trials prohibitively expensive. Immunogenicity studies and post-licensure effectiveness studies are used to evaluate meningococcal vaccines. Recently, several studies have published effectiveness data based on the use of meningococcal C conjugate vaccines for outbreak management followed by introduction into the routine schedule in Quebec(18), the UK(19) and Spain(20). Confidence interval around the estimates of disease in these observational studies are wide because of the relative rarity of cases. These studies have all shown excellent effectiveness in the first year after the mass immunization program. Two of them also provide data on longer-term follow-up(19,20). These studies raise concerns about the long-term effectiveness of the vaccine among children who received the meningococcal C conjugate vaccine as infants.

In the UK, infants received the meningococcal C conjugate vaccine at 2, 3 and 4 months of age. Surveillance data were available for 4 years after the introduction of the vaccination program. Trotter et al.(19) found that at > 1 year after the series, effectiveness in the children vaccinated at 2, 3 and 4 months had fallen to –81% (95% CI, -7430% to 71%). Those vaccinated at 5 to 11 months of age and 1 to 2 years of age had somewhat better long-term protection with vaccine effectiveness at > 1 year after vaccination of 82% (95% CI, -8% to 97%) and 61% (95% CI, -327% to 94%) respectively in these age groups. Despite the apparent lack of protection in older children vaccinated as young infants, the total number of cases in this cohort remains low, partly as a result of herd immunity. On the basis of its modeling study, the UK decided to change its meningococcal C conjugate schedule to offer two doses at 3 and 4 months of age with a booster dose at 12 months of age(21).

In Spain, infants were vaccinated with meningococcal C conjugate vaccine at 2, 4 and 6 months of age. Surveillance data were available for 4 years after the introduction of the vaccination program. At > 1 year after vaccination, the effectiveness in those vaccinated as infants was 78% (95% CI, 3.1%-95.0%). Those vaccinated at 7 months to 5 years of age had greater protection, with a vaccine effectiveness at > 1 year after vaccination of 94.3% (95% CI, 71.2% to 98.8%)(20).

Current provincial/territorial recommendations for infants and toddlers

As of June 2007, the publicly funded programs in Alberta and the Yukon offer routine meningococcal C conjugate vaccine to infants < 12 months of age. Alberta offers three doses of vaccine at 2, 4 and 6 months of age, and Yukon provides two doses at 2 and 6 months. Eight provinces/territories offer vaccine at 12 months of age. Manitoba offers the vaccine in Grade 4, and British Columbia and the Northwest Territories offer it at 2 and 12 months of age. Ten jurisdictions have also offered catch-up campaigns for older age groups (22).

Recommendations

Because of the short incubation period of meningococcal disease, circulating antibodies may be required for protection against IMD. Immunologic data have demonstrated that protective titres following infant meningococcal C conjugate vaccination decrease in the second year of life. Effectiveness studies have demonstrated that protection decreases after 1 year following the completion of the infant vaccination series.

On this basis, NACI recommends that if meningococcal C conjugate vaccine is given to infants < 12 months of age, a booster dose be given in the second year of life (from 12 to 23 months of age). A dose at 12 or 18 months of age would be a convenient time to provide this booster. This replaces NACI's recommendation that one dose of a primary infant immunization series of meningococcal C conjugate vaccine be given after 5 months of age.

Monitoring of the epidemiology of IMD and the effectiveness of meningococcal C conjugate vaccines is ongoing. Recommendations may be adjusted as additional information becomes available.

NACI has assessed that there is a good rationale for the above recommendation: the strength of the recommendation is A (Table 1), and the level of evidence is assessed as II-2.

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Table 1. Quality and strength of evidence

Level of evidence(23,24)

I

Evidence obtained from at least one properly randomized, controlled trial.

II-1

Evidence obtained from well-designed, controlled trials without randomization.

II-2

Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one centre or research group (including immunogenicity studies).

II-3

Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments could also be included in this category.

III

Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Strength of recommendations

A

There is good evidence to recommend the clinical preventive action.

B

There is fair evidence to recommend the clinical preventive action.

C

The existing evidence is conflicting and does not allow a recommendation to be made for or against the clinical preventive action; however, other factors may influence decision-making.

D

There is fair evidence to recommend against the clinical preventive action.

E

There is good evidence to recommend against the clinical preventive action.

I

There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making.

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References

  1. National Advisory Committee on Immunization (NACI). Statement on recommended use of meningococcal vaccines. CCDR 2001;27(ACS-6):2-36.

  2. National Advisory Committee on Immunization (NACI). Update on meningococcal C conjugate vaccines. CCDR 2005;31(ACS-3):1-4.

  3. Snape MD, Pollard AJ. Meningococcal polysaccharide-protein conjugate vaccines. Lancet Infect Dis 2005;5:21-30.

  4. National Advisory Committee on Immunization (NACI). Statement on conjugate meningococcal vaccine for serogroups A, C, Y and W135. CCDR 2007;33(ACS-3):1-24.

  5. GlaxoSmithKline Inc. NeisVac-C® : vaccine product monograph. Mississauga, Ontario: GlaxoSmithKline Inc., 2006.

  6. Wyeth Canada. Meningitec™: product monograph. Montreal, Quebec: Wyeth Canada, 2007.

  7. Halperin SA, McDonald J, Samson L et al. Simultaneous administration of meningococcal C conjugate vaccine and diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine in children: A randomized double-blind study. Clin Invest Med 2002;25:243-51.

  8. MacLennan JM, Shackley F, Heath PT et al. Safety, immunogenicity and induction of immunologic memory by a serogroup C meningococcal conjugate vaccine in infants: A randomized controlled trial. JAMA 2000;283:2795-801.

  9. Richmond P, Borrow R, Miller E et al. Meningococccal serogroup C conjugate vaccine is immunogenic in infancy and primes for memory. J Infect Dis 1999;179:1569-72.

  10. Borrow R, Goldblatt D, Finn A et al. Immunogenicity of, and immunologic memory to, a reduced primary schedule of meningococcal C-tetanus toxoid conjugate vaccine in infants in the United Kingdom. Infect Immun 2003;71(10):5549-55.

  11. Borrow R, Balmer P, Miller E. Meningococcal surrogates of protection – serum bactericidal antibody activity. Vaccine 2005;23:2222-27.

  12. Borrow R, Goldblatt D, Andrews N et al. Antibody persistence and immunological memory at age 4 years after meningococcal group C conjugate vaccination in children in the United Kingdom. J Infect Dis 2002;186:1353-57.

  13. Richmond P, Borrow R, Goldblatt D et al. Ability of 3 different meningococcal C conjugate vaccines to induce immunologic memory after a single dose in UK toddlers. J Infect Dis 2001;183:160-63.

  14. Richmond P, Borrow R, Findlow J et al. Evaluation of de-O-acetylated meningococcal C polysaccharide-tetanus toxoid conjugate vaccine in infancy: Reactogenicity, immunogenicity, immunologic priming and bacteriocidal activity against O-acetylated and de-O-acetylated serogroup C strains. Infect Immun 2001;69:2378-82.

  15. Southern J, Crowley-Luke A, Borrow R et al. Immunogenicity of one, two or three doses of a meningococcal C conjugate vaccine conjugated to tetanus toxoid, given as a three-dose primary vaccination course in UK infants at 2, 3 and 4 months of age with acellular pertussis-containing DTP/Hib vaccine. Vaccine 2006;24:215-19.

  16. Conterno LO, Silva Filho CR, Rüggeberg JU et al. Conjugate vaccines for preventing meningococcal C meningitis and septicaemia. Cochrane Database Syst Rev 2006, Issue 3. Art No: CD001834. DOI: 10.1002/14651858.CD001834.pub2.

  17. Meningococcal infection – meningococcal meningitis. In: Heymann DL, ed. Control of communicable disease manual, 18th ed. Washington: American Public Health Association, 2004:359-66.

  18. De Wals P, Deceuninck G, Boulianne N et al. Effectiveness of a mass immunization campaign using serogroup C meningococcal conjugate vaccine. JAMA 2004;292(20):2491-94.

  19. Trotter CL, Andrews NJ, Kaczmarski EB et al. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 2004;364:365-67.

  20. Larrauri A, Cano R, Garcia M et al. Impact and effectiveness of meningococcal C conjugate vaccine following its introduction in Spain. Vaccine 2005;23:4097-100.

  21. Trotter CL, Edmunds WJ, Ramsay ME et al. Modeling future changes to the meningococcal serogroup C conjugate (MCC) vaccine program in England and Wales. Human Vaccines 2006;2:68-73.

  22. Public Health Agency of Canada and the Canadian Nursing Coalition for Immunization. Publicly funded immunization programs in Canada. Routine schedule for infants and children. Available at: http://www.phac-aspc.gc.ca/im/ptimprog-progimpt/index.html. Accessed on 26 June, 2007.

  23. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. Can Med Assoc J 2003;169:207-8.

  24. Canadian Task Force on the Periodic Health Examination. The Canadian guide to clinical preventive health care. Ottawa: Minister of Supply and Services Canada, 1994. Report No.: Cat. no. H21-117/1994E.


Members: Dr. J. Langley (Chairperson), Dr. T. Tam (Executive Secretary), Dr. S. Dobson, Dr. B. Duval, Ms. A. Hanrahan, Dr. J. Kellner, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. M.-N. Primeau, Dr. B. Seifert, Dr. D. Skowronski, Dr. B. Tan, Dr. B. Warshawsky (Vice-chair).

Liaison Representatives: Dr. P. Hudson (CPHA), Dr. B. Bell (CDC), Dr. D. Money (SOGC), Dr. B. Larke (CCMOH), Dr. M. Salvadori (CPS), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE), Dr. P. Orr (AMMI Canada).

Ex-Officio Representatives: Dr. H. Rode (BGTD), Dr. R. Ramsingh (FNIHB), Dr. P. Laforce, Dr. B. Law (IRID).

† †This statement was prepared by Drs. Bryna Warshawsky and Shelley Deeks and approved by NACI and the Public Health Agency of Canada.


[Canada Communicable Disease Report]