Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Meningococcal Vaccine

Epidemiology Preparations approved for use in Canada Efficacy and immunogenicity Recommended usage Schedule and dosage Route of administration Booster doses and re-immunization

Serologic testing Storage requirements Simultaneous administration with other vaccines Adverse reactions Contraindications and precautions Other considerations Selected references

Since the publication of the 2002 Canadian Immunization Guide, a third meningococcal C conjugate vaccine has been approved for use, guidelines for the prevention and control of meningococcal disease have been published and further information concerning the duration of protection provided by meningococcal C conjugate vaccines in infancy has been published.

Epidemiology

Invasive meningococcal disease (IMD) is endemic in Canada, showing periods of increased activity roughly every 10 to 15 years with no consistent pattern. The incidence rate varies considerably with different serogroups, age groups, geographic locations and time. Implementation of universal meningococcal C immunization programs will also affect disease epidemiology.

Since 1985, the overall incidence of IMD has remained at or below 2 per 100,000 per year (range 0.5 to 2.1). Overall, the incidence rate has been highest among children < 1 year of age and then declines as age increases, except for a smaller peak in the 15 to 19 year age group. An average of 298 cases of meningococcal disease have been reported annually. Disease occurs year round, but there is seasonal variation with the majority of cases occurring in the winter months.

Serogroups A and C Neisseria meningitidis were the groups most frequently identified from 1971 to 1974. From 1975 to 1989, serogroup B predominated. Since 1993, serogroups B and C have been responsible for most of the cases of endemic disease in Canada (incidence rates ranging between 0.13 to 0.65 per 100,000 population and 0.2 to 0.44 per 100,000 population for C and B respectively). However, there has been less fluctuation in the incidence of serogroup B than of serogroup C disease over time. Between the years 2000 and 2003, the average number of serogroup C cases per year in children < 1 year was 4 (range 1-8). In those aged 1-4 the average was 9 (range 4-14). During the same time period, the average number of cases in the 15-19 and 20-24 age groups was 25 (range 12-40) and 13 (range 5-18) respectively. Meningococcal outbreaks are almost exclusively due to serogroup C. There were sporadic localized outbreaks and periods of elevated incidence of serogroup C disease during 1989-1993 and 1999-2001. Immunization campaigns using serogroup C polysaccharide and conjugate vaccines were implemented in some regions during the 1999-2001 outbreak period. Recent data suggest that incidence rates of serogroup C are decreasing; however, more data are needed.

An increasing trend in the incidence of serogroup Y disease has been observed in the United States during the past decade, although no such trends have been observed in Canada over this time. In this country, from 1993 to 2003, serogroup Y incidence has remained relatively stable at 0.06 to 0.13 per 100,000 population per year (average 28 confirmed cases per year, range 17 to 41). Serogroup Y disease has tended to affect older adults (median age 45 years, range 0-94).

Incidence rates for serogroup W135 have remained below 0.05 per 100,000 population. Cases of serogroup A disease remain rare in Canada (< 10 cases reported between 1993 and 2005).

The epidemiology of meningococcal disease varies throughout the world. International travellers should be aware of the risk of IMD at their destination of choice. IMD occurs sporadically worldwide and in focal epidemics. The traditional endemic or hyperendemic areas of the world (the "meningitis belt") include the savannah areas of sub-Saharan Africa extending from Gambia and Senegal in the west to Ethiopia and Western Eritrea in the east. Health care providers advising Canadian travellers should remain current with global meningococcal activity. The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides guidelines for health care providers counselling Canadian international travellers on meningococcal vaccination. In deciding on the need for immunization, there should be particular consideration of the destination to be visited, the nature and duration of exposure, and the age and health of the traveller. Current meningococcal outbreak information can be obtained through the Public Health Agency of Canada, Travel Medicine Program (http://www.travel-health.gc.ca) and the World Health Organization (WHO) (http://www.who.int/csr/don/archive/disease/meningococcal_disease/en/)

Preparations approved for use in Canada

This chapter will deal only with vaccines that are currently marketed in Canada.

Two different types of meningococcal vaccine are available: purified capsular polysaccharide vaccines and protein-polysaccharide conjugate C vaccines.

Conjugate vaccines (Men-C-C)

• Meningitec^™ (composed of N. meningitidis group C oligosaccharides conjugated to cross reacting material 197 [CRM197]), Wyeth Canada (distributor)
• Menjugate^™ (meningococcal group C oligosaccharides conjugated to a purified non-toxic variant of diphtheria toxin CRM197), Chiron Corporation
• NeisVac-C^™ (contains meningococcal group C polysaccharide conjugated to tetanus toxoids), GlaxoSmithKline Inc. (distributor)

Polysaccharide vaccines

Bivalent vaccines (Men-P-AC)

• Menomune^® A/C (meningococcal polysaccharide vaccine, groups A and C combined), Sanofi Pasteur Ltd.

Quadrivalent vaccine (Men-P-ACW135Y)

• Menomune^® A/C/Y/W-135 (containing capsular polysaccharide from serogroups A, C, Y and W135 meningococci), Sanofi Pasteur Ltd.

Efficacy and immunogenicity

Conjugate vaccines

A high level of protection produced by immunization with meningococcal C conjugate vaccine has been predicted from immunogenicity data. In addition, data related to the effectiveness of the meningococcal C conjugate vaccine program after its introduction in England in November 1999 are available. Children received three doses of the vaccine at ages 2, 3 and 4 months. Children from 5 months to 18 years of age were provided vaccination as part of a catch-up campaign. This involved two doses at least 4 weeks apart for children aged 5 months to 1 year and a single dose for children > 1 year of age. Assessment of the immunization program in its first year showed that vaccine effectiveness ranged from 87% to 98%. There was no significant difference in effectiveness between age groups. However, after 4 years of follow-up, the vaccine effectiveness among children who had received the routine infant immunization declined significantly to 66% and was lower than in the catch-up cohorts, in whom effectiveness remained high, ranging from 83% to 100%.

Polysaccharide vaccines

The immunogenicity and clinical efficacy of the serogroups A and C polysaccharide vaccines have been well established. The serogroup A polysaccharide induces antibody response among certain children as young as 3 months of age, although a response comparable with that occurring in adults is not achieved until 4-5 years of age; the serogroup C component is poorly immunogenic among recipients aged < 2 years. The serogroups A and C polysaccharide vaccines have demonstrated estimated clinical efficacies of 85% to 100% among older children and adults, and are useful in controlling epidemics. Serogroups Y and W-135 polysaccharides are safe and immunogenic in adults and in children > 2 years of age. Although clinical protection has not been documented, vaccination with these polysaccharides induces bactericidal antibody. The antibody responses to each of the four polysaccharides in the vaccine are serogroup-specific and independent.

Polysaccharide vaccines have been widely used to control outbreaks of serogroup A and C meningococcal disease in Canada and throughout the world. Vaccine efficacy within the year of immunization is between 87% and 94%. Lower efficacy (0% to 67%) has generally been observed in young children, especially those < 2 years of age. In Quebec, where 1.7 million doses of polysaccharide vaccine were given dur ing an outbreak of serogroup C disease in the early 1990s, efficacy after 5 years was estimated at 79% among children and young adults. After further follow-up in Quebec, protection from serogroup C meningococcal disease was observed in the first 2 years after vaccine administration (vaccine efficacy 65%) but not in the next 3 years (vaccine efficacy 0%). Vaccine efficacy was strongly related to age at immunization: 83% for ages 15 to 20 years, 75% for ages 10 to 14 years, and 41% for ages 2 to 9 years. There was no evidence of protection in children < 2 years.

During a serogroup A epidemic in Africa, the efficacy of polysaccharide vaccines against serogroup A was estimated as 87%. Although protection against serogroup A after use of polysaccharide vaccines may persist in school-aged children and adults for at least 3 years, the efficacy in children aged < 5 years may decrease markedly within this period.

Measurable levels of antibodies against the group A and C polysaccharides decrease markedly during the first 3 years after a single dose of vaccine. This decrease in antibody occurs more rapidly in children < 5 years of age than in adults.

Recommended usage

The meningococcal C conjugate vaccines have been approved for use in infants, children and adults, and the National Advisory Committee on Immunization (NACI) recommends that they be used as follows.

Infants

Meningococcal C conjugate vaccines are recommended for routine immunization of infants. The recommended schedule differs depending upon the vaccine used. Three doses of either Meningitec^™ or Menjugate^™ are recommended to be given to infants beginning no earlier than 2 months of age and separated by at least 1 month. Two doses of NeisVac-C^™ should be administered at least 2 months apart, with the first dose not to be administered before 2 months of age. At least one dose of the primary immunization series should be given after 5 months of age. Infants 4 to 11 months of age who have not previously received the vaccine should be immunized with two doses given at least 4 weeks apart. Infants born prematurely should receive the vaccine at the same chronological age as term infants.

Polysaccharide vaccine is not recommended for routine infant immunization.

Individuals ≥ 1 year of age

Meningococcal C conjugate vaccines are recommended for immunization of children aged 1-4 years and for adolescents and young adults to prevent the increased risk of serogroup C meningococcal disease in these age groups. For children ≥ 5 years of age who have not reached adolescence, immunization with a single dose of MenC-conjugate vaccine may also be considered. A single dose is required for any person ≥ 1 year of age.

Polysaccharide vaccine is not recommended for routine childhood immunization.

Contacts of cases

Close contacts of individuals with meningococcal infections are at increased risk of IMD; this risk is greatest for household contacts. The vaccination status of close contacts, including the type of meningococcal vaccine, the number of doses and age at vaccine administration, should be determined. Vaccination of susceptible close contacts, in addition to chemoprophylaxis, should be considered when the serogroup is vaccine preventable, as it may further reduce the risk of subsequent meningococcal disease; vaccination should be carried out as soon as possible. The increased risk of disease for household contacts persists for up to 1 year after disease in the index case and beyond any protection from antibiotic chemoprophylaxis. In general, this prolonged risk is not seen among other contacts who do not have ongoing exposure.

Thus, the following individuals are considered close contacts for whom immunoprophylaxis and chemoprophylaxis (as detailed in Table 9), should be given:

• Household contacts of a case
• Persons who share sleeping arrangements with the case
• Persons who have direct contaminations of their nose or mouth with oral/nasal secretions of a case (e.g., kissing on the mouth, shared cigarettes, shared drinking bottles)
• Children and staff in child care and nursery school facilities

The following individuals are close contacts who should receive only chemoprophylaxis (not immunoprophylaxis):

• Health care workers (HCWs) who have had intensive unprotected contact (without wearing a mask) with infected patients (i.e., intubating, resuscitating or closely examining the oropharynx)
• Airline passengers sitting immediately on either side of the case (but not across the aisle) when the total time spent aboard the aircraft was at least 8 hours

Table 9. Chemoprophylaxis* for Close Contacts of Individuals with Meningococcal Infection

For susceptible close contacts of known serogroup C disease, meningococcal C conjugate vaccine is preferred because of longer duration of protection and induction of immunologic memory; however, polysaccharide vaccines will provide protection in older children and adults during the 1-year period of increased risk. Polysaccharide vaccines are ineffective against serogroup C disease in children < 2 years of age, and meningococcal C conjugate vaccine should be given to children in that age group. Bivalent (A, C) or quadrivalent (A, C, Y, W135) polysaccharide vaccine should be considered for susceptible close contacts of cases with IMD known to be caused by serogroup A; quadrivalent polysaccharide vaccine should be considered for susceptible close contacts of cases of serogroup Y or W135 disease. No vaccine is currently available for contacts of individuals with serogroup B disease, and vaccine is not recommended for contacts of cases of disease in which the serogroup has not been determined. For decisions regarding persons previously immunized, please refer to the section on Booster Doses and Re-Immunization.

High-risk groups

Routine immunization with meningococcal vaccine is recommended for certain groups at increased risk of meningococcal disease. Such individuals include those with functional or anatomic asplenia (vaccines should be given at least 2 weeks before splenectomy) and people with complement, properdin or factor D deficiency. More durable protection against serogroup C meningococcal disease may be achieved by giving meningococcal C conjugate vaccine to these individuals in addition to polysaccharide vaccine. If the conjugate C vaccine is given first, a period of at least 2 weeks before immunization with polysaccharide vaccine is recommended to allow time for generation of an antibody response, as it is possible that a shorter interval may interfere with this response. If the polysaccharide vaccine is given first, an adequate response to conjugate vaccine has been observed after a delay of 6 months in adults. This is the recommended interval until further data are available. Children < 2 years of age with these immunodeficiencies should be immunized with conjugate vaccine as described in the routine infant schedule above, and should then receive polysaccharide vaccine at 2 years of age. Please refer to the Immunization of Immunocompromised Persons chapter for further information.

Routine immunization with the quadrivalent polysaccharide vaccine is recommended for military recruits and may be considered for other groups or institutions where there is an increased risk of disease. The choice between conjugate or polysaccharide meningococcal vaccine would depend on whether the individual is staying in Canada (conjugate C preferred as this strain is currently the most prevalent one circulating) or traveling to or working in areas where additional serogroups are prevalent (quadrivalent polysaccharide preferred).

Although there are no data to suggest an increased risk of meningococcal disease among students in Canada living in residential accommodation, an elevation in risk has been observed in the United States among freshmen living in dormitory accommodation and in the United Kingdom among university students in catered hall accommodation. Clusters of cases of meningococcal disease in students have been reported in a number of countries, and carriage rates increase rapidly among freshmen during the first week of term in the U.K. In this age group in Canada, there is an increase in the rate of meningococcal disease; the risk is mainly from serogroup C disease. NACI recommends that all Canadian adolescents and young adults be immunized with meningococcal C conjugate vaccine. As students attending colleges and universities are included in this recommendation by virtue of their age, there is no need to make special recommendations for this group of people.

Laboratory and health care workers

Nosocomial transmission of IMD is very uncommon, especially when routine practices and droplet (large) and contact precautions are followed to prevent the transmission of IMD. In rare instances, direct contact with respiratory secretions of infected persons (e.g., during mouth-to-mouth resuscitation) has resulted in transmission to HCWs. Therefore, HCWs are considered as close contacts only if they have had intensive, unprotected contact (without wearing a mask) with infected patients (e.g., intubating, resuscitating or closely examining the oropharynx). It is recommended that HCWs use barrier precautions to avoid direct contact with respiratory secretions of patients with meningococcal disease during the first 24 hours after commencement of antibiotic therapy. Routine immunization of HCWs is not recommended.

Laboratory-acquired meningococcal infection is believed to be rare. However, the rate of disease in a U.S. survey conducted by the Centers for Disease Control and Prevention (CDC), Atlanta, was higher than expected among microbiology laboratory workers dealing with N. meningitidis cultures in the absence of any breaches in laboratory safety practices. Research, industrial and clinical laboratory personnel who are routinely exposed to N. meningitidis should be offered immunization with quadrivalent polysaccharide vaccine and may be additionally offered conjugate C vaccine to provide enhanced protection against serogroup C meningococcal infection (see Booster Doses and Re-immunization).

Outbreaks of meningococcal disease

Consultation with public health officials and/or experts in communicable disease is important in the assessment and control of meningococcal disease outbreaks in various settings, and reference to published guidelines should be made. Most recent outbreaks of meningococcal disease in Canada have involved teenagers and young adults suffering from serogroup C disease. Such outbreaks may be controlled by the use of conjugate C vaccine or polysaccharide (either bivalent or quadrivalent) vaccine. The use of conjugate C vaccine may be preferable because of induction of immunologic memory and prolonged duration of protection. In those previously immunized with a polysaccharide vaccine for whom re-vaccination is considered, conjugate C vaccine is preferred (see Booster Doses and Re-immunization), as further immunization with polysaccharide vaccine may induce immunologic hyporesponsiveness, although the clinical significance of this phenomenon is unknown. In younger children (< 10 years) conjugate C vaccine is recommended for control of outbreaks in view of its superior immunogenicity and efficacy in this age group.

For the control of outbreaks of serogroup A meningococcal disease, which are exceedingly rare in Canada, bivalent or quadrivalent polysaccharide vaccine is recommended as a single dose for people ≥ 2 years of age. Children aged 3 to 23 months should receive two doses of vaccine given 2 to 3 months apart. For the control of outbreaks associated with serogroup Y or W135 meningococci, one dose of quadrivalent polysaccharide vaccine is recommended for people ≥ 2 years of age.

International travel

Quadrivalent polysaccharide vaccine is recommended for Canadian international travellers when meningococcal vaccine is indicated or required. Conjugate C vaccine alone is not appropriate for protection of travellers, as it does not protect against serogroup A, which is endemic in selected regions of the world, or serogroup W135 disease. Pilgrims making the annual Hajj pilgrim age to Mecca should receive a single dose of quadrivalent vaccine at least 2 weeks before departure. Despite the frequency of travel to regions where meningococcal epidemics occur, disease in travellers appears to be very unusual.

Schedule and dosage

Meningococcal C conjugate vaccine is given as a 0.5 mL dose. The recommended schedule differs depending upon the vaccine used and the age at vaccination (see Recommended Usage).

Bivalent and quadrivalent polysaccharide vaccines are given as a 0.5 mL dose to people aged ≥ 2 years. For specific protection against serogroup A meningococcal disease these vaccines may be given from 3 months of age, but two doses are required 2 to 3 months apart in infants 3-23 months of age.

There are no published data related to the interchangeability of the three conjugated meningococcal C vaccines, but the vaccines have been used safely in this manner in the U.K. without a noticeable decrease in efficacy. When possible, the infant series should be completed with the same vaccine.

Route of administration

Meningococcal C conjugate vaccine is to be given by intramuscular injection at a separate anatomic site from that of other co-administered vaccines.

Bivalent and quadrivalent polysaccharide vaccines are to be given by subcutaneous injection to people aged ≥ 2 years at a separate anatomic site from that of other co-administered vaccines.

Booster doses and re-immunization

Re-immunization with meningococcal C conjugate vaccines is not thought to be necessary at present, although there are insufficient data to predict persistence of immunologic memory (and presumed protection).

The need for, or effectiveness of, re-immunization with meningococcal polysaccharide vaccine has not been fully established. Repeated immunization may induce immunologic hyporesponsiveness to polysaccharide vaccines, although the clinical significance of this phenomenon is unknown. Re-immunization should be considered, according to Table 10, for those continuously or repeatedly exposed to serogroup A disease who have been previously immunized with bivalent or quadrivalent vaccine, particularly for children initially immunized at < 5 years of age. Children or adults with immunodeficiencies resulting in increased risk of meningococcal disease caused by serogroup A, Y or W135 meningococci may be re-immunized with quadrivalent polysaccharide vaccine according to Table 10.

Individuals who have previously received polysaccharide vaccine may receive conjugate C vaccine for continued protection against serogroup C disease. Since an adequate response to conjugate vaccine has been observed with a delay of 6 months after immunization with purified polysaccharide vaccine in adults, this remains the recommended interval until further data are available. In other circumstances, when conjugate C vaccine has already been administered and protection against serogroup A, Y or W135 meningococci is required, a period of 2 weeks should elapse before immunization with polysaccharide vaccine to allow time for generation of an antibody response and avoid possible interference with this response by the polysaccharide vaccine.

Table 10. Recommended Interval Between Repeat Doses of Meningococcal Polysaccharide Vaccines in Individuals Repeatedly or Continuously Exposed to Serogroup A, Y, W135 Disease

Serologic testing

There is no indication for pre- or post-immunization serology.

Storage requirements

All of the available products should be stored at a temperature between +2° C and +8° C and must not be frozen. The vaccines that need to be reconstituted should be done so immediately before use according to the manufacturer's instructions.

Simultaneous administration with other vaccines

If necessary or convenient, meningococcal C conjugate vaccine may be administered at the same time as IPV, DTaP, Td, Tdap, Hib, hepatitis B, MMR, varicella or pneumococcal conjugate vaccines, at separate sites and with a separate needle and syringe. The meningococcal polysaccharide vaccine may also be given simultaneously with other vaccines, except the meningococcal conjugate vaccine, at a separate location and using a separate needle and syringe.

When used after administration of the meningococcal C conjugate vaccine, a delay of at least 2 weeks is recommended before immunization with meningococcal polysaccharide vaccine to allow time for generation of an antibody response, as it is possible that a shorter interval may interfere with this response. If the meningococcal polysaccharide vaccine has been administered first, an adequate response to conjugate vaccine has been observed after a delay of 6 months in adults. This is the recommended interval until further data are available.

Adverse reactions

Conjugate vaccines

Mild reactions, including local reactions (redness, tenderness, and swelling at the injection site), occur in up to 50% of vaccinees, irritability in up to 80% of infants and fever of > 38° C in up to 9% when other vaccines were administered. Headaches and malaise occur in up to 10% of older children and adults. Severe reactions are very uncommon and include systemic allergic reactions in < 0.01%.

Purified polysaccharide vaccines

Both bivalent and quadrivalent polysaccharide vaccines have been used extensively in many countries for mass immunization programs and to immunize military recruits, people who are immunocompromised and travellers. Mild reactions to the vaccines include pain and redness at the injection site in up to 50% and transient fever in 5%, particularly infants. Severe reactions to these vaccines are very unusual but include systemic allergic reactions (urticaria, wheezing and rash) at a rate of ≤ 0.1/100,000 doses, anaphylaxis in < 1 per million doses and occasional neurologic reactions. These vaccines have an established safety record. No adverse events have been documented during pregnancy or in newborn infants of immunized mothers.

Contraindications and precautions

Contraindications

Conjugate vaccines and polysaccharide vaccines are contraindicated in people with a known hypersensitivity to any component of the vaccine and in those who have shown signs of hypersensitivity after previous administration of the vaccine.

Precautions

Meningococcal C conjugate vaccine will not protect against meningococcal diseases caused by any of the other types of meningococcal bacteria (A, B, 29e, H, I, K, L, W135, X, Y or Z, including non-typed). Complete protection against meningococcal serogroup C infection cannot be guaranteed. Conjugate vaccines containing CRM197 or tetanus toxoid should not be considered as immunizing agents against diphtheria or tetanus, and no changes in the schedule for administering vaccines containing diphtheria or tetanus toxoids are recommended. Conjugate C vaccine has not been studied in pregnant women; however, in specific circumstances in which the benefits outweigh the risks, its use can be considered.

Other considerations

The effect of meningococcal C conjugate vaccine on meningococcal population biology is unknown. With the use of widespread meningococcal immunization, close epidemiologic and laboratory-based surveillance is necessary to monitor changes in meningococcal biology and epidemiology.

New quadrivalent protein-polysaccharide conjugate vaccines are in development. At the time of publication of this edition of the Guide, Menactra^TM* (quadrivalent meningococcal conjugate vaccine, Sanofi Pasteur Ltd) had just been approved for use in Canada. Please see future NACI statements for recommendations. These vaccines might provide broad protection against the vaccine serogroups after introduction of an infant immunization program; they could presumably replace the currently used polysaccharide vaccines. None of these vaccines offers protection against serogroup B meningococci, a feature that limits the impact that any meningococcal vaccine can have on the invasive meningococcal disease burden, especially in children.

* Statement on conjugate meningococcal vaccine for serogroups A,C, Y and W135

Selected references

Anderson EL, Bowers T, Mink CM et al. Safety and immunogenicity of meningococcal A and C polysaccharide conjugate vaccine in adults. Infection and Immunity 1994;62(8):3391-95.

Borrow R, Fox AJ, Richmond PC et al. Induction of immunological memory in UK infants by a meningococcal A/C conjugate vaccine. Epidemiology and Infection 2000;124(3):427-32.

Borrow R, Southern J, Andrews N et al. Comparison of antibody kinetics following meningococcal serogroup C conjugate vaccine between healthy adults previously vaccinated with meningococcal A/C polysaccharide vaccine and vaccine-naive controls. Vaccine 2001;19(23-24):3043-50.

Centers for Disease Control and Prevention. Laboratory-acquired meningococcemia - California and Massachusetts. Morbidity and Mortality Weekly Report 1991;40(3):46-7, 55.

Centers for Disease Control and Prevention. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report 2005;54(RR-7):1-21.

Choo S, Zuckerman J, Goilav C et al. Immunogenicity and reactogenicity of a group C meningococcal conjugate vaccine compared with a group A+C meningococcal polysaccharide vaccine in adolescents in a randomised observer-blind controlled trial. Vaccine 2000;18(24):2686-92.

Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on meningococcal vaccination for travellers. Canada Communicable Disease Report 1999;25(ASC5):1-12.

Cooke RP, Riordan T, Jones DM et al. Secondary cases of meningococcal infection among close family and household contacts in England and Wales, 1984-7. British Medical Journal 1989;298(6673):555-58.

De Wals P, De Serres G, Niyonsenga T. Effectiveness of a mass immunization campaign against serogroup C meningococcal disease in Quebec. Journal of the American Medical Association 2001;285(2):177-81.

English M, MacLennan JM, Bowen-Morris JM et al. A randomised, double-blind, controlled trial of the immunogenicity and tolerability of a meningococcal group C conjugate vaccine in young British infants. Vaccine 2000;19(9-10):1232-38.

Erickson L, De Wals P. Complications and sequelae of meningococcal disease in Quebec, Canada, 1990-1994. Clinical Infectious Diseases 1998;26(5):1159-64.

Fairley CK, Begg N, Borrow R et al. Conjugate meningococcal serogroup A and C vaccine: reactogenicity and immunogenicity in United Kingdom infants. Journal of Infectious Diseases 1996;174:1360-63.

Gilmore A, Stuart J, Andrews N. Risk of secondary meningococcal disease in health-care workers. Lancet 2000;356(9242):1654-55.

Gold R, Lepow ML, Goldschneider I et al. Immune response of human infants of polysaccharide vaccines of group A and C Neisseria meningitidis. Journal of Infectious Diseases 1977;136:S31-5.

Hastings L, Stuart J, Andrews N. A retrospective survey of clusters of meningococcal disease in England and Wales, 1993 to 1995: estimated risks of further cases in household and educational settings. Communicable Disease Report 1997;7(13):R195-200.

MacDonald NE, Halperin SA, Law BJ et al. Induction of immunologic memory by conjugated vs plain meningococcal C polysaccharide vaccine in toddlers: a randomized controlled trial. Journal of the American Medical Association 1998;280(19):1685-89.

MacLennan J, Obaro S, Deeks J et al. Immune response to revaccination with meningococcal A and C polysaccharides in Gambian children following repeated immunisation during early childhood. Vaccine 1999;17(23-24):3086-93.

MacLennan J, Obaro S, Deeks J et al. Immunologic memory 5 years after meningococcal A/ C conjugate vaccination in infancy. Journal of Infectious Diseases 2001;183(1):97-104.

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 [see comments]. Journal of the American Medical Association 2000;283(21):2795-801.

National Advisory Committee on Immunization. Statement on recommended use of meningococcal vaccines. Canada Communicable Disease Report 2001;27(ACS-6).

Neal KR, Nguyen-Van-Tam J, Monk P et al. Invasive meningococcal disease among university undergraduates: association with universities providing relatively large amounts of catered hall accommodation. Epidemiololgy and Infection 1999;122(3):351-57.

PHLS Meningococcal Infections Working Group and Public Health Medicine Environmental Group. Control of meningococcal disease: guidance for consultants in communicable disease control. Communicable Disease Report 1995;5(13):R189-95.

Public Health Agency of Canada. Guidelines for the prevention and control of meningococcal disease. Canada Communicable Disease Report 2005;31(S1):1-26.

Ramsay ME, Andrews N, Kaczmarski EB et al. Efficacy of meningococcal serogroup C conjugate vaccine in teenagers and toddlers in England. Lancet 2001;357(9251):195-96.

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. Journal of Infectious Diseases 2001;183(1):160-63.

Richmond P, Borrow R, Miller E et al. Meningococcal serogroup C conjugate vaccine is immunogenic in infancy and primes for memory. Journal of Infectious Diseases 1999;179(6):1569-72.

Richmond P, Goldblatt D, Fusco PC et al. Safety and immunogenicity of a new Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in healthy adults. Vaccine 1999;18(7-8):641-46.

Richmond P, Kaczmarski E, Borrow R et al. Meningococcal C polysaccharide vaccine induces immunologic hyporesponsiveness in adults that is overcome by meningococcal C conjugate vaccine. Journal of Infectious Diseases 2000;181(2):761-64.

Trotter CL, Andrews NJ, Kaczmarski EB et al. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 2004;364(9431):365-67.

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