An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)*

STATEMENT ON RECOMMENDED USE OF MENINGOCOCCAL VACCINES

PDF Version (718 KB)

Preamble

The National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific, and public-health advice relating to immunization. Health 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. Persons administering or using 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 licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have only sought approval of the vaccine(s) and provided evidence as to its safety and efficacy when used in accordance with the product monographs.

Introduction

Neisseria meningitidis causes sporadic cases and outbreaks of meningococcal disease (invasive) in Canada at a rate of approximately one per 100,000 population per year with the greatest disease burden in children < 5 years of age⁽¹⁾. This Gram negative diplococcus is surrounded by a polysaccharide capsule, the chemical composition of which defines the serogroup of the organism. Five serogroups (A, B, C, Y and W-135) of N. meningitidis account for almost all cases of invasive disease caused by this organism in Canada⁽¹⁾. Currently available purified capsular polysaccharide vaccines can provide some protection against serogroups A, C, Y and W-135 but have limited immunogenicity in early childhood and provide a relatively short period of protection. A new vaccine - consisting of serogroup C capsular polysaccharide conjugated to a protein carrier - is immunogenic from early infancy, induces immunologic memory and protects against serogroup C meningococcal disease. Since the epidemiology of serogroup C meningococcal disease is unpredictable and varies from region to region, the impact of implementation of this new vaccine may differ over time depending on location.

Epidemiology of meningococcal disease in Canada

Case definition

In Canada, meningococcal disease is reportable at the national level. A confirmed-case is currently defined as one with clinical features compatible with meningococcal disease with laboratory confirmation of infection through isolation of N. meningitidis from a normally sterile site (blood, cerebrospinal fluid [CSF], joint, pleural or pericardial fluid) or demonstration of N. meningitidis antigen in CSF. A probable case is defined as invasive disease with purpura fulminans or petechiae in the absence of a positive blood culture and no other apparent cause⁽²⁾. Some provinces and territories are now collecting data on cases detected by the demonstration of meningococcal DNA in blood or CSF using polymerase chain reaction (PCR). National case definitions are currently being revised to take into account new diagnostic techniques.

Diagnosis and bacterial typing

Laboratory confirmation of a clinical diagnosis of meningococcal disease is important for regional and national surveillance and in the identification and management of outbreaks. Gram stain of a skin aspirate, blood smear, CSF or other body fluids is helpful in diagnosis. Culture of blood, cerebrospinal fluid (in the absence of contraindications to lumbar puncture), and skin aspirate may all be considered for isolating bacteria for identification. Isolates recovered from throat swab culture may also assist in bacterial identification. Latex agglutination antigen testing is a useful adjunct in some cases although sensitivity ranges from 32% to 96%⁽³⁾. Data from Europe suggest that blood culture may fail to isolate meningococci in as many as 35% to 60% of cases confirmed using rapid molecular diagnosis^(4-6). PCR is now available in several centres in Canada including the National Microbiology Laboratory (NML), Health Canada for rapid molecular diagnosis of meningococcal infection and serogroup identification. PCR can distinguish serogroups A, B, C, Y and W-135 meningococci, on whole blood, cerebrospinal fluid or fluids from alternate normally sterile sites (Dr. R. Tsang, National Microbiology Laboratory, Winnipeg: personal communication, 2001)⁽⁷⁾. PCR has greater sensitivity than culture, particularly if there has been prior administration of antibiotics^(4-6,8) (Dr. A.J. Pollard, University of British Columbia, Vancouver: unpublished observations, 2001).

Several methods are used to track the epidemiology of N. meningitidis in Canada. An antibody or PCR method can be used to determine the serogroup, the capsular polysaccharide type of the organism. Serotyping and serosubtyping refers to the use of antibodies to further classify bacteria by detecting antigenic variation in proteins located in the outer membrane of the organism^(9,10). Multilocus enzyme electrophoresis (MLEE) divides bacteria into closely related groups based on the electrophoretic mobility of various bacterial highly conserved cytoplasmic - "housekeeping" - proteins^(11,12). Multilocus sequence typing (MLST) detects clones of meningococci based on differences in the nucleotide sequence of the genes that encode various housekeeping proteins⁽¹³⁾. In pulse field gel electrophoresis (PFGE) restriction endonucleases are used to fragment bacterial DNA before separating DNA on an electrophoretic gel. Patterns of separation of the DNA fragments allow comparison of genetic relatedness between different isolates⁽¹⁴⁾.

Meningococcal disease is endemic in Canada with periods of increased activity occurring roughly every 10 to 15 years, but with no consistent pattern. The incidence of meningococcal disease has varied considerably with different serogroups, age groups, geographic location and time. The last major epidemic of meningococcal disease occurred in 1940-1943 (serogroup A), when the peak incidence was close to 13 per 100,000 population per year. Since then, the overall incidence of disease has remained <= 2 per 100,000 per year (range 0.5 to 2.1). There have been sporadic localized outbreaks and periods of elevated activity (serogroup C) during 1989-1993 and 2000-present^(1,15,16).

Case by case data for meningococcal disease is available from 1985 to 2000. During this period, there were an average of 303 cases of the disease reported per year in Canada. Cases of meningococcal disease occur year round, but the majority present in the winter months. Overall, the incidence (per 100,000 population) has been highest among children < 1 year of age (14.8), followed by children 1 to 4 years of age (4.2) and adolescents 15 to 19 years of age (2.3). Age-specific incidences for all other age groups ranged from 0.5 to 1.2 per 100,000 population per year. Of the 4,483 cases reported in 1985-2000, children < 1 year of age accounted for 18% of cases (mean of 50 cases per year), those 1 to 4 years of age accounted for 21% (mean of 58 cases per year), those 5 to 9 years of age accounted for 7% (mean of 20 cases per year), those 10 to 14 years of age accounted for 8% (mean of 22 cases per year), those 15 to 19 years of age accounted for 14% (mean of 41 cases per year). One third of cases occurred in persons >= 20 years of age.

Of the small numbers of N. meningitidis isolates characterized from 1971 to 1974, serogroups A and C were the most frequently identified⁽¹⁷⁾. From 1975 to 1989, serogroup B predominated. The majority of the isolates were serotype 2b, 4 and 15 and the most common subtype was P1.2.⁽¹⁸⁾. In 1986 a new clone of serogroup C, serotype 2a characterized by MLEE as electrophoretic type 15 (ET-15), was identified in Canada for the first time⁽¹⁸⁾. Since then serogroups B and C have been responsible for most of the cases of endemic meningococcal disease in Canada. However, serogroup C isolates have almost exclusively been responsible for clusters or outbreaks in schools and communities.

The overall case fatality rate for meningococcal disease (all serogroups) rose from 9% in 1985 to 12% in 1993, with the emergence of the more virulent serogroup C ET-15 clone. The case fatality rate then declined steadily to 7% in 1998 and began to increase again in 1999 (11%), reflecting the fluctuations in serogroup C disease activity^(1,15).

Serogroup C epidemiology

From 1985 to 2000, there were an average of 111 group C cases reported per year (range 16 to 247) in Canada, with a peak in the incidence in 1992 at 0.9 per 100,000 population. The highest incidence rate (per 100,000 population) for serogroup C is seen in children < 5 years of age (2.9 and 1.6 respectively for infants < 1 year, and children 1 to 4 years), followed by those 15 to 19 years of age (1.23). In other age groups the highest rate is < 1.0 per 100,000 population.

The features of serogroup C disease include the occurrence of outbreaks in schools, a high incidence in adolescents and young adults (median age 15 years), a higher proportion of cases presenting as septicemia (88% vs. 79%)⁽¹⁹⁾, and a higher case fatality rate as compared to group B disease during the same period (14% vs. 6%)^(15,19). A retrospective study in Quebec for cases presenting during 1990 to 1994 showed that 15% of survivors of serogroup C disease had sequelae (skin scars 12%, amputations 5%, hearing loss 2%, renal problems 1% and other sequelae 4%) with the group between 20 to 59 years of age suffering the highest mortality and morbidity.

The emergence of the serogroup C ET-15 clone was associated with an increase in localized outbreaks (1989-1993) and in the proportion of endemic disease caused by this serogroup (25% of cases in 1985 vs. 64% in 1992). This increase in activity was first seen in Ontario in the 1988-1989 season, followed by the Atlantic provinces and Quebec, with the western provinces increasing later. Intensive selective vaccination campaigns with polysaccharide vaccines, ranging from high schools to larger populations were carried out between 1991-1993 in Ontario, Quebec, Prince Edward Island and British Columbia^(19-23). Several campaigns targeting persons > 1 year of age proved insufficient to curb continuing outbreak cluster activity in Quebec, and a province-wide mass immunization campaign was launched in November 1992, in which 84% of persons 6 months to 20 years of age were immunized with polysaccharide vaccines⁽²⁴⁾.

After a period of declining incidence from 1994 to 1999, there was a resurgence of serogroup C disease beginning in January 2000 with 101 confirmed-cases reported in 2000 and 87 in the first 6 months of 2001. Localized outbreaks, predominantly in adolescents and young adults, have been reported by five provinces (Alberta, British Columbia, Manitoba, Quebec and Ontario). In Quebec, cases have occurred in populations previously vaccinated in 1991-1992 (Dr. M. Douville-Fradet, Ministère de la santé et des services sociaux, Québec: personal communication, 2001). Vaccine campaigns which generally targeted high school-aged children and extending to a varying degree to include younger children and young adults were launched in the following areas: Alberta (province-wide campaign); Abbotsford, British Columbia; Winnipeg, Manitoba; London, Ontario, and Québec City, Quebec. Prior to May 2001 all vaccine campaigns used polysaccharide vaccines. British Columbia, Ontario and Quebec were the first provinces to use a conjugate meningococcal vaccine that was newly licensed in Canada in April 2001. Data from the NML showed that group C isolates in 2001 were predominantly of serotype 2a (91%) and the most common serosubtype amongst serotype 2a strains was P1.2,5. Since February 2001, serosubtype P1.1,7 has been increasingly identified in serotype 2a group C isolates from Quebec and Ontario. Of the 99 serogroup C invasive isolates tested at NML from 1 January, to 18 May, 2001, 96% belonged to ET-15.

Serogroup B epidemiology

There has been less fluctuation in the incidence of serogroup B disease over time compared to serogroup C. Children < 5 years of age account for the majority of serogroup B cases (median = 2 years of age, 1985-2000) and they have the highest incidence (per 100,000 population), with rates of 8.9 for infants < 1 year and 1.3 for children 1 to 4 years of age.

Serogroup B cases are more likely to present as meningitis (18%) as compared to group C cases. The case fatality rate for group B cases is 6%, with 3% of survivors developing physical sequelae. The highest morbidity and mortality occurs at the extremes of age⁽¹⁹⁾. In contrast to serogroup C isolates, recent serogroup B strains have showed considerable genetic diversity as reflected in the many different combinations of serotype and serosubtype antigens and varied electrophoretic types⁽²⁵⁾.

Serogroup Y Epidemiology

An increasing incidence in serogroup Y disease has been observed in the United States (U.S.) during the past decade⁽²⁶⁾. No such trends have been observed in Canada, where serogroup Y represented 7% of isolates characterized from 1985 to 2000 and serogroup-specific incidence remained relatively stable at an average of 0.06 per 100,000 population (mean: 14 confirmed-cases per year, range: 0 to 34 cases per year). Of note, however, is the recent increase in the incidence of serogroup Y disease in Ontario, accounting for 30% of laboratory confirmations (10 of 33 isolates) from the province during the first 4 months of 2001. Serogroup Y disease has tended to affect older adults (median: 25 years of age) and is associated with a case fatality rate (10%) intermediate between that of serogroup C and serogroup B cases.

Serogroup A and serogroup W-135 epidemiology

Neither serogroup A nor W-135 meningococcal disease are commonly reported in Canada. Since the epidemics of the early 1940's, the incidence of serogroup A disease has declined dramatically⁽¹⁷⁾. From 1985 to 2000, there were a total of 44 cases with invasive serogroup A disease reported (range 0 to 8 cases per year), with an average incidence of 0.01 per 100,000 population. There were no deaths attributed to serogroup A disease. During the same time period, there were a total of 101 cases with invasive serogroup W-135 disease reported (range 1 to 12 cases per year), with an average incidence of 0.02 per 100,000 population. The case fatality for serogroup W-135 was 5%. Median ages for serogroup A and W-135 cases were 18 and 19 years of age respectively. Serogroup A and W-135 remain risks for travellers to meningococcal-endemic areas and to Mecca, Saudi Arabia during the Hajj (see below).

Antibiotic resistance

The occurrence of N. meningitidis with decreased susceptibility to penicillin (DSP) has been observed in some areas of Canada. An outbreak caused by a single clone of N. meningitidis with DSP was reported in Saskatchewan in 1995⁽²⁷⁾. From 1997 to 2000, the percentage of invasive meningococcal isolates with DSP in Ontario increased from 10% to 35% (minimum inhibitory concentration [MIC] >= 0.12 mg/L), with serogroup W-135 having a much higher rate of DSP than other serogroups⁽²⁸⁾. The clinical significance of these meningococci that are relatively resistant to penicillin is uncertain, but there have been some rare case reports of failure of penicillin therapy for meningococcal disease caused by DSP strains in other countries⁽²⁹⁾.

Global epidemiology of meningococcal disease

Approximately 500,000 cases of endemic meningococcal disease are thought to occur annually worldwide⁽³⁰⁾, with many more cases reported when there are epidemics. There are marked differences in the incidence of meningococcal disease in different countries. The annual incidence varies between 1 and 12 per 100,000 population in industrialized nations, but may reach 10 to 20 per 100,000 in non-industrialized nations and over 200 per 100,000 during epidemics^(31,32). The reason for the high incidence of disease in some developed countries (e.g., United Kingdom [U.K.] 4/100,000; New Zealand, 12/100,000) and the low incidence in others (e.g., France, 0.6/100,000; U.S.1/100,000 and Canada 1/100,000) are unknown^(1,26,33,34). The majority of sporadic cases in developed countries are attributed to serogroup B and serogroup C meningococci. However, as mentioned above, in the U.S. serogroup Y now accounts for over 30% of cases⁽²⁶⁾. Elevated rates of (hyperendemic) serogroup B disease were noted in Norway and Iceland in the 1970's⁽³⁵⁾ and more recently in the Pacific Northwest U.S.⁽³⁶⁾, and a prolonged outbreak has continued for 10 years among the Maori and Pacific Islander ethnic groups in New Zealand⁽³⁷⁾. Recent global epidemiologic data is summarized in a report available from the World Health Organization website*.

Epidemics of serogroup A meningococcal disease have occurred in sub-Saharan Africa in an area known as the 'meningitis belt'⁽³²⁾ every 5 to 10 years for most of the past century⁽³⁸⁾. More recently, countries in Africa outside the meningitis belt have been affected by epidemic disease as a result of cross-border spread⁽³⁹⁾. Current policy in sub-Saharan Africa is to implement population vaccine programs only when numbers of cases reach the epidemic threshold for that region⁽⁴⁰⁾, although a new initiative is investigating the use of new protein-polysaccharide conjugate vaccines to provide population immunity through infant immunization⁽⁴¹⁾. Meningococcal disease is very unusual amongst travellers to Africa, however, the intercontinental spread of African clones has been clearly documented⁽¹¹⁾. This spread may have occured when healthy travellers with nasophareangeal carriage of N. meningitidis moved from one area to another. Cyclic epidemic serogroup A meningococcal disease has also occurred in China every 10 years for much of the past century^(42,43), and two pandemics of disease caused by clones of meningococci originating in China have been described⁽⁴⁴⁾. Outbreaks of serogroup A meningococcal disease in Mongolia⁽⁴⁵⁾, India^(44,46) and Nepal⁽⁴⁷⁾ have been described in the last 2 decades. Both serogroup A and W-135 meningococcal infections have affected pilgrims to Mecca in three separate outbreaks in the past 15 years with secondary cases associated with the pilgrims' return to their home countries^(46,48-50).

Risk factors

Over half of cases of meningococcal disease affect infants, children and adolescents < 19 years of age. The greatest disease burden is in infants and children < 5 years of age, with a peak incidence at 6 to 24 months of age^(1,16,26). There is an additional smaller peak during second decade of life, and the early part of the third decade. Disease is most common in late winter and early spring^(1,16,26), although sporadic cases may occur year round. The attack rate for household contacts exposed to patients who have sporadic meningococcal disease has been estimated to be four cases per 1,000 persons exposed, which is 500 to 1,000 times greater than in the general population⁽⁵¹⁾. Recent influenza A infection may also increase the risk of meningococcal infection^(52,53), and active and passive smoking are also associated with a higher incidence of disease^(54-57). Conditions of overcrowding likely contribute to increased meningococci transmission, thus contributing to outbreaks and epidemics of disease. Bar and nightclub patronage during outbreaks may also increase the risk of disease through close contact with potential carriers^(58-60). Certain immunodeficiencies result in a marked increase in the risk of meningococcal disease, these may include complement deficiencies (and properdin deficiency)^(61,62), hypogammaglobulinaemia^(63,64), anatomic and functional asplenia (e.g., sickle-cell disease)⁽⁶⁵⁾. Individuals with human immunodeficiency virus may also be at increased risk for sporadic meningococcal disease, but not nearly to the degree associated with their risk of infection with other encapsulated organisms such as Streptococcus pneumoniae⁽⁶⁶⁾. In the U.S., risk factors for meningococcal disease include ethnic origin and socio-economic status^(26,67). However, these factors are more likely to reflect differences in other known risks such as household crowding, urban residence, and exposure to tobacco smoke⁽⁶⁸⁾. At this point in time, our ability to predict the changing epidemiology of meningococcal disease is very limited.

Clinical spectrum

The most common form of meningococcal infection is asymptomatic nasopharyngeal carriage. Rates of carriage are low during early childhood, highest in late adolescence and during early adulthood, and may range from 10% to 30% in adolescents and adults^(69,70). Meningococcal disease usually presents as a febrile illness with features of meningitis or septicemia (meningococcemia), or both, and a characteristic non-blanching rash⁽⁷¹⁾. The clinical presentation of these syndromes range from a mild illness to a fulminant and fatal form (i.e., septic shock or meningitis with raised intracranial pressure). Occult bacteremia with N. meningitidis is also recognized⁽⁷²⁾. Thirty to fifty per cent of cases have meningitis alone, 7% to 10% have features of septicemia alone, and 40% present a mixed picture of meningitis with septicemia⁽⁷³⁾. Other clinical syndromes occur including primary meningococcal conjunctivitis, pneumonia (notably serogroup Y), arthritis and peritonitis. Meningococcal meningitis (mortality: 5%), in the absence of signs of meningococcemia, has a better prognosis than meningococcal septicemia (mortality 20% to 40%)^(73,74). Overall mortality is approximately 10% in most countries, including Canada^(1,26). Mortality rates have changed little in recent years⁽⁷⁵⁾; and, though they are similar across various populations, early and optimal management and specialist pediatric intensive care may reduce fatality in children with severe illness from 25% predicted mortality to a rate < 5% (Dr. A.J. Pollard, University of British Columbia, Victoria: personal communication, 2001).

Control of meningococcal disease

Guidelines on the control of meningococcal disease in Canada have been published previously⁽⁷⁶⁾ and are currently being revised. These guidelines cover the management of sporadic cases, outbreaks, and elevated rates of meningococcal disease (hyperendemic disease).

Meningococcal vaccines

Meningococcal polysaccharide vaccines

Protection against serogroup A and C meningococci is predicted by the presence of bactericidal antibodies, in serum, directed against the polysaccharide capsule that surrounds the organism⁽⁷⁷⁾. These antibodies may be induced by vaccination with purified meningococcal polysaccharide. For serogroups Y and W-135 meningococci, it is believed that the anti-capsular bactericidal antibody that develops after immunization⁽⁷⁸⁾ is similarly protective. The serogroup B polysaccharide is poorly immunogenic⁽⁷⁹⁾ and induces only transient low avidity antibody in humans. Subcapsular antigens are thought to be targeted by the bactericidal immune response that develops after serogroup B infection and vaccination^(80-83). No serogroup B vaccines are currently available in Canada or the U.S.

Meningococcal polysaccharide vaccines have been widely used in North America for the control of outbreaks of serogroup C meningococcal disease⁽⁸⁴⁾, and for the protection of those travelling to locations experiencing epidemic disease attributed to serogroup A meningococci. In addition, vaccination is recommended for certain individuals who may be at increased risk of meningococcal disease. Effectiveness data from several studies suggest that these vaccines achieve protection of > 85% against serogroup C meningococcal disease in children > 10 years of age and adults. However, they have a lower efficacy in children < 10 years of age and are ineffective in children < 2 years of age^(24,85-88).

Meningococcal polysaccharide vaccines are not recommended for routine immunization because they induce a T-cell independent immune response, resulting in poor immunogenicity and protection in early childhood and a short duration of protection⁽⁸⁹⁾.

Usually, only a small proportion of meningococcal disease cases can be attributed to outbreaks⁽⁹⁰⁾, or travel. Therefore, strategies aiming to reduce the overall burden of disease by only targeting high-risk groups, and travellers, cannot significantly reduce disease burden. Broad protection against meningococcal disease requires immunization against the five major disease-causing serogroups from infancy, and this cannot be achieved with the currently available polysaccharide vaccines which are poorly immunogenic in infancy.

Meningococcal protein-polysaccharide conjugate vaccines

Conjugation of meningococcal polysaccharide to a protein carrier induces T-cell dependent immune responses, as employed in the production of the successful Haemophilus influenzae conjugate vaccines and the recently available Streptococcus pneumoniae vaccines^(91-94). T cell-dependent immune responses are manifested from early infancy and imply a priming of immunologic memory so that immune responses are long-lasting. Monovalent serogroup C (MenC-conjugate) vaccines^(95-101) and bivalent serogroup A/C (MenAC-conjugate)^(102-108) polysaccharide-protein conjugate vaccines have been extensively studied, however only the monovalent serogroup C vaccines are currently marketed. Two different carrier proteins have been used for these meningococcal vaccines: a non-toxic mutant of diphtheria toxin, Cross Reacting Material 197 (CRM₁₉₇) is used in two vaccines⁽¹⁰⁹⁾ and tetanus toxoid in a third^(100,101). These vaccines were introduced into the routine infant immunization schedule in the U.K. in 1999 and, following an immunization catch-up campaign targeting all children and adolescents in the country, have had a major impact on serogroup C disease rates with estimated short-term effectiveness > 90% in all age groups⁽¹¹⁰⁾.

Combination protein-polysaccharide meningococcal vaccines containing A, C, Y and W-135 polysaccharides and pneumococcal-meningococcal combination conjugate vaccines are currently in trials and will likely replace purified polysaccharide and monovalent C-conjugate vaccines in the future.

Serogroup B vaccines

No serogroup B meningococcal vaccines are currently licensed for use in Canada or the U.S. and the meningocococcal vaccines currently available provide no protection against serogroup B disease. The serogroup B vaccines available today provide limited protection against sporadic serogroup B meningococcal disease in large-scale efficacy studies^(111-114). These vaccines have demonstrated poor immunogenicity in children < 4 years of age (who suffer the greatest burden of serogroup B disease) and also have had limited cross-protection against serogroup B strains not included in the vaccine. However, one serogroup B meningococcal vaccine is currently being used in Cuba for infant immunization, and another is planned for introduction in New Zealand to control a prolonged outbreak caused by a single serogroup B clone. Further development of these vaccines and data concerning new serogroup B meningococcal vaccines in clinical trials are anticipated.

Preparations used for immunization

Two different types of preparations of meningococcal vaccines are available: purified capsular polysaccharide vaccines (Men-Ps), and protein-polysaccharide conjugate vaccines (Men-conjugate). Products licensed in Canada include bivalent MenAC-Ps vaccines that contain capsular polysaccharides from serogroup A and C; a quadrivalent serogroup A, C, Y and W-135 vaccine (MenACYW-Ps), which contains capsular polysaccharide from serogroups A, C, Y and W-135 meningocococi; and, a newly licensed monovalent serogroup C meningococcal conjugate vaccine (MenC-conjugate) vaccine in which O-acetylated C-polysaccharide is conjugated to the protein CRM₁₉₇ (Menjugate^™; Chiron vaccines). Two other MenC-conjugate vaccines are produced (NeisVac-C^™, Baxter/North American Vaccine; and Meningitec^™, Wyeth-Lederle) and are not yet licensed in Canada. NeisVac-C^™ contains de-O-acetylated C-polysaccharide conjugated to tetanus toxoid and Meningitec^™ contains O-acetylated C-polysaccharide conjugated to the protein CRM₁₉₇. There is no effective vaccine available for serogroup B meningococci.

Storage and handling requirements

All of the available products should be stored at 2° C to 8° C and must not be frozen. Where appropriate, the vaccines should be reconstituted immediately prior to use according to manufacturer's instructions.

Route of administration and dosage

MenAC-Ps and MenACYW-Ps are given as a single 0.5 mL subcutaneous injection to children and adults > 2 years of age in a separate anatomic site from other co-administered vaccines. For specific protection against serogroup A meningococcal disease this vaccine may be given at >= 3 months of age.

MenC-conjugate is given as a single 0.5 mL dose to persons >= 1 year of age by intramuscular injection. For infants, three doses are given at 2, 4 and 6 months of age at the same time as the routine primary series administered in a separate site with a different syringe. Two doses are offered to infants from 4 to 11 months of age who missed the first dose. The minimum interval between doses is 4 weeks. Preferably, the vaccine should be administered in the anterolateral thigh in infants and in the deltoid region in older children and adults.

In persons with thrombocytopenia or other bleeding disorders, meningococcal vaccines should be administered with the smallest needle possible (see chapter on Immunization of Persons with Hemophilia and Other Bleeding Disorders, Canadian Immunization Guide, 5^th Edition⁽⁸⁹⁾).

Immunogenicity

Two different laboratory methods have been widely used to measure immunogenicity of meningococcal vaccines. The enzyme-linked immunosorbent assay (ELISA) measures antibody levels in serum from vaccinees compared with a standard serum⁽¹¹⁵⁾. Serum bactericidal activity (SBA) is a measure of the ability of serum to kill N. meningitidis in the presence of a complement⁽¹¹⁶⁾. When the complement source in SBA is human, a titre of >= 4 is considered protective based on data from adult military recruits⁽⁷⁷⁾ and may also correlate with an absolute antibody level >= 2 µg/mL as measured by ELISA⁽¹¹⁷⁾, although this may not be true for some ELISA methods^(118,119).

Purified polysaccharide vaccines

Immunogenicity of meningococcal polysaccharide vaccines, MenACYW-Ps and MenAC-Ps has been extensively studied.

Serogroup A polysaccharide. The serogroup A polysaccharide induces bactericidal antibody from 3 months of age, but levels are lower than in adults until 4 to 5 years of age^(120,121). The persistence of antibodies to the capsular polysaccharide of serogroup A N. meningitidis after vaccination is age-dependent. In infants < 12 months of age a significant antibody response is maintained for only 1 year, and in those 12 to 17 months of age titers remain elevated for 2 years. With increasing age, the decrease of vaccine-induced antibody levels is less⁽¹²²⁾, and more persistent antibody is obtained in children > 2 years of age⁽¹²³⁾. In one study, antibody titers in children vaccinated at 1 to 4 years of age, despite a booster dose 2 years after initial vaccination, had returned to prevaccination concentrations when reviewed 5 years later⁽¹²⁴⁾. Following vaccination of adults, anti-group A polysaccharide total antibody and bactericidal antibody peak at 1 month and decline rapidly over the next 2 years, but persist above baseline for 10 years⁽¹²⁵⁾.

Serogroup C polysaccharide. Although one study found that 90% of infants 3 months of age produced immune responses to serogroup C polysaccharide⁽¹²⁶⁾ others have not been able to demonstrate presence of protective titers of antibody following vaccination of infants or young children^(127,128). A study in the U.S. found that only 40% of children immunized at 18 to 24 months of age had adequate titres of bactericidal antibody in response to C polysaccharide vaccine⁽¹⁰⁴⁾. In the U.K. only 36% of children aged 4 to 62 months of age developed protective bactericidal titres >= 1:4 following immunization (only included one child < 2 years of age) during an outbreak of serogroup C disease⁽¹²⁹⁾, and in a study of response to vaccination in Montana only 18% of children 1 year of age, 32% of children 2 years of age, and 50% to 60% of children 3 to 5 years of age produced bactericidal titres >= 1:4. The results showed age-dependent differences in the production of bactericidal antibody that were not evident with ELISA antibody titres⁽¹¹⁸⁾.

The rise in bactericidal antibody to serogroup C polysaccharide is transient. During an outbreak in British Columbia, only 50% of children 2 to 6 years of age had detectable bactericidal antibody after 1 month, and only 20% by 1 year post-vaccination⁽¹³⁰⁾. In Spain, a single dose of MenAC-Ps induced bactericidal antibodies in 38% of children < 2 years of age, and 58% to 70% at 2 to 5 years of age measured after 1 month. However, after 12 months only 4% of these Spanish children had persistent bactericidal activity and none in those < 3 years of age⁽¹³¹⁾.

In adolescents, responses to MenAC-Ps are better, with 85% to 96% of youths 9 to 19 years of age in a British Columbia outbreak producing bactericidal antibody 1 month following vaccination. However, the proportion with protective levels of antibody fell to 40% to 50% after 1 year⁽¹³⁰⁾. Low concentrations of antibody are also found in more than half of recipients 6 to 8 years of age 1 year following vaccination⁽¹²³⁾. Conversely, in adults, following vaccination, anti-serogroup C polysaccharide total antibody and bactericidal activity peaked at 1 month post-vaccination and declined rapidly over the next 2 years but persisted above baseline for 10 years⁽¹²⁵⁾.

These observations have led to the recommendation that immunization be reserved for older children and adults, owing to unreliable antibody induction in children < 18 to 24 months of age^(76,89). It is clear from these data that there are benefits from serogroup C polysaccharide immunization in children < 2 years of age through induction of short-term protection against serogroup C meningococcal infection (e.g., during outbreaks), but prolonged immunity cannot be expected.

Serogroups Y and W-135 polysaccharides. Less information is available about these polysaccharides, but serogroups Y and W-135 polysaccharides are immunogenic in adults and in children > 2 years of age^(78,132-134).

The antibody responses to each of the four polysaccharides in the quadrivalent vaccine are serogroup-specific and independent. There is no cross-immunogenicity to serogroups not contained in the vaccine.

Both serogroup C and serogroup A polysaccharides may induce immunologic hyporesponsiveness in which there is a reduction in SBA compared with the previous immunization levels^{(99,103,107,126,134-139)}. The altered immunologic state occurs after a single dose of polysaccharide and has been observed in both children and adults. It is not known whether this phenomenon has clinical significance.

Protein-polysaccharide conjugate vaccines

A number of studies have examined immunogenicity of MenAC-conjugate and MenC-conjugate in children and adults. Only MenC-conjugate is currently available and immunogenicity of only the serogroup C component is considered here.

After immunization with a three-dose primary series of MenAC-conjugate or MenC-conjugate, > 95% of infants develop bactericidal antibody against serogroup C meningococci in studies conducted in Niger (immunizations at 6, 10 and 14 weeks of age)⁽¹⁴⁰⁾, Gambia⁽¹⁰⁶⁾ and the U.K. (immunizations at 2, 3 and 4 months of age)^{(95,97,98,102)}.

Following immunization of infants 7 to 11 months of age with two doses of MenC-conjugate, 100% developed SBA titres >= 1:8 (Dr. K. Cartwright and Dr. I. Jones, Chiron Corporation, California: unpublished data on file courtesy of Dr. L. Danzig, Chiron Corporation, California, 2001).

Immunization of preschool children in Canada with two doses of MenC-conjugate administered 2 months apart induced high levels of bactericidal antibody that persisted for >= 12 months⁽⁹⁹⁾. In a U.S. study MenC-conjugate induced higher ELISA and bactericidal antibody titres in toddlers than purified polysaccharide vaccine⁽¹⁰⁴⁾. In the U.K., a comparative study of the three MenC-conjugate vaccines that were available examined immunogenicity in children 12 to 18 months of age. Prior to vaccination 94% had SBA titres of < 1:4. After a single dose, 91% to 100% achieved a titre >= 1:8 and 89% to 100% achieved >= 4 fold rise in bactericidal activity⁽¹⁰¹⁾. Antibody responses were similar for all three vaccines. Based on this study, in the U.K., a single dose of vaccine was recommended for children > 1 year of age⁽¹⁴¹⁾.

In adolescents, one dose of MenC-conjugate induces higher IgG antibody levels and bactericidal antibody titres than MenAC-Ps at 1 and 12 months after a single dose⁽⁹⁶⁾. Higher salivary IgG antibody levels have also been documented with MenC-conjugate than with MenAC-Ps but similar IgA antibody levels are induced by both vaccines⁽¹⁴²⁾.

The phenomenon of immunologic hyporesponsiveness has not been observed with MenC-conjugate⁽¹³⁵⁾. In individuals rendered hyporesponsive by administration of purified polysaccharide (MenC-Ps), this phenomenon can be overcome by revaccination with MenC-conjugate^(103,136).

Protective levels of MenC-conjugate are induced within 10 days following vaccination in adults, whether or not prior MenAC-Ps has been administered⁽¹⁴³⁾.

Immunologic memory

Immunologic memory is demonstrated by a brisk antibody response to a booster dose of purified meningococcal polysaccharide after primary immunization, and also by the presence of high avidity antibodies.

Studies involving infants and young children in Gambia, comparing MenAC-conjugate with MenAC-Ps, have demonstrated that immunologic memory against serogroup C is induced by the protein-polysaccharide conjugate vaccine, MenAC-conjugate, but not by the purified polysaccharide, MenAC-Ps. Infants receiving one, two or three doses of MenAC-conjugate vaccine before 6 months of age had higher anti-serogroup C IgG and SBA levels at 18 to 24 months than controls who received MenAC-Ps. Conversely, infants who received one or two doses of polysaccharide vaccine in infancy had lower antibody levels than controls⁽¹⁰⁷⁾. In another study, children who received MenAC-Ps in infancy and either MenAC-conjugate or MenAC-Ps at 2 years of age were revaccinated at 5 years of age with MenAC-Ps. Prior vaccination with polysaccharide vaccine resulted in SBA titres lower than controls⁽¹⁰³⁾. Prior vaccination with MenAC-conjugate resulted in higher SBA for both A and C demonstrating memory priming⁽¹³⁸⁾. A single dose of MenAC-conjugate vaccine given at 6 months of age was enough to prime for memory at 5 years of age⁽¹³⁸⁾. Also in Gambia, children 1 to 4 years of age given MenAC-Ps had serogroup C antibody levels 6 years later that were the same as pre-vaccination and they were not influenced by a booster at 2 years of age⁽¹²⁴⁾.

Similarly, studies of MenC-conjugate undertaken in U.K., U.S., and Canada have demonstrated induction of immunologic memory in infants and toddlers. When U.K. infants were immunized with MenC-conjugate at 2, 3, or 4 months of age 97% demonstrated immunologic priming in response to a booster at 12 months of age⁽⁹⁸⁾. In studies in which infants were boosted at 14 months of age⁽¹⁴⁴⁾ or at 15 to 20 months of age⁽¹⁴⁵⁾ with MenAC-Ps immunologic memory could be demonstrated. Boosting of another group of infants in the third year of life following the same primary schedule also indicated immunologic priming⁽¹⁰⁸⁾.

In toddlers, 12 to 18 months of age, all three MenC-conjugate vaccines available in the U.K. induced immunological memory based on higher SBA than unvaccinated infants and higher avidity of antibody⁽¹⁰¹⁾. Canadian toddlers who were immunised at 15 to 23 months with two injections, 2 months apart, and then boosted 12 months later with MenACYW-Ps also demonstrated immunologic memory priming⁽⁹⁹⁾.

A study of MenC-conjugate immunization in 28 children with HIV infection (median CD4 count 731) found poor responses to this vaccine in this group with only 39% achieving titres >= 1:8⁽¹⁴⁶⁾.

It should be noted that it is not known whether presence of immunologic memory or persistence of high bactericidal antibody (SBA) titres is required for prolonged protection against the disease, although the standard for protection in the past has been persistence of SBA titres. Long term effects on nasophrayngeal carriage of meningococci or induction of herd immunity by MenC-conjugate vaccination have not yet been established.

Efficacy

Purified polysaccharide vaccine

MenAC-Ps and MenACYW-Ps have been widely used to control outbreaks and epidemics of serogroup A and C meningococcal disease. MenAC-Ps vaccine effectiveness at 2 months following immunization in U.S. military recruits was found to be 87% to 88%^(147,148), and 91% at 12 months in Italian military recruits⁽¹⁴⁹⁾. In Spain, 1 year after mass immunization in children 2 to 19 years of age, efficacy against meningococcal disease was 94% for serogroup C⁽⁸⁶⁾ . In a U.S. case-control study in children and adults 2 to 29 years of age, efficacy was 85%⁽⁸⁸⁾.

Lower efficacy has generally been observed in young children. After 17 months follow-up, in Brazil, there was no significant efficacy against meningococcal disease in children 6 to 36 months of age, but in a subgroup 24 to 36 months of age efficacy was 67%⁽¹⁵⁰⁾. C-polysaccharide vaccine was found to be non-protective in children < 2 years of age in another study⁽¹⁵⁰⁾ and only 52% effective in children 2 to 3 years of age after 17 months of follow-up⁽¹⁵¹⁾. In Quebec, where 1.7 million doses of polysaccharide vaccine were given during an outbreak in the early 1990's, efficacy was estimated at 79% in children and young adults after 5 years⁽²⁴⁾. After a 5 year follow-up, in Quebec, protection from serogroup C meningococcal disease was observed in the first 2 years after vaccine administration (vaccine effectiveness, 65%; 95% confidence interval [CI], 20% to 84%), but not in the next 3 years (vaccine effectiveness, 0%; 95% CI, -5% to 65%). Vaccine effectiveness was strongly related to age at vaccination: 83% (95% CI, 39% to 96%) for those 15 to 20 years of age, 75% (95% CI, -17% to 93%) for those 10 to 14 years of age, and 41% (95% CI, -106% to 79%) for those 2 to 9 years of age. There was no evidence of protection in children < 2 years of age; all eight meningococcal disease cases in this age group occurred in vaccinees⁽⁸⁵⁾.

These data demonstrate lack of efficacy < 2 years, poor efficacy in children 2 to 3 years of age and short duration of effectiveness of the serogroup C component of MenAC-Ps and MenACYW-Ps, particularly in children < 10 years of age.

During a serogroup A epidemic in Africa, efficacy of polysaccharide vaccines against serogroup A was estimated as 87%⁽¹⁵²⁾. Although, MenAC-Ps or MenACYW-Ps vaccine-induced protection against serogroup A may persist in school-aged children and adults for at least 3 years, the efficacy of the group A vaccine in children < 5 years of age may decrease markedly within this period. In one study, efficacy declined from > 90% to < 10% by 3 years after vaccination among children who were < 4 years of age when vaccinated. Efficacy was 67% at 1 year post-vaccination among children who were >= 4 years of age⁽¹⁵³⁾.

Vaccines containing serogroups Y and W-135 polysaccharides are safe and immunogenic in adults and in children > 2 years of age^(78,132,133), but clinical protection has not been studied following vaccination with polysaccharides of these serogroups.

Protein-polysaccharide conjugate vaccines

A high level of protection produced by vaccination with MenC-conjugate has been predicted from immunogenicity data described above, even in infants as young as 2 months of age. There is no efficacy data available for MenC-conjugate. Preliminary data from U.K. surveillance following introduction of vaccine throughout childhood has estimated short-term (follow-up was approximately 9 months) effectiveness of MenC-conjugate at 97% in adolescents and 92% in toddlers⁽¹¹⁰⁾.

Administration with other vaccines

Administration of MenC-conjugate at the same time as (but as a separate injection from) inactivated polio (IPV), diphtheria (DTP), Haemophilus influenzae type b (Hib), diphtheria and tetanus toxoid (DTaP), diphtheria tetanus toxoid (DT), tetanus toxoid Td and measles, mumps and rubella (MMR) vaccines or with live oral polio (OPV) does not reduce immunologic responses to any of these other antigens^(98,145). In a Canadian study, there was no interference noted with PENTACEL^TM antigens (Dr. S. Halperin et al., Dalhousie University, Halifax: personal communication, 2001). There is no information on co-administration of MenC-conjugate with hepatitis B vaccines.

Potential impact of routine vaccination with MenC-conjugate

The potential impact of routine infant immunization with MenC-conjugate is difficult to forecast because of uncertainty over the long-term protection conferred by the conjugate vaccine, and the unpredictable nature of the epidemiology of meningococcal disease. An increase or decrease in endemic disease rates or outbreaks could occur as has been seen in Canada and elsewhere. In the absence of routine molecular diagnosis, surveillance may underestimate the rate of disease by as much a 30% to 40%. The cost-effectiveness of a routine immunization strategy in Canada has not been studied. In addition, decisions to implement routine immunization must be weighed against other health priorities. Parental views on routine meningococcal vaccination in Canada have not been assessed. However, market research undertaken in the U.K., with higher rates of disease than in Canada, showed that meningococcal disease was the most feared disease by parents of young children⁽¹⁵⁴⁾ and a 'willingness-to-pay' study conducted by the Centers for Disease Control and Prevention (CDC) in the U.S. found that parents were prepared to pay for meningococcal vaccine to prevent disease in their children (Dr. N. Rosenstein, Centers for Disease Control and Prevention, Atlanta: personal communication, 2001). It is likely that implementation of immunization with MenC-conjugate will have greater impact in some regions than others because of differences in epidemiology.

The introduction of infant immunization with MenC-conjugate and a catch-up campaign to 19 years of age throughout Canada, has the potential to prevent 59 cases and 8 deaths in the first year after introduction if the following assumptions are made: incidence of serogroup C meningococcal disease in persons <= 19 years of age is 2.4/100,000; the age-specific CFR for serogroup C is 14% (incidence and CFR over the period 1985-2000); the estimated population of this age group in 2001 is 7,902,011⁽¹⁵⁵⁾; MenC-conjugate has 90% vaccine effectiveness; and, vaccine uptake is 80%. If only children < 5 years of age were included in the campaign only 22 cases and two deaths would be prevented in the first year, assuming that: the age-specific incidence of serogroup C meningococcal disease for those < 5 year of age is 1.7/100,000, the age-specific CFR for serogroup C meningococcal disease is 10% (incidence and CFR over the period 1985-2000); and the population for this age group in 2001 is 1,727,099⁽¹⁵⁵⁾.

Because most outbreak-associated cases and the highest case-fatality rate of serogroup C meningococcal disease in Canada over the past decade has occurred in persons 15 to 19 years of age, maximum cost-effectiveness and most rapid "pay-back" from a catch-up program may be achieved by immunizing this age group. An estimated 18 cases and 4 deaths among persons 15 to 19 year of age would be prevented in the first year following a catch-up campaign undertaken across Canada in this age group if the following assumptions are made: in 2001, the estimated Canadian population of those 15 to 19 year of age is 2,077,201⁽¹⁵⁵⁾, the age-specific incidence of serogroup C meningococcal disease for those 15 to 19 year of age is 1.2/100,000; the age-specific CFR for serogroup C is 20% (incidence and CFR over the period 1985-2000); MenC-conjugate has 90% vaccine effectiveness; and vaccine uptake is 80%.

Immunization with MenC-conjugate for persons 15 to 19 years of age throughout Canada has the potential to prevent 40 cases and 8 deaths in the first year if the following assumptions are made: for 1992 (year of peak incidence between 1985-2000), age-specific incidence persons 15 to 19 year of age was 2.7/100,000, the estimated population in this age group is 2,077,201 for 2001⁽¹⁵⁵⁾, MenC-conjugate has 90% vaccine effectiveness, serogroup C has a 20% mortality rate, and vaccine uptake is 80%.

Recommended usage

The MenC-conjugate vaccine has been licensed for use in infants, children, adolescents and adults and NACI recommends that it be used as follows:

Infants

The new vaccine, MenC-conjugate, is recommended for routine immunization of infants at 2, 4 and 6 months of age (three doses after at least a 4-week interval between doses), at the same visit as primary immunization for DTaP, IPV and Hib, to prevent serogroup C meningococcal disease. 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-born infants⁽¹⁵⁶⁾.

Purified polysaccharide vaccine (MenACYW-Ps or MenAC-Ps) is not recommended for routine infant immunization.

Persons >= 1 year of age

A single dose of MenC-conjugate is recommended for immunization of children 1 to 4 years of age 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 may also be considered.

Purified polysaccharide vaccine (MenACYW-Ps or MenAC-Ps) is not recommended for routine childhood immunization.

Contacts of cases

Household and intimate social contacts (e.g., kissing, sharing toothbrush) of sporadic cases of meningococcal disease have a considerably elevated risk of meningococcal disease^(157-159). Chemoprophylaxis should be administered to household and intimate social contacts of cases: rifampin 600 mg every 12 hours for 2 days for adults (10 mg/kg per dose in children >= 1 month of age [maximum = 600 mg every 12 hours]; 5 mg/kg < 1 month of age)⁽⁷⁶⁾; or ciprofloxacin as a single 500 mg oral dose for adults^(160-165); or ceftriaxone 250 mg intramuscularly for adults (50 mg/kg in children)^(165-167). Ceftriaxone is recommended in pregnancy and where oral antibiotic compliance is unlikely. The index case should also receive antibiotics that clear nasal carriage before discharge from hospital, when antibiotics that do not reliably eliminate nasopharyngeal carriage, such as penicillin, have been used for treatment^(76,168).

In certain countries where chemoprophylaxis of contacts is routinely administered for sporadic cases, as it is in Canada, 0.3% to 3% of cases of meningococcal disease occur in contacts of the index case^{(159,169-172)}, with a median interval between the index and secondary case in one study of 7 weeks⁽¹⁶⁹⁾. Some of these secondary cases can be attributed to failure of chemoprophylaxis (e.g., failure of administration, poor compliance, presence of antibiotic resistance)^{(170,173-175)}. The situation in Canada is unknown.

Vaccination of unimmunized household and intimate social contacts (e.g., kissing, sharing toothbrush) may further reduce the risk of secondary cases beyond the benefit of chemoprophylaxis^{(169,176,177)} and is recommended. MenACYW-Ps or MenAC-Ps should be used for contacts of cases with disease known to be caused by serogroup A meningococci; MenACYW-Ps should be used for contacts of cases of serogroup Y or W-135 disease. For contacts of known serogroup C disease, MenC-conjugate is preferred when available because of longer duration of protection and induction of immunologic memory, but MenACYW-Ps or MenAC-Ps will also provide useful protection in older children and adults for the 1 year period of increased risk. These polysaccharide vaccines are ineffective against serogroup C disease < 2 years of age and MenC-conjugate should be used in this situation where possible. No vaccine is currently recommended for contacts of individuals with serogroup B disease or contacts of cases of disease in which the serogroup has not been determined.

High-risk groups

Routine vaccination with quadrivalent MenACYW-Ps, is recommended for certain groups with increased risk of meningococcal disease. Such individuals include: those with functional or anatomic asplenia (vaccines should be given at least 10 to 14 days before splenectomy)⁽⁶⁵⁾, persons with complement, properdin or factor D deficiency^(61,178-181). More durable protection against serogroup C meningococcal disease may be achieved by giving MenC-conjugate to these individuals in addition to MenACYW-Ps. If the MenC-conjugate is given first, a period of >= 2 weeks before vaccination with MenACYW-Ps is recommended to allow time for generation of an antibody response⁽¹⁴³⁾. It is possible that the polysaccharide vaccine might cause interference with this response if it is administered within 2 weeks of the MenC-conjugate vaccine. If the MenACYW-Ps vaccine is given first an adequate response to MenC-conjugate has been observed after a delay of 6 months in adults⁽¹³⁶⁾ and this remains the recommended interval until further data are available. Children < 2 years of age with any of these immunodeficiencies should receive vaccination with MenC-conjugate as described in the routine infant schedule above, and then receive quadrivalent MenACYW-Ps at 2 years of age.

Institutions

Routine immunization with the quadrivalent polysaccharide vaccine, MenACYW-Ps, is recommended for military recruits and may be considered for other groups or institutions where there is an increased risk of disease. New guidance on management of outbreaks in institutions is in preparation.

Although there are no data to suggest an increased risk of meningococcal disease among students in Canada living in residence accommodation, an elevated risk has been observed in the U.S. amongst freshmen living in dormitories⁽⁹⁰⁾ and university students in halls of residence in the U.K.⁽¹⁸²⁾. Clusters of cases of meningococcal disease in students have been reported in a number of countries^{(59,157,183-185)} and carriage rates increase rapidly amongst freshmen during the first week of the term in the U.K.^(186,187). In this age group in Canada, as in other countries, there is an increase of the rate of meningococcal disease infection⁽¹⁾. Immunization against serogroup C meningococcal infection should be considered for students living in residence or dormitory accommodation. For these students the risk is mainly from serogroup C meningococcal disease and vaccination with a single dose of MenACYW-Ps, MenAC-Ps or MenC-conjugate is appropriate. MenC-conjugate may be preferred because of the induction of immunologic memory and the enhanced immunogenicity.

Laboratory and healthcare workers

Clinical healthcare workers are only at higher risk of meningococcal disease if exposed to respiratory secretions from individuals suffering from meningococcal infection around the time of admission. Significant exposure has been defined as intensive, unprotected contact (without wearing a mask) with infected patients (e.g., intubating, resuscitating, or closely examining the oropharynx of patients)⁽¹⁸⁸⁾. Twenty-four hours following commencement of antibiotics meningococci are undetectable in respiratory secretions of patients⁽¹⁸⁹⁾, therefore healthcare workers are at negligible risk. In the occasional case of healthcare staff who have direct exposure to respiratory secretions, the relative risk of meningococcal disease is estimated to be 25 times higher than the general population⁽¹⁹⁰⁾. It is recommended that healthcare workers use barrier precautions to avoid direct contact with respiratory secretions of patients with meningococcal disease during the first 24 hours following commencement of antibiotic therapy, and that those with significant exposure receive antibiotic chemoprophylaxis. Routine vaccination of healthcare workers is not currently recommended since the risk period for acquisition ends when contact with an untreated patient terminates, and antibiotic chemoprophyalxis should be sufficient in the high-risk situation described above.

Laboratory-acquired meningococcal infection is believed to be rare⁽¹⁹¹⁾, although the rate of disease in a recent U.S. survey conducted by the CDC, Atlanta, was higher than expected amongst microbiology laboratory workers dealing with N. meningitidis cultures in the absence of any breaches in laboratory safety practices (Dr. N. Rosenstein, Centers for Disease Control and Prevention, Atlanta: personal communication, 2001). In light of this, CDC is currently re-evaluating their recommendations for laboratory workers. The risk of meningococcal disease in laboratory workers handling cultures of N. meningitidis is also known to be elevated in the U.K. (Dr. J. Stuart, Public Health Laboratory Service, Gloucester, U.K.: personal communication, 2001). For research, industrial and clinical laboratory personnel who are routinely exposed to N. meningitidis cultures quadrivalent MenACYW-Ps is recommended. MenC-conjugate to provide enhanced protection against serogroup C meningococcal infection (see guidelines under 'Recommendations for revaccination' for advice on administration below) may also be offered. Vaccination should not replace good laboratory safety standards, in particular the use of safety cabinets for handling cultures of meningococci.

Outbreaks of meningococcal disease

Consultation with public health officials and experts in communicable disease is important in relation to assessment and control of meningococcal disease outbreaks in various settings and reference to published guidelines should be undertaken⁽⁷⁶⁾. Most recent outbreaks of meningococcal disease in Canada have involved adolescents and young adults suffering from serogroup C meningococcal disease. Outbreaks of serogroup C meningococcal disease in adolescents, young adults and adults may be controlled by use of MenACYW-Ps or MenAC-Ps or MenC-conjugate. The use of MenC-conjugate may be preferable because of induction of immunologic memory and prolonged duration of protection^{(98,99,101,108,138,145,192,193)}. In those previously immunized with a polysaccharide vaccine, and in whom revaccination is considered, MenC-conjugate is preferred (see 'Revaccination' section below), since further plain polysaccharide immunization may induce immunologic hyporesponsiveness^{(99,103,107,126,134-138)}, though the clinical significance of this phenomenon is unknown. In younger children (< 10 years of age) MenC-conjugate is recommended for control of outbreaks in view of superior immunogenicity and efficacy in this age group.

For the control of outbreaks of serogroup A meningococcal disease, MenACYW-Ps or MenAC-Ps is recommended as a single dose for children and adults >= 18 months of age. Children 3 to 17 months of age should receive two doses of vaccine given 3 months apart^(76,194-196). For the control of outbreaks associated with serogroup Y or W-135 meningococci one dose of MenACYW-Ps is recommended for persons >= 2 years of age.

International travel

Current Canadian guidelines (from Committee to Advise on Tropical Medicine and Travel [CATMAT]) for prevention of meningococcal disease in travellers should be consulted⁽³⁸⁾. In deciding the need for vaccination, particular consideration should be given to the travel destination, the nature and duration of exposure, the age of the traveller and the health of the traveller⁽³⁸⁾. Epidemic alerts are published regularly on the following websites:

• Travel Medicine Program, Centre for Emergency Preparedness and Response, Health Canada <http://www.TravelHealth.gc.ca>.
  
  
• Centers for Disease control and Prevention, U.S. <http://www.cdc.gov/travel/diseases/menin.htm>.
  
  
• World Health Organization (WHO) <http://www.who.int/disease-outbreak-news/disease_indices/men_index.html>.

The general aim of vaccination of travellers to areas known to experience epidemic meningococcal disease is to prevent serogroup A infection. Epidemics of serogroup A meningococcal disease have been documented every 5 to 10 years in the 'meningitis belt' of sub-Saharan Africa for much of the past century^(32,38). A similar epidemic pattern has also been described in Asia^(42-44,46). Despite the frequency of travel to regions experiencing meningococcal epidemics, disease in travellers appears to be very unusual. Where vaccine is indicated a single dose of MenACYW-Ps or MenAC-Ps should be given to infants >= 3 months of age, children, adolescents and adults to prevent serogroup A meningococcal infection.

Unlike the situation described above where meningococcal disease is very rare among travellers, in 1987 large outbreaks of meningococcal disease affected pilgrims travelling to, and returning from, Mecca, Saudi Arabia, involving serogroup A⁽⁴⁶⁾, and in 2000 and 2001 both serogroup A and W-135 were implicated^(49,50). Pilgrims making the annual Hajj pilgrimage to Mecca should receive a single dose of MenACYW-Ps >= 2 weeks prior to departure. MenC-conjugate alone is not appropriate for protection of travellers since it does not protect against outbreaks of serogroup W-135 or epidemics of serogroup A disease.

Revaccination

The need for, or effectiveness of, revaccination with Men-Ps has not been fully established. Repeated vaccination may induce immunologic hyporesponsiveness to polysaccharide vaccines (MenACYW-Ps and MenAC-Ps), although the clinical significance of this phenomenon is unknown. Revaccination should be considered according to Table 1 for those continuously or repeatedly exposed to serogroup A disease, who have been previously vaccinated with MenACYW-Ps or MenAC-Ps, particularly for children initially immunised when < 5 years of age. Children or adults with immunodeficiencies resulting in increased risk of meningococcal disease caused by serogroup Y or W-135 meningococci may be revaccinated with MenACYW-Ps according to Table 1.

The new MenC-conjugate is believed to induce immunologic memory that can be demonstrated for at least 5 years after primary immunization. Revaccination with MenC-conjugate is not thought to be necessary at present, although there is insufficient data to predict persistence of immunologic memory (and presumed protection) beyond 5 years and this recommendation may be revised in the future. Individuals who have previously received MenACYWPs or MenAC-Ps may receive MenC-conjugate for continued protection against serogroup C meningococcal disease after primary vaccination. Since an adequate response to MenC-conjugate has been observed after a delay of 6 months after vaccination with purified polysaccharide vaccine in adults⁽¹³⁶⁾, this remains the recommended interval until further data is available, although shorter intervals are likely to be acceptable. In other circumstances, where MenC-conjugate has already been administered and protection against serogroup A, Y or W-135 meningococci is required, a period of 2 weeks should be allowed to elapse before vaccination with MenACYW-Ps to allow time for generation of an antibody response⁽¹⁴³⁾, and to avoid possible interference by the polysaccharide vaccine with this response. Where both MenC-conjugate and MenACYW-Ps are to be administered, it may be preferable to use MenC-conjugate first, followed by MenACYW-Ps 2 weeks later.

Level of evidence
I = Evidence from randomized controlled trial
II = Evidence from other epidemiologic studies
III = Opinions of authorities

Contraindications

Both purified polysaccharide vaccines and the new protein-polysaccharide conjugate vaccine are contraindicated in persons with a known hypersensitivity to any component of the vaccine and in persons who have shown signs of hypersensitivity after previous administration of the vaccine (see 'Anaphylaxis' chapter in the Canadian Immunization Guide, 5^th Edition⁽⁸⁹⁾).

Precautions

The new MenC-conjugate will not protect against meningococcal diseases caused by any of the other types of meningococcal bacteria (A, B, 29-E, H, I, K, L, W-135, 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. No changes in the schedule for administering vaccines containing diphtheria or tetanus toxoids are recommended.

MenACYW-Ps and MenAC-Ps does not provide any cross-protection to meningococci not contained in these vaccines and does not provide complete protection against the vaccine serogroups.

MenC-conjugate has not been studied in pregnancy or lactation and the vaccine should not be used unless there are specific circumstances where the benefits outweigh the risks.

Adverse reactions/safety

Purified polysaccharide vaccines

Both MenACYW-Ps and MenAC-Ps have been been used extensively in many countries for mass vaccination campaigns and to immunize military recruits, the immunocompromised and travelers. Mild reactions to the vaccines include: pain and redness at the injection site in up to 50% of immunized individuals^(197,198); and, transient fever in 5% of vaccinees, particularly infants^(121,195). Severe reactions to these vaccines are very unusual^{(90,121,195,197-202)} and include: systemic allergic reactions (urticaria, wheezing, and rash) in <= 0.1/100,000 doses^(90,121,202), anaphylaxis in < 1 per million doses^(90,201) and occasional neurologic reactions^(90,198,201). These vaccines have an established safety record.

No adverse events have been documented during pregnancy or in newborn infants of vaccinated mothers^(203-205).

Protein-polysaccharide conjugate vaccines

Safety and adverse event data are available from a number of clinical trials of MenC-conjugate and MenAC-conjugate, in addition to accumulated data from spontaneous reporting on 12 million doses distributed in the U.K. in 1999-2000. Mild reactions were reported as follows: local reactions (i.e., redness, tenderness, and swelling at the injection site) in <= 50% of vaccinees, irritability in <= 80% of infants, and fever > 38^o C in <= 9% of individuals when administered with other vaccines^{(95-100,102,105-107,145)}(Dr.S. Halperin et al., Dalhousie University, Halifax: personal communication, 2001). These mild reactions occurred at a lower rate than that produced by other childhood immunizations or other purified polysaccharide vaccines^{(95,96,98-100,102,106,145)} (Dr. S. Halperin et al., Dalhousie University, Halifax: personal communication, 2001). Headaches and malaise occured in <= 10% of older children and adults^(96,100). There may be some variation in reactogenicity between the three MenC-conjugate vaccines, although one U.K. study found no significant differences in a comparison of the three MenC-conjugate products in toddlers⁽¹⁰¹⁾.

In one Canadian study MenC-conjugate (Menjugate^TM) was administered with PENTACEL^TM (DTaP/Hib/IPV) in a multi-centre, randomized controlled clinical study involving three centres that compared MenC-conjugate with hepatitis B vaccine (HBV) (Dr. S. Halperin et al., Dalhousie University, Halifax: personal communication, 2001). The frequency of local adverse reactions (e.g., tenderness, erythema and induration) in those receiving MenC-conjugate was lower than in those receiving routine infant immunization with PENTACEL^TM, but higher than in those receiving HBV, a vaccine used in a number of provinces for infant immunization. Systemic reactions were experienced at the same rate in those receiving HBV as those receiving MenC-conjugate.

The frequencies of rare adverse events are based on spontaneous reporting rates from the U.K., and have been calculated using the number of reports received as the numerator and the total number of doses distributed as the denominator. Severe reactions were very uncommon and include: systemic allergic reactions (lymphadenopathy, anaphylaxis, hypersensitivity reactions including bronchospasm, facial edema and angioedema) in < 0.01%; neurological responses (dizziness, convulsions including febrile convulsions, faints, hypesthesia, paresthesia and hypotonia) in < 0.01%; nausea or vomiting in < 0.01%; rash or urticaria or pruritis in 0.01%, and arthralgia in < 0.01%. No deaths have been attributed to this vaccine in the U.K.⁽²⁰⁶⁾.

There are no specific studies in humans of MenC-conjugate during pregnancy or lactation.

Public health issues, limitations of knowledge and areas for future studies

The studies described in this statement have clearly demonstrated that MenC-conjugate can induce immnological memory for at least 5 years following primary immunization⁽⁹⁸⁾. However, more so than the case with Hib vaccine, protection is important beyond early childhood. The need for a booster dose at some point after infancy to provide protection through adolescence and early adulthood is currently unknown⁽²⁰⁷⁾, and requires close monitoring and further investigation. The ability of MenC-conjugate to induce herd immunity is unknown.

Based on bactericidal antibody levels at 1 month post-immunization it is possible that two doses of MenC-conjugate in the first 6 months of life may be sufficient. Further data is required on the duration of protective levels of bactericidal antibody following different immunization regimes before this can be recommended as an alternative to the three-dose schedule for infants.

Although use of MenC-conjugate probably provides superior protection against serogroup C meningococcal disease than does MenC-Ps, there are no data available for its use in immunodeficient subjects.

There are no safety or immunogenicity data available regarding the use of MenC-conjugate in adults > 65 years of age. There are currently no data available regarding the use of MenC-conjugate in outbreak control, although it has been used recently in some Canadian outbreaks. There are no formal studies of use of MenC-conjugate in pregnancy or lactation.

The effect of MenC-conjugate on meningococcal population biology is unknown. It has been suggested that use of a monovalent meningococcal vaccine might induce capsule switching through immunologic pressure such that hypervirulent serogroup C clones adopt a B, Y or W-135 capsule. It may also be the case that use of a monovalent vaccine will have little overall effect on meningococcal disease burden if other meningococci simply replace the niche left by serogroup C meningococci (strain replacement)⁽²⁰⁸⁾. Data from the U.K. suggest that there is no increase in other serogroups with the introduction of Men-C conjugate vaccine. Following introduction of widespread meningococcal vaccination close epidemiological and laboratory-based surveillance must be undertaken to monitor changes in meningococcal population biology.

Cost-effectiveness data and information on parental attitudes to vaccination are not currently available but would help guide the use of meningococcal vaccines in routine immunization in Canada. The merits of MenC-conjugate relative to other vaccines (e.g., pneumococcal protein polysaccharide conjugate vaccines, adult pertussis vaccination and varicella vaccination) has not been studied.

New quadrivalent protein-polysaccharide conjugate vaccines (MenACYW-conjugate) are in development and might provide broad protection against the vaccine serogroups following introduction of an infant immunization program, and could presumably replace monovalent MenC-conjugate. None of these vaccines offer protection against serogroup B meningococci, a feature that limits the impact that any meningococcal vaccine can have on the disease burden, especially in children.

Acknowledgements

NACI gratefully acknowledges assistance in the preparation of this statement from: Dr. M. Bigham, British Columbia Centre for Disease Control, Vancouver; Dr. P. De Wals, Université de Sherbrooke, Sherbrooke; Dr. S. Halperin, Dalhousie University, Halifax; Dr. E. Miller, Public Health Laboratory Service, London, U.K.; Dr. N. Rosenstein, Centers for Disease Control and Prevention, Atlanta; Dr. D. Scheifele, University of British Columbia, Vancouver; Dr. J. Stuart, Public Health Laboratory Service, Gloucester, U.K.; Dr. R. Tsang, National Microbiology Laboratory, Winnipeg; S. Wilson, MHSc CH&E; candidate, University of Toronto, Toronto; H. Ge, MHSc CH&E; candidate, University of Toronto, Toronto; Dr. L. Danzig, Chiron Corporation, California; Dr. S. Lockhart, Wyeth Lederle Vaccines, Pennsylvania; Dr. P. Fusco, Baxter Health Corporation, Maryland. Dr. Andrew J Pollard is funded by the Pediatric Infectious Disease Society though an unrestricted educational grant provided by Pfizer, Inc.

References

1. Squires SG, Pelletier L, Mungai M et al. Invasive meningococcal disease in Canada, 1 January 1997 to 31 December 1998. CCDR 2000;26:177-82.

2. LCDC. Case definitions for diseases under national surveillance. CCDR 2000;26S3:49.

3. Sobanski MA, Barnes RA, Coakley WT. Detection of meningococcal antigen by latex agglutination. In: Pollard AJ, Maiden CJ, eds. Meningococcal disease. Totowa, New Jersey: Humana Press Inc., 2001.

4. Ragunathan L, Ramsay M, Borrow R et al. Clinical features, laboratory findings and management of meningococcal meningitis in England and Wales: report of a 1997 survey. Meningococcal meningitis: 1997 survey report. J Infect 2000;40:74-9.

5. Guiver M, Borrow R, Marsh J et al. Evaluation of the applied biosystems automated taqman polymerase chain reaction system for the detection of meningococcal DNA. FEMS Immunol Med Microbiol 2000;28:173-79.

6. Newcombe J, Cartwright K, Palmer WH et al. PCR of peripheral blood for diagnosis of meningococcal disease. J Clin Microbiol 1996;34:1637-40.

7. Pollard AJ, Bigham JM, Bhachu K et al. Meningococcal disease in British Columbia. BC Med J 2001;43:21-7.

8. Carrol ED, Thomson AP, Shears P et al. Performance characteristics of the polymerase chain reaction assay to confirm clinical meningococcal disease. Arch Dis Child 2000;83:271-73.

9. Frasch CE, Zollinger WD, Poolman JT. Serotype antigens of Neisseria meningitidis and a proposed scheme for designation of serotypes. Rev Infect Dis 1985;7:504-10.

10. Abdillahi H, Poolman JT. Whole-cell ELISA for typing Neisseria meningitidis with monoclonal antibodies. FEMS Microbiol Lett 1987;48:367-71.

11. Caugant DA, Frøholm LO, Bøvre K et al. Intercontinental spread of a genetically distinctive complex of clones of Neisseria meningitidis causing epidemic disease. Proc Natl Acad Sci U S A 1986;83:4927-31.

12. Caugant DA, Bøvre K, Gaustad P et al. Multilocus genotypes determined by enzyme electrophoresis of Neisseria meningitidis isolated from patients with systemic disease and from healthy carriers. J Gen Microbiol 1986;132:641-52.

13. Maiden MC, Bygraves JA, Feil E et al. Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci U S A 1998;95:3140-45.

14. Morelli G, Malorny B, Muller K et al. Clonal descent and microevolution of Neisseria meningitidis during 30 years of epidemic spread. Mol Microbiol 1997;25:1047-64.

15. Whalen CM, Hockin JC, Ryan A et al. The changing epidemiology of invasive meningococcal disease in Canada, 1985 through 1992. Emergence of a virulent clone of Neisseria meningitidis. JAMA 1995;273:390-94.

16. Deeks S, Kertesz D, Ryan A et al. Surveillance of invasive meningococcal disease in Canada, 1995-1996. CCDR 1997;23:121-25.

17. Varughese PV, Carter AO. Meningococcal disease in Canada. Surveillance summary to 1987. CDWR 1989;15:89-96.

18. Ashton FE, Mancino L, Ryan AJ et al. Serotypes and subtypes of Neisseria meningitidis serogroup B strains associated with meningococcal disease in Canada, 1977-1989. Can J Microbiol 1991;37:613-17.

19. Erickson L, De Wals P. Complications and sequelae of meningococcal disease in Quebec, Canada, 1990-1994. Clin Infect Dis 1998;26:1159-64.

20. Gemmill I. An outbreak of meningococcal disease in Ottawa-Carleton. December 1991-February 1992. Can J Public Health 1992;83:134-37.

21. Bouchard F, Banken R, Desilets J et al. Mass vaccination against meningococcal disease in three regions of the province of Quebec, January 1992. Can J Public Health 1992;83:131-33.

22. Sweet L. The Prince Edward Island meningococcal immunization program. January-February 1992. Can J Public Health 1992;83:129-30.

23. Farley JD, Osei W. Invasive meningococcal disease, British Columbia. December 1991-March 1992. Can J Public Health 1992;83:138-40.

24. De Wals P, Dionne M, Douville-Fradet M et al. Impact of a mass immunization campaign against serogroup C meningococcus in the province of Quebec, Canada. Bull WHO 1996;74:407-11.

25. Ashton FE, Caugant DA. The panmictic nature of Neisseria meningitidis serogroup B during a period of endemic disease in Canada. Can J Microbiol 2001;47:283-89.

26. Rosenstein NE, Perkins BA, Stephens DS et al. The changing epidemiology of meningococcal disease in the United States, 1992-1996. J Infect Dis 1999;180:1894-901.

27. Blondeau JM, Ashton FE, Isaacson M et al. Neisseria meningitidis with decreased susceptibility to penicillin in Saskatchewan, Canada. J Clin Microbiol 1995;33:1784-86.

28. Brown S, Riley G, Jamieson F. Neisseria meningitidis with decreased susceptibility to penicillin in Ontario, Canada 1997-2000. CCDR 2001;27:73-5.

29. Turner PC, Southern KW, Spencer NJ et al. Treatment failure in meningococcal meningitis. Lancet 1990;335:732-33.

30. Tikhomirov E, Santamaria M, Esteves K. Meningococcal disease: public health burden and control. World Health Stat Q 1997;50:170-77.

31. Riedo FX, Plikaytis BD, Broome CV. Epidemiology and prevention of meningococcal disease. Pediatr Infect Dis J 1995;14:643-57.

32. Lapeyssonnie L. La méningite cérébro-spinale en Afrique. Bull WHO 1963;28:3-114.

33. CDC. Notifiable diseases/deaths in selected cities weekly information. MMWR 1999;47:1125-30.

34. Wilson N, Baker M, Martin D et al. Meningococcal disease epidemiology and control in New Zealand. N Z Med J 1995;108:437-42.

35. Tikhomirov E, Hallaj Z. Control of epidemic meningococcal disease. WHO practical guidelines. 2^nd edition. Geneva: World Health Organization, 1998, WHO/EMC/BAC/98.3.

36. Diermayer M, Hedberg K, Hoesly F et al. Epidemic serogroup B meningococcal disease in Oregon: the evolving epidemiology of the ET-5 strain. JAMA 1999;281:1493-97.

37. Martin DR, Walker SJ, Baker MG et al. New Zealand epidemic of meningococcal disease identified by a strain with phenotype B:4:P1.4. J Infect Dis 1998;177:497-500.

38. LCDC. Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on meningococcal vaccination for travellers. CCDR 1999;25:ACS-5.

39. Hart CA, Cuevas LE. Meningococcal disease in Africa. Ann Trop Med Parasitol 1997;91:777-85.

40. Miller MA, Wenger J, Rosenstein N et al. Evaluation of meningococcal meningitis vaccination strategies for the meningitis belt in Africa. Pediatr Infect Dis J 1999;18:1051-59.

41. International Coordinating Group on Vaccine Provision for Epidemic Meningitis Control. Summary report of the fifth meeting of the International Coordinating Group (ICG) on Vaccine Provision for Epidemic Meningitis Control. Geneva: World Health Organization, 1999:1-24.

42. Wang JF, Caugant DA, Li X et al. Clonal and antigenic analysis of serogroup A Neisseria meningitidis with particular reference to epidemiological features of epidemic meningitis in the People's Republic of China. Infect Immun 1992;60:5267-82.

43. Zhen H. Prevalence of CSM over 30-year period: overview. In: Vedors NA, ed. Evolution of meningococcal disease. Vol. II. Boca Raton, Florida: CRC Press Inc., 1987:20-21.

44. Achtman M. Global epidemiology of meningococcal disease. In: Cartwright K, ed. Meningococcal disease. Chichester: John Wiley and Sons, 1995:159-75.

45. Meningococcal disease. Wkly Epidemiol Rec 1995;70:281-82.

46. Moore PS, Reeves MW, Schwartz B et al. Intercontinental spread of an epidemic group A Neisseria meningitidis strain. Lancet 1989;2:260-63.

47. Cochi SL, Markowitz LE, Joshi DD et al. Control of epidemic group A meningococcal meningitis in Nepal. Int J Epidemiol 1987;16:91-7.

48. Meningococcal disease associated with the Haj — update. CDR Wkly 2000;10:169.

49. CDC. Serogroup W-135 meningococcal disease among travelers returning from Saudi Arabia — United States, 2000. MMWR 2000;49:345-46.

50. CDC. Update: assessment of risk for meningococcal disease associated with the Hajj 2001. MMWR 2001;50:221-22.

51. Analysis of endemic meningococcal disease by serogroup and evaluation of chemoprophylaxis. J Infect Dis 1976;134:201-04.

52. Moore PS, Hierholzer J, DeWitt W et al. Respiratory viruses and mycoplasma as cofactors for epidemic group A meningococcal meningitis. JAMA 1990;264:1271-75.

53. Cartwright KA, Jones DM, Smith AJ et al. Influenza A and meningococcal disease. Lancet 1991;338:554-57.

54. Stanwell-Smith RE, Stuart JM, Hughes AO et al. Smoking, the environment and meningococcal disease: a case control study. Epidemiol Infect 1994;112:315-28.

55. Fischer M, Hedberg K, Cardosi P et al. Tobacco smoke as a risk factor for meningococcal disease. Pediatr Infect Dis J 1997;16:979-83.

56. Haneberg B, Tonjum T, Rodahl K et al. Factors preceding the onset of meningococcal disease, with special emphasis on passive smoking, symptoms of ill health. NIPH Ann 1983;6:169-73.

57. Yusuf HR, Rochat RW, Baughman WS et al. Maternal cigarette smoking and invasive meningococcal disease: a cohort study among young children in metropolitan Atlanta, 1989-1996. Am J Public Health 1999;89:712-17.

58. Imrey PB, Jackson LA, Ludwinski PH et al. Meningococcal carriage, alcohol consumption, and campus bar patronage in a serogroup C meningococcal disease outbreak. J Clin Microbiol 1995;33:3133-37.

59. Imrey PB, Jackson LA, Ludwinski PH et al. Outbreak of serogroup C meningococcal disease associated with campus bar patronage. Am J Epidemiol 1996;143:624-30.

60. Cookson ST, Corrales JL, Lotero JO et al. Disco fever: epidemic meningococcal disease in northeastern Argentina associated with disco patronage. J Infect Dis 1998;178:266-69.

61. Petersen BH, Lee TJ, Snyderman R et al. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency. Ann Intern Med 1979;90:917-20.

62. Figueroa J, Andreoni J, Densen P. Complement deficiency states and meningococcal disease. Immunol Res 1993;12:295-311.

63. Salit IE. Meningococcemia caused by serogroup W135. Association with hypogammaglobulinemia. Arch Intern Med 1981;141:664-65.

64. Hobbs JR, Milner RD, Watt PJ. Gamma-M deficiency predisposing to meningococcal septicaemia. Br Med J 1967;4:583-86.

65. Ellison EC, Fabri PJ. Complications of splenectomy. Etiology, prevention and management. Surg Clin North Am 1983;63:1313-30.

66. Stephens DS, Hajjeh RA, Baughman WS et al. Sporadic meningococcal disease in adults: results of a 5-year population-based study. Ann Intern Med 1995;123:937-40.

67. Jackson LA, Wenger JD. Laboratory-based surveillance for meningococcal disease in selected areas, United States, 1989-1991. MMWR 1993;42:21-30.

68. Fischer M, Harrison L, Farley M et al. Risk factors for sporadic meningococcal disease in North America. Denver, CO: Infectious Diseases Society of America, 1998:80.

69. Caugant DA, Høiby EA, Magnus P et al. Asymptomatic carriage of Neisseria meningitidis in a randomly sampled population. J Clin Microbiol 1994;32:323-30.

70. Gold R, Goldschneider I, Lepow ML et al. Carriage of Neisseria meningitidis and Neisseria lactamica in infants and children. J Infect Dis 1978;137:112-21.

71. Marzouk O, Thomson AP, Sills JA et al. Features and outcome in meningococcal disease presenting with maculopapular rash. Arch Dis Child 1991;66:485-87.

72. Edwards KM, Jones LM, Stephens DS. Clinical features of mild systemic meningococcal disease with characterization of bacterial isolates. Clin Pediatr (Phila) 1985;24:617-20.

73. Kirsch EA, Barton RP, Kitchen L et al. Pathophysiology, treatment and outcome of meningococcemia: a review and recent experience. Pediatr Infect Dis J 1996;15:967-78.

74. Havens PL, Garland JS, Brook MM et al. Trends in mortality in children hospitalized with meningococcal infections, 1957 to 1987. Pediatr Infect Dis J 1989;8:8-11.

75. Schoendorf KC, Adams WG, Kiely JL et al. National trends in Haemophilus influenzae meningitis mortality and hospitalization among children, 1980 through 1991. Pediatrics 1994;93:663-68.

76. LCDC. Guidelines for control of meningococcal disease. Canadian Consensus Conference on meningococcal disease. Can Med Assoc J 1994;150:1825-39.

77. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 1969;129:1307-26.

78. Griffiss JM, Brandt BL, Altieri PL et al. Safety and immunogenicity of group Y and group W135 meningococcal capsular polysaccharide vaccines in adults. Infect Immun 1981;34:725-32.

79. Finne J, Leinonen M, Mäkelä PH. Antigenic similarities between brain components and bacteria causing meningitis. Implications for vaccine development and pathogenesis. Lancet 1983;2:355-57.

80. Mandrell RE, Zollinger WD. Measurement of antibodies to meningococcal group B polysaccharide: low avidity binding and equilibrium binding constants. J Immunol 1982;129:2172-78.

81. Granoff DM, Kelsey SK, Bijlmer HA et al. Antibody responses to the capsular polysaccharide of Neisseria meningitidis serogroup B in patients with meningococcal disease. Clin Diagn Lab Immunol 1995;2;574-82.

82. Griffiss JM, Brandt BL, Broud DD et al. Immune response of infants and children to disseminated infections with Neisseria meningitidis. J Infect Dis 1984;150:71-9.

83. Zollinger WD, Mandrell RE. Importance of complement source in bactericidal activity of human antibody and murine monoclonal antibody to meningococcal group B polysaccharide. Infect Immun 1983;40:257-64.

84. Guidelines for controlling meningococcal disease. Can Med Assoc J 1992;146:939-42, 945-48.

85. De Wals P, De Serres G, Niyonsenga T. Effectiveness of a mass immunization campaign against serogroup C meningococcal disease in Quebec. JAMA 2001;285:177-81.

86. Salleras L, Dominguez A, Prats G. Control of serogroup C meningococcal meningitis by mass vaccination in Catalonia (Spain). Vaccine 1999;17(Suppl 3):S56-60.

87. Biselli R, Fattorossi A, Matricardi PM et al. Dramatic reduction of meningococcal meningitis among military recruits in Italy after introduction of specific vaccination. Vaccine 1993;11:578-81.

88. Rosenstein N, Levine O, Taylor JP et al. Efficacy of meningococcal vaccine and barriers to vaccination. JAMA 1998;279:435-39.

89. National Advisory Committee on Immunization. Meningococcal vaccine. In: Canadian immunization guide. 5^th edition. Ottawa, Ont.: Health Canada, 1998:125-29. (Minister of Public Works and Government Services Canada, Cat. No. H49-8/1998E.).

90. CDC. Meningococcal vaccine and college students: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(RR-7):11-20.

91. Heath PT. Haemophilus influenzae type b conjugate vaccines: a review of efficacy data. Pediatr Infect Dis J 1998;17:S117-22.

92. Buttery JP, Moxon ER. Designing meningitis vaccines. J R Coll Physicians Lond 2000;34:163-68.

93. Choo S, Finn A. New pneumococcal vaccines for children. Arch Dis Child 2001;84:289-94.

94. Ledwith M. Pneumococcal conjugate vaccine. Curr Opin Pediatr 2001;13:70-4.

95. 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;19:1232-38.

96. 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;18:2686-92.

97. Bramley JC, Hall T, Finn A et al. Safety and immunogenicity of three lots of meningococcal serogroup C conjugate vaccine administered at 2, 3 and 4 months of age. Vaccine 2001;19:2924-31.

98. 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.

99. 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. JAMA 1998;280:1685-89.

100. 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;18:641-46.

101. 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.

102. Fairley CK, Begg N, Borrow R et al. Conjugate meningococcal serogroup A and C vaccine: reactogenicity and immunogenicity in United Kingdom infants. J Infect Dis 1996;174:1360-63.

103. 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;17:3086-93.

104. Lieberman JM, Chiu SS, Wong VK et al. Safety and immunogenicity of a serogroups A/C Neisseria meningitidis oligosaccharide-protein conjugate vaccine in young children. A randomized controlled trial. JAMA 1996;275:1499-503.

105. Anderson EL, Bowers T, Mink CM et al. Safety and immunogenicity of meningococcal A and C polysaccharide conjugate vaccine in adults. Infect Immun 1994;62:3391-95.

106. Twumasi PA Jr, Kumah S, Leach A et al. A trial of a group A plus group C meningococcal polysaccharide-protein conjugate vaccine in African infants. J Infect Dis 1995;171:632-38.

107. Leach A, Twumasi PA, Kumah S et al. Induction of immunologic memory in Gambian children by vaccination in infancy with a group A plus group C meningococcal polysaccharide-protein conjugate vaccine. J Infect Dis 1997;175:200-04.

108. Borrow R, Fox AJ, Richmond PC et al. Induction of immunological memory in UK infants by a meningococcal A/C conjugate vaccine. Epidemiol Infect 2000;124:427-32.

109. Costantino P, Viti S, Podda A et al. Development and phase 1 clinical testing of a conjugate vaccine against meningococcus A and C. Vaccine 1992;10:691-98.

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

111. De Moraes JC, Perkins BA, Camargo MC et al. Protective efficacy of a serogroup B meningococcal vaccine in Sao Paulo, Brazil. Lancet 1992;340:1074-78.

112. Noronha CP, Struchiner CJ, Halloran ME. Assessment of the direct effectiveness of BC meningococcal vaccine in Rio de Janeiro, Brazil: a case-control study. Int J Epidemiol 1995;24:1050-57.

113. Sierra GV, Campa HC, Varcacel NM et al. Vaccine against group B Neisseria meningitidis: protection trial and mass vaccination results in Cuba. NIPH Ann 1991;14:195-207; discussion 208-10.

114. Boslego J, García J, Cruz C et al. Chilean National Committee for Meningococcal Disease. Efficacy, safety, and immunogenicity of a meningococcal group B (15:P1.3) outer membrane protein vaccine in Iquique, Chile. Vaccine 1995;13:821-29.

115. Gheesling LL, Carlone GM, Pais LB et al. Multicenter comparison of Neisseria meningitidis serogroup C anti-capsular polysaccharide antibody levels measured by a standardized enzymelinked immunosorbent assay. J Clin Microbiol 1994;32:1475-82.

116. Maslanka SE, Gheesling LL, Libutti DE et al. The Multilaboratory Study Group. Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. Clin Diagn Lab Immunol 1997;4:156-67.

117. Peltola H. Meningococcal vaccines. Current status and future possibilities. Drugs 1998;55:347-66.

118. Maslanka SE, Tappero JW, Plikaytis BD et al. Age-dependent Neisseria meningitidis serogroup C class-specific antibody concentrations and bactericidal titers in sera from young children from Montana immunized with a licensed polysaccharide vaccine. Infect Immun 1998;66:2453-59.

119. Granoff DM, Maslanka SE, Carlone et al. A modified enzyme-linked immunosorbent assay for measurement of antibody responses to meningococcal C polysaccharide that correlate with bactericidal responses. Clin Diagn Lab Immunol 1998;5:479-85.

120. Gold R, Lepow ML, Goldschneider I et al. Kinetics of antibody production to group A and group C meningococcal polysaccharide vaccines administered during the first six years of life: prospects for routine immunization of infants and children. J Infect Dis 1979;140:690-97.

121. Peltola H, Käyhty H, Kuronen T et al. Meningococcus group A vaccine in children three months to five years of age. Adverse reactions and immunogenicity related to endotoxin content and molecular weight of the polysaccharide. J Pediatr 1978;92:818-22.

122. Käyhty H, Karanko V, Peltola H et al. Serum antibodies to capsular polysaccharide vaccine of group A Neissera meningitidis followed for three years in infants and children. J Infect Dis 1980;142:861-68.

123. Lepow ML, Goldschneider I, Gold R et al. Persistence of antibody following immunization of children with groups A and C meningococcal polysaccharide vaccines. Pediatrics 1977;60:673-80.

124. Ceesay SJ, Allen SJ, Menon A et al. Decline in meningococcal antibody levels in African children 5 years after vaccination and the lack of an effect of booster immunization. J Infect Dis 1993;167:1212-16.

125. Zangwill KM, Stout RW, Carlone GM et al. Duration of antibody response after meningococcal polysaccharide vaccination in US Air Force personnel. J Infect Dis 1994;169:847-52.

126. Gold R, Lepow ML, Goldschneider I et al. Immune response of human infants to polysaccharide vaccines of group A and C Neisseria meningitidis. J Infect Dis 1977;136:suppl S31-5.

127. Goldschneider I, Lepow ML, Gotschlich EC et al. Immunogenicity of group A and group C meningococcal polysaccharides in human infants. J Infect Dis 1973;128:769-76.

128. Goldschneider I, Lepow ML, Gotschlich EC. Immunogenicity of the group A and group C meningococcal polysaccharides in children. J Infect Dis 1972;125:509-19.

129. Borrow R, Richmond P, Kaczmarski EB et al. Meningococcal serogroup C-specific IgG antibody responses and serum bactericidal titres in children following vaccination with a meningococcal A/C polysaccharide vaccine. FEMS Immunol Med Microbiol 2000;28:79-85.

130. Mitchell LA, Ochnio JJ, Glover C et al. Analysis of meningococcal serogroup C-specific antibody levels in British Columbian children and adolescents. J Infect Dis 1996;173:1009-13.

131. Espin Rios I, Garcia-Fulgueiras A, Navarro Alonso JA et al. Seroconversion and duration of immunity after vaccination against group C meningococcal infection in young children. Vaccine 2000;18:2656-60.

132. Armand J, Arminjon F, Mynard MC et al. Tetravalent meningococcal polysaccharide vaccine groups A, C, Y, W 135: clinical and serological evaluation. J Biol Stand 1982;10:335-39.

133. Ambrosch F, Wiedermann G, Crooy P et al. Immunogenicity and side-effects of a new tetravalent meningococcal polysaccharide vaccine. Bull WHO 1983;61:317-23.

134. Artenstein MS, Brandt BL. Immunologic hyporesponsiveness in man to group C meningococcal polysaccharide. J Immunol 1975;115:5-7.

135. Granoff DM, Gupta RK, Belshe RB et al. Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination. J Infect Dis 1998;178:870-74.

136.     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. J Infect Dis 2000;181:761-64.

137.     Borrow R, Richmond P, Kaczmarksi EB et al. Meningococcal C conjugate vaccine overcomes immunological hyporesponsiveness induced by meningococcal A/C polysaccharide vaccine in UK students. San Francisco, California: American Society for Microbiology, 1999:362.

138.     MacLennan J, Obaro S, Deeks J et al. Immunologic memory 5 years after meningococcal A/C conjugate vaccination in infancy. J Infect Dis 2001;183:97-104.

139.     Borrow R, Joseph H, Andrews N et al. Reduced antibody response to revaccination with meningococcal serogroup A polysaccharide vaccine in adults. Vaccine 2000;19:1129-32.

140.     Campagne G, Garba A, Fabre P et al. Safety and immunogenicity of three doses of a Neisseria meningitidis A + C diphtheria conjugate vaccine in infants from Niger. Pediatr Infect Dis J 2000;19:144-50.

141.     Chapter 23. Meningococcal. [Replacement chapter]. In: Salisbury DM, Begg NT, eds. Immunisation against infectious disease. London: Department of Health, 1996.

142.     Zhang Q, Choo S, Everard J et al. Mucosal immune responses to meningococcal group C conjugate and group A and C polysaccharide vaccines in adolescents. Infect Immun 2000;68:2692-97.

143.     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;19:3043-50.

144.     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 bactericidal activity against O-acetylated and De-O-acetylated serogroup C strains. Infect Immun 2001;69:2378-82.

145.     Richmond P, Borrow R, Miller E et al. Meningococcal serogroup C conjugate vaccine is immunogenic in infancy and primes for memory. J Infect Dis 1999;179:1569-672.

146.     Heath PT, DeMenzes C, Moxon R et al. Antibody responses to Neisseria meningitidis group C conjugate vaccine in children with human immunodeficiency virus infection. Arch Dis Child 2001;84:A62.

147.     Artenstein MS, Gold R, Zimmerly JG et al. Prevention of meningococcal disease by group C polysaccharide vaccine. N Engl J Med 1970;282:417-20.

148.     Gold R, Artenstein MS. Meningococcal infections. 2. Field trial of group C meningococcal polysaccharide vaccine in 1969-70. Bull WHO 1971;45:279-82.

149.     Biselli R, Casapollo I, D'Amelio R et al. Antibody response to meningococcal polysaccharides A and C in patients with complement defects. Scand J Immunol 1993;37:644-50.

150.     Taunay AE, de Glavao PA, de Morais JA et al. Disease prevention by meningococcal serogroup C polysaccharide vaccines in preschool children: results after 11 months in Sao Paulo, Brazil. Pediatr Res 1974;8:429.

151.     Amato Neto V, Finger H, Gotschlich EC et al. Serologic response to serogroup C meningococcal vaccine in Brazilian preschool children. Rev Inst Med Trop Sao Paulo 1974;16:149-53.

152.     Pinner RW, Onyango F, Perkins BA et al. The Kenya/Centers for Disease Control Meningitis Study Group. Epidemic meningococcal disease in Nairobi, Kenya, 1989. J Infect Dis 1992;166:359-64.

153.     Reingold AL, Broome CV, Hightower AW et al. Age-specific differences in duration of clinical protection after vaccination with meningococcal polysaccharide A vaccine. Lancet 1985;2:114-18.

154.     Salisbury DM. The introduction of group C conjugate meningococcalvaccine into the UK. In: Pollard AJ, Maiden MC eds. Meningococcal vaccines. Totowa, New Jersey: Humana Press, 2001.

155.     Statistics Canada. Annual demographic statistics, 1999. Ottawa: Statistics Canada, 1999.

156.     Slack M, Thwaites R, Schapira D et al. The immune response of premature infants to DTaP-Hib and Men C vaccines. Arch Dis Child 2001;84:A63.

157.     Hastings L, Stuart J, Andrews N et al. 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. CDR Rev 1997;7:R195-200.

158.     De Wals P, Hertoghe L, Borlee-Grimee I et al. Meningococcal disease in Belgium. Secondary attack rate among household,
day-care nursery and pre-elementary school contacts. J Infect 1981;3:53-61.

159.     Meningococcal Disease Surveillance Group. Meningococcal disease. Secondary attack rate and chemoprophylaxis in the United States, 1974. JAMA 1976;235:261-65.

160.     Pugsley MP, Dworzack DL, Horowitz EA et al. Efficacy of ciprofloxacin in the treatment of nasopharyngeal carriers of Neisseria meningitidis. J Infect Dis 1987;156:211-13.

161.     Gaunt PN, Lambert BE. Single dose ciprofloxacin for the eradication of pharyngeal carriage of Neisseria meningitidis. J Antimicrob Chemother 1988;21:489-96.

162.     Pugsley MP, Dworzack DL, Roccaforte JS et al. An open study of the efficacy of a single dose of ciprofloxacin in eliminating the chronic nasopharyngeal carriage of Neisseria meningitidis. J Infect Dis 1988;157:852-53.

163.     Renkonen OV, Sivonen A, Visakorpi R. Effect of ciprofloxacin on carrier rate of Neisseria meningitidis in army recruits in Finland. Antimicrob Agents Chemother 1987;31:962-63.

164.     Dworzack DL, Sanders CC, Horowitz EA et al. Evaluation of single-dose ciprofloxacin in the eradication of Neisseria meningitidis from nasopharyngeal carriers. Antimicrob Agents Chemother 1988;32:1740-41.

165.     Gaunt PN. Ciprofloxacin vs ceftriaxone for eradication of meningococcal carriage. Lancet 1988;2:218-19.

166.     Schwartz B, Al-Tobaiqi A, Al-Ruwais A et al. Comparative efficacy of ceftriaxone and rifampicin in eradicating pharyngeal carriage of group A Neisseria meningitidis. Lancet 1988;1:1239-42.

167.     Schwartz B. Chemoprophylaxis for bacterial infections: principles of and application to meningococcal infections. Rev Infect Dis 1991;13(Suppl 2):S170-73.

168.     Judson FN, Ehret JM. Single-dose ceftriaxone to eradicate pharyngeal Neisseria meningitidis. Lancet 1984;2;1462-63.

169.     Cooke RP, Riordan T, Jones DM et al. Secondary cases of meningococcal infection among close family and household contacts in England and Wales, 1984-87. Br Med J 1989;298:555-58.

170.     Stroffolini T, Rosmini F, Curiano CM. A one year survey of meningococcal disease in Italy. Eur J Epidemiol 1987;3:399-403.

171.     Olivares R, Hubert B. Clusters of meningococcal disease in France (1987-1988). Eur J Epidemiol 1992;8:737-42.

172.     Scholten RJ, Bijlmer HA, Dankert J et al. Secondary cases of meningococcal disease in the Netherlands, 1989- 1990; a reappraisal of chemoprophylaxis. Ned Tijdschr Geneeskd 1993;137:1505-08.

173.     Almog R, Block C, Gdalevich M et al. First recorded outbreaks of meningococcal disease in the Israel Defence Force: three clusters due to serogroup C and the emergence of resistance to rifampicin. Infection 1994;22:69-71.

174.     Samuelsson S, Hansen ET, Osler M et al. Prevention of secondary cases of meningococcal disease in Denmark. Epidemiol Infect 2000;124:433-40.

175.     Dawson SJ, Fey RE, McNulty CA. Meningococcal disease in siblings caused by rifampicin sensitive and rifampicin resistant strains. Commun Dis Public Health 1999;2:215-16.

176.     Greenwood BM, Hassan-King M, Whittle HC. Prevention of secondary cases of meningococcal disease in household contacts by vaccination. Br Med J 1978;1:1317-19.

177.     PHLS Meningococcal Infections Working Group and Public Health Medicine Environmental Group. Control of meningococcal disease: guidance for consultants in communicable disease control. CDR Rev 1995;5:R189-95.

178.     Densen P. Complement deficiencies and meningococcal disease. Clin Exp Immunol 1991;86(Suppl 1):57-62.

179.     Ross SC, Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore) 1984;63:243-73.

180.     D'Amelio R, Agostoni A, Biselli R et al. Complement deficiency and antibody profile in survivors of meningococcal meningitis due to common serogroups in Italy. Scand J Immunol 1992;35:589-95.

181.     Nicholson A, Lepow I. Host defense against Neisseria meningitidis requires a complement-dependent bactericidal activity. Science 1979;205:298-99.

182.     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. Epidemiol Infect 1999;122:351-57.

183.     Clusters of meningococcal disease in university students. Commun Dis Rep CDR Wkly 1997;7:393,396.

184.     Barker RM, Shakespeare RM, Mortimore AJ et al. Practical guidelines for responding to an outbreak of meningococcal disease among university students based on experience in Southampton. Commun Dis Public Health 1999;2:68-73.

185.     Ferson M, Young L, Hansen G et al. Unusual cluster of mild invasive serogroup C meningococcal infection in a university college. Commun Dis Intell 1999;23:261-64.

186.     Neal KR, Nguyen-Van-Tam JS, Jeffrey N et al. Changing carriage rate of Neisseria meningitidis among university students during the first week of term: cross sectional study. BMJ 2000;320:846-49.

187.     Paneth N, Kort EJ, Jurczak D et al. Predictors of vaccination rates during a mass meningococcal vaccination program on a college campus. J Am Coll Health 2000;49:7-11.

188.     Immunization of health-care workers: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR 1997;46:1-42.

189.     Abramson JS, Spika JS. Persistence of Neisseria meningitidis in the upper respiratory tract after intravenous antibiotic therapy for systemic meningococcal disease. J Infect Dis 1985;151:370-71.

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

191. CDC. Laboratory-acquired meningococcemia — California and Massachusetts. MMWR 1991;40:46-7,55.

192.     Maclennan JM, Deeks JJ, Obaro S et al. Meningococcal serogroup C conjugate vaccination in infancy induces persistent immunological memory. In: Nassif X, ed. Eleventh international pathogenic Neisseria conference, Nice, France. EDK, Paris 1998:151.

193.     Richmond PC, Borrow R, Clark S et al. Meningococcal C conjugate vaccines are immunogenic and prime for memory after a single dose in toddlers. San Francisco, California: American Society for Microbiology, 1999:362.

194.     Mäkelä PH, Peltola H, Käyhty H et al. Polysaccharide vaccines of group A Neisseria meningtitidis and Haemophilus influenzae type b: a field trial in Finland. J Infect Dis 1977;136:suppl S43-50.

195.     Gold R, Lepow ML, Goldschneider I et al. Clinical evaluation of group A and group C meningococcal polysaccharide vaccines in infants. J Clin Invest 1975;56:1536-47.

196.     Peltola H, Mäkelä H, Käyhty H et al. Clinical efficacy of meningococcus group A capsular polysaccharide vaccine in children three months to five years of age. N Engl J Med 1977;297:686-91.

197.     Lepow ML, Beeler J, Randolph M et al. Reactogenicity and immunogenicity of a quadrivalent combined meningococcal polysaccharide vaccine in children. J Infect Dis 1986;154:1033-36.

198.     Scheifele DW, Bjornson G, Boraston S. Local adverse effects of meningococcal vaccine. Can Med Assoc J 1994;150:14-5.

199.     Peltola H, Mäkelä PH, Elo O et al. Vaccination against meningococcal group A disease in Finland 1974-75. Scand J Infect Dis 1976;8:169-74.

200.     Hankins WA, Gwaltney JM Jr, Hendley JO et al. Clinical and serological evaluation of a meningococcal polysaccharide vaccine groups A, C, Y, and W135. Proc Soc Exp Biol Med 1982;169:54-7.

201.     Roberts JS, Bryett KA. Incidence of reactions to meningococcal A&C vaccine among U.K. schoolchildren. Public Health 1988;102:471-76.

202.     Yergeau A, Alain L, Pless R et al. Adverse events temporally
associated with meningococcal vaccines. Can Med Assoc J 1996;154:503-07.

203.     McCormick JB, Gusmao HH, Nakamura S et al. Antibody response to serogroup A and C meningococcal polysaccharide vaccines in infants born of mothers vaccinated during pregnancy. J Clin Invest 1980;65:1141-44.

204.     Letson GW, Little JR, Ottman J et al. Meningococcal vaccine in pregnancy: an assessment of infant risk. Pediatr Infect Dis J 1998;17:261-63.

205.     De Andrade Carvalho A, Giampaglia CM, Kimura H et al. Maternal and infant antibody response to meningococcal vaccination in pregnancy. Lancet 1977;2:809-11.

206.     Menjugate^TM: summary of product characteristics, December 2000. UK Marketing Authorization Number (2000) PL/13767/0014.

207.     Maclennan J. Meningococcal group C conjugate vaccines. Arch Dis Child 2001;84:383-86.

208.     Maiden MC, Spratt BG. Meningococcal conjugate vaccines: new opportunities and new challenges. Lancet 1999;354:615-16.

* World Health Organization (2000) WHO report on global surveillance of epidemic-prone infectious diseases. Department of communicable disease surveillance and response <http://www.who.int.emc/diseases/meningitis/index.html>.

* Members: Dr. V. Marchessault (Chairperson), Dr. J. Spika (Executive Secretary), J. Brousseau (Administrative Secretary), Dr. I. Bowmer, Dr. G. De Serres, Dr. S. Dobson, Dr. J. Embree, Dr. I. Gemmill, Dr. J. Langley, Dr. M. Naus, Dr. P. Orr, Dr. B. Ward, A. Zierler.

Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. V. Lentini (DND),Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. R. Massé (CCMOH), Dr. J. Salzman (CATMAT), Dr. L. Samson, (CIDS), Dr. D. Scheifele (CAIRE), Dr. M. Wharton (CDC).

Ex-Officio Representatives: Dr. A. King (CIDPC), Dr. L. Palkonyay (BBR), Dr. P. Riben (MSB).

This statement was prepared by Dr. Andrew J. Pollard and Dr. Theresa W.S. Tam and approved by NACI.

[Canada Communicable Disease Report]