Cochrane review: Conjugate vaccines for preventing meningococcal ...

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EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL Evid.-Based Child Health 2: 497–528 (2007) Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ebch.126

Conjugate vaccines for preventing meningococcal C meningitis and septicaemia (Review) Conterno LO, Silva Filho CR, Rüggeberg JU, Heath PT

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration, first published in The Cochrane Library 2007, Issue 1 http://www.thecochranelibrary.com

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Evid.-Based Child Health 2: 497–528 (2007) TABLE OF CONTENTS ABSTRACT . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW SEARCH METHODS FOR IDENTIFICATION OF STUDIES . METHODS OF THE REVIEW . . . . . . . . . . . . . DESCRIPTION OF STUDIES . . . . . . . . . . . . . METHODOLOGICAL QUALITY . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . POTENTIAL CONFLICT OF INTEREST . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . TABLES . . . . . . . . . . . . . . . . . . . . . Characteristics of included studies . . . . . . . . . . . Characteristics of excluded studies . . . . . . . . . . . GRAPHS AND OTHER TABLES . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . COVER SHEET . . . . . . . . . . . . . . . . . .

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Conjugate vaccines for preventing meningococcal C meningitis and septicaemia (Review) Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

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Conjugate vaccines for preventing meningococcal C meningitis and septicaemia (Review) Conterno LO, Silva Filho CR, Rüggeberg JU, Heath PT

This version first published online: 19 July 2006 in Issue 3, 2006 of The Cochrane Library. Conterno LO, Silva Filho CR, Rüggeberg JU, Heath PT. Conjugate vaccines for preventing meningococcal C meningitis and septicaemia. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD001834. DOI: 10.1002/14651858.CD001834.pub2. Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the review. Date of most recent substantive amendment: 15 May 2006

ABSTRACT Background Meningococcal polysaccharide (MPLS) vaccines protect against Serogroup C disease, but do not produce an immune response in infants less than two years of age. This limitation can be overcome by linking C polysaccharide to carrier proteins (’conjugating’), to create meningococcal serogroup C conjugate (MCC) vaccines. In the absence of trial data, the immune response to vaccination has been considered to be a reasonable surrogate for vaccine protection. Objectives To assess the immunogenicity, safety and efficacy of MCC vaccines for preventing meningitis and septicaemia. Search strategy We searched the Cochrane Central Register Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005); MEDLINE (1966 to September, Week 1 2005); and EMBASE (1990 to June 2005) and references of studies. Selection criteria Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) in humans comparing MCC vaccines against a control vaccine or none. In the absence of any trials on vaccine efficacy, population-based observational studies about effectiveness were included. Data collection and analysis Two authors independently screened the results of the literature searches, selected eligible studies, extracted the data and evaluated the quality of them. Main results The studies showed that MCC vaccine was highly immunogenic in infants after two and three doses, in toddlers after one and two doses and in older age groups after one dose. In general higher titres were generated after MCC than after MPLS vaccines. Immunological hypo-responsiveness seen after repeated doses of MPLS vaccine may be overcome with MCC. Observational studies have documented a significant decline in meningococcal C disease in countries where MCC vaccines have been widely used. The timing of the vaccinations schedules, the specific conjugate used, and the vaccines given concomitantly or combined, may be important. Authors’ conclusions The MCC vaccine appears to be safe, immunogenic and able to induce immunological memory in all age groups. Observational studies strongly suggest that MCC is clinically effective.

PLAIN LANGUAGE SUMMARY Traditional meningococcal polysaccharide (MPLS) vaccines protect against Serogroup C disease (caused by Neisseria meningitidis), but do not produce an immune response in infants less than two years of age Conjugate vaccines for preventing meningococcal C meningitis and septicaemia (Review) Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

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Evid.-Based Child Health 2: 497–528 (2007) This limitation can be overcome by linking C polysaccharide to carrier proteins (’conjugating’), to create meningococcal serogroup C conjugate (MCC) vaccines. This review looks at MCC vaccines to protect young children against Serogroup C disease. Trials found that MCC induces an immune response against serogroup C in all age groups, but especially younger children for whom the immune response is greater than that of the traditional MPLS. It appears to be safe. Clinical efficacy of MCC could not be assessed from randomised controlled clinical trials (there were none). However, weaker evidence from observational studies showed a decrease in meningococcal C disease and meningococcal C carriage in countries where vaccines have been widely used.

BACKGROUND Meningococcal meningitis and septicaemia are acute bacterial infections caused by Neisseria meningitidis (N. meningitidis). Although bacteria carried in the human nasopharynx are the source of infection, colonisation is usually asymptomatic. However, in a small minority, colonisation will progress to mucosal invasion, infection of the blood (septicaemia) and / or meningitis. Isolates from cases of invasive disease may be grouped together according to their surface polysaccharide. Serogroups A, B, C, W-135 and Y are responsible for most cases world-wide, but vary in their geographic distribution and pattern of disease (Tikhomirov 1997). Prior to the introduction of meningococcal serogroup C conjugate (MCC), serogroup C was primarily associated with endemic meningococcal disease in Europe, the Americas and Australasia and was also implicated in large outbreaks, small disease clusters and sporadic infections. Serogroup C was estimated to be responsible for 25% to 68% of all meningococcal cases in these countries (Anonymous 1998; Cartwright 2001; Connolly 1999; Deeks 1997; Jackson 1993). It has also contributed to large epidemics in Africa, the Middle East, and the Indian sub-continent (Broome 1989). Neonates are relatively protected from meningococcal disease by the transplacental transfer of maternal antibodies (Gold 1979). As the level of these antibodies wanes the incidence of meningococcal disease increases. Age-specific incidence of meningococcal disease peaks between 6 and 12 months after birth in developed countries (Jones 1993). Although the main burden of disease is in infants, a smaller but significant peak of incidence also occurs in the teenage years. Cases of meningococcal disease tend to cause considerable public anxiety. The onset of meningococcal disease is often sudden and a previously healthy individual can progress to fatal fulminant disease within a few hours. Despite advances in antibiotic therapy and intensive care facilities, the sudden onset and rapid progression means that meningococcal disease is still associated with high mortality and morbidity. In a Europe-wide survey, the overall case fatality rate for serogroup C disease was estimated at 8.3% (Connolly 1999) and other studies have documented sequelae in 7.9% to 15.3% of survivors (Erickson 1998; Healy 2002; Spanjaard 1987).

Vaccines that protect against serogroup C meningococcal disease have existed for some time. These are based on the polysaccharide from the capsule of the organism and are available in combination with serogroups A, W-135 and Y capsular polysaccharides. However, the polysaccharide vaccines have several limitations. The serogroup C component is not immunogenic in infants under two years old, thus failing to protect those at greatest risk of disease. In older children, who are capable of mounting a response, the protection is short-lived (Gold 1979; Jodar 2002; WHO 2002). Furthermore, there is evidence suggesting that polysaccharide vaccines may induce a hyporesponsive state in some recipients (Gold 1979; Granoff 1998; MacDonald 1998). The major deficiencies of meningococcal C polysaccharide vaccines have been overcome with the development of conjugate vaccines. This approach has proven highly effective for Hib (Robbins 1996). By covalently linking polysaccharides to carrier proteins, the thymus-independent polysaccharide is converted into a thymus-dependent immunogen. Engagement of T-cells results in the induction of antibodies in infants and memory responses. Tetanus toxoid, diphtheria toxoid or CRM197 , a non-toxic mutant of diphtheria toxin, have been used as carrier proteins. Laboratory assays used to evaluate and compare immune responses to meningococcal vaccines are functional assays (SBA) and antibody-binding assays (ELISA). The functional assays such as the serum bactericidal assay (SBA) tend to measure only high-avidity antibodies and are considered a better measure of protective efficacy. The serum bactericidal assay (SBA) can use human (h-SBA) or rabbit (r-SBA) as an external source of complement. Serogroup C meningococci are more susceptible to specific antibodies when using baby rabbit complement as opposed to human complement, resulting in higher SBA titres. The absence of bactericidal activity appears to predict susceptibility to disease and a titre of ≥ 4 by h-SBA or ≥8 by r-SBA correlates with short-term protection for meningococcal C disease (Balmer 2004; Borrow 2001; Goldschneider 1969; Jones 1993; Jodar 2000; Santos 2001). ELISA measures functional and non-functional antibodies. Low avidity antibodies are often not functional. The modified enzymelinked immunosorbent assay (Bm-ELISA) measures serum immunoglobulin G (IgG) antibody responses to meningococcal C polysaccharide and favours detection primarily of high-avidity antibodies, therefore providing results that correlate closely with mea-

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Evid.-Based Child Health 2: 497–528 (2007) surements of functional activity (Balmer 2004; Granoff 1998; Jodar 2000; Wall 2002). Although there is no consensus on a protective antibody level against group C meningococcus, levels above 2 µg/ml are considered likely to be associated with short-term protection (Peltola 1998). Serological correlates of long-term protection against meningococcal disease following vaccination are not well defined. It is not known whether the absolute bactericidal titre is the best measure of protection against invasive disease after conjugate vaccination, or whether lower titres may still be protective in the presence of immunologic memory. The recent UK experience with Hib conjugate vaccines (Ramsay 2003a) and the knowledge of the speed with which meningococcal disease can occur, suggests that the presence of both functional antibody and memory may be preferred. The attainment of clinical efficacy data on meningococcal C conjugate vaccines is problematic. Despite its high public profile, meningococcal disease is relatively rare. This makes the number of expected outcomes small and the number of participants required to give a study sufficient power very large. For this reason the immune response has been used as a surrogate of vaccine protection. Another approach has been to document vaccine effectiveness using the screening method. This requires population vaccine coverage data and case vaccination histories (Farrington 1993; Ramsay 2003a). Meningococcal C conjugate vaccines are currently recommended by the WHO for inclusion in national childhood immunisation programmes, for protection of high-risk individuals, and for targeted vaccinations during outbreaks, depending on the epidemiological situation, public health priorities and economy of the concerned countries (WHO 2002).

OBJECTIVES To assess the immunogenicity, safety and efficacy of conjugate vaccines against meningococcal serogroup C meningitis and septicaemia in infants, children and adults. Specifically, the following hypotheses will be tested: Comparing meningococcal C conjugate vaccine and placebo/control groups: • There is no difference in serum antibody response to N. meningitidis serogroup C. • There is no difference in the number or severity of adverse effects (both systemic and localised).

CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW Types of studies Randomised controlled trials (RCTs) and controlled clinical trials (CCTs). No RCTs were found regarding vaccine clinical effectiveness. Therefore data on effectiveness of MCC vaccine were gathered from observational studies. Types of participants Adults and children. Types of intervention RCTs and CCTs in humans comparing meningococcal C conjugate vaccine against placebo, control vaccine or no intervention. Studies comparing type, dose or schedule of meningococcal C conjugate vaccine were included. Types of outcome measures Immunological • Titre of anti-N. meningitidis serogroup C serum antibody concentration measured by standard or modified ELISA. • Titre of serum bactericidal antibody to N. meningitidis serogroup C. • The serum bactericidal antibody (SBA) titre to N. meningitidis serogroup C considered sufficient for short-term protection for meningococcal C disease was a titre of ≥4 if human serum was used as the complement source or ≥ 8 if pooled rabbit serum was the source of complement (Balmer 2004; Borrow 2001; Goldschneider 1969; Jones 1993). • The anti-N. meningitidis serogroup C serum antibody concentration considered sufficient for short-term protection was IgG more than 2 µg/ml measured by ELISA. Adverse events • Local and systemic adverse events following vaccination. Clinical: • Laboratory confirmed serogroup C meningococcal meningitis and/or septicaemia. • Laboratory confirmed meningococcal meningitis and/or septicaemia. • Clinically diagnosed meningococcal meningitis and/or septicaemia.

• There is no difference in the number or severity of meningococcal cases.

• Nasopharyngeal carriage of N. meningitidis serogroup C.

There is no difference in nasopharyngeal carriage of meningococci.

• Nasopharyngeal carriage of N. meningitidis.

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Evid.-Based Child Health 2: 497–528 (2007) SEARCH METHODS FOR IDENTIFICATION OF STUDIES

See: Cochrane Acute Respiratory Infections Group methods used in reviews. We searched the Cochrane Central Register Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005); MEDLINE (1966 to September, Week 1 2005); and EMBASE (1990 to June 2005) and references of studies. There were no language restrictions. MEDLINE and CENTRAL were searched using the following terms, which were modified to search EMBASE. 1 exp Meningitis, Meningococcal/ 2 (meningococc$ adj meningitis) 3 exp Neisseria meningitidis/ 4 Neisseria Meningitidis 5 exp Septicemia/ 6 septicaemia 7 Waterhouse Friderichsen 8 or/1-7 9 exp Vaccines, Conjugate/ 10 conjugate vaccine$ 11 or/9-10 12 8 and 11 13 Meningococcal conjugate vaccine$ 14 12 or 13 15 RANDOMIZED CONTROLLED TRIAL.pt. 16 CONTROLLED CLINICAL TRIAL.pt. 17 RANDOMIZED CONTROLLED TRIALS.sh. 18 RANDOM ALLOCATION.sh. 19 DOUBLE BLIND METHOD.sh. 20 SINGLE-BLIND METHOD.sh. 21 or/15-20 22 Animals/ 23 human.sh. 24 22 not 23 25 21 not 24 26 CLINICAL TRIAL.pt. 27 exp Clinical Trials/ 28 (clin$ adj25 trial$).ti,ab. 29 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. 30 PLACEBOS.sh. 31 placebo$.ti,ab. 32 random$.ti,ab. 33 or/26-32 34 33 not 24 35 25 or 34 36 14 and 35

METHODS OF THE REVIEW Two authors (LOC, CRSF) independently screened the results of the literature searches and selected eligible studies according to the pre-set criteria. Differences between authors were resolved by discussion. A data extraction form was developed to facilitate data extraction. The following data were extracted from each study: Date of trial; Location of trial; Characteristics of participants (number, age, sex); Characteristics of interventions; Type of vaccine, type of placebo or control vaccine, dose, schedule, length of follow up. Characteristics of outcome measures Type of laboratory assay used. Definitions of adverse events. Participants were divided into the following subgroups Children: 1st year of life; 1 to 2 years; 3 to 14 years; Adults (15 years and over). Methodological quality of trials Trial quality was assessed using the following questions (Jadad 1996): 1. Was the study described as randomised (this includes the use of words such as randomly, random and randomisation)? 2. Was the study described as double blind? 3. Was there a description of withdrawals and dropouts? 1. Randomisation A method to generate the sequence of randomisation was regarded as appropriate if it allowed each study participant to have the same chance of receiving each intervention and the investigators could not predict which treatment was used. Methods of allocation using date of birth or alternation were not regarded as appropriate. 2. Double blinding A study was regarded as double-blind if the word “double blind” was used. The method was regarded as appropriate if it was stated that neither the person doing the assessments nor the study participant could identify the intervention being assessed; or if in the absence of such a statement, the use of active placebos, identical placebos or dummies were mentioned. 3. Withdrawals and dropouts Participants who were included in the study but did not complete the observation period were not included in the analysis. The number and the reasons for withdrawal in each group must have been stated. If there were no withdrawals, it should have been stated in the article. If there were no statements on withdrawals, this item should not have been given any points.

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Evid.-Based Child Health 2: 497–528 (2007) One point was allocated for randomisation, double-blinding and description of withdrawals and dropouts; an extra point was added for methods of randomisation and blinding that were well described and adequate. Studies that used a clearly inadequate method of randomisation or blinding lost the point allocated. Disagreement was resolved by discussion. Additionally, allocation concealment will be judged in the following categories, as required for entry of study characteristics into Review Manager (RevMan) software: A - adequate; B - unclear; C - inadequate; D - allocation concealment not used. A indicates adequate concealment of the allocation (for example, by telephone randomisation, or use of consecutively numbered, sealed, opaque envelopes). B indicates uncertainty about whether the allocation was adequately concealed (for example, where the method of concealment was not known). C indicates that the allocation was definitely not adequately concealed (for example, open random number lists or quasi-randomisation such as alternate days, odd/even date of birth, or hospital number). Data synthesis Antibody concentrations in the trials were presented as geometric means which represented the logarithmic transformation of antibody concentration found. The measurement of serum antibodies was done in a sample of patients in many trials. Therefore the analysis represents available case analysis more than intentionto-treat analysis. Homogeneity of participants, interventions and outcomes were assessed. The trials were considered so heterogeneous in terms of vaccine compounds, concentration of oligosaccharide C, concentration of protein carrier material (CRM197 ), assays used to measure the antibody responses, schedule used and age of participants that we decided not to combine the results. Tables and figures The following were included: Characteristics of trials contributing to this review; List of trials excluded from the review, with reasons for exclusion.

DESCRIPTION OF STUDIES The electronic searches identified 352 abstracts; after excluding duplicates, 39 studies were identified as potentially eligible trials and full copies of the papers were obtained. After evaluation of each selected trial, we included 22 studies, which corresponded to 28 publications. Fourteen were RCTs (Anderson 1994; Borrow 2003, Burrage 2002; Buttery 2005; Campagne 2000; Choo 2000; English 2000; Halperin 2002; Lakshman 2002; Lieberman 1996; MacDonald 1998; Pichichero 2005; Richmond 2001; Tejedor

2004), four were RCTs in the first phase, but in the second phase, a non-randomised control group age strata-matched was added (Goldblatt 2002; MacLennan 2000; Richmond 2000; Twumasi 1995). We did not find any RCTs looking at the clinical effectiveness of meningococcal C conjugate vaccine. We decided to include four observational studies which addressed this (De Wals 2004; Larrauri 2005; Maiden 2002; Trotter 2004). Eleven studies evaluated meningococcal C conjugate vaccine (Borrow 2003; Burrage 2002; Choo 2000; English 2000; Goldblatt 2002; Halperin 2002; MacDonald 1998; MacLennan 2000; Richmond 2000; Richmond 2001; Tejedor 2004). Five studies evaluated meningococcal conjugate AC vaccine (Anderson 1994; Campagne 2000; Lakshman 2002; Lieberman 1996; Twumasi 1995). One study evaluated the meningococcal quadrivalent vaccine ACYW135 (Pichichero 2005). One trial (Buttery 2005) evaluated a combination 9-valent pneumococcal-MCC. The concentration of oligosaccharide C in vaccines used varied from 1 µg to 22 µg. The oligosaccharide C was conjugated to CRM197 (cross-reacting material) non-toxic mutant of diphtheria toxin in all but three trials. In these three trials the oligosaccharide was conjugated to 20 µg of tetanus toxoid (Borrow 2003; Burrage 2002; Richmond 2001). The concentration of CRM197 varied from 5.8 µg to 160.0 µg. The following vaccines were used: • Meningococcal C conjugate vaccine (Wyeth Lederle Vaccines and Pediatrics) containing 8 µg to 12 µg of meningococcal C oligosaccharide linked to 8 µg to 15 µg of CRM197 mutant Corynebacterium diphtheria (C. diphtheria) toxin and 1 mg aluminium hydroxide (Burrage 2002; English 2000; Goldblatt 2002; Lakshman 2001; Richmond 2000; Richmond 2001). • Meningococcal C conjugate vaccine (Chiron Vaccine SpA) containing 10 µg to 12 µg of meningococcal C oligosaccharide linked to 8 µg to 15 µg of CRM197 mutant C. diphtheria toxin and 1 mg of aluminum hydroxide (Burrage 2002; Choo 2000; Halperin 2002; Lakshman 2001; Lieberman 1996; MacDonald 1998; MacLennan 2000; Richmond 2001). • Meningococcal C conjugate vaccine (North American VaccineBaxter Hyland Immuno) containing 10 µg of meningococcal oligosaccharide linked to 20 µg of tetanus toxoid and 0.5 mg of aluminum hydroxide (Borrow 2003; Burrage 2002; Richmond 2001). • Meningococcal A-C conjugate vaccine (Biocine Siena Italy) contained 11 µg of each oligosaccharide, conjugate to 48.7 µg of CRM197 , and 1 µg of aluminum hydroxide, and 50 µg of thimerosal (Lieberman 1996; Twumasi 1995). • Meningococcal A-C conjugate vaccine (Meningivac A&C, Aventis Pasteur) contained 4 µg to 16 µg of each oligosaccha-

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Evid.-Based Child Health 2: 497–528 (2007) ride, conjugate to 48.7 µg of CRM197 and 1 mg of aluminum hydroxide (Goldblatt 2002; Lakshman 2002). • Meningococcal A-C conjugate vaccine (Aventis Pasteur, contained 1 µg or 4 µg or 16 µg of each oligosaccharide, conjugate to 5.8 µg or 32.2 µg or 16.0 µg of diphtheria toxoid (Campagne 2000). • Meningococcal A-C conjugate vaccine (Sclavo Siena Italy) containing 5.5 µg, 11 µg and 22 µg of meningococcal C oligosaccharide linked to 48.7 µg of CRM197 (Anderson 1994; Lakshman 2002; MacLennan 2000). • Meningococcal tetravalent conjugate vaccine (Menactra, Sanofi Pasteur, Inc Pennsylvania) containing 4 µg of each capsular polysaccharide from serogroup A, C Y and W135 conjugate to 48 µg of diphtheria toxin (Pichichero 2005). • Pnc9-MenC: 9 valente pneumococcal-group C meningococcal conjugate vaccine (Wyeth Vaccines, Maidenhead, UK) contained 2 µg of pneumococcal saccharide conjugates 1, 4, 5, 9v, 14,18C, 19F and 23F; 4 µg of pneumococcal saccharide conjugate 6B; 10 µg of meningococcal group C oligosaccharide and 38.5 µg of CRM197 (Buttery 2005). In 12 trials, the meningococcal conjugate vaccines were compared to meningococcal polysaccharide vaccines. These comparative vaccines were used: • Meningococcal A-C polysaccharide vaccine (Pasteur Mérieux Sérums and Vaccine) containing 50 µg each of serogroup A and C polysaccharide (Campagne 2000; Choo 2000; Goldblatt 2002; Lakshman 2002; Richmond 2000; Richmond 2001). • Meningococcal A-C polysaccharide vaccine (Menpovax, Biocine Siena Italy) containing 50 µg each of serogroup A and C polysaccharide (Twumasi 1995). • Meningococcal A-C polysaccharide vaccine (Smith Kline Beacham ) containing 10 µg each of serogroup A and C polysaccharide (Borrow 2003). • Meningococcal polysaccharide vaccine quadrivalent (Menomune, Connaught) containing 50 µg each of serogroup A ,C, Y, W135 polysaccharide (Anderson 1994; Lieberman 1996; MacDonald 1998; Pichichero 2005). In four trials (English 2000; Halperin 2002; MacDonald 1998; MacLennan 2000) the hepatitis B virus vaccine (SmithKline) was used as a control vaccine. One trial (Twumasi 1995) used inactivated poliomyelitis vaccine (Pasteur Mérieux) as a control vaccine. In eight trials (Borrow 2003; Buttery 2005; Campagne 2000; English 2000; Halperin 2002; Lakshman 2001; MacLennan 2000; Twumasi 1995) the meningococcal C conjugate vaccine was administrated concomitantly with routine vaccines (diphtheria, tetanus, pertussis, H. influenzae b, oral poliomyelitis and hepatitis B).

Nine trials included infants before 12 months of age at the first dose of vaccination (Borrow 2003; Buttery 2005; Campagne 2000; English 2000; Halperin 2002; Lakshman 2001; MacLennan 2000; Twumasi 1995; Tejedor 2004). Three trials included toddlers between 12 to 24 months of age (Lieberman 1996; MacDonald 1998; Richmond 2001). Two trials included children from 2 to 10 years of age (Burrage 2002; Pichichero 2005). Five were trials of adolescents and adults patients (Anderson 1994; Choo 2000; Goldblatt 2002; Lakshman 2002; Richmond 2000). In the Twumasi study (Twumasi 1995) the same children were vaccinated at 2 to 6 months, 18 to 24 months and at 5 years of age, which represented four publications; we included three of these. In the MacLennan study (MacLennan 2000) the same children were vaccinated at 2 to 12 months and at 4 years, which represented three publications and we included two of these. In the Choo study (Choo 2000) the data were reported in two publications and the Lakshman (Lakshman 2002) study represented two publications. The included studies evaluated the immunogenicity of meningococcal conjugate vaccine. Meningococcal serogroup C specific IgG concentrations were measured by standard ELISA assay (s-ELISA) in fourteen studies (Anderson 1994; Borrow 2003; Bramley 2001; Burrage 2002; Buttery 2005; Campagne 2000; English 2000; Goldblatt 2002; Lakshman 2002; Lieberman 1996; Richmond 2000; Richmond 2001; Tejedor 2004; Twumasi 1995), and by a modified ELISA (m-ELISA) in seven studies (Borrow 2003; Burrage 2002; Choo 2000; Halperin 2002; MacDonald 1998; MacLennan 2000; Richmond 2001). The values were expressed in geometric mean concentration (µg/ml) which represented the logarithmic transformation of antibody concentrations found. The Serum Bactericidal Antibodies (SBA) against meningococcal strains using pooled rabbit serum as an exogenous complement source were reported in sixteen trials (Anderson 1994; Borrow 2003; Bramley 2001; Burrage 2002; Buttery 2005; Campagne 2000; English 2000; Goldblatt 2002; Halperin 2002; Lakshman 2002; Lieberman 1996; Pichichero 2005; Richmond 2000; Richmond 2001; Tejedor 2004; Twumasi 1995). Three trials used human serum as the external complement source (Choo 2000; MacDonald 1998; MacLennan 2000). SBA titres were expressed in geometric mean titre (GMT /ml), and it represented the reciprocal of final serum dilution giving ≥50% killing at 60 minutes. Eleven trials described the percentage of patients with SBA ≥ 1:8 (Borrow 2003; Burrage 2002; Buttery 2005; Campagne 2000; Choo 2000; Goldblatt 2002; Halperin 2002; Lakshman 2002; MacDonald 1998; MacLennan 2000; Richmond 2001). Salivary concentration of specific meningococcal C antibodies of IgA, IgM and IgG classes were determined by ELISA and described in two trials (Choo 2000; Lakshman 2002).

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Evid.-Based Child Health 2: 497–528 (2007) METHODOLOGICAL QUALITY The overall quality of the trials was good. Ten trials were randomised with adequate allocation concealment (A) (Borrow 2003; Burrage 2002; Choo 2000; English 2000; Halperin 2002; Lakshman 2002; Lieberman 1996; MacDonald 1998; MacLennan 2000; Richmond 2001). In two trials the allocation concealment was unclear (Anderson 1994; Pichichero 2005). In six trials the allocation concealment was inadequate (Buttery 2005; Campagne 2000; Goldblatt 2002; Richmond 2000; Tejedor 2004; Twumasi 1995). Nine trials were double-blinded (Anderson 1994; Borrow 2003; Bramley 2001; Choo 2000; English 2000; Lakshman 2002; MacDonald 1998; MacLennan 2000; Richmond 2001). Each study was assessed using a 0 to 5 scale described by Jadad 1996. Five studies had a Jadad score of 5, three studies scored 4, five scored 3, one scored 2 and three had a score of 1. In many trials the measurement of serum antibodies was done in a sample of patients, therefore the analyses represent available case analysis rather than intention-to-treat analysis. The inclusion of RCTs only would have limited this review to evaluate the immunogenicity and safety of MCC vaccine. The relatively low incidence of meningococcal C disease has so far precluded any RCTs addressing the efficacy of MCC vaccines against clinical endpoints. Taking this into account, the authors decided to include population-based observational studies which looked at the impact of MCC vaccines on meningococcal disease and nasopharyngeal carriage and estimated vaccine effectiveness (De Wals 2004; Larrauri 2005; Maiden 2002; Trotter 2004).

RESULTS 1. Meningococcal C conjugate vaccine in infants Eight studies that evaluated the MCC in infants (Borrow 2003; Buttery 2005;Campagne 2000; English 2000; Halperin 2002; MacLennan 2000; Tejedor 2004; Twumasi 1995) were included. They were not combined because they were considered very heterogeneous (Alderson 2003). The heterogeneity was due to MCC vaccine components (concentration of oligosaccharide C and protein carrier). Seven trials used oligosaccharide conjugate to nontoxic mutant of diphtheria toxin (CRM197 ) (Buttery 2005; Campagne 2000; English 2000; Halperin 2002; MacLennan 2000; Tejedor 2004; Twumasi 1995) and one trial used conjugate to tetanus toxoid (Borrow 2003). The trials used different assays to measure the antibody responses to vaccines (s-ELISA, m-ELISA, r-SBA and h-SBA). The MCC vaccines used were: Meningitec Lederle: oligosaccharide C 10 µg and CRM197 25 µg; Menjugate, Chiron Corporation: oligosaccharide C 10 µg and CRM197 25 µg; Meningococcal A-C conjugate vaccine Biocine: oligosaccharides A-C 11 µg and CRM197 49 µg; Meningococcal C conjugate vaccine Baxter: oligosaccharide C 10 µg conjugate to tetanus toxoid 20 µg and

Meningococcal A-C conjugate vaccine Aventis Pasteur: oligosaccharide A-C 1 µg or 4 µg or 16 µg of each and tetanus toxoid 5.8 µg or 32.2 µg or 160 µg. 1.1. Three doses of Meningococcal conjugate vaccine up to 12 months of age Campagne 2000 Vaccine: MCC- Aventis Pasteur, each oligosaccharide A-C 1 µg or 4 µγ or 16 µg and tetanus toxoid 5.8 µg or 32.2 µg or 160 µg; Polysaccharide Meningococcal A-C with 50 µg of each oligosaccharide; Haemophilus influenzae type b conjugate vaccine Assays: s-ELISA and r-SBA This trial included 180 Nigerien infants who received 1 of 3 formulations of MCC at 6, 10 and 14 weeks of age: Group 1 (oligosaccharide 1 µg), Group 2 (oligosaccharide 4 µg), Group 3 (oligosaccharide 16 µg) , two doses of meningococcal polysaccharide (MPLS)AC at 10 and 14 weeks of age (Group 4) or Haemophilus influenzae type b conjugate vaccine (Group 5) . The geometric mean concentration (GMC) of serum antibodies after three doses was: 1.5 µg/ml (95% confidence interval (CI) 1.1 to 2.0) in Group 1; 2.8 µg/ml (95% CI 2.0 to 3.9) in Group 2; 4.8 µg/ml (95% CI 3.7 to 6.3) in Group 3; 5.3 µg/ml (95% CI 3.8 to 7.4 ) in Group 4; 0.5 µg/ml (95% CI 0.3 to 0.7) in Group 5, (p value less than 0.001 comparing Group 1 versus Group 3; p value 0.001 Group 1 versus Group 2 and Group 4) At 11 to 12 months the children were vaccinated with one dose of MPLS vaccine. The geometric mean concentration (GMC) of serum antibodies after the booster dose of MPLS -AC was: 8.9 µg/ml (95% CI 5.3 to 15.0) in Group 1; 8.1 µg/ml (95% CI 4.5 to 14.6) in Group 2; 8.3 µg/ml (95% CI 5.4 to 12.6) in Group 3; 2.8 µg/ml (95% CI 1.7 to 4.7) in Group 4 and Group 5: data not available. The GMT of serum bactericidal antibodies after the three doses of MC-AC was: 72.1 (95% CI 45.5 to 114) in Group 1; 189 (95% CI 128 to 278) in Group 2; 325 (95% CI 204 to 517) in Group 3; 25.4 (95% CI 14.4 to 44.6) in Group 4 and 7.3 (95% CI 7.7 to 11.3) in Group 5; (p value 0.01 comparing Group 1, Group 2 and Group 3 versus Group 4 and Group 5; p value = 0.01 comparing Group 1 versus Group 2 and Group 3) After the booster dose the GMT was: 264 (95% CI 104 to 677) in Group 1; 287 (95% CI 96.2 to 855) in Group 2; 178 (95% CI 63.6 to 499) in Group 3; 14.4 (95% CI 7.9 to 26.1) in Group 4; and Group 5: data not available. Adverse events

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Evid.-Based Child Health 2: 497–528 (2007) The most frequently observed local reactions were tenderness and redness at the site of injection: 37% and 18.1% in the groups that received MCC, 30.8% and 7.5% in MPLS Group and 19.6% and 11.2% in the Hib group. The systemic reactions in Group 3 range from 38.9% to 57.1% and in Groups 2 and Group 3 up to 37%. The rates of systemic reactions during the primary immunization series did not increase with the successive injections in any group. English 2000 Vaccine: Lederle, oligosaccharide C 10 µg and CRM197 25 µg and hepatitis B vaccine (SmithKline) Assays: S-ELISA and r-SBA This trial included 237 infants and compared three doses of MCC to HBV vaccine given at two, three and four months of age. The geometric mean concentration (GMC) of serum antibodies to meningococcal C polysaccharide was measured after the three doses of MCC. The GMC in MCC vaccine group was 23.93 µg/ml (95% CI 21.47 to 24.68) and in the control group (HBV) 0.10 µg/ml (95% CI 0.08 to 0.12). The geometric mean titre (GMT) of serum bactericidal antibodies was 1429 (95% CI 1125 to 1814) in the MCC vaccine group compared to 2.9 (95% CI 1.8 to 4.9) in the control group. Titres of r-SBA ≥ 8 after three doses were present in 100% (58/58) of the MCC vaccine group and in 13% (8/59) of the control group. Adverse events There were no severe local reactions. The adverse events reported were crying more than expected: 13% (MCC), 8% (HBV); fever 38ºC or above: 5% (MCC) and 1% (HBV); irritability: 67% (MCC) and 67% (HBV); any redness at vaccine site: 41% (MCC) and 40% (HBV); any swelling at vaccine site: 6% (MCC) and 8% (HBV); any tenderness at vaccine site: 13% (MCC) and 15% (HBV). Comparing the MCC and HBV groups, there were no significant differences in the occurrence of these adverse events. Halperin 2002 Vaccines: Menjugate, Chiron Corporation: oligosaccharide C 10 µg and CRM197 25 µg and hepatitis B vaccine (SmithKline) Assays: M- ELISA and r-SBA This trial included 348 infants and compared three doses of MCC vaccine to the control vaccine (HBV) given at two, four and six months. The GMC of serum antibodies to meningococcal C polysaccharide one month after three doses was 10 µg/ml (95% CI 9.2 to 11) in the MCC vaccine group and 0.2 µg/ml (95% CI 0.19 to 0.22) in the control group. The GMT of serum bactericidal antibodies was 232 (95% CI 207 to 260) in the MCC vaccine group compared to 2 (95% CI 1.8 to 2.3) in the control group (p value less than 0.001). Titres of r-SBA ≥ 8 after three doses were present in 100% (170/170) of the MCC vaccine group and in 1% (2/174) of the control group (p value less than 0.001). Nine months after vaccination the titres decreased in both groups to 0.8 µg/ml (95%

CI 0.7 to 0.9) in the MCC vaccine group and 0.2 µg/ml (95% CI 0.19 to 0.24) in the control group. The children received a booster dose of MCC or HVB at 15 months, at which point there was a significant rise in antibodies. The GMC of serum antibodies to meningococcal C polysaccharide after the booster dose was: 34 µg/ml (95% CI 31 to 37) in MCC vaccine group and 0.2 µg/ml (95% CI 0.19 to 0.23) in the control group. There was a 42-fold change after the booster dose in the MCC vaccine group. The GMT of r-SBA antibodies nine months after the three doses was 20 (95% CI 17 to 24) in the MCC vaccine group and 2.1 (95% CI 1.9 to 2.4) in the control vaccine group. After the booster, the GMT of SBA was 1344 (95% CI 1199 to 1506) in the MCC vaccine group and 2.1 (95% CI 1.8 to 2.5) in the control group (p value less than 0.001). There was a 17-fold change after the booster dose in the MCC vaccine group. Adverse events The adverse events reported after the first dose were crying more than expected: 1% (MCC) and 1% (HBV); fever 38ºC or above: 3% (MCC) and 3% (HBV); irritability: 38% (MCC) and 45% (HBV); sleepiness: 41% (MCC) and 36% (HBV); analgesic/antipyretic use: 20% (MCC) and 27% (HBV); any redness at vaccine site: 6% (MCC) and 6% (HBV); any swelling at vaccine site: 6% (MCC) and 8% (HBV); any tenderness at vaccine site: 11% (MCC) and 9% (HBV). Redness at the injection site was more commonly reported at four and six months in the MCC vaccine group (15% and 14%) than in the HBV group (7% and 9%). Induration at the site of injection at four and six months were more commonly reported in the MCC vaccine group (14% and 14%) than in HBV group (3% and 8%). Only persistent crying was reported more frequently with the booster dose of MCC (3%) than HBV (0%) (p value 0.02). MacLennan 2000 Vaccine: Chiron Corporation, oligosaccharide C 10 µg and CRM197 20 µg (MCC-1) or oligosaccharide C 10 µg and CRM197 13 µg (MCC-2) and hepatitis B vaccine (SmithKline) Assays: m-ELISA and h-SBA This trial included 182 infants and compared three doses of MCC vaccine with a control vaccine (HBV) given at two, three and four months. The GMC of serum antibodies to meningococcal C polysaccharide one month after the three doses was 21 µg/ml (95% CI 18 to 26) in the MCC-1 vaccine group and 17 µg/ml (95% CI 14 to 20) in the MCC-2 vaccine group and 0.2 µg/ml (95% CI 0.2 to 0.21) in the control group (p value less than 0.001). The GMT of SBA was 629 (95% CI 462 to 857) in the MCC-1 vaccine group and 420 (95% CI 311 to 566) in the MCC-2 vaccine group and 4.1 (95% CI 3.9 to 4.3) in the control vaccine group (p value less than 0.001). The children went on to receive a booster dose of MCC or MPLS vaccines at 12 months. In those who had previously received MCC, the GMC of serum antibodies to meningococcal C polysaccharide measured by m-ELISA was 63 µg/ml (95% CI 50 to 78) in children boosted with MCC vaccine and 25 µg/ml (95% CI 19

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Evid.-Based Child Health 2: 497–528 (2007) to 34) in children boosted with MPLS vaccine. These titres represented a 42-fold change from the pre- to post-booster titres in the MCC vaccine boosted group and a 16-fold change in the MPLS vaccine boosted group. In those who had previously received HBV the corresponding values were 2.7 ug/ml (95% CI 2.0 to 3.7) and 0.8 ug/ml (95% CI 0.53 to 1.2) respectively. In those who had previously received MCC, the GMT of h-SBA antibodies were 2448 (95% CI 1809 to 3311) in the group boosted with MCC and 789 (95% CI 542 to 1147) in the group boosted with MPLS. These titres represented a 113-fold change from the pre-booster titres in the MCC vaccine boosted group and a 44-fold change from the pre-booster titres in the MPLS vaccine boosted group. In those who had previously received HBV, the GMT was 15 (95% CI 9.8 to 22) and 4.5 (95% CI 2.6 to 7.6) respectively. Adverse events Local adverse events reported after the primary immunisation were any redness at vaccine site: 97% (MCC) and 95% (HBV); any induration at vaccine site: 42% (MCC) and 47% (HBV); any tenderness at vaccine site: 41% (MCC) and 40% (HBV). Local and systemic reactions after a booster dose were: antipyretic use 18% (MCC+MCC) and 37% (MCC+MPLS); irritability 18% (MCC+MCC) and 51% (MCC+MPLS); tenderness 11% (MCC+MCC) and 31% (MCC+MPLS); any redness at injection site: 83% (MCC+MCC) and 94% (MCC+MPLS). 1.2. Three doses of MCC versus two doses or one dose of MCC in infants younger than 12 months of age Twumasi 1995 Vaccine: Biocine, oligosaccharides C /A 11 µg and CRM197 49 µg Assay: s-ELISA This trial compared one dose of MCC-AC given at six months (Group 1), two doses at two and six months (Group 2) and three doses at two, three and four months (Group 3). The GMC of serum antibodies to meningococcal C polysaccharide one month after the vaccinations were: 2285 υ/ml (95% CI 1701 to 3069) in Group 1; 1370 υ/ml (95% CI 1062 to 1767) in Group 2; and 2760 υ/ml (95% CI 2316 to 3291) in Group 3. MacLennan 2000 Vaccine: Chiron Corporation, MCC-1: oligosaccharide C 10 µg and CRM197 20 µg or MCC-2: oligosaccharide C 10 µg and CRM197 13 µg Assays: m-ELISA, h-SBA This trial reported the GMC of serum antibodies to meningococcal C polysaccharide one month after the first dose, second and third doses of the two MCC vaccines. These were given at two, three and four months of age. The GMC after one dose were 0.92 µg/ml (95% CI 0.65 to 1.3) in the MCC-1 group and 0.87 µg/ml (95% CI 0.62 to 1.2) in the MCC-2 vaccine group. After the second dose 12 µg/ml (95% CI 8.5 to 17) in the MCC-1 group and 10 µg/ml (95% CI 7.2 to 15) in the MCC-2 group and after the third dose 21 µg/ml (95%

CI 18 to 26) in the MCC-1 group and 17 µg/ml (95% CI 14 to 20) in the MCC-2 group. The GMT of SBA after one dose was 13 (95% CI 8.8 to 19) in the MCC-1 group and 8.2 (95% CI 5.7 to 12) in the MCC-2 group; after the second dose was 302 (95% CI 180 to 506) in the MCC-1 group and 220 (95% CI 127 to 380) in the MCC-2 group and after the third dose was 629 (95% CI 462 to 857) in the MCC-1 group and 420 (95% CI 311 to 566) in the MCC-2 group. Borrow 2003 Vaccine: Baxter: oligosaccharide C 10 µg conjugate to tetanus toxoid 20 µg Assays: s-ELISA, m-ELISA and r-SBA This trial compared one, two and three doses of MCC vaccine in infants at two, three and four months. The GMC of serum antibodies to meningococcal C polysaccharide one month after the vaccination was: 8.3 µg/ml (95% CI 7.3 to 9.5) after one dose, 8.7 µg/ml (95% CI 7.9 to 9.7) after two doses and 13.3 µg/ml (95% CI 12 to 14.7) after three doses. The GMC of serum antibodies to meningococcal C polysaccharide using modified ELISA one month after the vaccination was: 63 µg/ml (95% CI 60 to 66.1) after one dose, 83.4 µg/ml (95% CI 79 to 88) after two doses and 78.9 µg/ml (95% CI 75.6 to 82.3) after three doses. The GMT of r-SBA in these groups were: 460 (95% CI 369 to 574) after one dose, 1326 (95% CI 1115 to 1575) after two doses and 1405 (95% CI 1164 to 1696) after three doses. No significant differences were seen between groups of two and three doses (p value 0.68). The r-SBA titres ≥ 8 were present in 98.4% (179/182) after one dose, 100% (188/188) after two doses and 99.4% (172/173) after three doses. These infants were boosted with MPLS vaccine at 13 to 14 months. Before the booster, the GMT declined and was: 10.4 (95% CI 7.5 to 14.3) in one the dose group, 20.7 (95% CI 14.6 to 29.4) in the two doses group and 21.5 (95% CI 15.8 to 29.2) in the three doses group. In pre-to post-primary series, ≥4 fold rises were seen in 96% (174/182) in the one dose group, 99.5% (187/188) in the two doses group and 98.8% (170/172) in the three doses group. The GMT after the booster was 6377 (95% CI 4888 to 8319) in one dose group, 3556 (95% CI 2699 to 4684) in two doses group and 2946 (95% CI 2116 to 4101) in three doses group. No significant differences were seen between groups of two and three doses (p value 0.37). There was a significant difference between the one dose group and the two and three dose groups (p value less than 0.01). All groups had a GMT higher after the booster with MPLS vaccine than after MCC vaccine (p value less than 0.001). Tejedor 2004 Vaccine: Meningitec Wyeth Lederle oligosaccharide C 10 µg and CRM197 15 µg Assays: ELISA and r-SBA This trial compared the MCC vaccine co-administrated with DTPa-HBV-IPV/Hib vaccine at two, four and six months of age

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Evid.-Based Child Health 2: 497–528 (2007) (Group 1) to MCC vaccine given separately at three, five and seven months of age (Group 2). The GMC of serum antibodies to meningococcal C polysaccharide after two doses of MCC was 12.8 µg/ml (95% CI 11.6 to 14.1) in the MCC Group 1 and 29.6 mg/ml (95% CI 26.4 to 33.2) in Group 2. The GMT of SBA after the two doses of MCC vaccine was 1033 (95% CI 875 to 1221) in Group 1 and 1590 (95% CI 1365 to 1853) in Group 2 and 99.5% of all infants in both groups had r-SBA ≥ 8. This compares with the GMC after 3 doses of MCC of 25.3 ug/ml (95% CI 23.3 to 27.6) in Group 1 and 55.5 (95% CI 49.6 to 62.2) in Group 2, with GMT of 1372.6 (95% CI 1196.7 to 1574.4) and 2257.1 (95% CI 1964.4 to 2593.5) in Groups 1 and 2 respectively. 1.3. MCC-AC versus MPLS-AC Twumasi 1995 Vaccine:Biocine, oligosaccharides C /A 11 µg and CRM197 49 µg Assay: s-ELISA This trial included 264 infants and compared different vaccination schedules. One group received three doses of MCC-AC at two, three and four months and the other group received two doses of MPLS-AC at three and six months. The GMT of serum antibodies to meningococcal C polysaccharide was 2760 mg/ml (95% CI 2316 to 3291) in the MCC vaccine group and 650 mg/ml (95% CI 485 to 873) in the MPLS group (p value less than 0.001). 1.4. One dose of MCC versus one dose of MPLS at 12 months MacLennan 2000 Vaccine: Chiron Corporation, MCC-1: oligosaccharide C 10 µg and MCC-2: CRM197 20 µg or oligosaccharide C 10 µg and CRM197 13 µg Assays: m-ELISA and h-SBA This trial included two groups of infants (108 in total) who had not previously received a meningococcal vaccine and were vaccinated at 12 months with one dose of MCC or MPLS vaccine. The GMC of serum antibodies to meningococcal C polysaccharide was 2.7 µg/ml (95% CI 2.0 to 3.7) in the MCC vaccine group and 0.8 µg/ml (95% CI 0.53 to 1.2) in the MPLS vaccine group (p value less than 0.001). The GMT of h-SBA was 15 (95% CI 9.8 to 22) in MCC vaccine group and 4.5 (95% CI 2.6 to 7.6) in the MPLS vaccine group (p value less than 0.001). 1.5. MCC and routine vaccines Tejedor 2004 Vaccine: Meningitec Wyeth Lederle oligosaccharide C 10 µg and CRM197 15 µg Assays: s-ELISA and r-SBA This trial included 452 infants who were vaccinated at two, four and six months of age with the MCC vaccine co-administered with DTPa-HBV-IPV-Hib vaccine (Group 1), or the MCC vaccine given separately at three, five and seven months of age (Group 2). The GMC of serum antibodies after three doses was 25.3 µg/ml (95% CI 23.3 to 27.6) in MCC Group 1 and 55.5 µg/ml (95% CI 49.6 to 62.2) in Group 2. The GMT of SBA to meningococcal

C polysaccharide one month after the three doses of MCC was 1372.6 (95% CI 1196.7 to 1574.4) in Group 1 and 2257.1 (95% CI 2196.4 to 2593.5) in Group 2. Adverse events Co-administration of both vaccines did not result in increased reactogenicity. The most frequently local adverse reactions reported were: pain 11.0% (Group 1) and 9.4% (Group 2); redness 14.4% (Group 1) and 21.3% (Group 2); swelling 9.5% (Group 1) and 12.8% (Group 2). Systemic reactions reported were: drowsiness 27.3% (Group 1) and 24.1% (Group 2); irritability 32.1% (Group 1) and 31.6% (Group 2); loss of appetite 24.0% (Group 1) and 20.6% (Group 2); fever 13.0% (Group 1) and 16.2% (Group 2); antipyretic use 14.5% (Group 1) and 14.9% (Group 2). 1.6. MCC combination with pneumococcal vaccine Buttery 2005 Vaccine: Pnc9-MenC Wyeth Vaccines , oligosaccharide 2µg of pneumococcal saccharide conjugates 1, 4, 5, 9v, 14,18C, 19F and 23F; 4 µg of pneumococcal saccharide conjugate 6B; and 10 µg of meningococcal group C oligosaccharide and 38.5 µg of CRM197 and Meningitec Wyeth Lederle oligosaccharide C 10 µg and CRM197 15 µg Assays: s-ELISA and r-SBA This trial included 240 infants who were vaccinated at 2, 3 and 4 months of age with Pnc9-MCC (Group 1) or MCC (Group 2), concomitant to DPTw P admixed with Hib. The GMC of serum antibodies after three doses was 4.88 µg/ml (95% CI 4.19 to 5.70) in Group 1 and 23.27 µg/ml (95% CI 20.18 to 26.84) in Group 2. The GMT of SBA to meningococcal C polysaccharide one month after the three doses of MCC was 179 (95% CI 133 to 243) in Group 1 and 808 (95% CI 630 to 1037) in Group 2 (p value less than 0.001). Titres of r-SBA 8 or above after three doses were present in 95% (109/115) of the Pnc9-MCC vaccine group and in 99% (117/118) of the MCC group (p value 0.05). Adverse events Local reactions were uncommon in both groups. A temperature of 38ºC or above was reported in 35.3% of Group 1 and 26.7% in Group 2 (p value 0.15). Irritability occurred in 65.2% in Group 1 versus 48.7% in Group 2 (p value 0.02); decrease activity 33.0% in Group 1 versus 20.2% in Group 2 (p value 0.03). 2. MCC versus MPLS vaccine in children between the ages of 12 months to 24 months Five trials (Lieberman 1996; MacDonald 1998; MacLennan 2000; Richmond 2001; Twumasi 1995) were included. 2.1. Two MCC versus two MPLS vaccines Lieberman 1996 Vaccine: Chiron Biocine, oligosaccharide A/C 11 µg/ of each and CRM197 48.7 µg and Menomune Connaught ACYW135 Assays: s-ELISA and r-SBA

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Evid.-Based Child Health 2: 497–528 (2007) This trial included 86 patients and compared two doses of MCCAC with two doses of MPLS-4 vaccine in children at 18 to 24 months. The GMC of serum antibodies to meningococcal C polysaccharide after one dose was 7.18 µg/ml (95% CI 5.98 to 8.69) in the MCC group and 5.28 µg/ml (95% CI 4.07 to 7.12) in MPLS group (p value 0.10). The GMC after two doses were 16.6 µg/ml (95% CI 14.0 to 19.81) in the MCC group and 8.3 µg/ml (95% CI 5.97 to 11.5) in MPLS group (p value less than 0.001). The GMT of SBA to meningococcal C polysaccharide after two doses was 3197.9 (95% CI 2277 to 4491.2) in the MCC group and 11.4 (95% CI 5.7 to 22.6 ) in the MPLS group (p value less than 0.00001). Adverse events Adverse events reported after the first dose were any redness at vaccine site: 0% (MCC) and 0% (MPLS); any tenderness at vaccine site: 11.5% (MCC) and 36.7% (MPLS); fever 38.3ºC or above, 11.4% (MCC) and 3.6 (MPLS); drowsiness 17% (MCC) and 16.7 (MPLS); poor appetite 20.8% (MCC) and 20% (MPLS); vomiting 7.5% (MCC) and 13.8% (MPLS). Adverse reaction rates between MCC and MPLS vaccines were comparable. Adverse reactions were no more common after the second dose of MCC than after the first. Two febrile seizures occurred 26 and 62 days after vaccination with MCC.

38.3ºC or above: 3% (MCC) and 6% (MPLS); irritability: 31% (MCC) and 29% (MPLS); change in eating habits: 18% (MCC) and 13% (MPLS). 2.2. MPLS after one, two or three doses of MCC Twumasi 1995 Vaccine: Vaccine:Biocine, oligosaccharides C /A 11 µg and CRM197 49 µg Assay: s-ELISA In this trial, some of the children 148 children who were vaccinated at two, three and four months, with one, two or three doses of MCC or MPLS vaccine, were boosted with MCC or MPLS vaccines at 18 months. The GMC after the booster dose was: 86.7 µg/ml (95% CI 58.1 to 129.3) in Group 1 (1 MCC+1 MCC); 77.8 µg/ml (95% CI 50 to 121) in Group 2 (1 MCC+1 MPLS); 57.9 µg/ml (95% CI 41.4 to 80.9) in Group 3 (2 MCC+1 MCC); 55.7 µg/ml (95% CI 33.5 to 87.3) in Group 4 (2 MCC+1 MPLS); 111.7 µg/ml (95% CI 80.2 to 170.5) in Group 5 (3 MCC+1 MCC); 46.9 µg/ml (95% CI 28.2 to 77.9) in Group 6 (3 MCC+1 MPLS); 38.6 µg/ml (95% CI 26.2 to 56.8) in Group 7 (2 MPLS+ 1 MCC); 9.4 µg/ml (95% CI 6.2 to 14.3) in Group 8 (2 MPLS+ 1 MPLS). Adverse events were not referred to.

MacDonald 1998 Vaccine: MCC Chiron, oligosaccharide C 10 µg, CRM197 25 µg and MPLS quadrivalent Menomune Connaught Assays: m-ELISA and h-SBA This trial included 211 children aged 15 to 23 months and compared two doses of MCC with two doses of MPLS .The GMC of serum antibodies to meningococcal C polysaccharide after one dose was 5 µ/ml (95% CI 3.8 to 6.5 ) in the MCC group and 1.5 µ/ml (95% CI 0.96 to 1.6) in the MPLS group (p value less than 0.001). The GMC after two doses was 20 µ/ml (95% CI 16 to 26) in the MCC group and 1.2 µ/ml (95% CI 1.1 to 1.9) in the MPLS group (p value less than 0.001). The titres of SBA ≥ 8 to meningococcal C polysaccharide after one dose was 90% (47/52) in the MCC group and 46% (15/32) in the MPLS group (p value less than 0.001). After the second dose the titres ≥ 8 were 98% (44/45) in the MCC group and 32% (15/47) in the MPLS group (p value less than 0.001).

2.3. MCC-CRM197 versus MCC-TT

The children were boosted with one dose of MPLS 12 months later. The GMC after booster dose was: 69 µ/ml (95% CI 50 to 96) in the MCC group and 1.3 µ/ml (95% CI 0.96 to 1.8) in the MPLS group. After the booster dose, the MCC group had a 43fold change from the pre- to post-vaccination titres and the MPLS group a 1.6-fold change.

The GMC of serum antibodies to meningococcal C polysaccharide measured by m-ELISA after the first dose were 69.8 µg/ml (95% CI 63.9 to 76.3) in the Chiron group, 72.5 µg/ml (95% CI 66.4 to 79.2) in the Lederle group and 52.9 µg/ml (95% CI 49.8 to 56.2) in the NAVA group. After the booster dose the GMC was 10.8 µg/ml (95% CI 8.2 to 14.2) in the Chiron group, 9.0 µg/ml (95% CI 6.9 to 11.8) in the Lederle group and 14.2 µg/ml (95% CI 11.4 to 17.7) in the NAVA group.

Adverse events Adverse events reported after the first dose were fever 38.3ºC or above: 0% (MCC) and 11% (MPLS); irritability: 35% (MCC) and 29% (MPLS); change in eating habits: 14% (MCC) and 19% (MPLS). After the second dose the adverse events were: fever

Richmond 2001 Vaccines: MCC Chiron, oligosaccharide C 10 µg and CRM197 25 µg; Lederle oligosaccharide C 10 µg and CRM197 15 µg and NAVA, oligosaccharide C 10 µg and tetanus toxoid 20 µg and MPLS Mengivac AC Pasteur Mérieux Assays: r-SBA, s-ELISA m-ELISA This trial included 192 children from 12 to 18 months of age and compared MCC vaccines from three different manufacturers. The children received one dose of MCC and they were boosted with one dose of MPLS vaccine six months later. The GMC of serum antibodies to meningococcal C polysaccharide measured by s-ELISA after the first dose was 8.03 µg/ml (95% CI 6.3 to 10.2) in the Chiron group, 11.1 µg/ml (95% CI 8.4 to 14.6) in the Lederle group and 13.3 µg/ml (95% CI 11 to 16) in the NAVA group.

The GMT of SBA after the first dose were not statistically different between the MCC-CRM vaccines: 123 (95% CI 78 to 195) in the Chiron group, 141 (95% CI 90 to 222) in the Lederle vaccine.

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Evid.-Based Child Health 2: 497–528 (2007) However, they were higher after the MCC-TT vaccine: 564 (95% CI 40 to 783) in the NAVA group (p value less than 0.001). The GMT of SBA after the booster dose was 1318 (95% CI 875 to 1986) in the Chiron group, 979 (95% CI 686 to 1400) in the Lederle group and 5272 (95% CI 3483 to 7983) in NAVA group (p value less than 0.001). Titres of SBA ≥ 8 after the first dose were observed in 92% (66/72) of the Chiron group, 91% (64/70) of the Lederle group and 100% (72/72) of the NAVA group. Titres of SBA ≥ 8 after the booster dose were observed in 98% (62/63) of the Chiron group, 100% (63/63) of the Lederle group and 100% (71/71) of the NAVA group (p value 0.64). Adverse events The author indicated that there were no significant differences in reactogenicity among the three MCC vaccines and that no serious illness or sequelae related to vaccination were reported in the seven months after immunisation. 3. Meningococcal conjugate vaccine in children from 2 to 17 years 3.1. 2 MCC-4 versus 2 MPLS-4 Pichichero 2005 Vaccines: MCC quadrivalent conjugate vaccine with 4 µg of A, C, Y, W135 polysaccharide conjugate to 48 µg of diphtheria toxoid protein and MPLS A,C,Y and W135 quadrivalent Aventis Pasteur Assay: rSBA This trial included 1375 children (80% of them between two to five years old) who were vaccinated with MCC-4 or quadrivalent MPLS A/C/Y/W135. The GMT of SBA 28 days after vaccination was 344 (95% CI 308 to 407) in the MCC-4 group vaccine and 231 (95% CI 198 to 270) in the MPLS-4 group (p value less than 0.001). After six months, the GMT of r-SBA was 137 (95% CI 116 to 161) in the MCC-4 group and 66 (95% CI 55 to 79) in MPLS-4 group (p value less than 0.001). Titres ≥ 128 were present in 81% (95% CI 78 to 100) in MCC-4 group and 73% (70 to 100) in MPLS-4 group. Adverse Events The adverse events reported were within 7 days of immunisation: any local reaction 58.8% (MCC-4) and 58.3% (MPLS-4); redness 29.5%(MCC-4) and 30.4% (MPLS-4); swelling 20.5% (MCC-4) and 16.6% (MPLS-4); induration 22.1% (MCC-4) and 15.6% (MPLS-4); pain 48.1% (MCC-4) and 46.9% (MPLS-4). Systemic reactions reported within seven days of immunisation were: any 53.3% (MCC-4) and 52% (MPLS-4); fever 38ºC or above, 11.4% (MCC-4) and 12% (MPLS-4); anorexia 22.7% (MCC-4) and 20.3% (MPLS-4); diarrhoea 15.9% (MCC-4) and 15.7% (MPLS-4); drowsiness 26.6% (MCC-4) and 24.1% (MPLS-4); fussiness 35.2% (MCC-4) and 30.1% (MPLS-4). 3.2 MCC-CRM or MCC-TT Burrage 2002

Vaccines: MCC Wyeth Lederle, oligosaccharide C 8 to 12 µg and CRM197 8 to 12 µg; MCC Chiron Vaccines oligosaccharide C 12 µg and CRM197 30 µg; MCC-TT Baxter vaccine oligosaccharide C 10 µg and toxoid tetanus 20 µg; Aventis Pasteur Dt or Td vaccines Assay: s-ELISA In this study 832 children with a mean age of 4.3 years and 917 with a mean age of 15.1 years received MCC from three different manufacturers. The study aimed primarily to investigate whether there was any interaction between MCC-TT vaccine or MCCCRM197 vaccines and diphtheria-tetanus vaccines (Dt or Td) given for boosting at school entry or leaving. The Dt or Td vaccines were given one month after or one month before or concurrently with one of the MCC vaccines. The GMC antibodies was: MCC vaccine given before: 14.8 µg/ml (Chiron), 23.8 µg/ml (Wyeth Lederle) and 10.7 µg/ml (Baxter); when MCC vaccines were given after Dt or Td, the GMC were: 14.7 µg/ml (Chiron), 23.7 µg/ml (Wyeth Lederle) and 29.1 µg/ml (Baxter); when MCC vaccines were given concurrently with Dt or Td the GMC were: 12.1 µg/ml (Chiron), 20.1 µg/ml (Wyeth Lederle) and 23.8 µg/ml (Baxter group). The GMT of r-SBA was: MCC vaccine given before: 740 (Chiron), 2048 (Wyeth Lederle) and 1400 (Baxter); when MCC vaccines were given after Dt or Td: 1142 (Chiron), 1898 (Wyeth Lederle) and 4412 (Baxter ); when MCC vaccines were given concurrently with Dt or Td the GMT was: 877 (Chiron), 1638 (Wyeth Lederle) and 2119 (Baxter group). 3.3 MCC or MPLS-AC Choo 2000 Vaccines: Chiron, oligosaccharide C 10 µg and CRM197 25 µg and Mengivac AC Pasteur Mérieux Assays: m-ELISA and h-SBA This study included 176 patients and compared one dose of MCC vaccine to one dose of MPLS vaccine in adolescents aged 11 to 17 years. GMC of serum antibodies to meningococcal C polysaccharide after one month of vaccination was 22.8 µg (95% CI 15.4 to 33.8) in the MCC group and 4 µg/ml (95% CI 2.7 to 5.9) in the MPLS group (p value less than 0.001). The GMC after 12 months was 6.1 µg/ml (95% CI 4.0 to 9.2) in the MCC group and 3.0 µg/ml (95% CI 2.0 to 4.6) in the MPLS group (p value less than 0.001). The GMT of SBA was 87.3 (95% CI 56.1 to 135.8) in the MCC group and 20.1 (95% CI 12.9 to 31.5) in the MPLS group (p value less than 0.001) and 12 months after vaccination was 81.3 (95% CI 54.5 to 121.3) in the MCC group and 20.2 (95% CI 13.5 to 35.3) in the MPLS group (p value less than 0.001). Titres ≥8 were observed one month after vaccination in 85% (74/87 ) of the MCC vaccine group and 68% (59/87) in the MPLS group (p value less than 0.01). Six months after the vaccination the titres ≥ 8 were observed in 91% (83/91) in the MCC vaccine group and 59% (53/90) in the MPLS group. Twelve months after the vaccination the titres ≥ 8

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Evid.-Based Child Health 2: 497–528 (2007) were observed in 95% (86/91) in the MCC vaccine group and 67% (60/90) in the MPLS vaccine group. Adverse Events The adverse events reported in the seven days after vaccination were: pain 75% (MCC) and 72% (MPLS); redness 32% (MCC) and 28% (MPLS); induration 22% (MCC) and 12% (MPLS); headache 49% (MCC) and 56% (MPLS); myalgia 56% (MCC) and 49% (MPLS); malaise 35% and 40% (MPLS); fever 38.3% or above: 3% (MCC) and 7% (MPLS); analgesic use 21% (MCC) and 17% (MPLS). The incidence of adverse events was not significantly different in the two vaccine groups. 4. Meningococcal conjugate vaccine in adults Four trials (Anderson 1994; Goldblatt 2002; Lakshman 2002; Richmond 2000) evaluated the MCC in adults. Anderson 1994 Vaccine: MCC Sclavo with three different concentrations of oligosaccharide C Assay: r-SBA This study evaluated three different concentrations of oligosaccharide C vaccine: 5.5 µg (Group 1), 11 µg (Group 2) and 22 µg (Group 3) conjugated to CRM197 48 µg. The study included 50 adults from 18 to 50 years of age and the conjugate vaccines were compared to MPLS-4 (Group 4). The GMT of SBA one month after the vaccination was 10,233 (Group 1), 7761 (Group 2), 13,489 (Group 3) and 4169 (Group 4). No statistically significant differences occurred among groups receiving different doses of MCC and MPLS vaccines. Richmond 2000 Vaccine: Wyeth Lederle, oligosaccharide C 10 µg and CRM197 15 µg and Mengivac AC Pasteur Mérieux Assays: s-ELISA and r-SBA This study included 190 students who had previously received one dose of MPLS-AC vaccine. After six months they received one dose of MCC or MPLS vaccine. Only the data of randomised groups were used. The GMC of serum antibodies to meningococcal C polysaccharide one month after the vaccination was 35.3 µg/ml (95% CI 28.3 to 43.9) in the group boosted with MCC and 16.9 µg/ml (95% CI 12.4 to 23.0) in the group boosted with MPLS vaccine. Comparing the GMC of pre- to post-booster dose there was a 1.9-fold change in the MCC boosted group and a 1.3-fold change in MPLS boosted group. The GMT of SBA to meningococcal C polysaccharide was 663 (95% CI 446 to 987) in the group boosted with MCC and 220 (95% CI 136 to 355) in the group boosted with MPLS vaccine. Titres ≥ 8 were present in 67% (57/83) of the MCC boosted group and in 73% (63/86) of the MPLS boosted vaccine. Comparing the GMT of SBA pre- to post-booster dose there was a 6.7-fold change in MCC boosted group and a 1.6-fold change in MPLS boosted group. Goldblatt 2002

Vaccine: MCC vaccine Wyeth Lederle, oligosaccharide 10 µg and CRM197 15 µg and MPLS vaccine, Mengivac AC Pasteur Mérieux Assays: s-ELISA, m-ELISA (avidity indices) and r-SBA This study included university students that had been vaccinated previously with MPLS vaccine and after six months received one dose of MCC or MPLS vaccine. Only the data of randomised groups were used. The GMC of serum antibodies to meningococcal C polysaccharide measured by s-ELISA one month after the vaccination was 30.4 µg/ml (95% CI 20.4 to 45.4) in the group boosted with MCC and 25.9 µg/ml (95% CI 17.6 to 38.2) in the group boosted with MPLS vaccine. Six months after the vaccination the GMC was 18.6 µg/ml (95% CI 10.4 to 33.3) in the group boosted with MCC and 10.9 µg/ml (95% CI 6.3 to 18.8) in the group boosted with MPLS vaccine. The GMC of serum antibodies to meningococcal C polysaccharide measured by m-ELISA one month after the vaccination was 204.4 µg/ml (95% CI 157.6 to 264.9) in the group boosted with MCC and 167.2 µg/ml (95% CI 129.6 to 215.8) in the group boosted with MPLS vaccine. Six months after the vaccination the GMC was 182.4 µg/ml (95% CI 136.4 to 244) in the group boosted with MCC and 214.1 µg/ml (95% CI 165.1 to 277.7) in the group boosted with MPLS vaccine. The r-GMT of SBA to meningococcal C polysaccharide one month after vaccination was 512 (95% CI 233.8 to 1121.3) in the group boosted with MCC and 428.6 (95% CI 205 to 896.2) in the group boosted with MPLS vaccine. Six months after the vaccination the GMT of r-SBA was 475.4 (95% CI 210.3 to 1074.6) in the group boosted with MCC and 137.9 (95% CI 50.8 to 374.2) in the group boosted with MPLS vaccine. Lakshman 2002 Vaccine: MCC vaccine, Paster Mérieux, oligosaccharide 4 µg and CRM197 48 µg and MPLS AC Aventis Pasteur Assay: s-ELISA, r-SBA This trial included 190 subjects between 17 and 30 years old and compared the MCC-AC to MPLS-AC. The GMC of serum antibodies to meningococcal C polysaccharide was 9.7 µg/ml (95% CI 7.21 to 13) after one dose of MCC-AC vaccine and 31.2 µg/ml (95% CI 23.7 to 41) after MPLS-AC vaccine (p value 0.0001). The GMT of SBA to meningococcal C polysaccharide was 2299 (95% CI 1745 to 3028) in the group vaccinated with MCC-AC and 3805 (95% CI 2899 to 4993) in the group vaccinated with MPLS-AC (p value 0.0052). After twelve months the subjects were boosted with MCC-AC or MPLS-AC. The GMC of serum antibodies was 7.11 (95% CI 4.5 to 11.2 ) in Group 1 (MCC+MCC), 31.2 (95% CI 23.2 to 42) in Group 2 (MCC+MPLS), 23.9 (95% CI 15.9 to 35.7) in Group 3 (MPLS+MPLS) and 25.5 (95% CI 15.6 to 41.6) in Group 4 (MPLS+MCC). The GMT of r-SBA was 718 (95% CI 527 to 977) in Group 1 (MCC+MCC), 1269 (95% CI 881 to 1828) in Group 2 (MCC+

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Evid.-Based Child Health 2: 497–528 (2007) MPLS), 584 (95% CI 360 to 947) in Group 3 (MPLS+MPLS) and 682 (95% CI 415 to 1120) in Group 4 (MPLS+MCC). 5. Mucosal antibodies Choo 2000 Vaccine: Chiron, oligosaccharide 10 µg, CRM197 10 µg Assays: m-ELISA A subset of the participants (106 participants between 11 and 17 years) that were vaccinated with MCC or with MPLS-AC were evaluated regarding mucosal immunity. Specific salivary antibodies against group C meningococcal polysaccharide were determined by modified ELISA. The GMC of salivary IgG were 7.32 U/ml (95% CI 4.71 to 11.7) one month after MCC and 2.66 U/ml (95% CI 1.86 to 3.8) one month after receiving the MPLS vaccine (p value less than 0.0001). Six months after the vaccination the GMC of salivary IgG was 2.84 U/ml (95% CI 1.74 to 4.62) in the MCC vaccine group and 1.6 U/ml (95% CI 1.12 to 2.27) in the MPLS vaccine group. Twelve months after the vaccination the GMC of salivary IgG was 1.34 U/ml (95% CI 0.9 to 2.1) in the MCC vaccine group and 0.76 U/ml (95% CI 0.85 to 0.98) in the MPLS vaccine group. The GMC of specific IgA against group C polysaccharide was 0.87 U/ml (95% CI 0.63 to 1.2) one month after MCC and 1.15 U/ml (95% CI 0.85 to 1.54) in the MPLS vaccine group (p value 0.09). Six months after the vaccination the GMC of salivary IgA was 0.4 U/ml (95% CI 0.31 to 0.52) in MCC vaccine group and 0.53/ml (95% CI 0.4 to 0.7) in the MPLS vaccine group. Twelve months after the vaccination the GMC of salivary IgA was 0.39 U/ml (95% CI 0.3 to 0.51) in the MCC vaccine group and 0.48 U/ml (95% CI 0.37 to 0.63) in MPLS vaccine group. Lakshman 2002 Vaccine: MCC vaccine, Aventis Pasteur, oligosaccharides 4 mg and CRM197 48 mg Assay: m-ELISA Some of the university students (195) who participated in the Lakshman 2002 study were evaluated regarding mucosal immunity. The university students were vaccinated with MCC-AC or MPLS-AC. Specific salivary antibodies against group C meningococcal polysaccharide were determined by modified ELISA. The GMC of salivary IgG was 15.69 ng/ml (95% CI 10.73 to 23.0) one month after MCC and 22.44 ng/ml (95% CI 15.64 to 32.2) one month after MPLS vaccine (p value more than 0.05). The GMC of salivary IgA was 33.81 ng/ml (95% CI 24.55 to 46.57) one month after MCC and 8.9 ng/ml (95% CI 6.56 to 12.05) one month after MPLS vaccine (p value less than 0.001). One year after the primary vaccine the students received a booster dose of MCC-AC or MPLS-AC. The GMC of IgG was 24.97 ng/ml (95% CI 14.64 to 42.6) in Group 1(MCC+MCC), 39.35 ng/ml (95% CI 24.2 to 64) in Group 2 (MPLS+MPLS), 18.54 ng/ml (95% CI 8.78 to 39.4) in Group 3 (MCC+MPLS) and 38.87 ng/ml (95% CI 23.44 to 64.46) in Group 4 (MPLS+ MPLS).

The GMC of specific IgA against group C polysaccharide was 8.22 ng/ml (95% CI 5.28 to 12.79) in Group 1 (MCC+MCC), 47.92 ng/ml (95% CI 33.57 to 68.39) in Group 2 (MPLS+MPLS), 30.3 ng/ml (95% CI 1.07 to 57.15) in Group 3 (MCC+MPLS) and 57.44 ng/ml (95% CI 35.08 to 94.19) in Group 4 (MPLS+ MPLS). 6. Observational studies Carriage of meningococcal serogroup C The impact of meningococcal C conjugate vaccine on reducing serogroup C carriage was reported in observational studies only. Maiden 2002 This study reported the results of cross-sectional surveys in the United Kingdom, which compared the carriage of meningococci in isolates from 14,064 students aged 15 to 17 years during the immunisation campaign in 1999 with those of 16,583 students in the same age group, surveyed one year later. The proportion of individuals carrying meningococci fell by an average of 66% (from 0.45% to 0.15%). The proportion of meningococci expressing serogroup C polysaccharide fell by 69% (p value 0.001). Analysis by self-reported vaccination status showed a C carriage rate of 0.127% in vaccinated individuals compared with 0.342% in unvaccinated individuals; a protective effectiveness against carriage of 63% (95% CI 50 to 80). Vaccine effectiveness The effectiveness of meningococcal serogroup C conjugate vaccine was described only in observational studies. Trotter 2004 This study describes surveillance data over the four years since the introduction of MCC into the UK immunisation programme (routine immunisation at two, three and four months of age plus catch-up campaign for children from 5 months to 18 years of age). In the follow up period 53 vaccine failures were identified, 21 (40%) of which occurred in children who had been routinely vaccinated as infants. Among the 53 failures, four deaths were registered. Using the screening method to determine vaccine effectiveness, the routine infant vaccination was estimated to be 66% (95% CI 6 to 86%) effective, but varied according to time since vaccination; it fell to low levels after one year. Vaccine effectiveness was 83% (95% CI 69 to 93%) in all children who had received MCC aged from 5 months to 18 years and remained high after four years. De Wals 2004 Vaccine: Menjugate, Chiron This is a population-based observational study on the effectiveness of a mass immunisation campaign with MCC to control an emerging epidemic in Quebec, Canada. The target population for vaccination was all residents of Quebec from 2 months to 20 years. Vaccination coverage was 82.1%. In 2001 the number of serogroup C meningococcal disease was 58. In 2002 the year following the mass campaign the number of cases of serogroup C de-

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Evid.-Based Child Health 2: 497–528 (2007) creased to 27. The incidence rates were 7.84 in 2001 and 3.63 in 2002 (p value 0.001). For the age group targeted for vaccination, the incidences were 21.47 in 2001 and 3.26 in 2002. In 2002 seven serogroup C cases were reported among unvaccinated individuals from the target population and two cases of vaccine failure were documented. Using a different method to Trotter (Trotter 2004) for calculating vaccine effectiveness, the overall effectiveness of conjugate vaccine was found to be 96.8% (95% CI 75.0% to 99.9%). Larrauri 2005 This study reported data on cases of meningococcal disease in Spain during the period of 1999 to 2004. The MCC vaccine was included in the Spanish childhood vaccination schedule at two, four and six months of age, in combination with a catch-up campaign in 2000. Coverage ranged from 90% to 95%. Vaccine effectiveness was estimated using the screening method. Forty-two cases of serogroup C meningococcal disease in children under the age of 10 years were reported in 2002 to 2003, versus 268 cases in 1999 to 2000. This represented an 85% reduction in the incidence of the disease in this age group. In 2002 to 2003, three deaths were reported in the under -10 age group versus 33 deaths before the introduction of the vaccine. Vaccine effectiveness estimated in children receiving routine immunisation at infancy was 95.2%. Vaccine effectiveness estimated in children immunised in a catchup campaign was 97.8%. There was a significant loss of vaccine protection after more than one year of receiving the vaccine, mainly among children vaccinated at two, four and six months of age (78.0%), compared with children vaccinated at seven months to five years of age (94.3%). Ramsay 2003b This study reports rates of meningococcal disease in vaccinated and unvaccinated UK children to assess the evidence for an indirect effect (herd immunity) from MCC. From December 1999 the vaccination history of all cases of serogroup C disease, confirmed by the national reference laboratory in age groups targeted for immunisation, were investigated. Between 1 July 2001 and 30 June 2002, a total of 37 cases were identified, eight (22%) in vaccinated children and 29 (78%) in unvaccinated children. Cases in unvaccinated children from each age group in the 2001-2 cohort were compared with those in the same age groups for the period from 1 July 1998 to 30 June 1999. Overall, in the age groups targeted for catch-up vaccination, a reduction of 67% (95% confidence interval 52% to 77%) in the attack rate occurred, with a range of 48% to 80% across the age groups.

DISCUSSION N. meningitidis is a significant cause of bacterial meningitis and septicaemia. Disease caused by serogroup C occurs primarily among infants and teenagers and outbreaks in other age groups are well described. The availability of serogroup C conjugate

meningococcal vaccines provides an opportunity to minimise the significant burden of hospitalisation, disability and death. The serogroup C conjugate meningococcal vaccines currently used in a number of countries were licensed on the basis of data on safety and immunogenicity, but not on clinical efficacy. Despite its high public profile, meningococcal disease is relatively rare. This makes the number of expected outcomes small and the number of participants required to give a study sufficient power extremely large. As a result the immune response to vaccination has been used as a surrogate of vaccine protection. Studies among military recruits conducted in the 1960s indicated that the absence of naturally acquired bactericidal antibodies was associated with susceptibility to meningococcal C disease. Arising from these observations SBA titres 4 or above, using a human exogenous complement source (hSBA), was established as a correlate of clinical protection against meningococcal C disease (Goldschneider 1969). However, because of difficulties with the availability of human complement, baby rabbit serum was proposed as an alternative complement source. It is generally accepted that serogroup C meningococci are more susceptible to serogroup Cspecific antibodies when using baby rabbit complement, as opposed to human complement, thus resulting in higher SBA titres (Borrow 2001). Bactericidal assays using baby rabbit complement were validated by comparison with those obtained using hSBA; it was concluded that rSBA titres with a value less than 8 predict susceptibility to meningococcal C disease post vaccination, and rSBA titres 128 or above predict protection. Further evaluation of these threshold values indicated that they were probably conservative and rSBA titres of 8 or above are now proposed as a correlate of short- term protection (Andrews 2003; Balmer 2004). A fourfold rise in titres pre- and post-vaccination has also been proposed. Other proposed indicators of long-term protection are the SBA response to polysaccharide boosters and avidity maturation (Borrow 2001; WHO 2002). Antibody avidity is a measure of antigen binding, as high avidity is characteristic of a T celldependent response and suggestive of immunological memory. This review included 17 randomised clinical trials on antibody responses to MCC vaccines. No randomised clinical trials were found on the clinical efficacy of MCC vaccine. The included studies were considered very heterogeneous in terms of the concentration of oligosaccharides C in the vaccines used and the concentration and type of protein carriers used. Considering that immune responses to vaccine may be affected by these different properties of conjugate vaccines (Jodar 2004) and because of the diversity of assays used by included studies, we decided not combine the results. Response of MCC in infants The studies included in the review showed that MCC was highly immunogenic and able to induce both a primary response and

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Evid.-Based Child Health 2: 497–528 (2007) immunologic memory in young infants, and was more immunogenic than MPLS. The MCC vaccine was evaluated in five trials in infants. Three doses of vaccine were given at two, three and four months of age or at two, four and six months of age. In all trials high titres of antibodies were induced by vaccination, 97% to 100% of infants achieving SBA 8 or above. There was some evidence that two doses of MCC in infants might be sufficient. Borrow 2003 reported no significant difference in titres of antibodies after two or three doses of MCC-TT vaccine. The GMT of r-SBA was 1326 µg/ml (95% CI 1115 to 1575) after two doses, and 1405 µg/ml (95% CI 1164 to 1696) after three doses. r-SBA more than 8 were present in 100% after two doses and 99.4% after three doses. Following the booster dose nine months later, there was a ≥4 fold rise of antibody titres in 99.5% of participants who received two doses, and 98.8% in those who received three doses. In contrast, the studies of MacLennan 2000 and Tejedor 2004 in which CRM197 MCC vaccines were used showed significant serological differences between two and three dose groups - suggesting that this conclusion may only be valid for the tetanus toxoid conjugate vaccine. The co-administration of MCC with routine vaccines was evaluated by Tejedor 2004. Responses after two and three doses of MCC vaccine in infants who received them either at the same time as routine vaccinations (at two, four and six months of age) or at different times (three, five and seven months of age) were compared. The GMT of r-SBA was higher when MCC was administered at different times. A number of possible explanations exist for this difference including the later age of the 2nd or 3rd doses in the separate group as well as the priming effect of prior diphtheria exposure for this group. Data from one trial suggests that the combination of MCC with other antigens may not be advantageous (Buttery 2005). The 9valent pneumococcal-group C meningococcal conjugate vaccine (Pnc9-MCC) was shown to be less immunogenic than MCC in inducing serogroup C meningococcal polysaccharide antibodies in infants. Immunological memory was evaluated by measuring the antibody response after a booster dose. The use of MCC or MPLS vaccine as the booster dose after the primary series was evaluated in different studies. Comparing the antibody titres pre- and postbooster doses, there was a fourfold or greater rise in serum antibodies, measured by ELISA or serum bactericidal antibodies in infants boosted with the MCC vaccine. In infants boosted with the MCC vaccine nine months after the primary series, a 42-fold change (Halperin 2002) in pre- and post-GMC by m-ELISA, and a 17-fold change of GMT by r-SBA were documented. The rise in antibodies pre- and post-booster vaccine was higher if a MCC was used as the booster dose, than if a MPLS vaccine was used. In infants boosted 12 months after the primary series a 42-fold

change in GMC by m-ELISA was seen if the booster vaccine was MCC, and 16-fold change if the booster vaccine was MPLS. The pre- and post-booster GMT by h-SBA changed 111-fold if the booster vaccine was MCC, and 44-fold change if MPLS was the booster vaccine (MacLennan 2000). In the Borrow 2003 study however, infants boosted with MPLS had higher titres than infants boosted with the MCC vaccine. The MacLennan 2000 study further demonstrated the difference in response to MPLS between those who had previously received MCC (that is to say, primed) and those who had previously received HBV control vaccine (unprimed). The former group had a 44 fold change in SBA titres and the latter a 1.1 fold change; a result consistent with immunological memory. The MCC vaccine was shown to be safe in infants. The adverse events more frequently reported in infants were: fever (1 to 5%), irritability (38 to 67%); crying more than expected (1 to 13%); redness at the site of vaccination (6 to 97%); tenderness at the site of vaccination (11 to 13%); and swelling at the site of vaccination (6 to 42%). The adverse events were similar in groups vaccinated with MCC and with the control vaccine (HBV), but following booster doses, they were more frequent in the MCC group in one trial. One dose of MCC given at 12 months of age induced a much higher concentration of bactericidal antibodies than one dose of polysaccharide vaccine. Two doses of MCC were immunogenic in toddlers and induced immunological memory. The MCC vaccine induced a much higher concentration of bactericidal antibodies than the polysaccharide vaccine in children aged 12 to 24 months; these persisted for at least 12 months. Studies which involved toddlers showed that they may also be susceptible to the induction of hyporesponsiveness by immunisation with meningococcal polysaccharide vaccine. In the MacDonald 1998 study, the children that received MPLS for the priming vaccination showed evidence of a hyporesponsive state 12 months later. Twelve months after receipt of two doses of MCC or MPLS vaccine, they were boosted with one dose of MPLS vaccine. The MCC primed group had a 43-fold change of h-SBA between the pre-to post-booster titres, while the MPLS primed group had only a 1.6-fold change. In the comparative study of Richmond 2001 in which children between 12 to 18 months of age received either a MCC-TT or one of 2 MCC-CRM197 vaccines, with a follow up of a MPLS booster, it was clear that the tetanus toxoid conjugate resulted in superior immunogenicity. In the study of Burrage 2002 in preschool and teenage children, however, it was apparent that the response to this particular conjugate might be susceptible to prior immunization with tetanus-containing vaccines. In this study the MCC-CRM197 vaccines were not similarly affected by prior use of diphtheria-containing vaccines.

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Evid.-Based Child Health 2: 497–528 (2007) The C component of a quadrivalent conjugate vaccine was more immunogenic than the C component of a quadrivalent polysaccharide vaccine in the study of Pichichero 2005. The majority of children in this study were between the ages of 2 and 5 years. There was also better persistence of functional antibody to 6 months after vaccination in the conjugate vaccine group. This was also evident in teenagers (Choo 2000) where MCC vaccine induced higher antibody concentrations than MPLS vaccine 1 and 12 months after vaccination. A single dose of MCC vaccine can induce significantly higher serum bactericidal antibody levels than MPLS vaccine in adults (Richmond 2000), but this was not universally seen (Lakshman 2002). The immunological hyporesponsiveness seen after a second dose of MPLS vaccine may be overcome with MCC vaccination (Goldblatt 2002 ; Lakshman 2002). The Lakshman 2002 study showed that while both conjugate and polysaccharide vaccines were immunogenic, a second dose of MPLS after either previous MPLS or MCC might induce lower bactericidal titres than those seen following a first dose of MPLS. Mucosal immunity is probably important in protecting the host against mucosal pathogens such as N. meningitidis. The human nasopharyngeal mucosa is the only natural reservoir of this organism and transmission is from person to person through direct contact or via respiratory secretions. MCC vaccine induces specific mucosal immune responses consisting of IgA and IgG. The data of two studies that analysed mucosal immunity were discordant as to whether the MCC vaccine induced greater IgG and IgA antibody responses than the MPLS vaccine. It was not determined in this study whether the MCC vaccine could reduce nasopharyngeal carriage of N. meningitidis C. However, an observational study showed a significant reduction in carriage of this organism in UK teenagers following the introduction of the MCC programme (Maiden 2002).This suggests that MCC vaccine can induce sufficient mucosal immunity to inhibit carriage of meningococcal serogroup C. A fall in the meningococcal carriage rate may reduce exposure among unvaccinated children and therefore enhance the effectiveness of meningococcal conjugate vaccine through herd immunity. The occurrence of such indirect protection was reported in the United Kingdom by a reduction in the attack rate in the unvaccinated population by 67% (Ramsay 2003b). It is however, possible that these observations may be explained by a natural decline in the incidence of serogroup C carriage and disease. The carriage study (Maiden 2002) showed no change in the prevalence of other meningococci during this time, providing some support for this being a vaccine-specific effect. A formal randomised control trial designed to define the efficacy of MCC would require an extremely large sample size. It seems unlikely that this will now be performed. As no RCTs exist it was necessary to include non-randomised studies to increase the relevance of the findings of this review. We therefore decided to include the data on effectiveness of MCC vaccines that have been

gathered from observational studies. Following the introduction of MCC vaccination into the routine infant schedule, together with an extensive catch-up vaccination campaign of young children and teenagers in England, Quebec and Spain, there was a rapid decline in group C meningococcal disease. Based on screening methods of analysis, after one year, the MCC vaccine effectiveness in Spain was estimated to be 98.4% (95% CI 95.7 to 99.4) in infants vaccinated at two, four and six months of age and 99.5% (95% CI 98.1 to 99.9) in those vaccinated after seven months of age. The vaccine effectiveness fell after the first year, especially in those vaccinated as infants. In England and Wales, the estimated effectiveness was 66% (95% CI 6 to 86) in infants vaccinated at two, three and four months of age and 83% (95% CI 69.5 to 93.0) in those vaccinated after seven months of age. It fell to low levels after one year in those vaccinated in the first year of life (Larrauri 2005; Trotter 2004). These early surveillance data suggest that the protection given by MCC vaccine may be age-dependent and that children vaccinated at an older age may have greater and longer-lasting protection than those vaccinated as infants. This suggests that booster doses of MCC may be required in order to extend the duration of protection offered by the vaccine. Experience with other conjugate vaccines, such as Hib, reinforces the possibility that long term protection will require further booster doses (Ramsay 2003a). It should be noted that the numbers of cases included in these effectiveness analyses are relatively small and the confidence intervals around these estimates are very wide. Further surveillance data are required.

AUTHORS’ CONCLUSIONS Implications for practice The MCC vaccine is more immunogenic than the MPLS vaccine amongst infants, toddlers and adolescents. Immune responses appear to be better when doses are given later in the first year of life. Three doses have been given to infants in most studies but fewer doses may be adequate as protective titres are generated in most infants after 2 doses, particularly with the tetanus toxoid conjugate. In children aged between 12 to 18 months of age, two doses of MCC generate high antibody titres and the majority have protective titres after one dose, particularly with the tetanus toxoid conjugate. One dose appears sufficient after 2 years of age. Observational studies suggest that protection may wane after primary vaccination and this may be more marked after vaccination in the first year of life. The MCC vaccine generates higher antibody responses than the MPLS vaccine and is preferred as a booster dose for those previously vaccinated with MPLS. In the absence of efficacy data from randomised controlled trials, the strength of the immunological data and of the effectiveness data from observational studies support the inclusion of MCC

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Evid.-Based Child Health 2: 497–528 (2007) vaccine into national immunisation programmes in areas where meningococcal C disease is a substantial public health problem.

ACKNOWLEDGEMENTS

Implications for research

The Common Services Agency of the National Health Service in Scotland, UK, provided assistance in 1999 in the writing of the protocol. The lead author would like to thank the Iberoamericano Cochrane Centre for providing support during the writing of this review. The authors wish to thank Liz Dooley and the following people for commenting on the draft review: Anne Lyddiatt, Caroline Trotter, Matthew Snape, Rob Ware and Tom Jefferson.

Double blind, randomised controlled clinical trials of efficacy would provide further confidence in these conclusions. Enhanced post-licensure surveillance of carriage, invasive disease and vaccine safety remain essential for providing information on long-term efficacy and safety. Studies which address the immunogenicity of MCC at different time schedules and the influence of other vaccines given concomitantly remain important.

SOURCES OF SUPPORT POTENTIAL CONFLICT OF INTEREST

External sources of support

PTH has received research funding from a number of different manufacturers of MCC vaccines. JUR has participated in studies funded by vaccine manufacturers and received assistance for travel to scientific conferences to present these studies.

• No sources of support supplied Internal sources of support • Iberoamericano Cochrane Centre, Barcelona SPAIN • Marilia Medical School BRAZIL

REFERENCES

References to studies included in this review Anderson 1994 {published data only} Anderson EL, Bowers T, Mink CM, Kennedy DJ, Belshe RB, Harakeh H, et al. Safety and immunogenicity of meningococcal A and C polysaccharide conjugate vaccine in adults. Infection and Immunity 1994;62(8):3391–5. Borrow 2003 {published data only} ∗ Borrow R, Goldblatt D, Finn A, Southern J, Ashton L, Andrews N, et al. Immunogenicity of, and immunologic memory to, a reduced primary schedule of meningococcal C-tetanus toxoid conjugate vaccine in infants in the United Kingdom. Infection and Immunity 2003; 71(10):5549–55. Burrage 2002 {published data only} ∗ Burrage M, Robinson A, Borrow R, Adrews N, Southern J, Findlow J, et al. Effect of vaccination with carrier protein on response to meningococcal C conjugate vaccine and values of different immunoassays as predictors of protection. Infection and Immunity 2002; 70(9):4946–54. Buttery 2005 {published data only} Buttery JP, Riddell A, McVernon J, Chantler T, Lane L, Bowen-Morris J, et al. Immunogenicity and safety of a combination pneumococcal-meningococcal vaccine in infants : a randomized clinical trial. Journal of American Medical Association 2005;293(14):1751–8. Campagne 2000 {published data only} Campagne G, Garba A, Fabre P, Schuchat A, Ryall R, Boulanger D, et al. Safety and immunogenicity of three doses of a Neisseria meningitidis A + C diphtheria conjugate vaccine in infants from Niger. Pediatric Infectious Disease Journal 2000;19(2):144–50.

Choo 2000 {published data only} Choo S, Zuckerman J, Goilav C, Hatzmann E, Everard J, Finn A. Immunogenicity and reactogenicity of a group C meningococcal conjugate vaccine compared with a group A+C meningococcal polysaccharide vaccine in adolescents in a randomised observer-blind controlled trial. Vaccine 2000;18(24):2686–92. Zhang Q, Choo S, Everard J, Jennings R, Finn A. Mucosal immune responses to meningococcal group C conjugate and group A and C polysaccharide vaccines in adolescents. Infection and Immunity 2000; 68(5):2692–7. De Wals 2004 {published data only} De Wals P, Boulianne N, De Serres G. Effectiveness of a mass immunization campaign using serogroup C meningococcal conjugate vaccine. The Journal of American Medical Association 2004;292:2491–4. English 2000 {published data only} English M, MacLennan JM, Bowen-Morris JM, Deeks J, Boardman M, Brown K, et al. A randomised, double-blind, controlled trial of the immunogenicity and tolerability of a meningococcal group C conjugate vaccine in young British infants. Vaccine 2000;19(9-10): 1232–8. Goldblatt 2002 {published data only} Goldblatt D, Borrow R, Miller E. Natural and vaccine-induced immunity and immunologic memory to Neisseria meningitidis serogroup C in young adults. Journal of Infectious Diseases 2002;185 (3):397–400. Halperin 2002 {published data only} Halperin SA, McDonald J, Samson L, Danzig L, Santos G, Izu A, et al. Simultaneous administration of meningococcal C conjugate vaccine and diphtheria-tetanus-acellular pertussis-inactivated

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Evid.-Based Child Health 2: 497–528 (2007) poliovirus-Haemophilus influenzae type b conjugate vaccine in children: a randomized double-blind study. Clinical & Investigative Medicine - Medecine Clinique et Experimentale 2002;25(6):243–51. Lakshman 2002 {published data only} Lakshman R, Burkinshaw R, Choo S, Finn A. Prior meningococcal A/C polysaccharide vaccine does not reduce immune responses to conjugate vaccine in young adults. Vaccine 2002;20(31-2):3778–82.

Richmond 2001 {published data only} Richmond P, Borrow R, Goldblatt D, Findlow J, Martin S, Morris R, et al. Ability of 3 different meningococcal C conjugate vaccines to induce immunologic memory after a single dose in UK toddlers. Journal of Infectious Diseases 2001;183(1):160–3.

Larrauri 2005 {published data only} Larrauri A, Cano R, Garcia M, Mateo S. Impact and effectiveness of meningococcal C conjugate vaccine following its introduction in Spain. Vaccine 2005;23:4097–100.

Tejedor 2004 {published data only} Tejedor JC, Omenaca F, Garcia-Sicilia J, Verdaguer J, Van Esso D, Esporrin C, et al. Immunogenicity and reactogenicity of a three-dose primary vaccination course with a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-haemophilus influenzae type b vaccine coadministered with a meningococcal C conjugate vaccine. The Pediatric Infectious Disease Journal 2004;23(12):1109– 15. Trotter 2004 {published data only} Trotter CL, Andrews N, Kaczmarski EB, Miller E, Ramsay ME. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. The Lancet 2004;364:365–7.

Lieberman 1996 {published data only} Lieberman JM, Chiu SS, Wong VK, Partidge S, Chang SJ, Chiu CY, et al. Safety and immunogenicity of a serogroups A/C Neisseria meningitidis oligosaccharide-protein conjugate vaccine in young children. A randomized controlled trial. Journal of the American Medical Association 1996;275(19):1499–503.

Twumasi 1995 {published data only} Leach A, Twumasi PA, Kumah S, Banya W, Jaffar S, Forrest BD, et al. Induction of immunologic memory in gambia children by vaccination in infancy with a group A plus C meningococcal polysaccharide-protein conjugate vaccine. The Journal of Infectious Diseases 1997;175:200–4.

MacDonald 1998 {published data only} MacDonald NE, Halperin SA, Law BJ, Forrest B, Danzig LE, Granoff DM. Induction of immunologic memory by conjugated vs plain meningococcal C polysaccharide vaccine in toddlers: a randomized controlled trial. Journal of the American Medical Association 1998;280 (19):1685–9.

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

Zhang Q, Lakshman R, Burkinshaw R, Choo S, Everard J, Akhtar S, et al. Primary and booster mucosal immune responses to meningococcal group A and C conjugate and polysaccharide vaccines administered to university students in the United Kingdom. Infection and Immunity 2001;69(7):4337–41.

MacLennan 2000 {published data only} Jonas C. Group C meningococcal vaccine trial: safety, immunogenicity and parents’ views of participation. Paediatric Nursing 2001;13 (1):23–6. MacLennan JM, Shackley F, Heath PT, Deeks JJ, Flamank C, Herbert M, 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(21):2795– 801. Maiden 2002 {published data only} Maiden MCJ, Stuart JM. Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination. Lancet 2002;359:1829–30. Pichichero 2005 {published data only} Pichichero M, Casey J, Blatter M, Rothstein E, Ryall R, Bybel M, et al. Comparative trial of the safety and immunogenicity of quadrivalent (A, C, Y, W-135) meningococcal polysaccharide-diphtheria conjugate vaccine versus quadrivalent polysaccharide vaccine in twoto ten-year-old children. Pediatric Infectious Disease Journal 2005;24 (1):57–62. Richmond 2000 {published data only} Richmond P, Kaczmarski E, Borrow R, Findlow J, Clark S, McCann R, et al. Meningococcal C polysaccharide vaccine induces immunologic hyporesponsiveness in adults that is overcome by meningococcal C conjugate vaccine. Journal of Infectious Diseases 2000;181(2): 761–4.

Twumasi Jr PA, Kumah S, Leach A, O’Dempsey TJD, Ceesay SJ, Todd J, et al. A trial of a group A plus group C Meningococcal polysaccharide-protein conjugate vaccine in African infants. Journal of Infectious Diseases 1995;171(3):632–8. 1995071123.

References to studies excluded from this review Balmer 2004 Balmer P, Falconer M, McDonald P, Andrews N, Fuller E, Riley C, et al. Immune response to meningococcal serogroup C conjugate vaccine in asplenic individuals. Infection and Immunity 2004;72(1): 332–7. 2004005926. Borrow 2000 Borrow R, Fox AJ, Richmond PC, Clark S, Sadler F, Findlow J, et al. Induction of immunological memory in UK infants by a meningococcal A/C conjugate vaccine. Epidemiology and Infection 2000;124 (3):427–32. 2000284569. Borrow 2001a Borrow R, Goldblatt D, Andrews N, Richmond P, Southern J, Miller E. Influence of prior meningococcal C polysaccharide vaccination on the response and generation of memory after meningococcal C conjugate vaccination in young children. Journal of Infectious Diseases 2001;184(3):377–80. Bose 2003 Bose A, Coen P, Tully J, Viner R, Booy R. Effectiveness of meningococcal C conjugate vaccine in teenagers in England. Lancet 2003;361 (9358):675–6. 2003090024. Bramley 2001 Bramley JC, Hall T, Finn A, Buttery RB, Elliman D, Lockhart Set al. Safety and immunogenicity of three lots of meningococcal serogroup

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in infants. Pediatric Infectious Disease Journal 2004;23(5):429–35. 2004210409.

Campbell 2002 Campbell JD, Edelman R, King CJ, Papa T, Ryall R, Rennels MB. Safety, Reactogenicity and Immunogenicity of a tetravalent meningococcal polysaccharide-diphtheria toxoid conjugate vaccine given to health adults. The Journal of Infectious Diseases 2002;186:1848–51.

Sikkema 2000 Sikkema DJ, Friedman KE, Corsaro B, Kimura A, Hildreth SW, Madore DV, et al. Relationship between serum bactericidal activity and serogroup-specific immunoglobulin G concentration for adults, toddlers, and infants immunized with neisseria meningitidis serogroup C vaccines. Clinical & Diagnostic Laboratory Immunology 2000;7(5):764–8.

Costantino 1992 Costantino P, Viti S, Podda A, Velmonte MA, Nencioni L, Rappuoli R. Development and phase 1 clinical testing of a conjugate vaccine against meningococcus A and C. Vaccine 1992;10(10):691–8. Granoff 2004 Granoff DM, Shannon L, Harris L. Protective activity of group C anticapsular antibodies elicited in two-year-olds by an investigational quadrivalent Neisseria meningitidis-Diphtheria toxoid conjugate vaccine. The Pediatrics Infectious Disease Journal 2004; Vol. 23, issue 6:490–7. Lakshman 2001 ∗ Lakshman R, Jones I, Walker D, McMurtrie K, Shaw L, Race G, et al. Safety of a new conjugate meningococcal C vaccine in infants. Archives of Diseases of Children 2001;85:391–7. Zhang Q, Pettitt E, Burkinshaw R, Race G, Shaw L, Finn A. Mucosal immune responses to meningococcal conjugate vaccines in infants. Pediatric Infectious Diseases 2002;21:209–13. MacLennan 1999 MacLennan J, Obaro S, Deek J, Williams D, Pais L, Carlone G. Immune response to revaccination with meningococcal A and C polysaccharides in Gambian children following repeated immunisation during early childhood. Vaccine 1999;17(23-4):3086–93.

Snape 2005 Snape MD, Kelly DF, Green B, Moxon ER, Borrow R, Pollard AJ. Lack of serum bactericidal activity in preschool children two years after single dose of serogroup C meningococcal polysaccharide-protein conjugate vaccine. The Pediatric Infectious Disease Journal 2005; 24(2):128–31. Zhang 2002 Zhang Q, Pettitt E, Burkinshaw R, Race G, Shaw L, Finn A. Mucosal immune response to meningococcal conjugate polysaccharide vaccines in infants. Pediatrics Infectious Diseases 2002;21(3):206–2013.

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Mcvernon 2002 Mcvernon J, Maclennan J, Buttery J, Oster P, Danzig E, Moxon R. Safety and immunogenicity of meningococcus serogroup C conjugate vaccine administered as a primary or booster vaccination to health four-year-old children. Pediatrics Infectious Diseases 2002;21:747–53.

Anonymous 1998 Anonymous. Annual report of the Australian Meningococcal Surveillance Programme, 1997. Communicable Diseases Intelligence 1998;22 (10):205–11. 99020436.

McVernon 2003 McVernon J, MacLennan J, Clutterbuck E, Buttery J, Moxon ER. Effect of infant immunisation with meningococcus serogroup C-CRM (197) conjugate vaccine on diphtheria immunity and reactogenicity in pre-school aged children. Vaccine 2003;21(19-20):2573–9.

Borrow 2001 Borrow R, Adrews N, Goldblatt D, Miller E. Serological basis for use of meningococcal serogroup C conjugate vaccine in the United Kingdom: reevaluation of correlates of protection. Infection and Immunity 2001;69(3):1568–73.

Rennels 2001 Rennels MB, Edwards KM, Keyserling HL, Reisinger K, Blatter MM, Quataert SA, et al. Safety and immunogenicity of four doses of Neisseria meningitidis group C vaccine conjugated to CRM197 in United States infants. Pediatric Infectious Disease Journal 2001;20(2):153–9.

Broome 1989 Schwartz B, Moore PS, Broome CV. Global Epidemiology of Meningococcal Disease. Clinical Microbiology Reviews 1989;2 (Suppl):118–24.

Rennels 2002 Rennels M, King Jr J, Ryall R, Manoff S, Papa T, Weddle A, et al. Dose escalation, safety and immunogenicity study of a tetravalent meninogococcal polysaccharide diphtheria conjugate vaccine in toddlers. Pediatric Infectious Disease Journal 2002;21(10):978–9.

Cartwright 2001 Cartwright K, Noah N, Peltola H, Meningococcal Disease Advisory Board. Meningococcal disease in Europe: epidemiology, mortality, and prevention with conjugate vaccines. Report of a European advisory board meeting Vienna, Austria, 6-8 October, 2000. Vaccine 2001;19(31):4347–56.

Rennels 2004 Rennels M, Kinf Jr J, Ryall R, Papa T, Froeschle J. Dosage escalation, safety and immunogenicity study of four dosages of a tetravalent meninogococcal polysaccharide diphtheria toxoid conjugate vaccine

Connolly 1999 Connolly M, Noah N. Is group C meningococcal disease increasing in Europe? A report of surveillance of meningococcal infection in Europe 1993-6. Epidemiology and Infection 1999;122:41–9. 99196420.

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Jodar 2004 Jodar L, Griffiths E, Feavers I. Scientific challenges for the quality control and production of group C meningococcal conjugate vaccine. Vaccine 2004;22:1047–53.

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Farrington 1993 Farrington CP. Estimation of vaccine effectiveness using the screening method. International Journal of Epidemiologia 1993;22:742–6.

Peltola 1998 Peltola H. Meningococcal vaccines. Current status and future possibilities. Drugs 1998;55(3):347–66.

Gold 1979 Gold R, Lepow ML, Goldschneider I, Draper TF, Gotshlich EC. 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. Journal of Infectious Diseases 1979;140(5):690-7 . 80116591.

Ramsay 2003a Ramsay ME, McVermon J, Andrews NJ, Heath PT, Slack MP. Estimating Haemophylus influenzae Type b Vaccine effectiveness in England and Wales by use of the screening methods. Journal of Infectious Diseases 2003;188:481–5.

Goldschneider 1969 Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. Journal of Experimental Medicine 1969;129(6):1307–26. 69194933. Granoff 1998 Granoff DM, Gupta RK, Belshe RB, Anderson EL. Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination. Journal of Infectious Diseases 1998;178(3):870–4. 98396734. Healy 2002 Healy CM, Butler KM, Smith EO, Hensey OP, Bate T, Moloney AC, et al. Influence of serogroup on the presentation, course, and outcome of invasive meningococcal disease in children in the Republic of Ireland, 1995-2000. Clinical Infectious Diseases 2002;34:1323–30. Jackson 1993 Jackson LA, Wenger JD. Laboratory-based surveillance for meningococcal disease in selected areas, United States, 1989-1991. Morbidity and Mortality Weekly Report 1993;42(2):21–30. 93287973. Jadad 1996 Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomised clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;17 (1):1–12. 96308458. Jodar 2000 Jodar L, Cartwright K, Feavers IM. Standardisation and validation of serological assays for the evaluation of immune responses to Neisseria meningitidis serogroup A and C vaccines. Biologicals 2000;28(3): 193–7. Jodar 2002 Jodar L, Feavers IM, Salisbury D, Granoff DM. Development of vaccines against meningococcal disease. Lancet 2002;359:1499–1508.

Ramsay 2003b Ramsay ME, Andrews NJ, Trotter CL, Kaczmarski EB, Miller E. Herd immunity from meningococcal serogroup C conjugate vaccination in England: database analysis. BMJ 2003;326:365–6. Robbins 1996 Robbins JB, Schneerson R, Anderson P, Smith DH. The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharidebased vaccines. JAMA 1996;276(14):1181–5. 96425585. Santos 2001 Santos GF, Deck RR, Donnelly J, Blackwelder W, Granoff DM. Importance of complement source in measuring meningococcal bactericidal titers. Clinical and Diagnostic Laboratory Immunology 2001;8 (3):616–23. Spanjaard 1987 Spanjaard L, Bol P, de Marie S, Zanen HC. Association of meningococcal serogroups with the course of disease in the Netherlands, 195983. Bulletin of the World Health Organization 1987;65(6):861–8. Tikhomirov 1997 Tikhomirov E, Santamaria M, Esteves K. Meningococcal disease: public health burden and control. World Health Statistics Quarterly 1997;50(3-4):170–7. 98138032. Wall 2002 Wall RA. Meningococcal disease: treatment and prevention. Annals of Internal Medicine 2002;77(40):329–40. WHO 2002 WHO. Meningococcal vaccines: polysaccharide and polysaccharide conjugate vaccines. Weekly Epidemiological Record 2002;77(40):329– 40. ∗

Indicates the major publication for the study

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Evid.-Based Child Health 2: 497–528 (2007) TABLES

Characteristics of included studies Study

Anderson 1994

Methods

Randomised double-blind controlled trial. Jadad score 3

Participants

50 adults of 18 to 50 years of age

Interventions

One dose of meningococcal A-C conjugate vaccine containing 5 g or 11 g or 22 g of each oligosaccharide or meningococcal A-C y w135 polysaccharide vaccine or saline

Outcomes

Serum specific antibodies to meningococcal A-C (IgG, IgA, IgM,standard-ELISA) oligosaccharide, serum bactericidal activity (rabbit source of complement) and adverse events

Notes

Meningococcal A-C conjugate vaccine (Sclavo, Sciena) containing 5.5 mcg or 11 mcg or 22 mcg of each oligosaccharide and 48.7 mcg of CMR197 or polysaccharide quadrivalent meningococcal vaccine (Menomune; Connaught) containing 50 mcg of each oligosaccharide

Allocation concealment

B – Unclear

Study

Borrow 2003

Methods

Randomised double-blind, controlled trial. Jadad score 3

Participants

586 infants at 6 to 11 weeks of age at first dose

Interventions

One or two or three doses of meningococcal C conjugate vaccine and one booster with meningococcal polysacaride A-C vaccine at 13 to 14 months of age, concomitant with routine vaccine

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (modified ELISA), serum bactericidal antibodies (rabbit complement source), SBA titre >= 8

Notes

Meningococcal C conjugate vaccine containing 10 mcg of oligosaccharide and 20 mcg of tetanus toxoid ( MCC-TT) and meningococcal A/C polysaccharide vaccine (AC Vax Smithkline) containing 10 mcg of each oligosaccharide

Allocation concealment

A – Adequate

Study

Burrage 2002

Methods

Randomised controlled trial, not blinded. Jadad score 3

Participants

843 children at between 3.5 years and 6 years of age and 923 children between 14 years to 17.8 years of age

Interventions

One dose of meningococcal C conjugate vaccine either 1 month before, 1 month after or concurrent to diphtheria-tetanus booster vaccine

Outcomes

Serum specific antibodies to meningococcal OAc+ and OAc - polysaccharide (standard-ELISA, modifiedELISA), serum bactericidal antibodies (rabbit complement source).SBA titre >= 8 mcg and > 2 mcg

Notes

Three meningococcal C conjugate vaccine: Wyeth Lederle (8 mcg to 12 mcg of oligosaccharide conjugate to 8 mcg to 12 mcg of CRM 197), Chiron vaccine (12 mcg of oligosaccharide conjugate to 30 mcg of CRM197) and Baxter Hyland Immuno (10 mcg) of oligosaccharide conjugate to 20 mcg tetanus toxoid)

Allocation concealment

A – Adequate

Study

Buttery 2005

Methods

Randomised clinical trial. Not blinded. Jadad score 3

Participants

240 infants at 7 to 11 weeks of age at the first dose

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Evid.-Based Child Health 2: 497–528 (2007) Characteristics of included studies (Continued ) Interventions

Three doses of Pnc9-MenC or MCC vaccine at 2, 3 and 4 months, concomitant with routine vaccine

Outcomes

Serum specific antibodies to meningococcal C polysacaride (standard-ELISA, serum bactericidal antibodies (rabbit complement source), SBA titre >= 8 and >32 and adverse events

Notes

Pneumococcal 9 valente vaccine Pnc9-MCC, ( Weyth Vaccines ) containing, oligosccharide 2mg of pneumococcal sacharide conjugates 1, 4, 5, 9v, 14,18C, 19F and 23F; 4mg of pneumococcal saccharide conjugate 6B; and 10mg of meningococcal group C oligosaccharide and 38.5 mg of CRM197; Meningitec (Wyeth Lederle) oligosaccharide C 10 mg and CRM197 15 mgand routine vaccine (DTwP, Hib PVO vaccines)

Allocation concealment

C – Inadequate

Study

Campagne 2000

Methods

Randomized clinical trial. Not blinded. Jadad score 1

Participants

180 infants at 6 weeks of age at the first dose

Interventions

Three dose of meningococcal A/C conjugate vaccine at 6, 10 and 14 weeks of age in polysaccharide C sequential dose escalation of 1 mg, 4 mcg and 16 mg

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (standard-ELISA) serum bactericidal activity using rabbit complement source, percentage of subjects with ELISA antibodies concentration > 2 mg/ml and SBA titers >= 8 mg/ml

Notes

Meningococcal conjugate vaccine A/C: Pasteur Merieux, containing 1 mg, 4 mg and 16 mg of each oligosaccharide and 5.5 mg, 32.2 mg and 161 mg of diphtheria toxoid. Meningococcal Ac polysaccharide vaccine containing 50 mg of each oligosaccharide and DPT vaccine and Haemophilus influenzae vaccine

Allocation concealment

C – Inadequate

Study

Choo 2000

Methods

Randomised, double blind controlled trial. Jadad score 5

Participants

182 adolescents from 11 years to 17 year of age; an 106 in the second phase

Interventions

One dose of meningococcal C conjugate vaccine or one dose of meningococcal A/C polysaccharide vaccine

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (modified-ELISA, serum bactericidal antibodies (human complement source). Adverse events. SBA titre >= 8. Salivary anti-meningococcal C polysaccharide specific IgG, IgA, SC, IgA1, IgA2, salivary rate

Notes

Meningococcal C conjugate vaccine (Chiron vaccine) containing 10 mcg of oligosaccharide and CRM 197 and meningococcal A/C polysaccharide vaccine containing 50 mcg of each oligosaccharide (Mengivac Pasteur Merireux)

Allocation concealment

A – Adequate

Study

De Wals 2004

Methods

Population-based observational study

Participants

Population of Quebec from 2 months to 20 years: 1,919,070 individuals

Interventions

Mass campaign of vaccination: 16,060,635 doses of meningococcal C conjugate vaccine

Outcomes

Incidence rate of invasive meningococcal C disease using polymerase chain reaction and strain characterisation test

Notes Allocation concealment

D – Not used

Study

English 2000

Methods

Randomised, double-blind, controlled trial. Jadad score 5

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Evid.-Based Child Health 2: 497–528 (2007) Characteristics of included studies (Continued ) Participants

248 infants at 2 months of age at first dose

Interventions

Three doses of meningococcal C conjugate vaccine or hepatitis B vaccine in infants at 2, 3 and 4 months of age, concomitant with routine vaccine

Outcomes

Serum specific antibodies to meningococcal C polysacaride (standard-ELISA, serum bactericidal antibodies (rabbit complement source), SBA titre > 2 mcg and adverse events

Notes

Meningococcal C conjugate vaccine (Lederle) containing 10 mcg of oligosaccharide and 25 mcg of CRM 197 or hepatitis B vaccine (Smith Kleine). Roitine vaccines (DPT, HIB, HVB, OPV)

Allocation concealment

A – Adequate

Study

Goldblatt 2002

Methods

Randomised controlled trials, with one non-randomised control group added. Jadad score 1

Participants

150 university students

Interventions

Meningococcal C conjugate vaccine after meningococcal A/C polysaccharide or after none

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (standard-ELISA, modified-ELISA) serum bactericidal antibodies (rabbit complement source)

Notes

Meningococcal C conjugate vaccine (Wyeth Lederle) containing 10 mcg of oligosaccharide and 15 mcg of CRM 197 and meningococcal polysaccharide A/C vaccine (Pasteur Meriex) containing 50 mcg of each polysaccharide

Allocation concealment

C – Inadequate

Study

Halperin 2002

Methods

Randomised double-blind, controlled trial. Jadad score 5

Participants

351 infants between 6 and 12 weeks of age at first the dose

Interventions

Four doses of meningococcal C conjugate vaccine or hepatitis B vaccine at 2, 4, 6 and at 15 to 18 months of age, concomitant to routine vaccine

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (modified-ELISA, serum bactericidal antibodies (rabbit source of complement), SBA titre >= 8, adverse events and antibodies to others vaccine used

Notes

Meningococcal C conjugate vaccine (Menjugate, Chiron Corporation, Emerville, Calif.) containing 10 mcg of oligosaccharide and CRM 197 or Hepatis B vaccine (Glaxo SmithKline) DtaP-IPV-Hib (Pentacel - Aventis Pasteur)

Allocation concealment

A – Adequate

Study

Lakshman 2002

Methods

Randomised double-blind controlled trial. Jadad score 4

Participants

195 university students of 17 to 30 years old

Interventions

Meningococcal conjugate A/C vaccine after meningococcal A/C polysaccharide or after none

Outcomes

Serum specific antibodies to meningococcal A and C oligosaccharide (standard-ELISA, serum bactericidal antibodies to meningococcal A and C (rabbit source of complement). SBA titre >= 8. Specific salivary IgG and IGA antibodies against serogroup A and C meningococcal polysaccharide, ratio of IgG and IgA specific to meningococcal A and C oligosaccharide

Notes

Meningococcal A/C conjugate vaccine (Aventis Pasteur) containing 4 mcg of each oligosaccharide and 48 mcg of CRM197 meningococcal A/C polysaccharide contained 50 mcg of each polysaccharide (Aventis Pasteur)

Allocation concealment

A – Adequate

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Evid.-Based Child Health 2: 497–528 (2007) Characteristics of included studies (Continued ) Study

Larrauri 2005

Methods

Population-based observational study

Participants

Population of Spain under 6 years of age

Interventions

Meningococcal C conjugate vaccine at 2, 4 and 6 months of age and a catch-up campaign mainly targeted at children under 6 years of age

Outcomes

Age-specific incidence rates and case fatality rate before and 4 years after vaccine introduction

Notes Allocation concealment

Cases of meningococcal disease obtained from Notificable Disease Sureveillance System. Screening method was used to calculate effectiveness D – Not used

Study

Lieberman 1996

Methods

Randomised single-blind, controlled trial. Jadad score 4

Participants

90 children between 18 and 24 months of age; 46 males and 44 females

Interventions

Meningococcal A-C conjugate vaccine or meningococcal quadrivalent polysaccharide vaccine, with 2 doses given 2 months apart

Outcomes

Serum specific total antibodies to meningococcal (standard-ELISA) and serum bactericidal activity (rabbit complement source), adverse events

Notes

Meningococcal A/C conjugate vaccine (Chiron Biocine Siena Italy ) with 11.15 mcg of group A oligosaccharide and 11.7 mcg or 5.5 mcg of group C oligosaccharide conjugate to CRM197 48.7 mcg and quadrivalent meningococcal polysaccharide vaccine A C Y W135, containing 50 mcg of each oligosaccharide (Connaught Laboratories)

Allocation concealment

A – Adequate

Study

MacDonald 1998

Methods

Randomised observer-blinded, controlled trial. Jadad score 4

Participants

211 children 15 to 23 months of age; 182 males, 103 females

Interventions

Two doses of meningococcal C conjugate vaccine or two doses of meningococcal quadrivalent polysaccharide vaccine (A, C, Y and W135) or two doses of hepatitis B vaccine in children of 15 to 23 months of age. One dose of meningococcal polysaccharide vaccine 12 months later

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (modified-ELISA) and serum bactericidal antibodies (human complement source). SBA titre >= 8 and adverse events

Notes

Meningococcal C conjugate vaccine (Chiron Vaccine) containing 10 mcg of oligosaccharide conjugate to CRM197 or quadrivalent meningococcal polysaccharide vaccine A C Y W135 , containing 50 mcg of each oligosaccharide (Menomune, Connaught) and hepatitis B vaccine (Recombivax, Merck Sharp and Dohme)

Allocation concealment

A – Adequate

Study

MacLennan 2000

Methods

Randomised double-blind trial (first phase). Jadad score 5

Participants

182 infants. Mean age at first vaccination 57 days: 103 males, 79 females

Interventions

Two lots of meningococcal C conjugate vaccine or a hepatitis B control vaccine, at 2, 3 and 4 months of age, concomitant routine vaccine. Meningococcal C conjugate vaccine or Meningococcal A/C polysacaride vaccine at 12 months of age.

Outcomes

Specific antibodies to meningococcal C polysaccharide (modified-ELISA) and serum bactericidal activity (human complement source) at 2, 3, 4, 5 and 12 months of age. SBA >= 8. Local and systemic reactions

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Evid.-Based Child Health 2: 497–528 (2007) Characteristics of included studies (Continued ) Notes

Meningococcal C conjugate vaccine (Chiron, SPA Siena, Italy) containing 10 mcg of oligosaccharide conjugate to 13 mcg or 20 mcg CRM197 and hepatitis B vaccine (Smith Kline), meningococcal AC polysaccharide vaccine (Mengivac Pasteur Merieux) and routine vaccine (DPT, Act Hib, Polio vaccines)

Allocation concealment

A – Adequate

Study

Maiden 2002

Methods

Cross-sectional surveys

Participants

14,064 students aged 15 to 17 years during the vaccination and 16,583 students one year later

Interventions

Meningococcal C conjugate vacine mass immunisation campaign in the UK

Outcomes

Oropharyngeal carriage of serogroup C Meningococci

Notes Allocation concealment

D – Not used

Study

Pichichero 2005

Methods

Randomised double-blind clinical trial. Jadad score 4

Participants

1398 children from 2 to 10 years old

Interventions

One dose of quadrivalent meningococcal conjugate vaccine or one dose of meningococcal polysaccharide vaccine. Serum specific antibodies to meningococcal polysaccharides before vaccination and at 28-days and 6 months after vaccination and serum bactericidal activity (rabbit source of complement). Adverse events

Outcomes Notes

Quadrivalent meningococcal conjugate vaccine (MCV-4) containing 4 mcg of each polysaccharide from serogroup A, C, Y and W135, conjugate to CRM 48 mcg of diphtheria toxoid protein; meningococcal polysaccharide vaccine (PSV-4, Menomune A/C/Y/W-135; Aventis Pasteur) containing 50 mcg of each polysaccharide

Allocation concealment

B – Unclear

Study

Richmond 2000

Methods

Randomised controlled trial with control group added. Jadad score 2

Participants

190 university students from 18 years to 25 year old

Interventions

Meningococcal C conjugate vaccine after meningococcal A/C polysaccharide vaccine or after none

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (standard-ELISA, serum bactericidal antibodies (rabbit complement source)

Notes

Allocation concealment

Meningococcal C conjugate vaccine (Wyeth Lederle) containing 10 mcg of oligosaccharide and 15 mcg of CRM 197 or Meningococcal polysaccharide A/C (Pasteur Merieux), containing 50 mcg of each oligosaccharide C – Inadequate

Study

Richmond 2001

Methods

Randomised controlled double-blind trial. Jadad score 3

Participants

226 children 12 to 18 months old at the first vaccine dose; 128 males, 98 females

Interventions

One dose of three different meningococcal C conjugate vaccines and six months after one booster dose of meningococcal AC polysaccharide vaccine

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (standard-ELISA, modified-ELISA) and serum bactericidal antibodies (rabbit complement source), SBA titer >= 8 and adverse reactions

Conjugate vaccines for preventing meningococcal C meningitis and septicaemia (Review) Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

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Evid.-Based Child Health 2: 497–528 (2007) Characteristics of included studies (Continued ) Notes

Meningococcal C vaccine containing 10 mcg of oligosaccharide and CRM 197 (Chiron Vaccines and Wyeth Lederle) and one with 20 mcg of tetanus toxoid conjugate (North American Vaccines Group), containing 10 mcg of oligosaccharide C. Meningococcal polysaccharide vaccine A/C (Pasteur Merieux) containing 10 mcg of each oligosaccharide and MMR-II (Pasteur Merieux)

Allocation concealment

A – Adequate

Study

Tejedor 2004

Methods

Randomised controlled trial, not blind. Jadad score 2

Participants

452 infants between 8 and 12 weeks of age at the first vaccine dose

Interventions

Three doses of meningococcal C conjugate vaccine

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (standard-ELISA) and Serum bactericidal activity (rabbit source of complement) and antibodies to each component of routine vaccine

Notes

Meningococcal C conjugate vaccine (Meningitec, Wyeth Lederele Vaccine) DTPa-HVB-IPV, Hib (Infanrix HexA Glaxo SmithKine)

Allocation concealment

C – Inadequate

Study

Trotter 2004

Methods

Population-based observational study

Participants

All individuals in England with confirmed serogroup C disease

Interventions

Meningococcal C conjugate vaccine into routine immunization schedule at 2, 3 and 4 months of age and a catch up campaign to children younger than 18 years

Outcomes

Laboratory-confirmed case of serogroup C disease and vaccine effectiveness

Notes

Vaccine effectiveness was estimate by screening method. The percentage reduction in the attack rate in vaccinated compared with unvaccinated children in the same birth cohorts, estimated from the proportion of case in vaccinated individuals and vaccine coverage in each case

Allocation concealment

D – Not used

Study

Twumasi 1995

Methods

Randomised controlled trial (first phase). Non-randomised control group added in a second and third phase (age strata-matched). Jadad score 3 (first phase) and 1 (second and third phase)

Participants

304 infants at 2, 3, 4 or 6 months of age at the first vaccine dose. Revacination of 242 children at 18 to 24 months. Re-vaccination of 176 children at 5 years of age

Interventions

One or two or three doses of meningococcal A/C conjugate vaccine or two doses of meningococcal polysaccharide vaccine at 2 to 6 months of age, concomitant with routine vaccine. At 2 years of age one dose of meningococcal A/C conjugate vaccine or one dose of meningococcal A/C polysaccharide vaccine or one dose of inactivated poliomyelitis vaccine. At 5 years of age, one dose of meningococcal A/C polysaccharide vaccine

Outcomes

Serum specific antibodies to meningococcal C polysaccharide (standard-ELISA, serum bactericidal antibodies (rabbit source of complement)

Notes

Meningococcal A/C conjugate vaccine (Biocine, Siena, Italy) containing 11 mcg of each oligosaccharide and 49 mcg of CRM 197 or meningococcal polysaccharide A/C (Menpovax, Biocine) containing 50 mcg of each oligosaccharide, meningococcal AC polysaccharide vaccine (Mengivac Pasteur Merieux) containing 10 mcg of each oligosaccharide. Inactivated poliomyelitis vaccine (Pasteur Merieux)

Allocation concealment

C – Inadequate

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Evid.-Based Child Health 2: 497–528 (2007) Characteristics of excluded studies Study

Reason for exclusion

Balmer 2004

Non-randomised clinical trial. Cohort of 130 splenectomised individuals of received meningococcal serogroup C conjugate vaccine were compared to historical control group.

Borrow 2000

Non-randomised clinical trial. Forty children previously vaccinated with three doses of meningococcal conjugate A-C, were re-vaccinated. Serum concentration of antibodies measured before and after the vaccines.

Borrow 2001a

Non-randomised clinical trial. Cohort of children vaccinated with meningococcal A-C polysaccharide vaccine was re-vaccinated 7 months later with meningococcal C conjugate vaccine and compared with age-matched meningococcal polysaccharide naive control children.

Bose 2003

Case-control study about effectiveness of MCC in teenagers; included 31 cases of laboratory confirmed meningococcal C disease and 6 controls.

Bramley 2001

Randomised clinical trial including 322 infants that received three different lots of the same meningococcal C conjugate vaccine.

Campbell 2002

Non-randomised clinical trial. Phase 1/2 open-label dose escalation study, including 90 healthy adults immunised with a tetravalent (serogroup A, C, Y, w135) meningococcal conjugate vaccine.

Costantino 1992

Non-randomised clinical trial. Pre-clinical and phase 1 clinical trial including 16 adults volunteers vaccinated with meningococcal conjugate vaccine.

Granoff 2004

Study derived from Pichichero. Non-randomised clinical trial in this phase. Data of immunisation with quadrivalent N. meningitidis-diphtheria toxoid conjugate vaccine in 60 children and 26 adults.

Lakshman 2001

Non-randomised clinical trial. Cohort of 2796 infants aged 2 months were vaccined with MCC at 2, 3 and 4 months along with routine vaccine. Data on adverse events occurring one month after the vaccination were collected.

MacLennan 1999

Trial derived from Twamasi 1995. Non-randomised clinical trial in this phase of study. The study reported the immune response to re-vaccination with meningococcal A and C polysaccharide in children following repeated immunisation during early childhood. A strata age-matched control group was added.

McVernon 2003

Trial derived from MacLennan 2000. The study reported antibodies to diphtheria in children with and without previous meningococcal C conjugate vaccine.

Mcvernon 2002

Trial derived from MacLennan 2000. Non-randomised clinical trial in this phase of study.

Rennels 2001

Randomised controlled trial comparing meningococcal conjugate vaccine versus 7-valent conjugate pneumococcal vaccine. No data about antibodies to meningococcal C polysaccharide in control group.

Rennels 2002

Non-randomised clinical trial. Phase 1, not blinded, open label, dosage escalation study including 30 children ages 12 to < 23 months.

Rennels 2004

Non-randomised clinical trial. Phase 1, not blinded, open label, dosage escalation study including 90 infants

Sikkema 2000

Non-randomised clinical trial. Quantification of IgG antibodies pre and post immunisation of adults, toddlers and infants.

Snape 2005

Cohort study including 91 children (median age 4.0 years) after 1.8 years after vaccination with serogroup C meningococcal vaccine

Zhang 2002

Study derived from trial of Lakshman 2001. Non-randomised trial in this part of study. 100 Children vaccinated with meningococcal conjugate vaccine and 40 control were evaluated about mucosal immune responses.

GRAPHS AND OTHER TABLES This review has no analyses. Conjugate vaccines for preventing meningococcal C meningitis and septicaemia (Review) Copyright © 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

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INDEX TERMS Medical Subject Headings (MeSH) Meningitis, Meningococcal [∗ prevention & control]; Meningococcal Vaccines [∗ therapeutic use]; ∗ Neisseria meningitidis, Serogroup C; Septicemia [∗ prevention & control]; Vaccines, Conjugate [therapeutic use] MeSH check words Humans; Infant

COVER SHEET Title

Conjugate vaccines for preventing meningococcal C meningitis and septicaemia

Authors

Conterno LO, Silva Filho CR, Rüggeberg JU, Heath PT

Contribution of author(s)

Dr Lucieni Oliveira Conterno: responsible for data extraction, study inclusion/exclusion, analysis, interpretation of results and writing the review. Dr Carlos Rodrigues Silva Filho: responsible for data extraction, study inclusion/exclusion, analysis and interpretation of results. Dr Jens Rüggeberg: responsible for commenting on the draft review. Dr Paul Heath: responsible for writing the protocol, interpreting the results and writing the review.

Issue protocol first published

1999/4

Review first published

2006/3

Date of most recent amendment

19 May 2006

Date of most recent SUBSTANTIVE amendment

15 May 2006

What’s New

Information not supplied by author

Date new studies sought but none found

Information not supplied by author

Date new studies found but not yet included/excluded

Information not supplied by author

Date new studies found and included/excluded

10 September 2005

Date authors’ conclusions section amended

Information not supplied by author

Contact address

Prof Lucieni de Oliveira Conterno Co-ordinator of Infectious Diseases Discipline and Clinical Epidemiology Discipline Department of Medicine Marilia Medical School - FAMEMA Avenida Monte Carmelo 800 Fragata Marilia São Paulo 17519-030 BRAZIL E-mail: [email protected] Tel: + 55 14 34021831 Fax: + 55 14 34335036

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DOI

10.1002/14651858.CD001834.pub2

Cochrane Library number

CD001834

Editorial group

Cochrane Acute Respiratory Infections Group

Editorial group code

HM-ARI

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