ARCHIVED - Advice for Consideration of Quadrivalent (A, C, Y, W135) Meningococcal Conjugate Vaccine, for use by Provinces and Territories

Vaccine Characteristics

Immunogenicity

Meningococcal conjugate vaccines, like other polysaccharide-protein conjugate vaccines, elicit a thymus-dependent immunologic response that is already present at birth, and is characterized by the development of memory B cells and by the production of a diversity of immunoglobulin classes and subclasses with high affinity for the capsular polysaccharide antigen (Stein, 1992). Regardless of the type of vaccine, age at vaccine administration and number of doses, serum antibody concentrations decrease with time, while memory is long-lasting (De Wals, 2006). The mechanisms of protection provided by meningococcal conjugate vaccines are not entirely understood, but it is known that both mucosal and serum antibodies directed against capsular polysaccharide play a major role through binding of bacterial surface structures and activation of complement leading to phagocytosis or direct bacterial killing (Pollard et al., 2001). Complement-mediated serum bactericidal activity (SBA) measured in vitro is a recognized marker of protection. In studies in the US, there was an inverse correlation between age-specific incidence of meningococcal disease and age-specific prevalence of SBA at the population level (Goldschneider at al., 1969). In a prospective study among military recruits, serogroup C IMD occurred rarely among individuals who had circulating SBA titres of ≥ 4 (Goldschneider at al., 1969). SBA titres of ≥ 4 using human complement have been proposed as a marker of protection against serogroup C IMD, and thresholds comprised between ≥ 8 and ≥ 128 have been proposed for assays relying on rabbit complement (Andrews et al., 2003; Borrow et al., 2005). These thresholds, however, are not associated with absolute protection and serogroup C IMD cases have been observed in individuals who had pre-existing SBA titres ≥ 4 using human complement (Goldschneider at al., 1969). Also, lower titres do not necessarily define susceptibility. In 25% of sera from unimmunized human adults with SBA titers < 4 (human complement), high-avidity anticapsular antibodies were present in a concentration insufficient to elicit complement-mediated bacteriolysis in vitro, but sufficient to confer protection in an in vivo bacteraemia rat model (Welsh et al. 2004). For serogroups A, W135 and Y, there is no established threshold of protection.

A first quadrivalent (A, C, W135, Y) meningococcal conjugate vaccine (Menactra™) was licensed in Canada in 2006, and has been approved for use in persons 2 to 55 years of age (Sanofi Pasteur Limited 2006; NACI 2007). One 0.5 mL dose of this vaccine contains 4µg each of the four polysaccharides conjugated to a total of 48µg of diphtheria toxoid protein carrier. Other products are under development, using either the CRM197 carrier protein derived from the diphtheria toxoid or the tetanus toxoid. The immunologic response to the quadrivalent (A, C, W135, Y) meningococcal diphtheria toxoid conjugate vaccine (Men4-DT) has been investigated in different age groups and different immunologic markers were provided in reports, including the geometric mean SBA (rabbit complement) titre on day 28 and at 6 months, the percentage of subjects who seroconverted (defined as a SBA titre < 1:8 on day 0, and ≥ 1:32 on day 28), the percentage of subjects with a ≥ 4-fold rise in SBA titre, and the percentage of subjects with a SBA titre on day 28 ≥ 1:128 or 1:8 (Sanofi Pasteur Limited 2006; Rennels et al. 2002; Rennels et al. 2004). Generally, the response was better for serogroup A than for other serogroups, and an age-related response was also observed. In infants, the proportion of subjects with SBA titres ≥ 1:8 one month after 3 doses was between 92% for serogroup A and only 54% for serogroup C (Rennels et al. 2004). In children aged between 12 and 22 months, two doses were needed for a satisfactory response (Rennels et al. 2002). In subjects aged 2-10 years, the percentage of seroconversion after one dose was 99% for serogroup A, 96% for serogroup W135, 88% for serogroup C, and 86% for serogroup Y (Pichichero et al., 2005). In another trial, the proportion of seroconverters was 97% for serogroups A and W135, and 100% for serogroups C and Y (Lagos et al., 2005). In children aged 2-3 years, Men4-DT induced serogroup C antibodies having higher functional activity than those induced by the quadrivalent polysaccharide vaccine (Granoff et al. 2004). For all serogroups, however, antibody concentrations decreased with time and 2-3 years after Men4-DT administration, many subjects had SBA titres (human complement) below 1:4 (Granoff et al., 2005). However, persistence of immune memory and absence of hyporesponsiveness were demonstrated following administration of one-tenth of a dose of tetravalent polysaccharide vaccine (Pichichero, 2005). In another trial, children aged 2 to 4 years, previously vaccinated more than one year earlier with a monovalent C conjugate vaccine received one dose of Men4-DT and the response to serogroup C was of high magnitude, consistent with a booster response in primed individuals (El Bashir et al., 2006). In adolescents and adults, Men4-DT induced a strong immunologic response with seroconversion rates higher than 90% for all serogroups (Sanofi Pasteur Limited, 2006). In adolescents, persistence of protective antibodies and of immunologic memory for all serogroups was demonstrated up to 3 years after one dose of Men4-DT (Pichichero, 2005; Vu et al., 2006).

Effectiveness

All meningococcal conjugate vaccines have been licensed on the basis of immunologic studies and criteria defined by experts (NACI 2007). In all trials in persons aged 2 years or more, short- term immunologic response to Men4-DT was non-inferior to the response to quadrivalent polysaccharide vaccine. Men4-DT generated antibodies having better functional characteristics and longer persistence, while inducing a strong anamnestic response following a booster dose with no hyporesponsiveness (Sanofi Pasteur Limited 2006; NACI 2007). For all these reasons, Men4-DT should be preferred to the quadrivalent polysaccharide vaccine for all indications of a quadrivalent or a serogroup A, Y or W135 meningococcal vaccine in those aged 2 years and older.

The field effectiveness of monovalent serogroup C conjugate vaccines has been evaluated in large post-marketing epidemiological studies, and results indicate a high level of protection in the first year following primary immunization with a variable number of doses in all age groups, sustained protection up to 4 years following administration of one dose in the second year of life or later, but no evidence of sustained protection for those who received a primary immunization series before the age of 6 months (Trotter et al., 2004; De Wals et al., 2004; Larrauri et al., 2005). To date, there is little evidence regarding sustained protection beyond 4 years in those who received monovalent serogroup C conjugate vaccine in the second year of life or later. Currently, there are no data on the clinical effectiveness of Men4-DT and there has been no immunologic study providing a head-to-head comparison of Men4-DT with field-tested serogroup C conjugate vaccines containing either the CRM197 carrier protein derived from the diphtheria toxoid (Meningitec™, Wyeth, and Menjugate™, Novartis Vaccines) or the tetanus toxoid (Neis Vac-C™, GlaxoSmithKline). Although the immune response of Menactra™ was compared to the response of the polysaccharide vaccine, and was non-inferior for serogroup C, it is established that the polysaccharide vaccine provides a low level of protection of short duration for this serogroup in children (De Wals et al., 2005). A case-control study aiming to assess effectiveness is underway in the U.S. (CDC, personal communication, 2007). For these reasons, until the results of new studies are available, the three monovalent serogroup C conjugate vaccines currently approved in Canada should be preferred for all indications of vaccination against serogroup C IMD, especially in children.

While the effectiveness of polysaccharide vaccines to prevent serogroup A and C IMD has been demonstrated in experimental and observational studies in adolescents and adults (Frasch 1995; De Wals et al., 2005), immunologic studies have shown that Men4-DT is a more potent vaccine. For this reason, Men4-DT could be considered for routine immunization of adolescents, as recommended in the US (ACIP 2005), including those already immunized with a monovalent serogroup C conjugate vaccine or a polysaccharide vaccine at a young age. The rationale for this booster dose is to ensure that circulating antibodies are present as adolescents enter the peak years of IMD beyond infancy, which are between 15 and 25 years of age. As the incubation period of IMD is short [range 2 to 10 days, commonly 3 to 4 days (Heyman, 2004)] it is now generally accepted that circulating antibodies are necessary to prevent IMD and that the ability to mount a memory response is not sufficient to prevent disease (Auckland et al., 2006; Snape et al., 2006). As well, carriage of meningococci is highest during adolescence (Cartwright, 1995) and preventing carriage in adolescents may have an impact on herd immunity in the community, indirectly protecting infants (Trotter et al., 2005).

Safety

Vaccines containing proteins are generally associated with slightly more common and severe local reactions than polysaccharide vaccines, and Men4-DT is no exception. However, the experience of administration of Men4-DT in nine clinical trials involving more than 10 000 subjects is very reassuring and adverse events were not substantially different than those reported in the control groups vaccinated with a quadrivalent polysaccharide vaccine (Sanofi Pasteur Limited, 2006).

In the US, Menactra™ is widely used for vaccinating adolescents and college students. A cluster of cases of Guillain-Barré syndrome (GBS) was reported in the 6-week period following vaccine administration (Woo et al., 2006). To date, 19 cases of GBS have been documented, mostly in adolescents and young adults. A statistically non-significant risk of approximately one case per million doses has been calculated (NACI, 2007). GBS is an acute autoimmune inflammatory demyelinating neuropathy affecting peripheral motor and/or sensory nerves. The causal mechanisms are still poorly understood (Hahn, 1998; Hughes et al., 2005). In 1976-1977, an excess risk of GBS was identified following the administration of inactivated swine influenza vaccines (Langmuir et al., 1984). However, this association was not seen or was of borderline significance with subsequent influenza vaccine preparations (Hurwitz et al., 1981; Kaplan et al., 1982; Lasky et al. 1998; Roscelli et al., 1991; Haber et al., 2004). In a large study in the UK focusing on GBS following the administration of routine vaccines in all age groups, no association was found (Hughes et al., 2006). In the UK, more than 18 million doses of three serogroup C meningococcal vaccines were administered during the 1999-2001 mass immunization campaign and no cluster of GBS was reported through the passive surveillance system of adverse events (Committee on Safety of Medicines Expert Working Group, 2002). In the province of Quebec, a study was performed to assess the risk of GBS following the administration of a CRM197 meningococcal serogroup C conjugate vaccine in a mass immunization campaign in 2001. Immunization records were linked with hospital discharge summaries, and medical records were reviewed. In the cohort of 1.9 million individuals, the frequency of GBS during the post-vaccination period was lower than expected for all comparisons (De Wals P, Deceuninck G, Buucher RM, Ouakki M. Risk of Guillain-Barré syndrome following serogroup C meningococcal conjugate vaccine in Quebec, Canada. Clin Infect Dis, 2008 Apr 15;46(8):e75-7). An association between meningococcal conjugate C vaccines and GBS can be reasonably excluded and a causal association between Men4-DT and GBS has not been established. In the US, a precautionary statement was issued for individuals with a history of GBS, but the recommendation to vaccinate high-risk groups was not altered (Woo et al., 2006).

NACI has reviewed the data on safety of Menactra™ (Canada Communicable Disease Report (CCDR), Volume 35, Advisory Committee Statement, National Advisory Committee on Immunziation, April 2009). The main concern is about the incidence of Guillan-Barré syndrome (GBS) post immunization. The Centers for Disease Control (CDC) in the United States have also reviewed the safety of Menactra™. “CDC is unable to determine if Menactra™ increases a risk of GBS in people who receive the vaccine. GBS is a rare illness, and the expected background population rates of GBS are not known precisely. An ongoing known risk for serious meningococcal disease exists. Therefore, CDC recommends continuation of current vaccination strategies.” See GBS Facsheet.

Concomitant Vaccine Administration

Ideally, new vaccines included in publicly funded programs should be given at the same time as other vaccines to increase coverage levels and minimize administration costs. Concomitant use of Men4-DT with the adult formulation of tetanus-diphtheria (Td) vaccine was assessed and no significant negative interaction was observed (Sanofi Pasteur Limited, 2006). This was the most important association to study because of the presence of the diphteria toxoid antigen in both products. There are currently no data on the concomitant administration of Men4-DT with other vaccines currently offered to adolescents in Canada, including Tdap, hepatitis A and B, and HPV.