- Email: [email protected]
Quadrivalent meningococcal vaccines: Hyporesponsiveness as an important consideration when choosing between the use of conjugate vaccine or polysaccharide vaccine
Travel Medicine and Infectious Disease (2010) 8, 47e50
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/tmid
COMMENTARY
Quadrivalent meningococcal vaccines: Hyporesponsiveness as an important consideration when choosing between the use of conjugate vaccine or polysaccharide vaccine ¨ker*, Keith Veitch Michael Bro Novartis Vaccines and Diagnostics GmbH, Global Medical Affairs, Emil-von-Behring-Straße 76, 35041 Marburg, Germany Received 23 July 2009; received in revised form 7 December 2009; accepted 9 December 2009 Available online 8 January 2010
KEYWORDS Meningococcal vaccines; Hyporesponsiveness; Conjugate vaccine; Polysaccharide vaccine
Summary Regional variations in the incidence and the distribution of serogroups which are responsible of meningococcal disease necessitate multivalent vaccines to ensure broad coverage for travelers. For almost 30 years, this has been provided by quadrivalent polysaccharide vaccine to protect against serogroups A, C, W-135 and Y, but with the advent of quadrivalent conjugate vaccines is there still a case to use the polysaccharide? The well documented hyporesponsiveness induced by polysaccharide vaccines after repeated administration, most clearly observed against serogroup C, suggest that, where available, conjugate vaccines should always be considered ahead of polysaccharide vaccine. ª 2009 Published by Elsevier Ltd.
Introduction Meningococcal disease caused by Neisseria meningitidis, is a devastating and unpredictable disease, associated with rapid onset, and potentially severe if not fatal consequences.1 The disease-causing serogroups vary geographically and temporally,2 so travelers need to adopt a broad coverage approach to ensure protection. For example, although the African meningitis belt is associated primarily
* Corresponding author. Tel.: þ49 6421 392 912; fax: þ49 6421 394 667. E-mail address: [email protected] (M. Bro ¨ker). 1477-8939/$ - see front matter ª 2009 Published by Elsevier Ltd. doi:10.1016/j.tmaid.2009.12.001
with epidemic cycles of serogroup A disease there have been recent outbreaks of W-135 in Burkina Faso.3 Similarly, the quadrivalent meningococcal polysaccharide (MPS-4) vaccine against serogroups A, C, W-135 and Y is mandatory for Hajj and Umra pilgrims, where it has replaced the bivalent polysaccharide serogroups AC vaccine following serogroup W-135 outbreaks in Saudi Arabia in 2000/2001.4 However, meningococcal polysaccharide (MPS) vaccines have several drawbacks. Although they are immunogenic in older children, adolescents and adults, where they provide protection for 3e5 years, they have only limited immunogenicity children under 2 years of age (with the exception of serogoup A antigen). As T-cell independent antigens, they neither induce immunological memory, nor boost the
48
M. Bro ¨ker, K. Veitch
response after primary immunization and do not contribute to herd immunity. Furthermore, polysaccharide can induce the phenomenon of hyporesponsiveness, which is characterized by a diminished immune response upon repeated administration of vaccine.5 To overcome these drawbacks, quadrivalent meningococcal conjugate vaccines (MCV-4) have been developed with different carrier proteins: either diphtheria toxoid (MenACWY-D), cross-reacting material (CRM197) a natural mutant of the diphtheria toxin with one amino acid exchange (MenACWY-CRM),6 or tetanus toxoid (MenACWYT).7 These conjugate vaccines have several advantages over MPS vaccines: they induce higher levels of serum bactericidal antibodies, provide longer-lasting protection, are T-cell dependent antigens and thus are boostable, can potentially reduce the carrier rates and contribute to herd immunity. Interestingly, they do not induce hyporesponsiveness after repeated administration of vaccine. This characteristic led Granoff and Pollard in 20078 to propose that rather than administering MPS-4 to 2e10 year-old children at risk of meningococcal disease, they should receive MCV-4 off-label, before it was eventually approved for use in this age group. When Keyserling et al.9 investigated the boostability of the response in adolescents to MenACWY-D and MPS-4, they provided clear evidence of hyporesponsiveness, most notably for serogroup C. The response for serogroup C in subjects vaccinated 3 years earlier with MPS-4 was lower than in those who had previously received MenACWY-D (Figure 1), but also much lower than in subjects who received MenACWY-D as their first ever meningococcal vaccine. There were also numerically lower responses in the MPS-4 primed group for serogroups A, W-135 and Y than in the naı¨ve group. These data confirm previous reports of hyporesponsiveness to serogroup C, and the conflicting reports of this effect with the other serogroups.
Day 28 Post-Menactra Booster response MCV-4
10000
PSV-4 Naïve
8000
GMT
6000
4000
2000
0
A
C
W135
Y
Figure 1 Geometric mean titres (with 95% CI) of serum bactericidal antibodies (with baby rabbit complement) 28 days after one dose of MCV-4 in 11e18 year-olds vaccinated 3 years previously with either MCV-4 (N Z 76) or MPS-4 (N Z 77), and an age-matched vaccine-naı¨ve group (N Z 88) receiving their first dose of MCV-4. (Figure prepared based on data published by Keyserling et al. (2005)9).
Serogroup C Most of our knowledge about hyporesponsiveness induced by meningococcal polysaccharide vaccine comes from experience with serogroup C. Induction of serogroup C hyporesponsiveness by a previous dose of MPS vaccine has been observed in different age groups: in infants,10 toddlers11 and adults12,13 However, it has also been shown that group C conjugate vaccine can overcome hyporesponsiveness induced by prior dose of plain polysaccharide vaccine.12e14 Implementation of Men C conjugate vaccine into the infant and child vaccination calendar in many European countries, Canada and Australia was a great success and has reduced significantly the number of cases of serogroup C where the majority of children were vaccinated.15 It has been suggested that by first vaccinating with the Men C conjugate vaccine, a long-lasting T-cell dependent immune response would be induced, which could be boosted by vaccination with MPS-4 vaccine. Hyporesponsiveness would be avoided in the event that a traveller needed to be vaccinated again with serogroup C antigens at a later date. If the second vaccination was with MPS-4, this would enhance the antibody response against serogroup C and give short-term protection against serogroup A, Y and W-135.16 However, with the licensure of quadrivalent conjugate vaccines such a procedure should become redundant to ensure there is no potential induction of hyporesponsiveness against serogroups A, W-135 and Y.
Serogroup A There are conflicting data about hyporesponsiveness induced by serogroup A polysaccharide. In a clinical study in the Gambia,17 infants received two doses at 3 and 6 months of age of bivalent (serogroups A and C) conjugate or MPS vaccines (with a further dose at 2 years for the MPS group). At 5 years of age the MPS-primed group demonstrated hyporesponsiveness to a MPS booster, with responses only half of those observed in vaccine-naı¨ve 5 year-olds. Hyporesponsiveness against serogroup A was observed in young adults following a second dose of bivalent A/C MPS vaccine. Six months after priming, the serum bactericidal antibody response to a second dose was only one third of the original response.18 However, booster responses, rather than hyporesponsiveness, to serogroup A, have been demonstrated in young children,19 adolescents,20 and 10e29 year-old Saudi Arabian subjects.21 The reason for this difference between studies is unclear, but could be related to a number of factors, including that populations selected in the studies differed with regard to age, possible previous contact with meningococci (one study was carried out after an outbreak) and vaccines produced by different manufactures. Significantly, the project to develop an effective monovalent serogroup A vaccine for Africa is based on a conjugate vaccine, MenAfriVac (3). It remains to be seen whether the success of this vaccine is compromised by the lack of protection against serogroup W-135 and X, which have recently been the cause of outbreaks in that continent.5,22
Quadrivalent meningococcal vaccines
Serogroup W-135 and Y Prior to the Keyserling study, there were only a few data available for serogroups W-135 and Y, which have become increasingly important in recent years. In 2003, the Saudi Arabian Ministry of Health conducted an immunization campaign with MPS-4, which included an evaluation of the immune response in children under 5 years of age.23 While there was reasonable protection against serogroup A from 18 months of age, with a steady age-dependent increase in the proportion of individuals with serum bactericidal antibody titres of at least 1:8, two doses of MPS-4 in children <24 months old gave poor protection against serogroups C, W-135 and Y. Values for children 24 months of age and older were significantly higher for these three serogroups, suggesting that serogroup C, W-135 and Y polysaccharides behave differently from the serogroup A antigen. A recent study in Saudi Arabian adolescents given Men ACWY-D vaccine having previously received one dose of MPS-4 and one or more doses of biovalent A/C MPS vaccine, demonstrated hyporesponsiveness for all four serogroups. Post-vaccination serum bactericidal antibody GMTs were significantly higher in the vaccine-naı¨ve for all serogroups than in either of the MPS-primed groups. Unlike the Keyserling study, in the MPS-primed groups revaccination with conjugate resulted in significantly higher GMTs to serogroup C than revaccination with polysaccharide vaccine, when adjusting for pre-vaccination GMTs.24 Another Saudi Arabian study, in which 5e8 year-olds who had received two doses of MPS-4 when under the age of 1 year, received a dose of MenACWY-D vaccine, found no statistically significant differences in either the pre- or the post-vaccination serum bactericidal antibody GMTs between primed and vaccine-naı¨ve controls with the exception of serogroup C, which was significantly lower in the MPS-primed group.25 These data suggest that hyporesponsiveness does occur with serogroups W-135 and Y in adolescents, but in children primed under the age of 2 years, when the immune response to polysaccharides in general is weak, such an effect does not seem to occur.
Discussion The data presented above clearly demonstrates that hyporesponsiveness to serogroup C occurs in all age groups with polysaccharide vaccines, and there is increasing evidence this also occurs for the other serogroups in adolescents and adults. Although the clinical relevance of this effect is unknown, the nature of meningococcal disease, with rapid onset of a severe infection with potentially fatal consequences, suggests that circulating antibodies play a key role in protection against the disease.8 Therefore, anything which diminishes this antibody response to immunisation should be avoided. The fact that conjugate vaccines do not induce hyporesponsiveness and may even overcome to some extent the hyporesponsiveness induced by MPS vaccines suggests that when they are available conjugates should always be preferred over polysaccharide vaccines for adolescents and adults, as
49 stated by Granoff and Pollard for children.8 Furthermore, the varied and dynamic epidemiology of meningococcal disease requires that travelers are provided with the broadest coverage available, making a sound basis for the exclusive use of quadrivalent conjugate meningococcal vaccines in countries where they are licensed. MPS vaccines have been mandatory for pilgrims to the Hajj and in fact this type of vaccine was given every 3 years to the local population of Mecca, to health care workers, military and National Guard personnel and seasonal workers serving in Hajj. MCV-4 vaccine will be introduced in the Kingdom of Saudi Arabia (KSA) in time for the next Hajj, as the decision makers in KSA have assessed MCV-4 vaccine to not only have medical benefits over the MPS vaccine, but also to be more cost-effective (Mohamed Khalil, personal communication), because the routine 3-year revaccination can be omitted. They are also seeking to make MCV-4 the preferred vaccine for pilgrims from abroad to avoid possible import of meningococci by asymptomatic carriers, including possibly third party sponsorship for those pilgrims coming from less prosperous countries (Mohamed Khalil, personal communication). To conclude, while MPS vaccines have a great success in combating outbreaks of meningococcal disease, and at low cost, their long-term use is compromised by their deficiencies, in particular the potential of hyporesponsiveness. Ultimately this aspect, together with the failure to provide long-term protection and herd immunity, may mean that the cost-benefit ratio of MPS to conjugates is less in favour of the MPS vaccines than thought previously, and conjugates will replace MPS vaccines even in those underdeveloped countries where it is currently believed that they are too expensive.
Conflict of interest The authors are full-time employees of Novartis Vaccines and Diagnostics.
Acknowledgement The authors are grateful to Christopher Webster for editing the manuscript.
References 1. Ericson L, De Wals P. Complication and sequelae of meningococcal disease in Quebec, Canada, 1990e1994. Clin Infect Dis 1998;26:1159e64. 2. Harrison LH, Trotter CL, Ramsey ME. Global epidemiology of meningococcal disease. Vaccine 2009;27(Suppl. 2):B51eB63. 3. LaForce FM, Ravenscroft N, Djingarey M, Viviani S. Epidemic meningitis due to group A Neisseria meningitidis in the African meningitis belt: a persistent problem with an imminent solution. Vaccine 2009;27(Suppl. 2):B13eB19. 4. Wilder-Smith A. Meningococcal disease: risk for international travellers and vaccine strategies. Travel Med Infect Dis 2008;6: 182e6. 5. Harrison IH. Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev 2006;19:142e64. 6. Pace D, Pollard AJ, Messonier NE. Quadrivalent meningococcal conjugate vaccines. Vaccine 2009;275:830e41.
50 7. Østergaard L, Lebacq E, Poolman J, Maechler G, Boutriau D. Imunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15e25 years. Vaccine 2009;27:161e8. 8. Granoff DM, Pollard AJ. Reconsideration of the use of meningococcal polysaccharide vaccine. Pediatr Infect Dis J 2007;26: 716e22. 9. Keyserling H, Papa T, Koranyi K, et al. Safety, immunogenicity, and immune memory of a novel meningococcal (groups A, C, Y and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4) in healthy adolescents. Arch Pediatr Adolesc Med 2005;159:907e13. 10. Gold R, Lepow ML, Goldschneider I, Draper TL, Gotschlich EC. Clinical evaluation of group A and group C meningococcal polysaccharide vaccines in infants. J Clin Invest 1975;56: 1536e47. 11. MacDonald N, Halperin SA, Law BJ, Forrest B, Danzig LE, Granoff DM. Induction of immunological memory by conjugated vs plain meningococcal C polysaccharide vaccine in toddlers. J Am Assoc Am 1998;280:1685e9. 12. Richmond P, Kaczmarski E, Borrow R, et al. Meningococcal C polysaccharide vaccine induces hyporesponsiveness in adults that is overcome by conjugate vaccine. J Infect Dis 2000;181: 761e4. 13. Southern J, Deane S, Ashton L, et al. Effects of prior polysaccharide vaccination on magnitude, duration, and quality of immune responses to and safety profile of a meningococcal serogroup C tetanus toxoid conjugate vaccination in adults. Clin Diagn Lab Immunol 2004;11:1100e4. 14. MacDonald NE, Halperin SA, Law BJ, Danzig LE, Granoff DM. Can meningococcal C conjugate vaccine overcome immune hyporesponsiveness induced by previous administration of plain polysaccharide vaccine? J Am Med Assoc 2000;283: 1826e7. 15. Trotter CL, McVernon J, Ramsey ME. Optimising the use of conjugate vaccines to prevent disease caused by Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae. Vaccine 2008;26:4434e45.
M. Bro ¨ker, K. Veitch 16. Bro ¨ker M. Vaccination against meningococcal disease: which vaccine to use? J Travel Med 2002;9:168e9. 17. MacLennan J, Obaro S, Deeks J, et al. Immune response to revaccination with meningococcal A and C polysaccharides in Gambian children following repeated immunisation during early childhood. Vaccine 1999;17:3086e93. 18. Borrow R, Joseph H, Andrews N, et al. Reduced antibody response to revaccination with meningococcal serogroup A polysaccharide vaccine in adults. Vaccine 2001;19:1129e32. 19. Jokhdar H, Borrow R, Sultan A, et al. Immunologic hyporesponsiveness to serogroup C but not to serogroup A following repeated meningococcal A/C polysaccharide vaccination in Saudi Arabia. Clin Diagn Lab Imunol 2004;11:83e8. 20. Gold R, Lepow ML, Goldschneider I, Draper T, Gotschlich EC. Kinetics of antibody production to group A an group C meningococcal polysaccharide vaccine administered during the first six years of life: prospects for routine immunization of infants and children. J Infect Dis 1979;140:690e7. 21. Ka ¨yhty H, Karanko V, Peltola H, Sarna S, Ma ¨kela ¨ H. Serum antibodies to capsular polysaccharide vaccine of group A Neisseria meningitidis followed for three years in infants and children. J Clin Infect Dis 1980;142:861e8. 22. Nathan N, Rose AMC, Legros D, et al. Meningitis serogroup W135 outbreak, Burkina Faso, 2002. Emerg Infect Dis 2007;13:920e3. 23. Al Mazrou Y, Khalil M, Borrow R, et al. Serologic response to ACYW135 polysaccharide meningococcal vaccine in Saudi children under 5 years of age. Infect Immun 2005;73:2932e9. 24. Al-Mazriou Y, Khalil M, Bravo C et al. Meningococcal conjugate vs meningococal polysaccharide vaccine in Saudi Arabian adolescents previously vaccinated with multiple doses of meningococcal polysaccharide vaccine. Abstract O002. 10th Meeting of the European Monitoring Group for Meningococci (EMGM), Manchester, UK, June 17e19, 2009. 25. Khalil M, Al-Mazrou Y, Bravo C et al. Response to quadrivalent meningococcal conjugate vaccine in Saudi Arabian children who previously received 2 doses of quadrivalent meningococcal polysaccharide vaccine before 1 years of age. Abstract P008. 10th Meeting of the European Monitoring Group for Meningococci (EMGM), Manchester, UK, June 17e19, 2009.
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/tmid
COMMENTARY
Quadrivalent meningococcal vaccines: Hyporesponsiveness as an important consideration when choosing between the use of conjugate vaccine or polysaccharide vaccine ¨ker*, Keith Veitch Michael Bro Novartis Vaccines and Diagnostics GmbH, Global Medical Affairs, Emil-von-Behring-Straße 76, 35041 Marburg, Germany Received 23 July 2009; received in revised form 7 December 2009; accepted 9 December 2009 Available online 8 January 2010
KEYWORDS Meningococcal vaccines; Hyporesponsiveness; Conjugate vaccine; Polysaccharide vaccine
Summary Regional variations in the incidence and the distribution of serogroups which are responsible of meningococcal disease necessitate multivalent vaccines to ensure broad coverage for travelers. For almost 30 years, this has been provided by quadrivalent polysaccharide vaccine to protect against serogroups A, C, W-135 and Y, but with the advent of quadrivalent conjugate vaccines is there still a case to use the polysaccharide? The well documented hyporesponsiveness induced by polysaccharide vaccines after repeated administration, most clearly observed against serogroup C, suggest that, where available, conjugate vaccines should always be considered ahead of polysaccharide vaccine. ª 2009 Published by Elsevier Ltd.
Introduction Meningococcal disease caused by Neisseria meningitidis, is a devastating and unpredictable disease, associated with rapid onset, and potentially severe if not fatal consequences.1 The disease-causing serogroups vary geographically and temporally,2 so travelers need to adopt a broad coverage approach to ensure protection. For example, although the African meningitis belt is associated primarily
* Corresponding author. Tel.: þ49 6421 392 912; fax: þ49 6421 394 667. E-mail address: [email protected] (M. Bro ¨ker). 1477-8939/$ - see front matter ª 2009 Published by Elsevier Ltd. doi:10.1016/j.tmaid.2009.12.001
with epidemic cycles of serogroup A disease there have been recent outbreaks of W-135 in Burkina Faso.3 Similarly, the quadrivalent meningococcal polysaccharide (MPS-4) vaccine against serogroups A, C, W-135 and Y is mandatory for Hajj and Umra pilgrims, where it has replaced the bivalent polysaccharide serogroups AC vaccine following serogroup W-135 outbreaks in Saudi Arabia in 2000/2001.4 However, meningococcal polysaccharide (MPS) vaccines have several drawbacks. Although they are immunogenic in older children, adolescents and adults, where they provide protection for 3e5 years, they have only limited immunogenicity children under 2 years of age (with the exception of serogoup A antigen). As T-cell independent antigens, they neither induce immunological memory, nor boost the
48
M. Bro ¨ker, K. Veitch
response after primary immunization and do not contribute to herd immunity. Furthermore, polysaccharide can induce the phenomenon of hyporesponsiveness, which is characterized by a diminished immune response upon repeated administration of vaccine.5 To overcome these drawbacks, quadrivalent meningococcal conjugate vaccines (MCV-4) have been developed with different carrier proteins: either diphtheria toxoid (MenACWY-D), cross-reacting material (CRM197) a natural mutant of the diphtheria toxin with one amino acid exchange (MenACWY-CRM),6 or tetanus toxoid (MenACWYT).7 These conjugate vaccines have several advantages over MPS vaccines: they induce higher levels of serum bactericidal antibodies, provide longer-lasting protection, are T-cell dependent antigens and thus are boostable, can potentially reduce the carrier rates and contribute to herd immunity. Interestingly, they do not induce hyporesponsiveness after repeated administration of vaccine. This characteristic led Granoff and Pollard in 20078 to propose that rather than administering MPS-4 to 2e10 year-old children at risk of meningococcal disease, they should receive MCV-4 off-label, before it was eventually approved for use in this age group. When Keyserling et al.9 investigated the boostability of the response in adolescents to MenACWY-D and MPS-4, they provided clear evidence of hyporesponsiveness, most notably for serogroup C. The response for serogroup C in subjects vaccinated 3 years earlier with MPS-4 was lower than in those who had previously received MenACWY-D (Figure 1), but also much lower than in subjects who received MenACWY-D as their first ever meningococcal vaccine. There were also numerically lower responses in the MPS-4 primed group for serogroups A, W-135 and Y than in the naı¨ve group. These data confirm previous reports of hyporesponsiveness to serogroup C, and the conflicting reports of this effect with the other serogroups.
Day 28 Post-Menactra Booster response MCV-4
10000
PSV-4 Naïve
8000
GMT
6000
4000
2000
0
A
C
W135
Y
Figure 1 Geometric mean titres (with 95% CI) of serum bactericidal antibodies (with baby rabbit complement) 28 days after one dose of MCV-4 in 11e18 year-olds vaccinated 3 years previously with either MCV-4 (N Z 76) or MPS-4 (N Z 77), and an age-matched vaccine-naı¨ve group (N Z 88) receiving their first dose of MCV-4. (Figure prepared based on data published by Keyserling et al. (2005)9).
Serogroup C Most of our knowledge about hyporesponsiveness induced by meningococcal polysaccharide vaccine comes from experience with serogroup C. Induction of serogroup C hyporesponsiveness by a previous dose of MPS vaccine has been observed in different age groups: in infants,10 toddlers11 and adults12,13 However, it has also been shown that group C conjugate vaccine can overcome hyporesponsiveness induced by prior dose of plain polysaccharide vaccine.12e14 Implementation of Men C conjugate vaccine into the infant and child vaccination calendar in many European countries, Canada and Australia was a great success and has reduced significantly the number of cases of serogroup C where the majority of children were vaccinated.15 It has been suggested that by first vaccinating with the Men C conjugate vaccine, a long-lasting T-cell dependent immune response would be induced, which could be boosted by vaccination with MPS-4 vaccine. Hyporesponsiveness would be avoided in the event that a traveller needed to be vaccinated again with serogroup C antigens at a later date. If the second vaccination was with MPS-4, this would enhance the antibody response against serogroup C and give short-term protection against serogroup A, Y and W-135.16 However, with the licensure of quadrivalent conjugate vaccines such a procedure should become redundant to ensure there is no potential induction of hyporesponsiveness against serogroups A, W-135 and Y.
Serogroup A There are conflicting data about hyporesponsiveness induced by serogroup A polysaccharide. In a clinical study in the Gambia,17 infants received two doses at 3 and 6 months of age of bivalent (serogroups A and C) conjugate or MPS vaccines (with a further dose at 2 years for the MPS group). At 5 years of age the MPS-primed group demonstrated hyporesponsiveness to a MPS booster, with responses only half of those observed in vaccine-naı¨ve 5 year-olds. Hyporesponsiveness against serogroup A was observed in young adults following a second dose of bivalent A/C MPS vaccine. Six months after priming, the serum bactericidal antibody response to a second dose was only one third of the original response.18 However, booster responses, rather than hyporesponsiveness, to serogroup A, have been demonstrated in young children,19 adolescents,20 and 10e29 year-old Saudi Arabian subjects.21 The reason for this difference between studies is unclear, but could be related to a number of factors, including that populations selected in the studies differed with regard to age, possible previous contact with meningococci (one study was carried out after an outbreak) and vaccines produced by different manufactures. Significantly, the project to develop an effective monovalent serogroup A vaccine for Africa is based on a conjugate vaccine, MenAfriVac (3). It remains to be seen whether the success of this vaccine is compromised by the lack of protection against serogroup W-135 and X, which have recently been the cause of outbreaks in that continent.5,22
Quadrivalent meningococcal vaccines
Serogroup W-135 and Y Prior to the Keyserling study, there were only a few data available for serogroups W-135 and Y, which have become increasingly important in recent years. In 2003, the Saudi Arabian Ministry of Health conducted an immunization campaign with MPS-4, which included an evaluation of the immune response in children under 5 years of age.23 While there was reasonable protection against serogroup A from 18 months of age, with a steady age-dependent increase in the proportion of individuals with serum bactericidal antibody titres of at least 1:8, two doses of MPS-4 in children <24 months old gave poor protection against serogroups C, W-135 and Y. Values for children 24 months of age and older were significantly higher for these three serogroups, suggesting that serogroup C, W-135 and Y polysaccharides behave differently from the serogroup A antigen. A recent study in Saudi Arabian adolescents given Men ACWY-D vaccine having previously received one dose of MPS-4 and one or more doses of biovalent A/C MPS vaccine, demonstrated hyporesponsiveness for all four serogroups. Post-vaccination serum bactericidal antibody GMTs were significantly higher in the vaccine-naı¨ve for all serogroups than in either of the MPS-primed groups. Unlike the Keyserling study, in the MPS-primed groups revaccination with conjugate resulted in significantly higher GMTs to serogroup C than revaccination with polysaccharide vaccine, when adjusting for pre-vaccination GMTs.24 Another Saudi Arabian study, in which 5e8 year-olds who had received two doses of MPS-4 when under the age of 1 year, received a dose of MenACWY-D vaccine, found no statistically significant differences in either the pre- or the post-vaccination serum bactericidal antibody GMTs between primed and vaccine-naı¨ve controls with the exception of serogroup C, which was significantly lower in the MPS-primed group.25 These data suggest that hyporesponsiveness does occur with serogroups W-135 and Y in adolescents, but in children primed under the age of 2 years, when the immune response to polysaccharides in general is weak, such an effect does not seem to occur.
Discussion The data presented above clearly demonstrates that hyporesponsiveness to serogroup C occurs in all age groups with polysaccharide vaccines, and there is increasing evidence this also occurs for the other serogroups in adolescents and adults. Although the clinical relevance of this effect is unknown, the nature of meningococcal disease, with rapid onset of a severe infection with potentially fatal consequences, suggests that circulating antibodies play a key role in protection against the disease.8 Therefore, anything which diminishes this antibody response to immunisation should be avoided. The fact that conjugate vaccines do not induce hyporesponsiveness and may even overcome to some extent the hyporesponsiveness induced by MPS vaccines suggests that when they are available conjugates should always be preferred over polysaccharide vaccines for adolescents and adults, as
49 stated by Granoff and Pollard for children.8 Furthermore, the varied and dynamic epidemiology of meningococcal disease requires that travelers are provided with the broadest coverage available, making a sound basis for the exclusive use of quadrivalent conjugate meningococcal vaccines in countries where they are licensed. MPS vaccines have been mandatory for pilgrims to the Hajj and in fact this type of vaccine was given every 3 years to the local population of Mecca, to health care workers, military and National Guard personnel and seasonal workers serving in Hajj. MCV-4 vaccine will be introduced in the Kingdom of Saudi Arabia (KSA) in time for the next Hajj, as the decision makers in KSA have assessed MCV-4 vaccine to not only have medical benefits over the MPS vaccine, but also to be more cost-effective (Mohamed Khalil, personal communication), because the routine 3-year revaccination can be omitted. They are also seeking to make MCV-4 the preferred vaccine for pilgrims from abroad to avoid possible import of meningococci by asymptomatic carriers, including possibly third party sponsorship for those pilgrims coming from less prosperous countries (Mohamed Khalil, personal communication). To conclude, while MPS vaccines have a great success in combating outbreaks of meningococcal disease, and at low cost, their long-term use is compromised by their deficiencies, in particular the potential of hyporesponsiveness. Ultimately this aspect, together with the failure to provide long-term protection and herd immunity, may mean that the cost-benefit ratio of MPS to conjugates is less in favour of the MPS vaccines than thought previously, and conjugates will replace MPS vaccines even in those underdeveloped countries where it is currently believed that they are too expensive.
Conflict of interest The authors are full-time employees of Novartis Vaccines and Diagnostics.
Acknowledgement The authors are grateful to Christopher Webster for editing the manuscript.
References 1. Ericson L, De Wals P. Complication and sequelae of meningococcal disease in Quebec, Canada, 1990e1994. Clin Infect Dis 1998;26:1159e64. 2. Harrison LH, Trotter CL, Ramsey ME. Global epidemiology of meningococcal disease. Vaccine 2009;27(Suppl. 2):B51eB63. 3. LaForce FM, Ravenscroft N, Djingarey M, Viviani S. Epidemic meningitis due to group A Neisseria meningitidis in the African meningitis belt: a persistent problem with an imminent solution. Vaccine 2009;27(Suppl. 2):B13eB19. 4. Wilder-Smith A. Meningococcal disease: risk for international travellers and vaccine strategies. Travel Med Infect Dis 2008;6: 182e6. 5. Harrison IH. Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev 2006;19:142e64. 6. Pace D, Pollard AJ, Messonier NE. Quadrivalent meningococcal conjugate vaccines. Vaccine 2009;275:830e41.
50 7. Østergaard L, Lebacq E, Poolman J, Maechler G, Boutriau D. Imunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15e25 years. Vaccine 2009;27:161e8. 8. Granoff DM, Pollard AJ. Reconsideration of the use of meningococcal polysaccharide vaccine. Pediatr Infect Dis J 2007;26: 716e22. 9. Keyserling H, Papa T, Koranyi K, et al. Safety, immunogenicity, and immune memory of a novel meningococcal (groups A, C, Y and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4) in healthy adolescents. Arch Pediatr Adolesc Med 2005;159:907e13. 10. Gold R, Lepow ML, Goldschneider I, Draper TL, Gotschlich EC. Clinical evaluation of group A and group C meningococcal polysaccharide vaccines in infants. J Clin Invest 1975;56: 1536e47. 11. MacDonald N, Halperin SA, Law BJ, Forrest B, Danzig LE, Granoff DM. Induction of immunological memory by conjugated vs plain meningococcal C polysaccharide vaccine in toddlers. J Am Assoc Am 1998;280:1685e9. 12. Richmond P, Kaczmarski E, Borrow R, et al. Meningococcal C polysaccharide vaccine induces hyporesponsiveness in adults that is overcome by conjugate vaccine. J Infect Dis 2000;181: 761e4. 13. Southern J, Deane S, Ashton L, et al. Effects of prior polysaccharide vaccination on magnitude, duration, and quality of immune responses to and safety profile of a meningococcal serogroup C tetanus toxoid conjugate vaccination in adults. Clin Diagn Lab Immunol 2004;11:1100e4. 14. MacDonald NE, Halperin SA, Law BJ, Danzig LE, Granoff DM. Can meningococcal C conjugate vaccine overcome immune hyporesponsiveness induced by previous administration of plain polysaccharide vaccine? J Am Med Assoc 2000;283: 1826e7. 15. Trotter CL, McVernon J, Ramsey ME. Optimising the use of conjugate vaccines to prevent disease caused by Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae. Vaccine 2008;26:4434e45.
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