Comment
The prevalence of acute bacterial meningitis and septicaemia due to Haemophilus influenzae b (Hib), Streptococcus pneumoniae, and Neisseria meningitidis has greatly decreased in Europe and North America since the successful introduction of capsular polysaccharide conjugate vaccines targeting Hib, serogroup C (and ACWY in the USA) meningococci, and S pneumoniae. Incidence of meningitis due to N meningitidis serogroup A has also decreased in sub-Saharan Africa since the introduction of the meningococcal serogroup A conjugate vaccine (MenAfriVac).1 A key point in the success of conjugate vaccines is that not only can they prevent disease directly, but they can also reduce carriage of these bacteria, and thereby provide indirect protection in unvaccinated people.2 Further reduction of the burden of these diseases can be achieved by development and implementation of vaccines against serogroup B meningococci, additional S pneumoniae serotypes (or a universal pneumococcal vaccine), and a serogroup B streptococcal vaccine (for newborn babies). N meningitidis serogroup B is now the most common cause of meningitis in children in Europe.3 Capsular polysaccharide from N meningitidis serogroup B is poorly immunogenic because its homology to neural cell adhesion molecules prevents development of capsular-based vaccines.4 The licensing of a multicomponent protein-based vaccine (4CMenB, Bexsero) against meningococci of serogroup B in December, 2013, crowned a period of pioneering research in reverse vaccinology.5 This vaccine is expected to be effective against 78% of cases of N meningitidis serogroup B in Europe,6 creating the opportunity for tailoring of national European recommendations. The UK Joint Committee on Vaccination and Immunisation recommended vaccination in infants with a schedule of two plus one (two doses, one at 2 months and one at 4 months, and a booster at 12 months).7 In France, the technical committee for vaccination recommended the vaccine for at-risk individuals and for outbreak control.8 Both committees emphasised the need to understand the effect of the vaccine on carriage of meningococci to assess potential herd immunity. In The Lancet, Robert Read and colleagues9 report a phase 3, observer-blind, randomised controlled trial
that assessed the effects on carriage of meningococci in nearly 3000 students (aged 18–24 years) at 10 university sites in England who received two doses of 4CMenB, one dose of MenACWY-CRM plus one dose of placebo, or two doses of Japanese encephalitis virus vaccine (control vaccine) in a 1:1:1 ratio, followed-up for 12 months. By 1 month, no significant difference was recorded in carriage between controls and people in the 4CMenB or MenACWY-CRM groups. However, from 3 months, a significant reduction in carriage of isolates of serogroups CWY was recorded in the MenACWY-CRM group (36·2%, Odds Ratio 0·6, 95% CI 0·5–0·8) compared with the control group. This reduction was higher for CWY capsule-producing isolates than it was when all CWY isolates were considered on the sole basis of harbouring the CWY genes, irrespective of detectable production of the capsule. This observation is explained by the fact that MenACWY-CRM vaccine efficiently targets the CWY isolates when the capsule is expressed on the bacterial surface. One could argue that vaccinated people mount an immune response that then affects acquisition of these bacteria, rather than carriage clearance. Similar observations were also seen in the 4CMenB group 3 months after completion of vaccination. However, there was a reduction in carriage of all meningococcal isolates (BCWY) irrespective of their serogroups. No significant difference in carriage prevalence was noted between the 4CMenB and control groups for all B isolates or disease-associated sequence types of B isolates. The effect of the vaccine on all meningococci is not surprising, because the 4CMenB vaccine does not target the capsular polysaccharides and is directed against proteins that are present in meningococcal isolates independently from their serogroups. It is noteworthy that the effect of 4CMenB and MenACWY-CRM vaccines on carriage isolates was most pronounced against serogroup Y isolates. Whether this indicated the relatively high incidence of serogroup Y carriage, especially in first-year students during the study period, remains to be explored. The 4CMenB vaccine was predicted to be effective against serogroup B meningococci, if the isolates produced at least one of the vaccine components at a similar or higher concentration than a threshold that
www.thelancet.com Published online August 19, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60935-1
Science Photo Library
Meningococcal carriage: the dilemma of 4CMenB vaccine
Published Online August 19, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60935-1 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)60842-4
1
Comment
is correlated with, and required for, the bactericidal protective activities of antibodies.6,10 This might also be true for isolates of other serogroups, as has been suggested for serogroup X isolates,11 and outer membrane vesicle-based vaccines might reduce carriage of all meningococcal isolates.12 These observations would explain the expected effect of the vaccine on carriage isolates across all serogroups. The results of Read and colleagues’ trial might suggest that carriage reduction is small; however, the reduction of carriage in vivo should consider the reproduction number for meningococci. If the reproduction number (the average number of secondary infections produced by an infected individual) that was reported for serogroup C (1·36)13 is the same for serogroup B, the slight effect of 4CMenB on carriage might be translated into significant herd immunity, as has been shown in the introduction of the conjugate vaccine against serogroup C meningococci.2 However, the 4CMenB vaccine was licensed against serogroup B, for which no significant effect on carriage was detected.9 It is therefore unclear how to infer the potential herd immunity afforded by the vaccine if only meningococcal B disease is considered. One possibility is to try to match MenB carriage isolates with the vaccine components as is presently done for invasive isolates.6 Measurement of the expression of vaccine antigens in MenB carriage isolates (using the Meningococcal Antigen Typing System) in correlation with bactericidal titres would be helpful, and might provide evidence of local immune response in the nasopharynx. Comprehensive disease surveillance must be maintained to monitor the efficacy of the 4CMenB vaccine. A community survey on the implementation of vaccination should enable measurement of the reduction of meningococcal carriage.
2
*Muhamed-Kheir Taha, Ala-Eddine Deghmane Unit of Invasive Bacterial Infections and National Reference Center for Meningococci, Institut Pasteur, 75724 Paris Cedex 15, France [email protected] M-KT has consulted for and received travel support from GlaxoSmithKline, Novartis, Pfizer, and Sanofi Pasteur, and has done contract research for Novartis, Pfizer, and Sanofi Pasteur. A-ED declares no competing interests. 1
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Marc LaForce F, 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): B13–19. Maiden MC, Stuart JM. Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination. Lancet 2002; 359: 1829–31. European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe 2008/2009. Stockholm: ECDC, 2011. Eckhardt M, Muhlenhoff M, Bethe A, Koopman J, Frosch M, Gerardy-Schahn R. Molecular characterization of eukaryotic polysialyltransferase-1. Nature 1995; 373: 715–18. Bambini S, Rappuoli R. The use of genomics in microbial vaccine development. Drug Discov Today 2009; 14: 252–60. Vogel U, Taha MK, Vazquez JA, et al. Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis 2013; 13: 416–25. Wise J. Meningitis B vaccine to be introduced in UK after U turn on its cost effectiveness. BMJ 2014; 348: g2327. French High Council for Public Health. The place of the Bexsero vaccine in the vaccination against invasive meningococcal infections due to serogroup B (in French). Dec 11, 2013. http://www.hcsp.fr/explore.cgi/ avisrapportsdomaine?clefr=386 (accessed Aug 14, 2014). Read RC, Baxter D, Chadwick DR, et al. Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial. Lancet 2014; published online Aug 19. http://dx.doi.org/ 10.1016/S0140-6736(14)60842-4. Donnelly J, Medini D, Boccadifuoco G, et al. Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines. Proc Natl Acad Sci USA 2010; 107: 19490–95. Hong E, Giuliani MM, Deghmane AE, et al. Could the multicomponent meningococcal serogroup B vaccine (4CMenB) control Neisseria meningitidis capsular group X outbreaks in Africa? Vaccine 2013; 31: 1113–16. Delbos V, Lemee L, Benichou J, et al. Impact of MenBvac, an outer membrane vesicle (OMV) vaccine, on the meningococcal carriage. Vaccine 2013; 31: 4416–20. Trotter CL, Gay NJ, Edmunds WJ. Dynamic models of meningococcal carriage, disease, and the impact of serogroup C conjugate vaccination. Am J Epidemiol 2005; 162: 89–100.
www.thelancet.com Published online August 19, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60935-1
The prevalence of acute bacterial meningitis and septicaemia due to Haemophilus influenzae b (Hib), Streptococcus pneumoniae, and Neisseria meningitidis has greatly decreased in Europe and North America since the successful introduction of capsular polysaccharide conjugate vaccines targeting Hib, serogroup C (and ACWY in the USA) meningococci, and S pneumoniae. Incidence of meningitis due to N meningitidis serogroup A has also decreased in sub-Saharan Africa since the introduction of the meningococcal serogroup A conjugate vaccine (MenAfriVac).1 A key point in the success of conjugate vaccines is that not only can they prevent disease directly, but they can also reduce carriage of these bacteria, and thereby provide indirect protection in unvaccinated people.2 Further reduction of the burden of these diseases can be achieved by development and implementation of vaccines against serogroup B meningococci, additional S pneumoniae serotypes (or a universal pneumococcal vaccine), and a serogroup B streptococcal vaccine (for newborn babies). N meningitidis serogroup B is now the most common cause of meningitis in children in Europe.3 Capsular polysaccharide from N meningitidis serogroup B is poorly immunogenic because its homology to neural cell adhesion molecules prevents development of capsular-based vaccines.4 The licensing of a multicomponent protein-based vaccine (4CMenB, Bexsero) against meningococci of serogroup B in December, 2013, crowned a period of pioneering research in reverse vaccinology.5 This vaccine is expected to be effective against 78% of cases of N meningitidis serogroup B in Europe,6 creating the opportunity for tailoring of national European recommendations. The UK Joint Committee on Vaccination and Immunisation recommended vaccination in infants with a schedule of two plus one (two doses, one at 2 months and one at 4 months, and a booster at 12 months).7 In France, the technical committee for vaccination recommended the vaccine for at-risk individuals and for outbreak control.8 Both committees emphasised the need to understand the effect of the vaccine on carriage of meningococci to assess potential herd immunity. In The Lancet, Robert Read and colleagues9 report a phase 3, observer-blind, randomised controlled trial
that assessed the effects on carriage of meningococci in nearly 3000 students (aged 18–24 years) at 10 university sites in England who received two doses of 4CMenB, one dose of MenACWY-CRM plus one dose of placebo, or two doses of Japanese encephalitis virus vaccine (control vaccine) in a 1:1:1 ratio, followed-up for 12 months. By 1 month, no significant difference was recorded in carriage between controls and people in the 4CMenB or MenACWY-CRM groups. However, from 3 months, a significant reduction in carriage of isolates of serogroups CWY was recorded in the MenACWY-CRM group (36·2%, Odds Ratio 0·6, 95% CI 0·5–0·8) compared with the control group. This reduction was higher for CWY capsule-producing isolates than it was when all CWY isolates were considered on the sole basis of harbouring the CWY genes, irrespective of detectable production of the capsule. This observation is explained by the fact that MenACWY-CRM vaccine efficiently targets the CWY isolates when the capsule is expressed on the bacterial surface. One could argue that vaccinated people mount an immune response that then affects acquisition of these bacteria, rather than carriage clearance. Similar observations were also seen in the 4CMenB group 3 months after completion of vaccination. However, there was a reduction in carriage of all meningococcal isolates (BCWY) irrespective of their serogroups. No significant difference in carriage prevalence was noted between the 4CMenB and control groups for all B isolates or disease-associated sequence types of B isolates. The effect of the vaccine on all meningococci is not surprising, because the 4CMenB vaccine does not target the capsular polysaccharides and is directed against proteins that are present in meningococcal isolates independently from their serogroups. It is noteworthy that the effect of 4CMenB and MenACWY-CRM vaccines on carriage isolates was most pronounced against serogroup Y isolates. Whether this indicated the relatively high incidence of serogroup Y carriage, especially in first-year students during the study period, remains to be explored. The 4CMenB vaccine was predicted to be effective against serogroup B meningococci, if the isolates produced at least one of the vaccine components at a similar or higher concentration than a threshold that
www.thelancet.com Published online August 19, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60935-1
Science Photo Library
Meningococcal carriage: the dilemma of 4CMenB vaccine
Published Online August 19, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60935-1 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)60842-4
1
Comment
is correlated with, and required for, the bactericidal protective activities of antibodies.6,10 This might also be true for isolates of other serogroups, as has been suggested for serogroup X isolates,11 and outer membrane vesicle-based vaccines might reduce carriage of all meningococcal isolates.12 These observations would explain the expected effect of the vaccine on carriage isolates across all serogroups. The results of Read and colleagues’ trial might suggest that carriage reduction is small; however, the reduction of carriage in vivo should consider the reproduction number for meningococci. If the reproduction number (the average number of secondary infections produced by an infected individual) that was reported for serogroup C (1·36)13 is the same for serogroup B, the slight effect of 4CMenB on carriage might be translated into significant herd immunity, as has been shown in the introduction of the conjugate vaccine against serogroup C meningococci.2 However, the 4CMenB vaccine was licensed against serogroup B, for which no significant effect on carriage was detected.9 It is therefore unclear how to infer the potential herd immunity afforded by the vaccine if only meningococcal B disease is considered. One possibility is to try to match MenB carriage isolates with the vaccine components as is presently done for invasive isolates.6 Measurement of the expression of vaccine antigens in MenB carriage isolates (using the Meningococcal Antigen Typing System) in correlation with bactericidal titres would be helpful, and might provide evidence of local immune response in the nasopharynx. Comprehensive disease surveillance must be maintained to monitor the efficacy of the 4CMenB vaccine. A community survey on the implementation of vaccination should enable measurement of the reduction of meningococcal carriage.
2
*Muhamed-Kheir Taha, Ala-Eddine Deghmane Unit of Invasive Bacterial Infections and National Reference Center for Meningococci, Institut Pasteur, 75724 Paris Cedex 15, France [email protected] M-KT has consulted for and received travel support from GlaxoSmithKline, Novartis, Pfizer, and Sanofi Pasteur, and has done contract research for Novartis, Pfizer, and Sanofi Pasteur. A-ED declares no competing interests. 1
2
3 4
5 6
7 8
9
10
11
12
13
Marc LaForce F, 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): B13–19. Maiden MC, Stuart JM. Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination. Lancet 2002; 359: 1829–31. European Centre for Disease Prevention and Control. Surveillance of invasive bacterial diseases in Europe 2008/2009. Stockholm: ECDC, 2011. Eckhardt M, Muhlenhoff M, Bethe A, Koopman J, Frosch M, Gerardy-Schahn R. Molecular characterization of eukaryotic polysialyltransferase-1. Nature 1995; 373: 715–18. Bambini S, Rappuoli R. The use of genomics in microbial vaccine development. Drug Discov Today 2009; 14: 252–60. Vogel U, Taha MK, Vazquez JA, et al. Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis 2013; 13: 416–25. Wise J. Meningitis B vaccine to be introduced in UK after U turn on its cost effectiveness. BMJ 2014; 348: g2327. French High Council for Public Health. The place of the Bexsero vaccine in the vaccination against invasive meningococcal infections due to serogroup B (in French). Dec 11, 2013. http://www.hcsp.fr/explore.cgi/ avisrapportsdomaine?clefr=386 (accessed Aug 14, 2014). Read RC, Baxter D, Chadwick DR, et al. Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial. Lancet 2014; published online Aug 19. http://dx.doi.org/ 10.1016/S0140-6736(14)60842-4. Donnelly J, Medini D, Boccadifuoco G, et al. Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines. Proc Natl Acad Sci USA 2010; 107: 19490–95. Hong E, Giuliani MM, Deghmane AE, et al. Could the multicomponent meningococcal serogroup B vaccine (4CMenB) control Neisseria meningitidis capsular group X outbreaks in Africa? Vaccine 2013; 31: 1113–16. Delbos V, Lemee L, Benichou J, et al. Impact of MenBvac, an outer membrane vesicle (OMV) vaccine, on the meningococcal carriage. Vaccine 2013; 31: 4416–20. Trotter CL, Gay NJ, Edmunds WJ. Dynamic models of meningococcal carriage, disease, and the impact of serogroup C conjugate vaccination. Am J Epidemiol 2005; 162: 89–100.
www.thelancet.com Published online August 19, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60935-1
