Comment
In the past two decades, meningitis and septicaemia caused by capsular group B Neisseria meningitidis have been responsible for more deaths and severe sequelae among previously healthy young children in the UK than any other infectious disease. The disease poses a particular challenge for frontline medical staff because it is rare (there are about 600–1400 cases per year in England and Wales1) and the early stages of the disease are indistinguishable from the large number of cases of minor viral infections that present to primary care and emergency services. Management of sequelae, such as neurological injury and limb amputations, place a large burden on health systems2 and the disease is much feared by parents of young children. For these reasons, prevention of disease caused by capsular group B meningococcus has been a public health priority for many years. The development of a vaccine, however, has been difficult because the disease is caused by antigenically diverse strains of capsular group B meningococcus. In January, 2013, the European Medicines Agency licensed a novel four-component meningococcal serogroup B vaccine, 4CMenB (licensed as Bexsero, Novartis Vaccines and Diagnostics, Siena, Italy) after a careful review of safety and immunogenicity data from clinical trials.3–5 According to in-vitro studies, 4CMenB might cover up to 88% of strains of capsular group B meningococcus currently circulating in the UK.6 In 2011, the UK Joint Committee on Vaccination and Immunisation (JCVI), a statutory body constituted to provide independent expert scientific advice to the Department of Health, England, began a careful review of the available clinical and laboratory data pertaining to 4CMenB. According to the National Health Service (NHS) constitution,7 the JCVI can recommend adoption of new vaccines only if the programme is found to be costeffective. To avoid redirection of NHS resources from other more cost-effective interventions, the JCVI’s deliberations included an analysis from the NHS perspective8 of the estimated cost per quality-adjusted life-year averted by 4CMenB. To ensure that all health-care interventions are treated equitably, this analysis followed the guidance of the National Institute for Health and Care Excellence (NICE), adapted for immunisation programmes.9 Despite the JCVI’s view that there was strong evidence that the vaccine could prevent some of the burden of www.thelancet.com Vol 383 March 29, 2014
disease caused by capsular group B meningococcus, the decision was complicated by uncertainty about various assumptions that were key to the overall costeffectiveness of a programme. These assumptions included uncertain knowledge of: the most plausible annual number of cases of meningococcal disease (given historic variations in incidence); the proportion of cases with different types of complications, and their shortterm and long-term effect on quality of life; the actual level and duration of protection from vaccination (in the absence of pre-licensure efficacy trials); the longterm strain coverage; the number of doses of vaccines required; and the potential of the vaccine to induce herd immunity, and thus reduce additional cases beyond those in vaccinees themselves. The complexity and difficulty of the review of the cost-effectiveness of 4CMenB has been unprecedented and attracted considerable attention.10,11 In July, 2013, on the basis of the best evidence available at that time, the JCVI produced an interim statement which found that 4CMenB would not be cost-effective in an infant vaccination programme at any price.12 However, in view of the concerns of JCVI members about the uncertainty around the cost-effectiveness model inputs (parameters such as effectiveness, herd immunity, among others that affect the costs and savings to the NHS), the JCVI requested a stakeholder consultation to identify additional information that could improve the robustness of the model. There was a good response and, in October, 2013, the JCVI asked for the cost-effectiveness analysis to be repeated with additional information and amended assumptions, as permitted within NICE guidance.13 In addition, the Department of Health was asked to commission an independent review of the model’s inputs. The JCVI reviewed these analyses during a 2-day meeting in February, 2014, and examined the new cost-effectiveness model for 4CMenB and a range of alternative scenarios.14 The JCVI and the independent economic group agreed that the chosen model parameters were plausible. Various sensitivity analyses were also done to investigate the robustness of the model to the remaining uncertainty, according to previously agreed upon criteria. The JCVI’s assessment showed that 4CMenB would not be cost-effective for the NHS at the current UK list-price for any age group. However, in line with the approach for other
Life in View/Science Photo Library
Group B meningococcal vaccine: recommendations for UK use
Published Online March 21, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60226-9
1103
Comment
new vaccines, the JCVI can consider recommending a programme subject to the ability to procure vaccines at a cost-effective price. The highest burden of meningococcal disease is in infants and the JCVI found that an infant 4CMenB vaccination programme could be cost-effective for this age group in a four-dose schedule (at age 2, 3, 4, and 12 months), but only if the vaccine price was very low. However, the JCVI had considered evidence that an abbreviated schedule was likely to be sufficiently immunogenic and, therefore, concluded that cost-effectiveness could be improved by using a three-dose schedule (at age 2, 4, and 12 months). The JCVI also noted that herd immunity against capsular group C N meningitidis infection in the UK is excellent, and will be further strengthened by the introduction of the capsular group C meningococcal vaccine programme for adolescents in 2014,15 and that 4CMenB could cover some strains of capsular group C meningococcus. Removing the dose of meningococcal C vaccine at age 3 months, a schedule successfully used in other countries, would reduce the financial burden of an infant immunisation programme using 4CMenB.14 The JCVI also found that in some scenarios adolescent vaccination with 4CMenB was cost-effective. However, the burden of disease caused by capsular group B meningococcus is low in teenagers, and so the costeffectiveness of adolescent vaccination would be highly dependent on the vaccine inducing long-term protection against disease in vaccinees and carriage of strains of capsular group B meningococcus, a characteristic which is highly uncertain. The JCVI advised that further evidence should be accumulated about the effect of 4CMenB on carriage before a recommendation on an adolescent programme could be further considered.14 On the basis of these considerations the JCVI therefore recommended that the Department of Health plan to implement a 2, 4, and 12 month (2+1) infant immunisation programme with 4CMenB, subject to procurement at a cost-effective price, and also advised the removal of the 3-month dose of capsular group C meningococcal vaccine subject to the effective implementation of the group C meningococcal adolescent booster programme.14 This programme has the potential to reduce the burden of meningococcal disease among those at greatest risk and to therefore protect the health of UK children. 1104
*Andrew J Pollard, Andrew Riordan, Mary Ramsay Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK (AJP); Alder Hey Children’s NHS Foundation, Liverpool, UK (AR); and Immunisation, Hepatitis and Blood Safety Department, Public Health England, London, UK (MR) [email protected] AJP is Chair of the Joint Committee on Vaccination and Immunisation (JCVI). AR is Chair of the Meningococcal Subcommittee of the JCVI and was Acting Chair (2013) of the JCVI. MR is Head of Public Health England’s Immunisation, Hepatitis and Blood Safety Department. AJP has conducted clinical trials of capsular group B meningococcal vaccines on behalf of Oxford University funded by the Wellcome Trust, Novartis Vaccines, and Pfizer, but has no personal pecuniary or other interests with any vaccine manufacturer. AR was lead editor for a Royal College of Paediatrics and Child Health eLearning package which was sponsored by Novartis. MR declares that she has no competing interests. 1
2
3
4
5
6
7
8
9
10 11 12
13
14
15
Health Protection Agency. Invasive meningococcal infections laboratory reports, England and Wales by capsular group and epidemiological year, 1998–2012. Sept 14, 2012. http://www.hpa.org.uk/webc/HPAwebFile/ HPAweb_C/1317136087786 (accessed March 2, 2014). Viner RM, Booy R, Johnson H, et al. Outcomes of invasive meningococcal serogroup B disease in children and adolescents (MOSAIC): a case-control study. Lancet Neurol 2012; 11: 774–83. Vesikari T, Esposito S, Prymula R, et al. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. Lancet 2013; 381: 825–35. Gossger N, Snape MD, Yu LM, et al. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA 2012; 307: 573–82. Santolaya ME, O’Ryan ML, Valenzuela MT, et al. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observerblind, placebo-controlled study. Lancet 2012; 379: 617–24. Frosi G, Biolchi A, Lo Sapio M, et al. Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage. Vaccine 2013; 31: 4968–74. Department of Health. NHS Constitution for England. 2013. https://www. gov.uk/government/publications/the-nhs-constitution-for-england (accessed March 3, 2014). Christensen H, Hickman M, Edmunds WJ, Trotter CL. Introducing vaccination against serogroup B meningococcal disease: an economic and mathematical modelling study of potential impact. Vaccine 2013; 31: 2638–46. Joint Committee on Vaccination and Immunisation. Code of Practice June 2013. 2013. https://www.gov.uk/government/uploads/system/uploads/ attachment_data/file/224864/JCVI_Code_of_Practice_revision_2013_-_ final.pdf (accessed March 18, 2014). Moxon R, Snape MD. The price of prevention: what now for immunisation against meningococcus B? Lancet 2013; 382: 369–70. Mekalanos JJ. Vaccine economics: what price human life? Sci Transl Med 2013; 5: 204ed16. Joint Committee on Vaccination and Immunisation. JCVI interim position statement on the use of Bexsero meningococcal B vaccine in the UK, July, 2013. London: Department of Health, 2013. https://www.gov.uk/ government/publications/jcvi-interim-position-statement-on-the-use-ofbexsero-meningococcal-b-vaccine-in-the-uk (accessed March 2, 2014). Joint Committee on Vaccination and Immunisation. Minute of the meeting on Wednesday 2 October 2013. 2013. https://www.gov.uk/government/ policy-advisory-groups/joint-committee-on-vaccination-andimmunisation (accessed March 2, 2014). Joint Committee on Vaccination and Immunisation. Minute of the meeting on 11th/12th February 2014. 2014. https://www.gov.uk/government/ policy-advisory-groups/joint-committee-on-vaccination-andimmunisation (accessed March 21, 2014). Joint Committee on Vaccination and Immunisation. Minute of the meeting on Wednesday 3 October 2012. 2012. https://www.gov.uk/government/ policy-advisory-groups/joint-committee-on-vaccination-andimmunisation (accessed March 17, 2014).
www.thelancet.com Vol 383 March 29, 2014
In the past two decades, meningitis and septicaemia caused by capsular group B Neisseria meningitidis have been responsible for more deaths and severe sequelae among previously healthy young children in the UK than any other infectious disease. The disease poses a particular challenge for frontline medical staff because it is rare (there are about 600–1400 cases per year in England and Wales1) and the early stages of the disease are indistinguishable from the large number of cases of minor viral infections that present to primary care and emergency services. Management of sequelae, such as neurological injury and limb amputations, place a large burden on health systems2 and the disease is much feared by parents of young children. For these reasons, prevention of disease caused by capsular group B meningococcus has been a public health priority for many years. The development of a vaccine, however, has been difficult because the disease is caused by antigenically diverse strains of capsular group B meningococcus. In January, 2013, the European Medicines Agency licensed a novel four-component meningococcal serogroup B vaccine, 4CMenB (licensed as Bexsero, Novartis Vaccines and Diagnostics, Siena, Italy) after a careful review of safety and immunogenicity data from clinical trials.3–5 According to in-vitro studies, 4CMenB might cover up to 88% of strains of capsular group B meningococcus currently circulating in the UK.6 In 2011, the UK Joint Committee on Vaccination and Immunisation (JCVI), a statutory body constituted to provide independent expert scientific advice to the Department of Health, England, began a careful review of the available clinical and laboratory data pertaining to 4CMenB. According to the National Health Service (NHS) constitution,7 the JCVI can recommend adoption of new vaccines only if the programme is found to be costeffective. To avoid redirection of NHS resources from other more cost-effective interventions, the JCVI’s deliberations included an analysis from the NHS perspective8 of the estimated cost per quality-adjusted life-year averted by 4CMenB. To ensure that all health-care interventions are treated equitably, this analysis followed the guidance of the National Institute for Health and Care Excellence (NICE), adapted for immunisation programmes.9 Despite the JCVI’s view that there was strong evidence that the vaccine could prevent some of the burden of www.thelancet.com Vol 383 March 29, 2014
disease caused by capsular group B meningococcus, the decision was complicated by uncertainty about various assumptions that were key to the overall costeffectiveness of a programme. These assumptions included uncertain knowledge of: the most plausible annual number of cases of meningococcal disease (given historic variations in incidence); the proportion of cases with different types of complications, and their shortterm and long-term effect on quality of life; the actual level and duration of protection from vaccination (in the absence of pre-licensure efficacy trials); the longterm strain coverage; the number of doses of vaccines required; and the potential of the vaccine to induce herd immunity, and thus reduce additional cases beyond those in vaccinees themselves. The complexity and difficulty of the review of the cost-effectiveness of 4CMenB has been unprecedented and attracted considerable attention.10,11 In July, 2013, on the basis of the best evidence available at that time, the JCVI produced an interim statement which found that 4CMenB would not be cost-effective in an infant vaccination programme at any price.12 However, in view of the concerns of JCVI members about the uncertainty around the cost-effectiveness model inputs (parameters such as effectiveness, herd immunity, among others that affect the costs and savings to the NHS), the JCVI requested a stakeholder consultation to identify additional information that could improve the robustness of the model. There was a good response and, in October, 2013, the JCVI asked for the cost-effectiveness analysis to be repeated with additional information and amended assumptions, as permitted within NICE guidance.13 In addition, the Department of Health was asked to commission an independent review of the model’s inputs. The JCVI reviewed these analyses during a 2-day meeting in February, 2014, and examined the new cost-effectiveness model for 4CMenB and a range of alternative scenarios.14 The JCVI and the independent economic group agreed that the chosen model parameters were plausible. Various sensitivity analyses were also done to investigate the robustness of the model to the remaining uncertainty, according to previously agreed upon criteria. The JCVI’s assessment showed that 4CMenB would not be cost-effective for the NHS at the current UK list-price for any age group. However, in line with the approach for other
Life in View/Science Photo Library
Group B meningococcal vaccine: recommendations for UK use
Published Online March 21, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60226-9
1103
Comment
new vaccines, the JCVI can consider recommending a programme subject to the ability to procure vaccines at a cost-effective price. The highest burden of meningococcal disease is in infants and the JCVI found that an infant 4CMenB vaccination programme could be cost-effective for this age group in a four-dose schedule (at age 2, 3, 4, and 12 months), but only if the vaccine price was very low. However, the JCVI had considered evidence that an abbreviated schedule was likely to be sufficiently immunogenic and, therefore, concluded that cost-effectiveness could be improved by using a three-dose schedule (at age 2, 4, and 12 months). The JCVI also noted that herd immunity against capsular group C N meningitidis infection in the UK is excellent, and will be further strengthened by the introduction of the capsular group C meningococcal vaccine programme for adolescents in 2014,15 and that 4CMenB could cover some strains of capsular group C meningococcus. Removing the dose of meningococcal C vaccine at age 3 months, a schedule successfully used in other countries, would reduce the financial burden of an infant immunisation programme using 4CMenB.14 The JCVI also found that in some scenarios adolescent vaccination with 4CMenB was cost-effective. However, the burden of disease caused by capsular group B meningococcus is low in teenagers, and so the costeffectiveness of adolescent vaccination would be highly dependent on the vaccine inducing long-term protection against disease in vaccinees and carriage of strains of capsular group B meningococcus, a characteristic which is highly uncertain. The JCVI advised that further evidence should be accumulated about the effect of 4CMenB on carriage before a recommendation on an adolescent programme could be further considered.14 On the basis of these considerations the JCVI therefore recommended that the Department of Health plan to implement a 2, 4, and 12 month (2+1) infant immunisation programme with 4CMenB, subject to procurement at a cost-effective price, and also advised the removal of the 3-month dose of capsular group C meningococcal vaccine subject to the effective implementation of the group C meningococcal adolescent booster programme.14 This programme has the potential to reduce the burden of meningococcal disease among those at greatest risk and to therefore protect the health of UK children. 1104
*Andrew J Pollard, Andrew Riordan, Mary Ramsay Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK (AJP); Alder Hey Children’s NHS Foundation, Liverpool, UK (AR); and Immunisation, Hepatitis and Blood Safety Department, Public Health England, London, UK (MR) [email protected] AJP is Chair of the Joint Committee on Vaccination and Immunisation (JCVI). AR is Chair of the Meningococcal Subcommittee of the JCVI and was Acting Chair (2013) of the JCVI. MR is Head of Public Health England’s Immunisation, Hepatitis and Blood Safety Department. AJP has conducted clinical trials of capsular group B meningococcal vaccines on behalf of Oxford University funded by the Wellcome Trust, Novartis Vaccines, and Pfizer, but has no personal pecuniary or other interests with any vaccine manufacturer. AR was lead editor for a Royal College of Paediatrics and Child Health eLearning package which was sponsored by Novartis. MR declares that she has no competing interests. 1
2
3
4
5
6
7
8
9
10 11 12
13
14
15
Health Protection Agency. Invasive meningococcal infections laboratory reports, England and Wales by capsular group and epidemiological year, 1998–2012. Sept 14, 2012. http://www.hpa.org.uk/webc/HPAwebFile/ HPAweb_C/1317136087786 (accessed March 2, 2014). Viner RM, Booy R, Johnson H, et al. Outcomes of invasive meningococcal serogroup B disease in children and adolescents (MOSAIC): a case-control study. Lancet Neurol 2012; 11: 774–83. Vesikari T, Esposito S, Prymula R, et al. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. Lancet 2013; 381: 825–35. Gossger N, Snape MD, Yu LM, et al. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA 2012; 307: 573–82. Santolaya ME, O’Ryan ML, Valenzuela MT, et al. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observerblind, placebo-controlled study. Lancet 2012; 379: 617–24. Frosi G, Biolchi A, Lo Sapio M, et al. Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage. Vaccine 2013; 31: 4968–74. Department of Health. NHS Constitution for England. 2013. https://www. gov.uk/government/publications/the-nhs-constitution-for-england (accessed March 3, 2014). Christensen H, Hickman M, Edmunds WJ, Trotter CL. Introducing vaccination against serogroup B meningococcal disease: an economic and mathematical modelling study of potential impact. Vaccine 2013; 31: 2638–46. Joint Committee on Vaccination and Immunisation. Code of Practice June 2013. 2013. https://www.gov.uk/government/uploads/system/uploads/ attachment_data/file/224864/JCVI_Code_of_Practice_revision_2013_-_ final.pdf (accessed March 18, 2014). Moxon R, Snape MD. The price of prevention: what now for immunisation against meningococcus B? Lancet 2013; 382: 369–70. Mekalanos JJ. Vaccine economics: what price human life? Sci Transl Med 2013; 5: 204ed16. Joint Committee on Vaccination and Immunisation. JCVI interim position statement on the use of Bexsero meningococcal B vaccine in the UK, July, 2013. London: Department of Health, 2013. https://www.gov.uk/ government/publications/jcvi-interim-position-statement-on-the-use-ofbexsero-meningococcal-b-vaccine-in-the-uk (accessed March 2, 2014). Joint Committee on Vaccination and Immunisation. Minute of the meeting on Wednesday 2 October 2013. 2013. https://www.gov.uk/government/ policy-advisory-groups/joint-committee-on-vaccination-andimmunisation (accessed March 2, 2014). Joint Committee on Vaccination and Immunisation. Minute of the meeting on 11th/12th February 2014. 2014. https://www.gov.uk/government/ policy-advisory-groups/joint-committee-on-vaccination-andimmunisation (accessed March 21, 2014). Joint Committee on Vaccination and Immunisation. Minute of the meeting on Wednesday 3 October 2012. 2012. https://www.gov.uk/government/ policy-advisory-groups/joint-committee-on-vaccination-andimmunisation (accessed March 17, 2014).
www.thelancet.com Vol 383 March 29, 2014
