Introducing a new group B meningococcus vaccineBMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g2415 (Published 02 April 2014) Cite this as: BMJ 2014;348:g2415
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The process around the decision to recommend routine vaccination with the 4CMenB vaccine has been a controversial one. Isaacs and McVernon summarise some of the issues and raise some controversial points in turn. As they point out, the introduction of a new vaccine is highly complex, particularly a new category of vaccine with no biological precedent. Of course while true, this concept has fortunately not stopped us introducing novel vaccines, such as the highly successful HPV vaccines which were, at that time, a completely new class of vaccine whose introduction was indeed “with no biological precedent” (1). In fact, millions of doses of other OMV-based meningococcal vaccines have already been given in other countries (2,3).
It is also certainly true that the considerations around this vaccine have been the subject of unprecedented attention from healthcare workers, charities and the general public. Such involvement and enthusiasm in contemplating a new vaccine is welcome and should be harnessed further as we move toward potential vaccine introduction. Meningitis is uniformly the top fear that parents have for their children, preventing it is their highest priority. If there is a "cost" in terms of more reactogenicity and fevers, we need to share and discuss this with parents so that they can anticipate and manage it as well as recognise the risks and benefits involved. The response from the public thus far suggests that this is a "cost" that they will accept (4). At its introduction there was no alternative to the highly reactogenic whole cell pertussis vaccine - would the same argument have been sustained i.e. this is a vaccine that is too reactogenic to introduce? Fortunately history has shown us the wisdom of this decision. History has also shown us that flexibility in decision making is required as new vaccines are developed and introduced.
(1) Schiller JT, Lowy DR. Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol. 2012 Oct;10(10):681-92.
(2) Holst J, Oster P, Arnold R, Tatley MV, Næss LM, Aaberge IS, Galloway Y, McNicholas A, O'Hallahan J, Rosenqvist E, Black S. Vaccines against meningococcal serogroup B disease containing outer membrane vesicles (OMV): lessons from past programs and implications for the future. Hum Vaccin Immunother. 2013 Jun;9(6):1241-53.
(3) McNicholas A, Galloway Y, Stehr-Green P, Reid S, Radke S, Sexton K, Kieft C, Macdonald C, Neutze J, Drake R, Isaac D, O'Donnell M, Tatley M, Oster P, O'Hallahan J. Post-marketing safety monitoring of a new group B meningococcal vaccine in New Zealand, 2004-2006. Hum Vaccin. 2007 Sep-Oct;3(5):196-204.
(4) Joint Committee on Vaccination and Immunisation Meningococcal subcommittee. Minute of the meeting held on Friday 13th July 2012. London: Department of Health, 2012. https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-...
Competing interests: PTH has conducted clinical trials of capsular group B meningococcal vaccines on behalf of St Georges, University of London funded by Novartis Vaccines and Pfizer, but has no personal pecuniary or other interests with any vaccine manufacturer.
Meningitis Research Foundation was concerned to read Isaacs and McVernon’s editorial which strongly implies the JCVI decision-making process for the meningococcal B vaccine was distorted by political and public pressure. Their suggestion that the final decision of the JCVI was arrived at only “after an outcry” is highly misleading.
It was very clear that the interim statement from the JCVI published in July 2013 was exactly what its name suggests, an interim opinion. The JCVI actively invited consultation on this at the time.
As a stakeholder in the process since the JCVI’s initial call for evidence in 2010, Meningitis Research Foundation was pleased to have the opportunity to respond to this consultation and submit new information not previously taken into account. This included, inter alia, the high NHS costs of litigation as a result of medical negligence claims and information about quality of life impact of the illness on family. We were encouraged that other new information was also considered in subsequent cost effectiveness calculations.
It is the mark of a fair and just process that decisions are adapted and refined as new evidence becomes available. It would be completely unacceptable if a scientific body like the JCVI were to open a consultation, call for submissions and then ignore good quality new information as it came to light. Quite rightly they did not do so. Pejorative references to “u-turns” in this context are quite misplaced.
The procurement of the new meningococcal B vaccine for the infant immunisation schedule still has to be completed at a cost-effective price. Nobody can be in any doubt this will mean a very tough negotiation process, but we urge the vaccine manufacturer and the Government to conclude this as quickly as possible to avoid any unnecessary delay in providing the protection the vaccine affords to children in the future.
Competing interests: Meningitis Research Foundation is a medical research charity and patient group representing approximately 16,000 members affected by meningitis and septicaemia. The charity has received occasional grants from several vaccine manufacturers, including Novartis, Pfizer, Baxter and GSK for educational activities such as its international conference. LG and CW have received consultancy fees from pharmaceutical companies including Novartis and Pfizer which have been donated to the charity.
Isaacs and McVernon (1) appear to be sniping at the most recent JCVI recommendation from several different directions at once.
First they criticise the possible effects of lobbying by patient groups (in this case mainly people who have relatives or close friends who have been killed or maimed by meningitis or who have themselves been affected) and by doctors and other health professionals upon the politicians who take health policy decisions, including those on introduction of vaccines like this one. They do not actually say that such lobbying affects advisory committees but they suggest that campaigners may be being manipulated by manufacturers and that they may "distort the decision making process". Is this a reasonable position to take? Advisory committees do the best they can, using very imprecise methodologies to reach objective decisions but cost benefit prediction is not an exact science. People with strong views held from direct experience would, I suspect, deny that they are doing so egged on by manufacturers with vested interests and would argue that they are informing rather than distorting debate and are uniquely well qualified to do so. Is it really sensible to propose that expert committees be left to do their work on a background of silence? Would this really increase public trust?
Second they criticise the decision to announce the recommendation to use the vaccine in infants before a price had been negotiated, on the basis that this may increase the pressure on the authorities to make a deal and may result in a higher price. Is it not as easy to argue that it increases the pressure on the manufacturer to make a deal and may result in a lower price? Either way, keeping recommendations secret as they seem to propose is surely only another way to reduce public confidence in the process.
Third they appear to argue that there were better reasons to expect effectiveness of MenC immunisation than MenB prior to introduction because it was a conjugate vaccine like Hib and pneumococcal vaccines. In fact the first MenC vaccine was licensed and introduced in the UK before the first pneumococcal conjugate vaccine had been licensed or used anywhere. They seem also to be suggesting that conjugate vaccines at the time could have been expected to have indirect effects while bacterial protein vaccines now cannot. Actually, although there was evidence of herd immunity from Hib conjugate programmes by 1999, the great importance of such effects of conjugate vaccines was only just beginning to be appreciated and schedules were still being designed and used primarily to generate direct protection in infancy and childhood. Universal immunisation programmes which include diphtheria vaccine - which consists of just a single bacterial protein - have been associated with virtual disappearance of toxigenic C. diphtheriae from circulation (2) so bacterial protein vaccines can cause indirect effects too. There are already data suggesting an effect of 4CMenB on carriage (3) whereas at the time of licensure and introduction of MenC vaccines there were no such data available.
Fourth they criticise the authorities for paying too much for the vaccine. This appears a little premature before any price has even been agreed. This argument begins to sound very hollow indeed if comparisons are drawn between the prices one can estimate are being paid for other new vaccines recently introduced in the UK (4) compared to those paid elsewhere. The UK taxpayer generally gets very good deals on vaccines. There's nothing that suggests that this is about to change.
Fifth they try to construct an argument around reactogenicity. They call into question the decision to switch from the more reactogenic whole cell pertussis vaccines to less reactogenic acellular vaccines because many areas are experiencing re-emergence of pertussis. Actually most cases of pertussis in the UK 2012 epidemic had received whole cell vaccine in childhood, but raising this issue in the context of attacking a MenB vaccine that often causes fever is puzzling. How does arguing for continued use of a more reactogenic pertussis vaccine - one which generated rates of fever more or less identical to those we might expect to see when 4CMenB goes into use - fit with the predictions of loss of public confidence they then go on to make? Actually the British public happily accepted whole cell pertussis vaccine - fever and all - for their children for many years. What caused a collapse in confidence in that vaccine - much earlier - and with disastrous consequences - was not such side-effects but the poorly judged public pronouncements of an ill-informed paediatrician (5).
Most parents very much want to protect their children as completely as possible against meningitis by vaccination. As with all previous childhood vaccines against this fell disease at the time of their introduction, just how effective this one will be and the optimal dose regimen are still uncertain. But for what it's worth, all the others so far have turned out to be as or more effective than expected. There are reasonable grounds to expect that this one will be no different.
1. Isaacs D, McVernon J. Introducing a new group B meningococcus vaccine. Bmj 2014;348:g2415
2. Wagner KS, White JM, Neal S, et al. Screening for Corynebacterium diphtheriae and Corynebacterium ulcerans in patients with upper respiratory tract infections 2007-2008: a multicentre European study. Clin Microbiol Infect 2011; 17: 519-525
3. Read RC, Baxter D, Chadwick DR, et al. Ipmact of a quadrivalent conjugate (MenACWY-CRM) or a serogroup B (4cMenB) meningococcal vaccine on meningococcal carriage in English university students. ESPID May 2013 Milano, Italy. Abstract at http://www.sessionplan.com/espid2013/ (accessed 12th April 2014)
4. http://www.nhs.uk/news/2012/11November/Pages/New-vaccine-to-prevent-rota... (accessed 12th April 2014)
5. Kulenkampff M, Schwartzman JS, Wilson J. Neurological complications of pertussis inoculation. Arch Dis Child. 1974 Jan;49(1):46-9.
David Baum Professor of Paediatrics
University of Bristol, UK
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: AF is undertakes consultancy, clinical research and trials as investigator and gives talks on behalf of the University of Bristol and its sister NHS Foundation Trust sponsored by several vaccine manufacturers including Novartis. All income and honoraria are paid to his employing institutions. He holds no shares and owns no patents or intellectual property of any sort.
Isaacs and McVernon in their editorial highlight the importance and complexity of policy decision-making for a group B meningococcal vaccine based on cost-effectiveness. We agree with the authors that, despite the seriousness of group B meningococcal disease, the public interest in its prevention, and the commercial considerations, any cost-effectiveness analysis has to be undertaken based only on the best available scientific evidence. We are concerned therefore, that Isaacs and McVernon have misrepresented the process which was used in formulating careful and evidence-based recommendations for prevention of this serious disease, which did adhere to this principle.
The health economic analysis for a group B meningococcal vaccine is difficult because there are uncertainties about critical parameters which determine whether the vaccine meets the required threshold for cost-effectiveness. Indeed, the first health economic model made available to the independent scientific committee which advises the UK Departments of Health, the Joint Committee on Vaccination and Immunisation (JCVI), demonstrated that a vaccine programme for such a rare disease would be cost-effectiveness at a price of around £10 per dose. Further revisions of the parameters used in the model resulted in an interim statement by the Committee in July 2013 which showed that the vaccine was unlikely to be cost-effective even at £0 per dose. Following a period of formal stakeholder consultation, the robustness of the model was improved by including a more plausible range of incidence and updated evidence, with all parameters permitted within the National Institute for Health and Care Excellence guidance , JCVI found that the vaccine could be cost-effective at a low vaccine price. It is important to note that the stakeholder consultation was initiated by the committee to improve the robustness of the model data “before” the public outcry rather than “in response to it” as incorrectly suggested by Isaacs and McVernon. These three iterations of the model, which were run without prejudice about the possible outcome of the analysis, are consistent in showing that cost-effectiveness of the vaccine is borderline in the UK epidemiological setting. They do not therefore represent a major change of direction by JCVI; the final recommendation is that the programme is only cost-effective if the Department of Health can negotiate a low vaccine price. This process is a far cry from the conspiracy proposed by Isaacs and McVernon, but it is easy to see how their speculation makes more compelling news.
Isaacs and McVernon comment about the potential for MenB vaccine-induced fever to undermine the immunisation programme1. Both Isaacs and McVernon are members of the Australian Technical Advisory Group on Immunisation (ATAGI) who have made a number of recommendations for use of the same Group B meningococcal vaccine, including the use of prophylactic paracetamol when the vaccine is used in infants, which seems at odds with their comments about the risks to the UK programme. However, we agree that the impact on the immunisation programme is an important consideration for all new vaccine introductions. Such issues are considered as part of the implementation plan for any new vaccine intervention in the UK. There was, therefore, attitudinal research undertaken, which was provided to JCVI and noted in the JCVI meningococcal subgroup minutes: “The sub-committee considered the findings of attitudinal research on the likely acceptability by parents and uptake of meningococcal B vaccine. The research suggested that a vaccine against meningococcal serogroup B would be welcomed by parents who did not regard a potentially higher rate of post-vaccination fever with particular concern as this could be managed by use of paracetamol.”
The work of JCVI does not end at the point of a recommendation and all programmes are kept under review to ensure that safety and effectiveness are acceptable and to ensure no adverse effect on other programmes.
Professor Andrew J Pollard FRCPCH PhD,Department of Paediatrics, University of Oxford, Oxford,UK
Dr Andrew Riordan FRCPCH MD, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
Dr Mary Ramsay, MRCP FFPH, Immunisation, Hepatitis and Blood Safety Department, Public Health England, London, UK
1. Isaacs D, McVernon J. Introducing a new group B meningococcus vaccine. Bmj 2014;348:g2415.
2. 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(23):2638-46.
3. Joint Committee on Vaccination and Immunisation. JCVI interim position statement on the use of Bexsero meningococcal B vaccine in the UK. London: Department of Health, 2013. https://www.gov.uk/government/publications/jcvi-interim-position-stateme...
4. Joint Committee on Vaccination and Immunisation. Minute of the meeting on 11th/12th February 2014. London: Department of Health, 2014. https://www.gov.uk/government/policy-advisory-groups/joint-committee-on-...
5. Australian Technical Advisory Group on Immunisation. Australian Technical Advisory Group on Immunisation (ATAGI) Statement: Advice for immunisation providers regarding the use of Bexsero®: Australian Government Department of Health, 2014. http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Conte...
6. Joint Committee on Vaccination and Immunisation Meningococcal subcommittee. Minute of the meeting held on Friday 13th July 2012. London: Department of Health, 2012. https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-...
Competing interests: 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.
To the Editor
In their editorial, Isaacs and McVernon (1) reflect on the proposed introduction of Bexsero, a novel licensed vaccine against the dreaded and highly pathogenic bacterium, the meningococcus. Two issues are of particular concern. First, their assertion that government and advisory committees bowed to political and public pressure. Second, their concerns about introducing Bexsero into the UK immunisation programme given its reactogenicity and uncertain effectiveness.
The JCVI, the UK government’s advisory committee on vaccines, has acted by the book. They have not performed a U-turn, even if the press and some medical journals find it serves their purpose to say so. It is a matter of great concern that the JCVI’s deliberations have been so unjustly characterised. After a careful review of available evidence, including a cost effectiveness (CE) analysis, the JCVI were not able to recommend the implementation of Bexsero in the UK routine infant or adolescent immunisation programmes (2). Using accepted procedures, JCVI sought comments from stakeholders and, after receiving multiple evidence-based comments, they revised the inputs of their previous CE model and concluded that Bexsero could be cost- effective (3). Crucially, they did not specify at what price. This variability in the outcome of CE modelling is hardly surprising given that these analyses are highly sensitive to changes in input data. Importantly, as stated by Isaacs and McVernon (1), both the UK government and JCVI deny any interference in the process. There is no evidence of conspiracy and no evidence that the scientific advisory process was subjected to political manipulation. Scientists and the public are surely entitled to participate in securing the best available evidence on which to make decisions on vaccine policy as they were urged to do (4) and which they did (5). In what is undoubtedly a complex process, JCVI has provided an evidence-based recommendation. Of course, politicians take into consideration the impact of their policies on voters and hold firmly to the view that there is more to their decisions than scientific evidence. This is surely not unique to this decision process.
Bexsero was licensed in January 2013 after 17 years of research and development. The European Medicines Agency considered data from more than 6 thousand infants, toddlers and older individuals generated in just over 6 years of clinical trials that aimed to define the safety, immunogenicity and estimated efficacy of Bexsero. The vaccine is associated with fever, confined to a period not exceeding 72 hours after injecting the vaccine (6). An excess of febrile seizures was not observed in pre-licensure studies (7), but it is possible that a low level of risk may be detected once large populations are immunized. Similar risks have been detected with vaccines currently in use. Meantime, since Bexsero was licensed in early 2013, there have been more than a thousand cases of meningococcal septicaemia and acute meningitis in the UK (8) associated with the inevitable deaths and disability.
For any vaccine, the crucial population-based data on rare event safety cannot be provided by pre-licensure data. Should this deter vaccine implementation in a routine immunisation programme and effectively deny its potential benefits? Isaacs and McVernon warn of the potential detrimental backlash from a public averse to even short-term self limited vaccine-related problems, and reinforce their point by adding concerns about the uncertainties of Bexsero’s effectiveness. Again, without a large population-based evaluation, estimates of efficacy based on immunogenicity are predictably uncertain. But Isaacs and McVernon offer no solution to this conundrum while making the important point that the data generated from implementing Bexsero in the UK are also of critical importance to other countries (1). This is analogous to the introduction of pneumococcal conjugate vaccines where the true vaccine impact was not determined until after the vaccine was introduced despite the availability of data from a large phase three efficacy trial (9). In order to assess the actual impact of Bexsero on disease, it will be necessary to introduce the vaccine into a well-characterised and monitored population. With the recommendation proposed by the JCVI’s 2+1 schedule and the excellent surveillance capacity of Public Health England, final assessment of effectiveness and the potential for herd immunity will be definitively assessed. There is no a priori reason why, if adopted, this policy should not be subject to review over time. In fact, there are numerous examples of vaccines and vaccine schedules being adjusted in the UK as new evidence regarding the use of these vaccines was accumulated. However, it is surely injudicious to argue that the current uncertainties should irrevocably block the future routine use of the vaccine. Meantime, an outbreak of a few cases of serogroup B meningococcal disease in USA Universities (10) has galvanised an emergency implementation of Bexsero by the US CDC for which the manufacturers were expected to provide thousands of doses of vaccine post-haste. This demonstrates that, despite uncertainties, the public and public health infrastructure are intolerant of standing by while watching healthy people needlessly die of meningococcal disease.
What must be considered in the future is a different modus operandi for bridging between licensure and essential post-licensure studies. Governments depend on the commercial sector for vaccines. Without identifying a mechanism for generating the predictable and essential population-based data after licensure, how does such a desperately needed vaccine, or the development of other vaccines for that matter, have a future? Change is needed, one in which governments work with the vaccine manufacturers to shoulder a reasonable and shared contribution to the implementation of a licensed vaccine that for years the UK Department of Immunisation has unreservedly encouraged. Rightly so; because as has been clearly documented (11), there has been a need to prevent meningococcal disease through immunisation for decades and that imperative has not changed.
Richard Moxon. Emeritus Professor. University of Oxford Department of Paediatrics. John Radcliffe Hospital, Oxford OX3 9DU. UK.
Steven Black. Professor of Pediatrics, Center for Global Health, University of Cincinnati Children’s Hospital
Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: ERM is a member of the Scientific Advisory Boards of Novartis Vaccines and GlycoVaxyn. SB is a consultant for WHO and Novartis and serves on DSMBs for GSK.
1. Isaacs DI and McVernon J. Introducing a new group B meningococcus vaccine. Many forces affect the final decision. B.M.J. March 2014.
2. Joint Committee on Vaccination and Immunisation. JCVI interim position statement on the use of Bexsero meningococcal B vaccine in the UK, July, 2013. Department of Health, 2013. https://www.gov.uk/government/publications/jcvi-interim-position-stateme...
3. Joint Committee on Vaccination and Immunisation. Minute of the meeting on 11th/12th February 2014. https://www.gov.uk/government/uploads/system/uploads/attachment_data/fil...
4. Moxon R, Snape M. The price of prevention: what now for immunisation against meningococcus B? Lancet 2013;382:369-70.
5. Pollard AJ, Riordan A, Ramsay M. Group B meningococcal vaccine: recommendations for UK use. Lancet 2014; published online 21 Mar
6. Prymula R et al (2009). Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet. 17;374(9698):1339-50
7. A Multi-Component Meningococcal Serogroup B Vaccine (4CMenB): The Clinical Development Program. Miguel O’Ryan. Jeffrey Stoddard. Daniela Toneatto. James Wassil. and Peter M. Dull. Drugs. DOI 10.1007/s40265-013-0155-7
8. "Notification of Infectious Disease Data from Public Health England and Health Protection Scotland"http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/Notificatio... eases/NOIDSReportsAndTables/
9. http://www.hps.scot.nhs.uk/publichealthact/WeeklyData.aspxRay GT, Whitney CG, Fireman BH, Ciurrla V, Black SB. Cost-Effectiveness of Pneumococcal Conjugate Vaccine: Evidence From the First 5 Years of Use in the United States Incorporating Herd Effects. Pediatric Infectious Disease Journal. 2006 25. 494-501
11. Martin NG, Sadarangani M, Pollard AJ, Goldacre MJ. Hospital admission rates for meningitis and septicaemia caused by Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae in children in England over five decades: a population-based observational study. Lancet Infect Dis. 2014 Mar 13. pii: S1473-3099(14)70027-1. doi: 10.1016/S1473-3099(14)70027-1.
Competing interests: RM is on the scientific advisory boards of GlycoVaxyn and Novartis Vaaccines. SB consults for WHO and Novartis Vaccines and is on DMSBs for GSK