Do we need a new approach to making vaccine recommendations?BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h308 (Published 30 January 2015) Cite this as: BMJ 2015;350:h308
All rapid responses
Thank you to Wright and colleagues (1) for a thoughtful response to our article. We are glad they welcome the idea of an ethics framework and more equal balance between the forces of evidence, economics and ethics. We also called for greater transparency and public engagement, which are important to emphasize. Much of their commentary, perhaps unintentionally, illustrates some of the very issues we were trying to reveal and reinforces our call for a new approach.
Firstly, we did not imply that lobbying changed the decision of JCVI. We observed that lobbying took place, but have no opinion on its impact as none of us was involved in the decision making by JCVI. Our real concern was about ethics and transparency. An organization like the Meningitis Research Foundation would be expected to lobby for vaccines such as Bexsero. This would be a reasonable expectation of such an organization by its supporters. Because of lack of an explicit ethical framework, lack of transparency and public engagement, the general public might perceive that lobbying was influential, and that this might impact the public’s confidence in vaccines or vaccine decision making. The question whether (or not) it would be wrong for the JCVI to bow to public pressure is an example of one of the ethical issues to be addressed. Furthermore, we suggest that the general public didn’t actually have a voice in the process. More transparency and an ethical framework might have helped ensure that public engagement actually occurred and that it was meaningful.
In relation to the evidence that Wright et al cite as influencing or supporting the JCVI’s change in decision, this was not transparent to the public at either of the times the JCVI was developing its two position statements. Safety data that Wright et al cite from use of the vaccine in the US University outbreaks and Quebec did not exist at that time. Clearly the recent data are very useful and informative, and many National Immunization Technical Advisory Groups choose to wait for these kinds of data to be available before making a decision.
The application of standard health economic approaches to public health interventions has long been recognised to be problematic, and this does not only apply to uncommon but severe illnesses in children. It also applies to illness that are prevented years after the immunization program (e.g., cervical cancer). We are glad to hear that JCVI is considering how this should be addressed.
There is a real challenge sustaining immunization programs, and vaccine hesitancy is one of the greatest problems facing immunization programs globally. Unfortunately the UK’s “enviable” immunization uptake over the past 20 years has not been high enough to have prevented the re-emergence of measles, an ongoing legacy of a discredited story that vaccines are not safe and that too many antigens are given at the same time. If parents thought the schedule was overcrowded 20 years ago, then they have even more justification to feel that way with the real increase in number of vaccines and complexity of schedules since then. Worse, in Canada, a survey in 2011 showed that parents do not just perceive that children are receiving too many vaccines, they also think vaccines are less safe than they used to be (2). These beliefs seem impervious to the facts; new vaccines undergo rigorous safety review, including very large clinical trials, and vaccine safety assurance and surveillance is stronger than it has ever been. These are really important messages for public confidence in vaccines and should not be dismissed.
The high acceptability of vaccines for meningococcal B vaccine by parents is completely understandable from the perspective of a parent wanting to prevent a horrific illness. It also reflects a well-known cognitive bias in risk perception, which leads people in general to fear severe memorable but rare events more strongly than less memorable events that are more likely to happen. Hence we fear flying in airplanes more than driving our cars, even though we are far more likely to die on the road than in an airplane crash. The public may well prefer money to be spent on a vaccine to meningitis rather than, for example, road safety. Using vaccine examples, the public may also prefer money being spent on a vaccine for meningococcal disease, rather than measles, rotavirus or chicken pox, due to the different perception of severity of these diseases.
Traditionally, the public health field takes a utilitarian approach of seeking the greatest benefit for the greatest number. This can collide with the individualist (“deontological”) approach, exemplified by severe but rare illnesses, if the position is taken that it is absolutely wrong for any suffering to occur that can be prevented. In modern society choices are however made daily that lead to deaths, including in children. We observe that some causes of death seem to be more acceptable than others, or at least easier to ignore. Going back to our road safety analogy, we choose as societies not to prevent every single death of a child on our roads because we apparently are unwilling to spend the money or place the restrictions on our transportation that this would entail (3). Such societal decisions need, apparently, to be made as long as we as a society do not prioritize the saving of a life above everything else. We would prefer them to be made transparently, within an ethics framework, and in a way that enables the public health and economic impacts of the different choices we are making to be compared fairly and transparently.
1. Wright CL, Head C and Glennie L. Response to “Do we need a new approach to making vaccine recommendations?” http://www.bmj.com/content/350/bmj.h308/rr-3
2. EKOS research associates Limited. Survey of Parents on Key Issues Related to Immunization http://resources.cpha.ca/immunize.ca/data/1792e.pdf
3. Dramatic rise in road deaths as numbers of traffic police falls. http://www.independent.co.uk/news/uk/home-news/dramatic-rise-in-road-dea...
Competing interests: No competing interests
Michal-Teitelbaum and Cunningham make thoughtful and thought-provoking observations.
No one is going to declare an interest, unless it is monetary and there is a trackable trail.
But the more dangerous conflicts of interest are the untraceable ones. Where the clinician or the non-clinical public health consultant follows the written or spoken "guidance" from the Department of Health, even if in his (her) personal judgement, the guidance is unworthy. After all there can be benefits in following my leader.
Do we have a true and complete record of paralysis following oral polio vaccination in a member of the family or a social contact? We ought to search through the records of the virus reference laboratories, going back to the beginning of Sabin vaccination at least in this country.
Related (since now I am talking of community treatment) request: did we collect the incidence of harm resulting from our Afghanistan attack on soil-related helminth infections? Is the Indian government collecting data in its Community Treatment of Helminth Infections?
Somewhere in West Africa, a part of the world we know little about but which has been in the news for Ebola, a vaccine is going to be tried out. Can anyone please tell me the name of the Research Ethics Committee that approved the trial? Is the protocol available in the local languages and in English?
Maybe the nearest approach in such matters (vaccines, drugs) is to ask yourself - would I do this to my own child?
Competing interests: No competing interests
I appreciate the light shed by Natasha Crowcroft and colleagues about Bexsero and recommendations for vaccines in general. I particularly agree with the statement that “options need to be placed in the context of all healthcare, not just compared with other vaccines”.
In fact, new vaccines are preventive tools for diseases that are more and more rare, so that no benefit can be identified at a public health and statistical level, although they are more frequently recommended for mass vaccination. Which in turn, automatically and mathematically, increases the probability that the risks overweigh the benefits of a vaccine at a public health level.
So, the main ethical issue in this debate is to have irrefutable and methodologically rigorous clinical trials interpreted by scientists and agency officers that have no competing interests, which is not actually the case.
Since a vaccine is designed for mass vaccination this means a long term and a public health perspective that seems rather inconsistent with the limited vision of a charity centered on a particular disease and with the short term profit outlook of pharmaceutical companies.
Also, with the Vioxx scandal, the passive surveillance of vaccines and drugs has proved ineffective to detect much more frequent adverse effects that those that would reverse the benefit risk balance for a vaccine designed for such a rare condition, there other realistic concerns that have to be taken into account.
These concerns are about fundamental science and virology and are disregarded when assessing a vaccine. In fact I’ve noticed we don’t talk anymore about science when we talk about vaccines. We talk about money, emotion, belief and technology. Nevertheless the scientific point of view is most relevant for this topic.
Jean-Louis Velizier, a now retired virologist, had anticipated, in the early nineties that, as technology allows that, pharmaceutical industry could be tempted to use little proteins or even peptides to make up vaccines instead of whole bacteria or virus. And he warned that this strategy wouldn’t be correct, because, first, little proteins and peptides immunogenicity is very poor and this would bring to use more and more adjuvant in vaccine. This was true and squalene adjuvant of Pandemrix, the influenza vaccine used in most European countries during the pandemic episode, is thought to have caused narcolepsy. And second, the adjuvant only enhances quantitatively the immunogenic response, but an adjuvant can’t replace the dissection of a virus by T lymphocytes, or the intrastructural and tridimensional recognition of molecules by B and T lymphocytes.
Some will say that is only theory and that has nothing to do with empiric science, which is the only one that matters.
But sometimes is useful to have some knowledge about fundamental science to understand rather strange phenomenon.
I would give just a few examples.
First, acellular pertussis vaccine, for whooping cough, which immunogenicity has been shown to be waning with boosters and in the general population . This is probably related to the capacity of B pertussis to evolve and to adapt to the vaccine that is a chimera created by technology and doesn’t exist in the world. New emergent strains of B Pertussis don’t bear anymore pertactin which is a main component of the vaccine, and then make the vaccine ineffective .
A second example, is the Sanofi blockbuster, Menactra, which is a quadrivalent meningococal vaccine designed for serotypes A, C, Y and W 135 combined with a diphtheria toxoid conjugate vaccine. After introducing the vaccine in 2007 in the United States the Advisory committee for immunization practices (ACIP) recommended the vaccine for adolescents from 11 to 18 years. In 2011 a number of cases of meningitis in vaccinated adolescents (mean time 3,25 years after vaccination) lead to new recommendations adding a booster at the age of 16 .
In my opinion, this shows that a long term vision in needed, ant this kind of vision is rather inconsistent with the way the decisions are taken in this field.
 Nicolas P Klein and coll, Waning Protection after Fifth Dose of Acellular Pertussis Vaccine in Children. N Engl J Med 2012; 367:1012-1019
 Seppa N. Whooping cough bounces back. Science News, april 2014. https://www.sciencenews.org/article/whooping-cough-bounces-back
Competing interests: No competing interests
We read with interest Natasha Crowcroft and colleagues’ analysis of the controversies surrounding decisions about public funding of the novel menB vaccine Bexsero1.
In their analysis the authors strongly imply that lobbying and pressure from clinicians, meningitis charities and the vaccine manufacturer caused the Joint Committee on Vaccination and Immunisation (JCVI) in the UK to amend their initial negative recommendation of the vaccine to a positive one. In fact the change in recommendation was as a result of updated evidence following a formal stakeholder consultation initiated by the JCVI at the same time as their interim negative recommendation was published2.
As a stakeholder, Meningitis Research Foundation was pleased to have the opportunity to respond to this consultation and submit new information not previously taken into account3. This included, inter alia, the high NHS costs of litigation as a result of medical negligence claims and new quantifiable data on the detrimental health effects to close family members of those who survived this disease. The adaptation of the initial decision was in truth the mark of a fair and just process taking into account newly available evidence rather than the JCVI bowing to public pressure.
We are however, in agreement with the authors when they suggest that evidence, economics and ethics should be treated with equal importance when it comes to deciding whether to publicly fund vaccines. We agree that ethics can sometimes be the poorer partner in the decision making process and that a more robust framework that takes ethical considerations into account is needed for the evaluation of vaccines. However, some of the examples of ethical consideration used by the authors to back up their arguments we believe were actually considered in the JCVI’s deliberations on Bexsero.
Potential unintended negative effects of vaccination should always be an important consideration when deciding whether to implement vaccines, but we strongly disagree with the sentiment that “the vaccine schedule is already so full that parents and healthcare professionals are objecting to giving further vaccines at any single visit”, a sentiment the authors back up with a citation more than 20 years old. We agree that public acceptance of potential new vaccines is of extreme importance. However, if the UK had taken such a conservative attitude towards vaccine introduction 20 years ago then we would have forgone the public health benefits afforded from numerous vaccines that successfully protect us against group C meningococcal disease, pneumococcal disease, HPV, rotavirus and influenza. It is also important to note that despite numerous new vaccines being introduced to the UK schedule over the past 20 years we have maintained an enviable vaccination uptake rate of over 90% amongst the under 5s4.
The authors state that “adverse events may affect public acceptability of other routine vaccines” and imply that this was not considered by the JCVI when making their decision on Bexsero. In fact, attitudinal research on the likely acceptability by parents and uptake of meningococcal B vaccine was considered by the JCVI meningococcal subgroup5. 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 JCVI considered clinical trials data from nearly 8,000 people including more than 5,000 infants and toddlers 6-9, which demonstrated that Bexsero had a good safety profile. It is also important to note that new data and real-world experience of using Bexsero is growing all the time. Nearly 17,000 students in the US were vaccinated in response to an outbreak of MenB disease at Princeton University in late 2013 and the University of California, Santa Barbara in early 2014. Additionally, in the summer of 2014 over 45,000 people between 2 months to 20 years of age, were vaccinated as part of a public immunisation program in the Saguenay-Lac-St-Jean region of Quebec, Canada10. No serious adverse events were reported following the program and rates of fever and local reactions were similar to that of other routine immunisations. The vaccine has also been administered to nearly 4,000 students at the University of Bristol with no serious adverse events reported.
It has become apparent from the controversy surrounding decisions about whether Bexsero should be publicly funded that the framework for CEA is inherently biased against interventions that prevent uncommon but severe illnesses in children for the following reasons:
• The EQ-5D, the tool used by the National Institute for Health and Care Excellence and the JCVI for assessing impact on quality of life, is insensitive in young children
• The high discount rates applied to the costs and benefits of an intervention disadvantages children and preventative interventions such as vaccines by placing much higher importance on immediate health gains compared with future ones.
In addition to this there is no consideration of public preference. For example, there is strong evidence that the public prefers prevention over cure and would rather prevent severe disability in a few than mild illness among many11 yet there is no mechanism in the framework to allow for this.
These flaws inherent in the current methodology of CEA have been recognised by the JCVI and as a result a working group on cost-effectiveness set has been set up to address how vaccination programmes that prevent rare diseases of high severity should assessed and whether there are aspects of cost-effectiveness in relation specifically to children that should be considered12. We welcome this decision and are actively seeking to be involved in discussions with the working group.
Crowcroft and colleagues assert that “the backlash against the UK decision on Bexsero was not about money; it was about the priority placed on child health and the emotional impact of a life changing illness”. However, priority is about willingness (or lack of willingness) to invest limited NHS resources, so it was at least partially about money. The conclusion that the vaccine was “highly unlikely to be cost effective at any vaccine price”2 indicated an immense undervaluing of the prevention of such a severe childhood illness. Although we were pleased to be able to provide new evidence that led to a more favourable analysis at the time, the biases in the framework remain unresolved.
Price negotiations between the DoH and Novartis have been underway since August 2014, leading us to believe they have stalled. Unless there is a rapid and positive conclusion to the current negotiations between the Department of Health and the vaccine manufacturer, we will continue to see lives blighted and lost from what is now a vaccine preventable disease.
1. Crowcroft. N, D.S., Upshur. R, , Do we need a new approach to making vaccine recommendations? BMJ, 2015.
2. JCVI. JCVI interim position statement on use of Bexsero meningococcal B vaccine in the UK. 2013 [cited 2013 August]; Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/fil....
3. Meningitis Research Foundation. Response to the JCVI Interim position statement on the use of Bexsero meningococcal B vaccine in the UK. 2013; Available from: http://www.meningitis.org/news-media/our-response-to-the-jcvi-72756.
4. Public Health England. Cover of vaccination evaluated rapidly (COVER) programme 2013 to 2014: quarterly data. [cited 2015 February]; Available from: https://www.gov.uk/government/statistics/cover-of-vaccination-evaluated-....
5. Joint Committee on Vaccination and Immunisation Meningococcal subcommittee. Minute of the meeting held on Friday 13th July 2012. . Available from: https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-....
6. Gossger, N., 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(6): p. 573-82.
7. Findlow, J., et al., Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy. Clin Infect Dis, 2010. 51(10): p. 1127-37.
8. Vesikari T et al., Immunogenicity of an investigational, multicomponent, meningococcal serogroup b vaccine in healthy infants at 2, 4, and 6 months of age., in Presented at IPNC, Sept 11-16, 2010; Banff, Canada. Poster #180.
9. Prymula, R., et al., A phase 2 randomized controlled trial of a multicomponent meningococcal serogroup B vaccine (I): Efects of prophylactic paracetamol on immunogenicity and reactogenicity of routine infant vaccines and 4CMenB. Hum Vaccin Immunother, 2014. 10(7).
10. Novartis. Novartis vaccine Bexsero® sees high uptake in first large-scale public vaccination program to help protect against devastating meningitis B. 2014 [cited 2014 October]; Available from: http://www.novartis.com/newsroom/media-releases/en/2014/1840453.shtml.
11. Luyten, G.P., Goos, P., Kessels, R., Beutels, P.,. Prevention, cure and public preferences for funding health care: a D-efficient discrete choice experiment. in International Health Economics Association, 9th World Congress. 2013. Sydney, Australia.
12. Joint Committe on Vaccination and Immunisation. Minute of the meeting on Wednesday 2 October 2013. Available from: https://app.box.com/s/iddfb4ppwkmtjusir2tc/1/2199012147/18992166933/1.
Competing interests: Meningitis Research Foundation is a medical research charity and patient group representing over 17,000 people 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 research conference but 95% of its income is derived from individual gifts and public donations. LG and CH have received speaker fees from pharmaceutical companies which have been donated to the charity.
We need a documentary showing the deaths and side effects of measles.
People today don't know about the deaths, encephalitis, hearing loss and other complications before we had vaccines.
US gov or someone should pay for a documentary
Interview the persons that had the measles and are deaf or other. Those who lost a loved one to measles.
Without this documentary the argument is about morality and common sense which is lacking.
Competing interests: No competing interests
Thank you for a succinct, informative, balanced, honest, well written and unemotional dissertation. That is as we should be expecting from the BMJ, and nothing else. It helps me to better make an informed decision about interventions and reassures me of the independence of the acquired knowledge.
It is greatly appreciated.
Competing interests: No competing interests
With some confusion, I have followed the news about Bexsero, the new group B meningococcus vaccine and am now grateful to Natasha Crowcroft and her Canadian colleagues for clarifying some of the questions at issue. They suggest: 1) There is much uncertainty about vaccine effectiveness...2) There are serious concerns about vaccine safety...3) Even if effectiveness is proved the number of lives saved will be small...4) The vaccine is expensive...5) Lobbying has played a substantial role in its approval in Europe, Australia, Canada, and now the U.S. (FDA news release 1/23/15)....6) Including it in vaccine schedules will not be cost-effective and may threaten uptake of truly life-saving vaccines, as well as support for non-vaccine programs important for preventing morbidity and mortality
Group B meningococcal disease is rare, but adverse effects of Bexsero are not. There were 5 cases of Kawasaki Disease in 4340 trial infants; this is 115 KD cases per 100,000 infants, about 10 times the background incidence of KD in the U.S. More than one-third of infants had high fever the day of vaccination, including 8 who had seizures; this is nearly 3 times the seizure rate with the old DTwP vaccine and 5-6 times the seizure rate with DTaP/IPV/Hib vaccine (Lancet 381:785 & 825, 2013. JAMA 307:573 & 614, 2012).
Crowcroft et.al. refer to the public loss of confidence in vaccines and vaccine experts; they suggest a need for greater transparency and higher ethical standards for decision-making. They cite the tensions between individual benefit from vaccines vs. population benefit; between clinicians and public health professionals; between governments and industry; and between advocates for children and other members of society....Somewhat blandly they state, "Technical and economic considerations currently dominate ethical ones" where vaccine policies are concerned. Similar issues were raised more obliquely regarding the activities of the Advisory Committee on Immunization Practice (ACIP) in the U.S. (Schwartz & Mahmoud, NEJM 371:1953--Nov. 20, 2014).
Over a 40 year pediatric career I supervised or administered over a million doses of various vaccines. Sometime after 1990 I became aware of the commercial, as opposed to the humanitarian motives driving vaccine programs, and the tendency for manufacturers and officialdom to exaggerate the benefits of vaccines while paying little attention to rare but serious adverse effects.....I very much appreciate Dr. Crowcroft and her colleagues' analysis of the Bexsero controversy and its application to general concerns about vaccine policies.
Competing interests: No competing interests
Since August 2, 2014 our Centers for Disease Control has received reports of 107 cases of 'acute flaccid myelitis' (AFM), a polio-like illness in children in 34 states. During the same interval there have been 1153 cases of respiratory illnesses associated with enterovirus D-68 (CIDRAP News 1/16/15. CDC update 1/15/15. Catherine Saint Louis, NY Times 1/13/15). AFM affects motor neurons in spinal cord gray matter, resulting in asymmetrical limb weakness; 34% of patients have cranial nerve motor dysfunction. Median age of patients is 7.6 years/range: 5 months-20 years (MMWR 63: 1243--January 9, 2015). So far only one child has fully recovered. EV-D68 is a suspected cause but, thus far, no viruses have been found in the spinal fluid of patients, and only a minority have had an antecedent illness associated with EV-D68. Case-control studies are planned to look for clues, but presently AFM is a mystery disease of unknown cause.
It is taboo to suggest a role for vaccines, but some old-timers remember "provocation poliomyelitis" or "provocation paralysis." This is paralytic polio following intramuscular injections, typically with vaccines. PP was most convincingly documented by Austin Bradford Hill and J. Knowelden during the 1949 British polio epidemic when the risk of paralytic polio was increased 20-fold among children who had received the DPT injection (BMJ 2:1--July 1, 1950). Similar observations were made by Greenberg and colleagues in New York City; their literature review cited suspected cases as far back as 1921 (Am J Public Health 42:142--Feb.1952). I first became aware of PP 10 years ago while browsing through "Krugman's Infectious Disease of Children" (page 128 of the 2004 edition).
AFM may result from a direct virus attack on the spinal cord, or by an immune attack triggered by a virus, or by something else. If a polio-like virus is circulating in the U.S., the possibility of its provocation by one or more vaccines has to be considered.
Competing interests: No competing interests