Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Emperor's clothes exposed
- Nick Hardwick (28 October 2006)
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Vested interests will always trump evidence
- GH Hall (28 October 2006)
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Policy versus evidence: policy in the lead
- Peter Doshi (29 October 2006)
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Influenza vaccination: what evidence can we rely on?
- Stuart J cornell (29 October 2006)
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Protection from disease versus disease severity
- Christian W Mandl (30 October 2006)
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No gap between policy and evidence for influenza vaccination
- David S. Fedson, Kristin L Nichol (31 October 2006)
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Some published UK data
- John Stone (2 November 2006)
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Flu vaccination: handle with care
- Richard M Dawood (3 November 2006)
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influenza and fatal heart disease
- Paul D Griffiths (4 November 2006)
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Is the death rate from influenza declining in the elderly?
- John J Cannell (6 November 2006)
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Influenza vaccination: the case for a gap in the evidence is flawed
- Punam Mangtani, Andrew J Hall, Ben E Armstrong. (7 November 2006)
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Can influenza vaccine overcome vitamin D deficiency?
- John J Cannell (8 November 2006)
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Re: Influenza vaccination: the case for a gap in the evidence is (NOT)flawed
- GH Hall (8 November 2006)
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Flu vaccine production capacity
- Dr Charlie Easmon (12 November 2006)
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Evidence hunters versus public health workers
- Angus Nicoll, Pier Luigi Lopalco and Johan Giesecke (13 November 2006)
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Re: Flu vaccine production capacity
- John Heptonstall (15 November 2006)
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Author’s response
- Tom Jefferson (20 November 2006)
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Policy vs Evidence: A Case Study
- Alan R Haycox, Adrian Bagust and Martyn Regan (21 November 2006)
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Side effects of mercury containing vaccines like influenza
- Joachim Mutter (22 November 2006)
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Call to order: assessing the evidence
- Jochen Mau (23 November 2006)
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Re: Side effects of mercury containing vaccines like influenza
- John Stone (23 November 2006)
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Influenza vaccine uptake among British Muslims attending Hajj-2005 and 2006.
- Shuja Shafi, Harunor Rashid, Kamal Ali, Haitham El Bashir, Elizabeth Haworth, Ziad A Memish, Robert Booy (29 November 2006)
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A provocation that makes reflection
- Luisella Grandori (6 December 2006)
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Influenza seasonal vaccination: is it enough?
- Sergio Mariotti (13 December 2006)
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Nick Hardwick, Consultant Dermatologist Mid Staffs General Hospitals ST16 3SA
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Over the past few decades the practice of Medicine has moved from a basis of personal experience and understanding of the disease process and its treatment, towards the application of authorized protocols and guidelines. The body of Medical knowledge is now so great that this has many advantages. Nevertheless, we do recognize the importance of in-depth understanding, both in applying guidelines sensibly, and managing uncommon conditions for which rigorous evidence-based recommendations are not available. Tom Jefferson's article raises concern about the situation in which an inadequate evidence base has become canonised into established guidelines, Government policy and incentivised practice. It takes a bold man indeed to challenge this set of Emperor's clothes. Perhaps we need a forum within which such nagging concerns can be raised by lesser mortals in order to build up a sufficient groundswell of opinion to challenge the court tailors. Competing interests: None declared |
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GH Hall, Retired Physician EX1 2HW
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5 years ago I asked my GP what the facts were about the pros and cons of ‘flu vaccination, and I was referred to the propaganda hand outs from the Department of Health. These were long on assertion and short on facts. Perhaps unwisely I embarked on a literature search and running correspondence with various civil service mandarins (including Sir Liam Donaldson) with the limited ambition of getting data on what actual tests- of efficacy and safety- were done on current vaccines and with what results. After much evasive action and stalling I was informed that such information was confidential. The Lancet (2001:357:2141) published my scepticism about the extra ordinary claims being made for the ability of ‘flu vaccine to prevent not only the ‘flu but death as well, whatever the cause. Since then there have been a few papers expressing concern about the inconclusive nature of the evidence for its efficacy (1,2). On the other hand, there have been repeated exhortations to the public to “protect themselves.” The enormous expense of this futile exercise doesn’t seem to register- partly, I fear, because of payment inducements offered to GPs. They, perhaps, may claim they believed the recommendations of the DH and carried out the vaccination programs in good faith. This “only carrying out orders” excuse is of doubtful validity. There can be no excuse for the harmful public health decisions and refusal to come clean about what precisely were the reasons for their them. It is too much to hope for repentance and reversal, however. The Faustean contract exemplified in the structure of the Medicines and healthcare products regulatory agency will see to that. 1.van der Wouden et al, Respiratory Medicine (2005) 99,1341-1349. 2. Simonsen L et al, Arch Int Med (2005) 165, 265-272 Competing interests: None declared |
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Peter Doshi, Graduate student Massachusetts Institute of Technology, Cambridge, MA
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In his 28 October review of the available literature, Tom Jefferson finds that there is a "large gap between [influenza vaccination] policy and what the data tell us."[1] What the data tell us, he writes, is that the inactivated vaccines have "little or no effect on the effects measured" and the comparative evidence is insufficient to demonstrate the vaccines are safe. Jefferson's results are consistent with previous epidemiological reviews of the effects of influenza vaccination. A 2005 National Institutes of Health review of over 30 influenza seasons "could not correlate increasing vaccination coverage after 1980 with declining mortality rates in any age group" and concluded "observational studies substantially overestimate vaccination benefit." [2] Annually, public health agencies in the US and UK launch massive campaigns aimed at convincing doctors of the importance of influenza vaccination. Is this necessary? Safe and effective interventions for diseases that truly pose a threat to morbidity and/or mortality are unlikely to be controversial. It is interesting to note here that not only is the evidence supporting the safety and effectiveness of influenza vaccination lacking, but there are also reasons to doubt conventional estimates of the mortality burden of influenza. As I have documented previously, [3] the mortality data is a mess--over the period in which CDC statistical modeling of flu-associated mortality has estimated an 80% rise in deaths, officially recorded flu deaths have dropped 30%. Complicating this is the fact that influenza-like illness is not only indistinguishable from influenza, but far more common, leading to unrealistic expectations of influenza vaccination. The policy questions raised by these reviews are crucial to answer. While it is often said that influenza poses a serious burden to health, influenza vaccines impose their own particular burden--to the tune of billions of dollars annually. If policy is going to be driven by evidence, this requires us, first of all, to consider the evidence. References:
Competing interests: None declared |
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Stuart J cornell, GP Barnsley
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Dear Editor, I concur largely with the sentiments in this paper. However, I have a question regarding why we are still in the position of needing such a paper and three minor points on the paper itself. Fundamentally,the author questions the value of a number of studies in terms of the quality of their study design. At least two of these were published in the last two years in reputable journals. Is it reasonable to ask why are poor quality studies still being funded and published, despite the efforts of this journal and others to improve standards. I agree the cost effectiveness of the influenza vaccination campaign is of vital importance but so is the cost effectivenss of basic research. At the very least, we should be able to rely on studies to do "what they say on the tin" - even varnish does that! Three more minor points. Is this article a personal interpretation of the evidence or does it have the weight of the Cochrane Collaboration behind it? Secondly, on the point of bias in cohort studies it would have been helpful to state whether in fact the cohorts were different (either from studying the papers or by questioning the authors directly) rather than a statement that seems like speculation - "In this case, the vaccinated hemi -cohort MAY have been nore mobile, healthy etc..." I do not have the time to look at original papers and rely on reviews such as this to provide me with the appropriate information. As the author indicates, such information is key to interpreting the reliabiltiy of the study conclusions. Clearly the question of whether the cohorts were comparable is key. Thirdly, there doesn't appear to be any specific reference to the work of the General Practice Research Unit in Birmingham which collects lots of data on flu from general practice. If this data does not provide a useful contribuiton to this issue is it worth collecting? Competing interests: None declared |
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Christian W Mandl, Professor of Virology Medical University of Vienna, A-1095 Vienna, Austria
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In Jefferson's provocative article one reads: "It is impossible for a vaccine that does not prevent influenza to prevent its complications, including admission to hospital." This is very clearly a false statement. It is well known that immunity induced by some vaccines (or for that matter also by some natural infections) does not necessarily protect against (re-)infection. Immunologists distinguish between so-called "sterilizing" immunity which completely prevents replication of an intruding virus and "non-sterilizing" immunity, in which case replication of the pathogen can still occur, but its spread and thus induction of disease symptoms may be reduced to various extents. To prevent severe forms of disease and the likelihood of complications such as secondary infections can be a meaningful objective for a vaccine even though the vaccine may not be able to protect against infection and milder forms of the disease. The author's misjudgement as expressed by the cited statement makes me wonder about the plausibility of his interpretation of the existing data. Competing interests: None declared |
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David S. Fedson, retired 57, chemin du Lavoir, 01630 Sergy Haut, France, Kristin L Nichol
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No gap between policy and evidence for influenza vaccination Sir: Tom Jefferson notes the enormous effort that goes into implementing policies for influenza vaccination each year and asks whether these efforts are justified [1]. After reviewing the evidence from his systematic reviews, he concludes, “inactivated vaccines have little or no effect on the effects measured.” He wonders why there is such a gap between his evidence and policy. Much of Jefferson’s evidence is summarized in Table 2 of his commentary [1]. In randomized controlled trials in children 6 or more years of age and in healthy adults, vaccination reduced the occurrence of influenza and influenza-like illness (ILI). In cohort studies, some of them reported elsewhere [2], vaccination of elderly people living in the community reduced hospitalisation and death from influenza-related pneumonia (P&I) by 26- 27%, respiratory diseases by 22%, cardiac diseases by 24% and all-cause mortality by 42-47%. Among elderly people living in nursing homes, vaccination similarly reduced P&I hospitalisations and deaths by 42% and all-cause mortality by 60%. All of these estimates of vaccine efficacy and vaccination effectiveness (VE) were statistically significant. Jefferson’s believes his summary estimates of relative risk reductions (VE) in vaccinated compared with unvaccinated individuals contradict stated policies for influenza vaccination. He identifies three reasons to explain this contradiction. First, vaccination policies rely heavily on non-randomised studies. Randomized controlled trials are preferred by many investigators, but this preference is based on historical, pragmatic and heuristic reasons, and cannot be justified on epistemological grounds alone [3]. He cites the absence of details in published reports on the viruses in circulation and the virus content of vaccines used during study periods, yet it is difficult to understand how this could invalidate the results obtained; if such information were required, it could easily be obtained from public sources. Heterogeneity among studies and study years does exist and can be a problem [4], but Jefferson argues this can be overcome by “averaging” the outcome measurements over several years. His findings for observational studies among older adults yield relative risk reductions that are statistically significant and robust. Second Jefferson cites the lack of convincing evidence of vaccination on the effects “at the centre of campaign objectives”. Leaving aside his documentation of vaccination effectiveness for elderly and high-risk adults, still the centre of all campaigns [5], he notes the failure to show a vaccine effect on influenza in children less than 2 years of age, undoubtedly due to small numbers, but he is unable to consider its effects on influenza- related otitis media, a very frequent complication. In healthy adults, he fails (barely) to show fewer days off work or reductions in serious but infrequent complications and death, while ignoring significant reductions in influenza and ILI. Third, Jefferson is concerned about the lack of vaccine safety data in published studies, ignoring the fact that 300 million doses or more are used each year [5]. If there were important safety problems, we wouldn’t need a systematic review to detect them. When health officials recommend influenza vaccination, their primary goal is not to "prevent seasonal outbreaks" of influenza, as Jefferson believes (see his summary points), but to prevent costly hospitalizations for influenza- related conditions and reduce influenza-related mortality. In formulating policy, they must consider three types of evidence. First, as a biological product, influenza vaccine must ‘work’. Randomized controlled trials and their systematic reviews provide evidence for vaccine efficacy. Second, health officials must have some evidence of the population burden of disease and an indication of whether it can be reduced by vaccination. Observational (cohort and case-control) studies can help document reductions in attributable (not relative) risk following vaccination, and this is the information health officials need [4, 6]. Third, given other costly healthcare priorities (a point strongly emphasized by Jefferson), health officials must determine whether their vaccination policies will be economically worthwhile. The evidence they need cannot be obtained from the reports of Jefferson and his colleagues; it must come from other sources [7-10]. It should be abundantly clear that there is no “gap between policy and evidence” [1]. Systematic reviews alone can never provide the three types of evidence needed by health officials to formulate their policies for influenza vaccination. References 1. Jefferson T. Influenza vaccination: policy versus evidence. BMJ 2006; 333: 28 October bmj.com. 2. Jefferson T, Rivetti D, Rivetti A, Rudin M, Pietrantoni CC, Demichelli V. Efficacy and effectiveness of influenza vaccine in elderly people: a systematic review. Lancet 2005; 366: 1165-74. 3. Abel U, Koch A. The role of randomization in clinical studies: myths and beliefs. J Clin Epidemiol 1999; 52: 487-97. 4. Nichol KL. Heterogenity of influenza case definitions and implications for interpreting and comparing study results. Vaccine 2006; [Epub ahead of print]. 5. The Macroepidemiology of Influenza Vaccination (MIV) Study Group. The macroepidemiology of influenza vaccination in 56 countries, 1997-2003. Vaccine 2005; 23: 5133-43. 6. Nichol KL. Influenza vaccination in the elderly: impact on hospitalisation and mortality. Drugs Aging 2005; 22: 495-515. 7. Heikkinen T, Booy R, Campins M, Finn A. Olcen P, Peltola H, et al. Should healthy children be vaccinated against influenza? A consensus report of the Summits of Independent European Vaccination Experts. Eur J Pediatr 2006; 165: 223-8. 8. Nichol KL. Cost-benefit analysis of a strategy to vaccinate healthy working adults against influenza. Arch Intern Med 2001; 1611: 749-59. 9. Turner DA, Wailoo AJ, Cooper NJ, Autton AJ, Abrams KR, Nicholson KG. The cost effectiveness of influenza vaccination of health adults 50-65 years of age. Vaccine 2006; 24: 1035-43. 10. Maciosek MV, Solberg LI, Coffield AB, Edwards NM, Goodman MJ. Influenza vaccination health impact and cost effectiveness among adults 50 to 64 and 65 and older. Am J Prev Med 2006; 31: 72-9. Competing interests: David S. Fedson has received honoraia from sanofi pasteur for lectures on influenza vaccination, and in 2003-2004 served as a part-time consultant to the Influenza Vaccine Supply Internatinal Task Force |
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John Stone, none London N22
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G H Hall complains about secrecy regarding UK flu and flu vaccination data. Some information is available from Government websites, but it is anomalous and confusing to say the least. According to the Chief Medical Officer's publication 'Explaining Pandemic Flu'(1 March 2005): "Ordinary flu occurs every year during the winter months in the UK. It affects 10-15% of the UK population, causing around 12,000 deaths every year." [1] On the other hand according to another official publication 'Summary of flu immunisation policy' (3 October 2004): "Even during a winter where the incidence of flu is low, 3-4000 deaths may be attributed to 'flu; this can rise much higher in epidemic years, for example there were an estimated 13,000 deaths in 1993 which were attributable to 'flu and 29,000 in 1989/90." [2] Thus according to first statement flu causes 12,000 deaths every year, while according to the second statement in low years the figure is 3 -4,000 but unlike the 12,000 this is not even a hard figure, only "may be". We need real figures, and clear criteria. It is also surely essential to know what impact the vaccination campaign has on mortality. The BBC reported that take up in the target vulnerable population in 2004-5 was 71.5% [3]. Did this have any impact on the alleged annual death-toll of 12,000? Can it be shown that flu mortality was substantially less in the vaccinated amongst the target population, as opposed to the unvaccinated, and what was the effect on general mortality? If the Government cannot provide transparent data - only fragments without context - the question remains "why". [1] http://www.dh.gov.uk/PublicationsAndStatistics/Publications/ PublicationsPolicyAndGuidance/PublicationsPAmpGBrowsableDocu ment/fs/en?CONTENT_ID=4106931&MULTIPAGE_ID=5093031&chk=2UuNhx [2] http://www.dh.gov.uk/PolicyAndGuidance/HealthAndSocialCareTo pics/Flu/FluGeneralInformation/FluGeneral/fs/en? CONTENT_ID=4001688&chk=BbJebs [3]'Q & A: Flu Jabs', 23 November 2005: http://news.bbc.co.uk/1/hi/health/4459140.stm Competing interests: None declared |
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Richard M Dawood, Director Fleet Street Clinic, 29 Fleet Street, London EC4Y 1AA
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Publishing an article1 that undermines the UK’s annual flu vaccination programme just as it was due to start, demonstrates questionable editorial wisdom on the part of the BMJ. So too does the decision to promotion this article by way of a press release, circulated widely to the national news media with the clear intention of achieving maximum press coverage; the resulting tabloid headlines contrasted somewhat with the more reasoned scientific debate that the article purported to be urging. Flu vaccine is a scarce and valuable commodity. The economics of producing it are precarious, and for the handful of remaining producers, the margins are small and the risks are considerable. This year’s supplies have already been made and paid for. If news coverage of the article results in reduced public inclination to be vaccinated, there will be no cost savings, simply vaccine going to waste. Next years’ supplies, however, have not yet been ordered or manufactured. If fewer doses are produced, our capacity to respond to a serious outbreak, or indeed a pandemic, will have been harmed. The BMJ should have shown greater sensitivity in handling this issue. 1. Influenza vaccination: policy versus evidence, Jefferson T, BMJ 2006;333:912-915 Competing interests: My practice offers flu vaccination. |
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Paul D Griffiths, Professor of Virology Centre for Virology, RFUCMS, Rowland Hill St, London NW3 2PF
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When you own a hammer, everything in the world resembles a nail. When you are an expert in the analysis of double-blind randomized placebo controlled trials, it must be frustrating to find an area with limited contemporary data; such frustration is evident throughout Dr. Jefferson’s recent article on influenza vaccine. Vaccines are evaluated for efficacy and safety by means of double- blind randomized placebo controlled trials; witness the recent results from the novel vaccines against human papillomaviruses (1,2). Yet, once the vaccine has been licensed, there is an ethical limit to the additional studies which can be placebo controlled. The influenza field is particularly difficult because, as Dr. Jefferson summarizes, strains of influenza virus change annually, as does the vaccine and there are varying degrees of mismatch between the vaccine deployed and the vaccine which actually circulates subsequently in any one season. There is also the problem of the non-specific clinical diagnosis of influenza or influenza- like illness. We would all like to have more data in this area, but one statement in the article concerns me: “A meta-analysis of inactivated vaccines in elderly people showed a gradient from no effect against influenza or influenza-like illness to a large effect (up to 60%) in preventing all- cause mortality. These findings are both counterintuitive and implausible, as other causes of death are far more prevalent in elderly people even in the winter months. It is impossible for a vaccine that does not prevent influenza to prevent its complications, including admission to hospital.” In contrast to what Dr. Jefferson says, it is well recognized that viruses can trigger adverse outcomes even if they do not declare themselves clinically with their classical syndromes. The resulting indirect effects can nevertheless be prevented by Dr. Jefferson’s beloved double-blind randomized placebo controlled trials using drugs active against the provoking viruses (reviewed in 3). Furthermore, additional studies show that the inflammatory response to respiratory tract infection, but not to vaccination, are associated statistically with an increased risk of myocardial infarction and stroke (4) while epidemics of proven influenza infection are associated with episodes of death attributed to ischaemic heart disease (5). All of this information provides a plausible explanation for the reported survival benefit associated with receipt of influenza vaccine. 1. Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, et al. Efficacy of bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004; 364(9447): 1757-65. 2. Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncology 2005; 6(5): 271-8. 3. Griffiths PD. The indirect effects of virus infections. Rev Med Virol 2003; 13: 1-3. 4. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004; 351(25): 2611-8. 5. Fleming DM, Cross KW, Pannell RS. Influenza and its relationship to circulatory disorders. Epidemiology Infection 2005; 133(2): 255-62. Competing interests: I receive influenza vaccine annually. I am a member of the Department of Health Joint Committee on Vaccination and Immunisation, although I am writing this reply in a personal capacity. |
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John J Cannell, psychiatrist Atascadero State Hospital
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Tom Jefferson points out that, for ethical reasons, it is difficult to conduct a truly random interventional study for influenza effectiveness. That is, it is difficult to take a large group of well matched elderly people and deny half of them a flu shot while giving the other half a flu shot and then wait to see who dies. However, influenza-associated deaths in the United States more than doubled between 1976 and 1999 and 90% of those deaths were in patients 65 years and older, a trend that can only be partially explained by the aging population. (1) If flu shots are effective, and if more and more older Americans have been getting them, why have more and more older American been dying of the flu? 1. Thompson WW, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-86. Competing interests: Director, The Vitamin D Council |
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Punam Mangtani, Senior Clinical Lecturer London School of Hygiene and Tropical Medicine, Andrew J Hall, Ben E Armstrong.
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Jefferson’s article attempts to use evidence, ours included, to question the seasonal influenza vaccination campaign, but raises a number of issues. Firstly the article is not one that follows established Cochrane procedures in that it provides incomplete evidence. Although noted in table 2, Thomas Jefferson does not discuss the high, over 70%, efficacy against laboratory confirmed illness from influenza by the trivalent inactivated vaccine in healthy adults and children in the Cochrane reviews or, in fact, other meta-analyses (e.g. reference 1appendix 20 page 249). In a trial in over 60 year olds vaccine efficacy was only slightly lower at 58% (95% CI 95% CI 26-77%))2. This last trial is not mentioned in the article but is key. As there is clear evidence of benefit against laboratory confirmed illness from influenza vaccination including in over 60 year olds, a trial now, with mortality as an endpoint, would not be ethical. Instead we have to rely on observational studies - which Thomas Jefferson dismisses. Such studies have an important role but we have to deal with the following constraints: the presence of both positive and negative confounding and the restriction to easily measured outcomes. It is well known that vaccine recipients may be different to non- recipients in many ways. In some populations there may be a “healthy vaccine effect” with non-smokers and those with higher educational or social status more likely to have influenza vaccine3;4. This positive confounding would bias upwards any protective effect of the vaccine. Negative confounding “by indication”, in which those identified as more frail are more likely to be offered the vaccine, would bias downwards any protective effect of the vaccine. The predominance of negative confounding explains some of the crude estimates of effect showing no effect of the influenza vaccine in the table in the Cochrane review of influenza vaccine in the elderly5. Statistical methods are commonly used to control for both positive and negative confounding. By doing so a protective effect obscured by negative confounding is then possible to see. Residual confounding is however often a problem because measured factors are not able to capture all the differences between vaccine recipients and non recipients. Residual negative confounding will act to underestimate an effect. Less well recognised though, is the scope to over-estimate the true benefit of an intervention if there is residual confounding by the “healthy vaccine” effect. Luckily the presence of residual confounding can be assessed by seeing if there is any effect of the vaccine in seasons where no influenza is circulating. This method was first used for influenza vaccine by Ohmit and Monto looking at hospital admissions in the elderly. A 31% protective effect against hospitalisation for pneumonia and influenza was noted that was not seen in the corresponding peri-influenza winter season6. More recently we conducted a large UK cohort study using the General Practice research Database over several years that included over 2 million person- years of follow-up. Overall vaccine effectiveness was 21% (95% CI 17-26%) for respiratory disease hospitalisations and 12% for respiratory deaths (95% CI 8-16%) in over 64 year olds, with no protective effect seen in the corresponding non-influenza winter season. In contrast a protective effect against all-cause mortality was seen in the non-influenza season suggesting a “healthy vaccinee” effect for that outcome. This protection against respiratory disease deaths, after adjustment for confounding, is missing from the full Cochrane review7 and incorrectly noted as not significant in the summary paper5. An analysis with similar logic found that though unvaccinated elderly persons showed mortality peaks following peaks of influenza circulating in the community, those vaccinated were substantially protected from these mortality peaks. 8 It would have been preferable that the systematic review of observational studies in the elderly that Thomas Jefferson refers to had conducted a more rigorous assessment of the methods studies used to deal with confounding. As experts in systematic reviews have pointed out, the presence of heterogeneity in the results of studies, especially observational studies, should be carefully examined rather than dismissed9 . The final constraint of observational studies also applies to trials without laboratory confirmation of the aetiological agent - misclassification error in measuring outcome. Such error can be easily shown to under-estimate any effect of an exposure 10. Given outcomes that are inevitably non-specific it is thus not surprising that estimated effects of vaccine are often low. A related issue is Jefferson’s inappropriately dismissive interpretation of the modest effect of the influenza vaccine. A just over 20% protective effect on a non-specific outcome such as an admission for acute respiratory disease must reflect a much larger effect in more specific outcomes. Finally the article suggests that influenza vaccination requires resources which could be used for other interventions. Seasonal influenza can be mild. It is certainly so in some years but not in others. The seasonal epidemic in 1989/90 is but one example with about 18,000 excess deaths in the UK after taking into account a slight deficit of deaths after the epidemic11 ; with an average of over 12,000 deaths per year when crudely compared with death rates in similar weeks in other years when influenza is not circulating12. These are rough estimates as laboratory tests to confirm seasonal influenza as the cause of death are not usually done. Because the severity of seasonal influenza as a result of antigenic drift cannot be easily predicted, yearly influenza vaccination is required. Cost-effectiveness studies of influenza vaccine have been conducted with sensitivity analyses of the results to varying the attack rate or assuming no deaths occurred1. In those at high risk for complications of influenza, including over 64 year olds, the cost per quality adjusted years of life saved of vaccination is under a few thousand pounds, well below the accepted threshold for funding in the heath sector in the UK including smoking cessation activities or breast cancer screening13. In short, inactivated trivalent influenza vaccines are highly effective against laboratory confirmed influenza, with more evidence in younger adults but also clear evidence in elderly people. In addition observational studies have shown that the influenza vaccine currently in use prevents not only hospitalisations but also death in over 64 year olds. It is not clear why the BMJ should publish such a flawed article, contrary to the judgement of virtually all other scientists who have looked at the question, particularly at a time of year when optimising influenza vaccine coverage can save lives. Reference List (1) Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Health Technol Assess 2003; 7(35):iii- xiii, 1. (2) Govaert TME, Thijs CTMCN, Masurel N, Sprenger N, Dinant GJ. The efficacy of influenza vaccination in elderly individuals: a randomised double-blind placebo-controlled trial. JAMA 1994; 272:1661-1665. (3) Christensen B, Lundbergh P. Comparison between cohorts vaccinated and unvaccinated against influenza and pneumococcal infection. Epidemiol Infect 2002; 129:515-524. (4) Mangtani P, Breeze E, Kovats S, Ng ES, Roberts JA, Fletcher A. Inequalities in influenza vaccine uptake among people aged over 74 years in Britain. Prev Med 2005; 41(2):545-553. (5) Jefferson T, Rivetti D, Rivetti A, Rudin M, Di PC, Demicheli V. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet 2005; 366(9492):1165-1174. (6) Ohmit SE, Monto AS. Influenza vaccine effectiveness in preventing hospitalization among the elderly during influenza type A and type B seasons. Int J Epidemiol 1995; 24:1240-1248. (7) Rivetti D, Jefferson T, Thomas R, Rudin M, Rivetti A, Di PC et al. Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev 2006; 3:CD004876. (8) Armstrong B, Mangtani P, Fletcher AE, et al. Influenza vaccination protects against excess deaths occurring during periods of high circulation of influenza. BMJ 2004; 329:660-661. (9) Egger M, Smith GD, Altman D. Systematic reviews in health care: meta-analysis in context. 2nd Ed ed. London: BMJ; 2001. (10) Mertens TE. Estimating the effects of misclassification. Lancet 1993; 342:418-421. (11) Ashley J, Smith T, Dunnell K. Deaths in Great Britain associated with the influenza epidemic of 1989/90. Population Trends 1991; 65:16-20. (12) Fleming DM. The contribution of influenza to combined acute respiratory infections, hospital admissions and deaths in winter. Communicable Disease and Public Health 2000; 3:32-38. (13) Mason J, Drummond M, Torrance G. Some guidelines on the use of cost effectiveness league tables. BMJ 1993; 306:570-572. Competing interests: None declared |
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John J Cannell, psychiatrist Atascadero State Hospital, Atascadero, CA, 93423
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Tom Jefferson points out that, for ethical reasons, it is difficult to conduct a truly random interventional study of influenza vaccine effectiveness. That is, given current recommendations, it is difficult for investigators to take a large group of well-matched elderly people, deny half of them a flu shot, and then wait to see who dies. Another way to look at his argument is to ask if influenza related deaths have decreased in age groups most likely to be immunized (persons over age 65) more than in age groups less likely to be immunized (persons under age 65). If influenza vaccines are effective, then death rates should be falling over time in the heavily-vaccinated elderly but unchanged over time in lightly-vaccinated younger persons – all other things being equal. In fact, influenza mortality and the influenza related hospitalization rates significantly increased for elderly Americans between 1980 and 2000, a phenomenon only partly explained by the aging population.(1,2) Increasing hospitalization and death rates among the elderly stands in stark contrast to annual mortality changes in persons less likely to be immunized. Excess pneumonia and influenza (P&I) deaths for persons under age 65 dramatically decreased between 1975 and 1994.(3) Childhood mortality rates due to all respiratory illnesses fell markedly in the 1990’s.(4) If flu shots are effective - and if more older Americans have been getting them - why have more older Americans been dying of the flu? Furthermore, why has the P&I death rate in the younger - and less likely to be immunized - population declined so dramatically during this same time? All other things being equal, such changes in P&I death rates are inconsistent with vaccine effectiveness, indeed they suggest the vaccine is dangerous. As is often the case in medicine, all other things are not equal. Recently, in Epidemiology and Infection, my co-authors and I reviewed the substantial evidence that suggests vitamin D favorably affect influenza infection.(5) Indeed, the extant epidemiological and interventional evidence is so suggestive that we asked, “Is influenza infection a sign of vitamin D deficiency as much as Pneumocystis carinii pneumonia is a sign of AIDS.” As 25(OH)D levels are dependent on surface UVB radiation, increased surface UVB radiation over time will tend to increase 25(OH)D levels over time. Surface UVB radiation, as inferred from satellite-based measurements, has increased since 1990, probably due to ozone depletion.(6) Furthermore, the incidence of non-melanoma skin cancer, the skin cancer most closely associated with sunlight, dramatically increased in the 1980’s and 1990’s.(7,8) Likewise, cataracts are thought to be related to UVB radiation. Cataract extraction rates in Minnesota quadrupled between 1980 and 1992.(9) Both the increasing incidence of non-melanoma skin cancers and increasing cataract extraction rates suggest that surface UVB radiation has significantly increased in the last 20 years. Increasing surface UVB should also increase average 25(OH)D levels, assuming no change in sun avoidance or global weather patterns. To my knowledge, no serial measurements of 25(OH)D levels in stored sera exist to confirm the hypothesis that increasing surface UVB radiation has translated into higher year-over-year 25(OH)D levels. As surface UVB radiation increased, 25(OH)D levels would only have increased in those whose sun-exposure habits had either increased or not changed over time. Despite recent government campaigns to limit sun exposure, the young often ignore that advice while the elderly follow it.(10) Indeed, one estimate of sun exposure in the young actually showed it increased during the 1990’s.(11) That is, there are age- discrepant time trends in sun exposure habits over the last 20 years. The vitamin D theory of influenza would predict that, despite influenza vaccines, P&I mortality among the elderly would have serially increased due to falling 25(OH)D levels, while P&I mortality among the young would have serially decreased due to increasing 25(OH)D levels. The age-discrepant time trends in P&I mortality that are being observed are exactly what the vitamin D theory of influenza would predict. As Mr. Jefferson reported, "a messy blend of truth conflicts and conflicts of interest making it difficult to separate factual disputes from value disputes" in the debate about influenza vaccines. Perhaps the elderly, virtually all of whom are vitamin D deficient, would be better off getting an injection of vitamin D in the fall, rather than a flu shot?(12) 1. Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004 Sep 15;292(11):1333-40. 2. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-86. 3. Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, et al. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis. 1998;178:53-60. 4. Panickar JR, Dodd SR, Smyth RL, Couriel JM. Trends in deaths from respiratory illness in children in England and Wales from 1968 to 2000. Thorax. 2005;60:1035-8. 5. Cannell JJ, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006 Dec;134(6):1129-40. Epub 2006 Sep 7. 6. Pinker RT, Zhang B, Dutton EG. Do satellites detect trends in surface solar radiation? Science. 2005;308:850-4. 7. Christenson LJ, Borrowman TA, Vachon CM, Tollefson MM, Otley CC, et al., Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA. 2005;294:681-90. 8. Karagas MR, Greenberg ER, Spencer SK, Stukel TA, Mott LA. Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. New Hampshire Skin Cancer Study Group. Int J Cancer. 1999 May 17;81(4):555-9. 9. Baratz KH, Gray DT, Hodge DO, Butterfield LC, Ilstrup DM. Cataract extraction rates in Olmsted County, Minnesota, 1980 through 1994. Arch Ophthalmol. 1997 Nov;115(11):1441-6. 10. Stoebner-Delbarre A, Thezenas S, Kuntz C, Nguyen C, Giordanella JP, et al. [Sun exposure and sun protection behavior and attitudes among the French population] Ann Dermatol Venereol. 2005;132:652-7. (abstract only) 11. Robinson JK, Rigel DS, Amonette RA. Trends in sun exposure knowledge, attitudes, and behaviors: 1986 to 1996. J Am Acad Dermatol. 1997;37:179-86. 12. Kaplan M. Sunshine may beat the winter flus. Seasonal illnesses could be down to lack of vitamin D. Nature. 3 November 2006; | doi:10.1038/news061030-12 Competing interests: Director, The Vitamin D Council |
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GH Hall, Rtd Physician EX1 2HW
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I agree that ref 2 (Govaerts et al) is indeed a key reference as it describes a rare randomised control trial of vaccine in the elderly. It is only fair to point out however that it was explicitly stated in that paper that "with an increase in age,the effect of vaccination disappeared." I find it difficult to interpret this as "clear evidence of benefit" and therefore excusing the need for further properly conducted double blind RCT's as recommended by Jefferson. Competing interests: None declared |
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Dr Charlie Easmon, Medical Director The Number ONe Health Group, 1 Harley Street, London W1G 9QD
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Jefferson could use his views to dismantle a lot of the healthcare we currently provide. In some instances this could be for the good. With a potential flu pandemic on the way I believe he does mankind a disservice. The current flu campaigns help to ensure a vaccine production capacity which we all know needs to be increased rather than decreased. For 'ordinary flu' we all take his point and that from the evidence - in a high incidence flu year the vaccines are worthwile in a low incidence year perhaps not - but we do not have crystal balls to know which type of year we are about to get. In my view governments are taking sensible pragmatic decisions to ensure vaccine production both for those years that it really is needed for high-incidence flu and from now to ensure we have high-levels of capacity against a possible pandemic. Competing interests: I run a private clinic that sells flu vaccinations |
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Angus Nicoll, Seconded National Expert European Centre for Disease Prevention and Control, Pier Luigi Lopalco and Johan Giesecke
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Though there is little new in this review article (much is reiterating previous publications by the same author [1-3]) and there are significant gaps in the data he presents [4] the views of the author require careful consideration. This is especially the case since the article appeared at a time when flu vaccination campaigns are at their peak in most European countries and the paper was interpreted by the media in some countries as meaning that immunisation of the recognised risk groups (the elderly, those with chronic diseases and health care workers) was of no value. We are really concerned about the conflicting views that sometimes exist between "evidence hunters" and public health workers, even though we are sure that a serene scientific discussion at the proper time can benefit prevention policies. The author considers two issues which we wish to comment on: Effectiveness. "The heavy reliance on non-randomised studies (chiefly cohort studies) especially in the elderly" ... "Either the absence of evidence or the absence of convincing evidence on most of the effects at the centre of campaign objectives". Placebo controlled randomised controlled trials (RCTs) are one gold standard, but in fact RCT data are available both on efficacy and effectiveness of flu inactivated vaccines, including in the elderly and these indicate a protective effect. [2,4-6]. Nevertheless they are few trials as performing RCTs is difficult, especially among particular higher risk populations. Even in the face of incomplete knowledge, many people would consider it unethical to allow high risk population groups to miss this opportunity of protecting themselves in order to generate RCT data. [4] Observational studies may be affected by bias and confounding but dealing with this is a large part of the science of epidemiological research and many studies have attempted to allow for it and still found protective effect. The bias also operates in both directions with tendencies for better off groups to be immunised counterbalanced by people with more severe underlying conditions being immunised preferentially.[4] While unknown sources of bias and confounding can never be absolutely ruled out, the large body of evidence points to immunisation is protective against influenza or influenza like illness). Even if it’s incomplete, the list provided by the Author in his table 2 shows a majority of studies having positive (protective) outcomes, especially regarding the efficacy/effectiveness in the elderly who remain the principle target of the vaccination campaign in EU countries. Estimated point efficacy range from 23% to 95% in this age group, depending on the considered outcome and the study design. [1] Safety. "The small and heterogeneous dataset on the safety of inactivated vaccines" – Inactivated influenza vaccines are widely used worldwide from decades and data on safety are available from routine adverse event surveillance systems and focused studies. These sufficient to assert that the current used inactivated vaccines are generally very safe and are among the safest vaccines used in the targeted population groups. The only serious enduring adverse effect being an increase of Guillan-Barre syndrome in older recipients at a rate of around one per million vaccine recipients. [7] Hence it is important to underline that vaccination is the most effective available measure to lessen the burden of seasonal influenza. The current vaccination policy carried out in EU countries (mainly centred on the selective vaccination of high risk groups such as elderly people and persons with underlying chronic disease) is based on strong scientific evidence. Even if such evidence does not fit the gold standard placebo- controlled, double-blinded-RCT criteria “Lack of evidence” doesn’t necessarily mean “evidence of lack of efficacy”. Not every scientific question can be answered only by RCTs [8]. Nevertheless, this article shows that there is room for discussion and further investigation and development in influenza vaccination. Better and more universal vaccines are needed but presently the field efficacy of influenza vaccines is not routinely estimated in the European Union. This is an important gap given that the mix of circulating viruses and the vaccine combination changes over time.[9] Also there is the issue of the vaccination children vaccination, where the lack of knowledge is particularly evident (and that’s the reason why no EU country has started routine vaccination in children). Producing an expert independent opinion on childhood vaccination is a priority in ECDC’s current (2006) work-plan and developing a plan for routine monitoring of vaccine efficacy in the EU is central in its proposed 2007 work-plan. 1. Jefferson T. Influenza vaccination: policy versus evidence. BMJ 2006; 333:912-5 http://www.bmj.com/cgi/content/full/333/7574/912 2. Jefferson T, Rivetti D, Rivetti A, Rudin M, Pietranjoni C, Demiceli V. Efficacy and effectiveness of influenza vaccines in elderly person: a systematic review. Lancet 2005; 366: 1165-74 3. Rivetti D, Demicheli V, Di Pietrantonj C, Jefferson TO, Thomas R. Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev 2006; (3):CD004876. 4. Mangtani P, Hall AJ, Armstrong BE. Influenza vaccination: the case for a gap in the evidence is flawed. BMJ Rapid response (Nov 7 2006) http://www.bmj.com/cgi/eletters/333/7574/912#148768 5. Mazick A, Christiansen AH, Samuelsson S, Mølbak K. Using sentinel surveillance to monitor effectiveness of influenza vaccine is feasible: A pilot study in Denmark. Eurosurveillance 2006; 11 (10) http://www.eurosurveillance.org/em/v11n10/1110-226.asp. 6. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisor Committee on Vaccination Practices (ACIP). Morbid Mortal Wkly Rep 2006; 55:1-41. 7. WHO Influenza vaccines (WHO position paper): WER 2005; 80: 279- 286. http://www.who.int/wer/2005/wer8033/en/index.html 8. Gordon C S Smith and Jill P Pell. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ, 2003; 327: 1459-61. http://www.bmj.com/cgi/reprint/327/7429/1459.pdf 9. Gerdil C. The annual production cycle for influenza vaccine. Vaccine 2003; 21: 1776-9. Competing interests: None declared |
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John Heptonstall, Director of the Morley Acupuncture Clinic Leeds LS27 8EG
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Dr Easmon's point could be valid were the problem with flu jabs only caused by the inability of each year's output to be married to the flu strain but it is not. Also, as Dr Cannell points out, flu jabs cause death and debility; and this may be to an extent that is probably - as anyone in practice recognises from anecdotal reports - far in excess of reported events. Apart from this fact being denied by some authorities, the reasoning behind the fallout from such jabs is not clear but ought to concern anyone who intends to manufacture or use a single strain vaccine - as has been postulated by 'experts' in the field - that might not be an exact match for bird flu strain but may 'provide some protection against that strain'. Jefferson's excellent work suggests such a startegy may not be best practice, may indeed as Dr Cantell argues be dangerous, and may be better met by Vitamin D and other protective nutrients (A, C etc.) than any vaccine. Regards John H. Competing interests: None declared |
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Tom Jefferson, Coordinator Cochrane Vaccines Field
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The responses by Mandl, Fedson and Nichol, Nicoll et al and Griffith all have one common theme: the authors’ obstinate refusal to look in a dispassionate fashion at the totality of comparative evidence of the effects of inactivated vaccines for seasonal influenza. My analyses was based on 206 studies (several million observations’ worth of data) included in systematic reviews spanning some 40 years. No one so far has challenged my key conclusion that the optimistic WHO statement that vaccination of the elderly reduces the risk of serious complications or of death by 70%-85% is not based on evidence. The interesting hypotheses by Mandl and Griffith do not fit some of the evidence in the elderly population. They cannot explain how in years of good matching between vaccine antigenic content and circulating viruses the vaccines fail to prevent deaths from all respiratory diseases in elderly community dwellers (1.32, 95% CI 1.25 to 1.39, 426668 observations) while at the same time preventing 42% (25% to 55%, 404759 observations) of deaths from all causes1, presumably including deaths from falls, accidental poisoning, accidents, hypothermia and so on. Fedson and Nichol deride my choice of example of poor methodological quality of a large number of available cohort studies: failure to report vaccine content, its match to circulating viruses and the level of circulation. The authors of the studies either did not know such details or like Fedson and Nichol thought them irrelevant and would leave a reader -Sherlock Holmes to work them from “official records”. Vaccine matching and level of circulating influenza viruses are the most important predictor of vaccine efficacy and effectiveness. The closer the match and the higher the viral circulation, the better the performance of the vaccine2. Without such knowledge it would be very difficult to give an honest and reliable assessment of the effects of the vaccine. That is one of the reasons why these studies are of poor quality. I note with worry their statement that decisions should be made on three of the most notoriously biased sources of information: non- randomised studies, expert opinion and economic evaluations3 4. It is precisely because the vast majority of comparative evidence on the elderly comes from non-randomised studies that we are left with the question: are the effects we witness due to the vaccines or are they due to confounding? The tone of the response by Fedon and Nichol (lack of vaccines’ effect in small children is “undoubtedly due to small numbers” and my concern over “lack of vaccine safety data” a statement from which they conveniently omitted the key word “comparative”) would suggest that my review appeared to be questioning a dogma. Heretics like me get short shrift. I repeat my statement that especially in the elderly there are at present an insufficient numbers of field trials (5, of which only one has been carried out in the last decade) to allow reasonable certainty of the effects of inactivated vaccines. The nature of the evidence from non- randomised designs when analysed critically and exhaustively is weak and contradictory. I repeat my observation that the totality of safety evidence from comparative (i.e. studies in which a proportion of participants were contemporaneously exposed or not to the vaccines) sources is tiny in small children (35 observations) and small in the elderly (2963 observations). Nicoll and co-authors claim that there is little new in my review. Certainly the evidence I quote has been in the public domain for some time. So why has an independent policy evaluation not taken place before? Such an evaluation is welcome but I fear it may take the guise of a descriptive (e.g. ecological) or non-randomised design (i.e. retrospective cohort). If that were the case, we may have to find out whether inactivated influenza vaccines do protect vulnerable people in potentially the most disagreeable and inhuman way: the hard way. Tom Jefferson
1. Rivetti D, Demicheli V, Di Pietrantonj C, Jefferson TO, Thomas R. Vaccines for preventing influenza in the elderly. The Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004876. DOI: 10.1002/14651858.CD004876. 2. Demicheli V, Rivetti D, Deeks JJ, Jefferson TO. Vaccines for preventing influenza in healthy adults. The Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD001269.pub2. DOI: 10.1002/14651858.CD001269.pub2. 3. Kunz R, Oxman AD. The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials. BMJ 1998; 317; 1185-1190 4. Jefferson T, Demicheli V, Vale L. Quality of systematic reviews of economic evaluations in health care JAMA2002; 287 (21): 2809-2812. Competing interests: TJ owned shares in Glaxo SmithKline and received consultancy fees from Sanofi- Synthelabo (2002) and Roche (1997-1999). |
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Alan R Haycox, Senior Lecturer University of Liverpool Management School, Chatham Street, Liverpool, L69 7ZH, Adrian Bagust and Martyn Regan
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Tom Jefferson’s paper1 is welcome if it leads policy-makers to acknowledge evidence being more than a non-essential afterthought to their policy-making. The NHS R&D HTA programme undertook an RCT evaluating the extension of routine influenza immunization to the healthy elderly2,3. The study was undertaken in a primary care setting and adequately powered given the anticipated efficacy of the vaccine. A diary system was employed to capture all episodes of influenza-like illness irrespective of whether they led to contact with the health services. Quality of life was evaluated at 2, 4 and 6 months and adverse reactions were analysed to assess possible side-effects. Finally, an impact model was used to assess the generalisability of results throughout the NHS. In short, this trial generated exactly the type of robust and high quality evidence required to inform national policy-making. Unfortunately, while our study was still in progress, new guidelines were introduced that extended routine vaccination to all people over 65. In such circumstances, we had no option but to stop randomising patients to placebo as we felt that this could disadvantage them in comparison to routine clinical care. In effect, our attempt to gain evidence had been obviated by extending vaccination to precisely the patient group that we were in the process of evaluating. Because of this, the quality of evidence that we were able to generate was severely constrained. However, even with this limited evidence base, we questioned the potential benefits and cost savings associated with extending vaccination to the healthy elderly as it compared poorly with standards applied in recent NICE guidelines and introduced the danger of the worried well ‘crowding out’ patients in whom vaccination would provide greater clinical benefits. The existing gap between policy and evidence will remain until evidence-based policy-making supplants political expediency in the NHS. 1 Jefferson T. Influenza vaccination: policy versus evidence. BMJ 2006; 333: pp912-915. 2 Allsup S, Haycox A, Regan M, Gosney M. Is influenza vaccination cost effective for healthy people between ages 65 and 74 years? A randomised controlled trial. Vaccine 2004; 23: pp639-645. 3 Allsup S, Gosney M, Haycox A, Regan M. Cost-benefit evaluation of routine influenza immunisation in people 65-74 years of age. Health Technology Assessment NHS R&D HTA Programme 2003; Vol 7: No 24. Competing interests: None declared |
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Joachim Mutter, Medical Doctor Hospital Epidemiology, University Medical Center, Breisacherstr. 115 B, 79106 Freiburg
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Sir: Tom Jefferson notes that there are no sound studies regarding the safety of vaccines [1]. This is especially true for thimerosal in vaccines, an organic mercury compound. Most vaccines, especially for developing countries, contain thimerosal, an organic mercury compound. It has been shown recently that this additional mercury body burden may be a factor for the development of autism [2]. In the U.S. there are actually 1.5 Million children diagnosed with austism spectrum disorders (ASD) and additional thimerosal containing vaccines may have caused this epidemic 16 years ago [3]. Many reviews regarding this topic state that the increase in the incidence of autism occured mostly after cessation of thimerosal-containing vaccine use, which is an argument against this hypothesis [4]. But these studies have many methodological flaws. For example one study, which was done in Denmark, found that autism cases rose after cessation of thimerosal-containing vaccines [5]. Two important methodical flaws must be noted:
Interestingly, thimerosal was introduced in 1931 in vaccinations and regressive autism was first described in 1943 in children born in the 1930s by Dr. Kanner. It should be noted that after removing thimerosal from most vaccines (exept influenza) in the U.S., the prevalence of autism is for the first time in the medical history decreasing [6]. 1. Jefferson T. Influenza vaccination: policy versus evidence. BMJ 2006; 333: 28 October bmj.com. 2. Mutter J, Naumann J, Schneider R, Walach H, Haley B. Mercury and autism: Accelerating Evidence? Neuro Endocrinol Lett 2005; 26: 431-7. 3. Bernard S, Enayati A, Roger H, Binstock T, Redwood L. The role of mercury in the pathogenesis of autism. Mol. Psychiatry 2002; 7: S42-3. 4. Kurita H. Disorders of the autism spectrum. Lancet 2006; 368:179- 81. 5. Madsen KM, Lauritsen MB, Pedersen CB, Thorsten P, Plesner AM et al. Thimerosal and the Occurrence of Autism: Negative Ecological Evidence From Danish Population-Based Data. Pediatrics 2003; 112: 604-6. 6. Geier DA, Geier MR. An assessment of downward trends in neurodevelopmental disorders in the United States following removal of Thimerosal from childhood vaccines. Med Sci Monit 2006; 12:CR231-9. Competing interests: None declared |
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Jochen Mau, Professor and Director Institute of Statistics in Medicine, Heinrich Heine University Hospital, 40001 Duesseldorf
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By assessing the evidence for influenza vaccination, Thomas Jefferson started a discussion that seems to demonstrate some lack of common understanding of important concepts in empirical research that will make it difficult for the scientific community to interact with policy makers in a coherent way. Much of the debate is around the insights (or epistemiological merits) that can be expected from (the results of) randomized controlled trials (RCT). It should be clear that Karl Popper's falsification paradigm for empirical research provides the rationale, and RCT is only a technique for its implementation: Causal inference must exclude all other possible causes that could explain the observed treatment effect, and the RCT is a convincing design, then. However, a RCT cannot accomplish more than a test of the concept (efficacy), and it can never replace a study of effectiveness, on any logical grounds. As with car racing, in which a care maker gives evidence of knowing how to make cars (the proof of concept) while the real-life (market) setting is every-day car driving in the streets, RCT efficacy may be considered sufficient empirical evidence that the test compound works in the test stand; a positive efficacy trial may also justify regulatory approval and market entry, but by no logical means would the RCT give re-assurance of success in the target population, as long as a logical basis for extrapolating from the test setting is lacking. When it is commonly understood that efficacy is a research goal, and effectiveness is the health service objective, when it is accepted that proof of concept (efficacy) is necessary, but must not be substituted for proper effectiveness studies, then no dissent about the value of currently available evidence will remain: it does not seem compelling, as Thomas Jefferson pointed out. Competing interests: None declared |
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John Stone, none London N22
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Joachim Mutter raises two important issues. i) In the US, where the mercury content of infant vaccine has been progressively removed over a number of years, most infants will now be re- exposed to it through flu-vaccine. In the UK some flu vaccine still evidently contains mercury, though I have no uptodate information. This constitutes an unnecessary risk, particularly to infants. ii) Mercury to exposure to infants through vaccine goes on unabated in the developing world. Andrews et al [1], which recommended the continued use of thimerosal in the developing world stated that the then UK exposure through DPT vaccine (75 µg between 2 and 4 months) was the same as the WHO exposure: "This level of Hg exposure, although lower than the maximum of 187.5 µg received in the United States by 6 months of age, is similar to the level received by 3 to 4 months of age in the United States. It is also the same as the amount of thimerosal used by developing countries that follow the expanded immunization schedule [1]. However, a contemporaneous Committee for Safety of Medicines document obtained under a Freedom of Information Request gave the WHO exposure as 187.5 µg by 14 weeks [2]. No satisfactory explalnation of this discrepancy has ever been offered. The indifference of the WHO to this concern must call the whole present motivation behind the programme into question. A study in north east London (Lingam et al) focussing on MMR showed diagnosed autism incidence double synchronous with the accelerated DPT schedule in 1990, although this important confounder was not noted [3]. Four of the authors were identical with the Thimerosal study [1]. [CSM document submitted] [1] Andrews N, Miller E, Grant A, Stowe J, Osborne V, and Taylor B, 'Thimerosal Exposure in Infants and Developmental Disorders: A Retrospective Cohort Study in the United Kingdom Does Not Support a Causal Association', PEDIATRICS Vol. 114 No. 3 September 2004, pp. 584-591 (doi:10.1542/peds.2003-1177-L), http://pediatrics.aappublications.org/cgi/content/full/114/3/584 [2] Stone J, 'Mercury and Autism in the United Kingdom', Red Flags February 2006, http://www.jabs.org.uk/pages/article1.doc [3] Lingam R, Simmons A, Andrews N, Miller E, Stowe J and Taylor B, 'Prevalence of autism and parentally reported triggers in a north east London population', Archives of Disease in Childhood 2003;88:666-670, http://adc.bmj.com/cgi/content/full/88/8/666 Competing interests: Autistic son |
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Shuja Shafi, Consultant Microbiologist Clinical and HPA Collaborating Laboratory, Northwick Park Hospital, Harrow, Middlesex HA6 4UJ, Harunor Rashid, Kamal Ali, Haitham El Bashir, Elizabeth Haworth, Ziad A Memish, Robert Booy
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Correspondence to: Dr Shuja Shafi, Consultant Microbiologist, Department of Microbiology and HPA Collaborating Laboratory, Northwick Park Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ Email: shuja.shafi@nwlh.nhs.uk Word count: 660 EDITOR--In recent years the overall rate of influenza vaccine coverage among people of 65 years of age and over in the UK has been exceeding the national target of 70%.1 However uptake by the minority ethnic population in the same age group in the UK and USA has been much lower.2 Muslims are the largest religious minority in the UK and every year 1% of British Muslims travel to Saudi Arabia on Hajj pilgrimage. High rates of influenza have been reported amongst pilgrims at the Hajj3 4 and the Saudi Arabian Ministry of Health recommends that all travellers should receive influenza vaccination before travelling on Hajj. In this context our aim was to determine the uptake of influenza vaccination among British Hajj pilgrims, particularly those in risk groups due to age or disease. We studied pilgrims, who attended the British Hajj Delegation Clinic in Mecca and mobile clinics set up by the investigators in Mina in the years 2005 and 2006. Patients' demographic details, occupation, vaccination status and the date and place of vaccination were recorded. Subsequently vaccination histories were verified by contacting primary care staff in the UK, and clarified by phoning the patients where inconsistent reports were obtained. Pilgrims with "Green Book" specified underlying medical conditions and those aged 65 years or more were categorised as "at risk" individuals. The others were grouped as "not at risk". One hundred and ninety six pilgrims were recruited in 2005 and 146 in 2006 creating a data set of 342. Age ranged from 2 to 83; 313 (92%) were men; ethnically 41% were Pakistani, 28% Bangladeshi, 14% Indian, 7% other Asian, 3% African, 2% White British, and for the rest (5%) ethnicity was unknown. One hundred and four (30%) participants were from London. Ninety two pilgrims (27%) were categorised at risk of influenza, one fifth (n=19) of them solely because of age ¡Ý65 years and the rest because of chronic diseases with or without age. One hundred and eight pilgrims (32%) were vaccinated. Apart from two pilgrims, all received the vaccine from their GPs. Vaccine coverage among "at risk" and "not at risk" pilgrims were 55% (51/92) and 23% (57/250) respectively (P<0.001). Coverage among over-65s and under-65s regardless of underlying chronic disease was 63% (19/30) and 52% (32/62) respectively. Immunisation uptake by all pilgrims in 2005 and 2006 was 27% (53/196) and 38% (55/146) respectively (P=0.036) and the coverage among "at risk" people in these years were 51% (29/57) and 63% (22/35) respectively (P=0.26). Uptake by all pilgrims who lived in London in these two years was 20% (21/104) compared to 37% (87/238) in other centres (P=0.003). These rates compare with uptake by "at risk" residents of London of 38% (10/26) compared with 62% (41/66) elsewhere (P=0.04) (Table). Among "at risk" people: those in professional and technical occupations had full (100%) vaccine coverage while students had low (25%) uptake. Of the 342 pilgrims recruited, 47(14%) proved to have influenza infection by PCR, 13 (28%) of these cases were vaccinated against influenza. This study reveals that the rate of vaccination among "at risk" Muslims is worryingly low (55%) as compared to nationwide uptake rate among the target population;1 it is even lower among the residents of London. Uptake could be improved by advertising, phone calls, patient and staff education, standing orders, targeting people with high risk behaviours at their meeting venues and offering home visit by the nurses.5 Clinics set up, in partnership with community leaders travel agents and Imams, for pilgrims planning to go on Hajj might further improve uptake. Hajj is presently occurring during winter months; this poses an extra threat, over the extreme crowding of millions of people, that a novel seasonal (or even pandemic) virus will emerge. Uncertainties about the effectiveness of immunisation against seasonal influenza have been raised6 and as UK government policy does not advocate influenza vaccination for all Hajjis a unique opportunity offered by the Hajj could be to perform well-designed studies to obtain evidence of flu immunisation effectiveness. Acknowledgement This work was supported from a DH grant We thank British Hajj Delegation team, European Hajj Mission and the GPs for help with the data collection and staff at HPA laboratory, London & Respiratory Virus Unit, Health Protection Agency, Centre for Infections, London, for performing the PCR tests. Ethical Approval Multicentre Research Ethics Committee, UK (MREC 02/2/12). Competing interests Roche supplied free courses of Tamiflu for treatment of pilgrims with influenza infection on near-patient testing. SS served as Chair, Health and Medical Committee of the Muslim Council of Britain (until August 2006) 1 Muller D, Nguyen-Van-Tam JS, Szucs TD. Influenza vaccination coverage rates in the UK: A comparison of two monitoring methods during the 2002-2003 and 2003-2004 seasons. Public Health 2006; 120:1074-80. 2 Marin MG, Johanson WGJr, Salaz-Lopez D. Influenza vaccination among minority populations in the United States. Prev Med 2002; 34:235-41. 3 El Bashir H, Haworth E, Zambon M, Shafi S, Zuckerman J, Booy R. Influenza among UK pilgrims to Hajj, 2003. Emerg Infect Dis 2004;10:882-3. 4. Balkhy HH, Memish ZA, Bafaqeer S, Almuneef MA. Influenza a common viral infection among Hajj pilgrims: time for routine surveillance and vaccination. J Travel Med 2004; 11:82-6. 5 Ompad DC, Galea S, Vlahov D. Distribution of influenza vaccine to high- risk groups. Epidemiol Rev 2006; 28:54-70. 6. Jefferson T. Influenza vaccination: policy versus evidence. BMJ 2006; 333:912-5. Table: Distribution of pilgrims according to addresses and ethnicities with their vaccination rates. Number of participants Vaccinated Not at Risk At Risk Not at risk n(%) At Risk n(%) Addresses London 78 26 11(14) 10(38) Birmingham 19 11 6(32) 8(73) Dewsbury 14 2 4(29) 2(100) Batley 11 4 0(0) 3(75) Bradford 12 2 5(42) 1(50) Leicester 9 2 1(11) 0(0) Blackburn 8 3 1(13) 1(33) Luton 6 4 3(50) 2(50) Others 93 38 26(28) 24(63) Ethnicity Pakistani 102 39 31(30) 21(54) Bangladeshi 64 32 9(14) 16(50) Indian 39 8 8(21) 6(75) Other Asian 19 5 3(16) 3(60) African 10 1 0(0) 0(0) White British 6 2 1(17) 1(50) Others 1 0 0(0) 0(0) Unknown 9 5 5(56) 4(80) Competing interests: Roche supplied free courses of Tamiflu for treatment of pilgrims with influenza infection on near-patient testing. SS served as Chair, Health and Medical Committee of the Muslim Council of Britain (until August 2006) |
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Luisella Grandori, paediatrician Public Health Office of Emilia-Romagna Region, 41100 Bologna, Italy
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The article by Tom Jefferson, published in the British Medical Journal the 28 October (1), is a lucid and intelligent provocation that shakes the foundations of vaccination strategy against influenza and, at the same time, suggests methods and solutions. Jefferson’s analysis covers all aspects of complexity (often underestimated) connected with the study of continuously mutating viruses such as influenza viruses, and variable and unforeseeable epidemic. Jefferson describes all methodological mistakes and inadequacy of studies made up to now, to investigate similar matter and explains how these weakness can distort results and lead to incorrect conclusions. From too short times of observation, lack of randomisation and control groups, to the unreliability of case definition (influenza like illness or true influenza?). The conclusions are that available evidence is weak and that benefits expected from vaccine are unrealistic. Nevertheless, his call to make randomized controlled trials as the only tool to assess vaccine efficacy, raises ethical problems that are not easy to resolve. The vaccination of elderly people is amply widespread and, even if there is lack of evidence (2), we can’t exclude that vaccination could protect them from complications or even save their lives. So, we can’t propose to suspend vaccination and choose whom to randomize to vaccination to verify the effects on deaths. A similar study could rather be proposed to assess the vaccination efficacy in healthy children, because in most places in the world, as for example in all Europe, children aren’t vaccinated. But hypothesis of vaccination should rise from knowledge of burden of disease in childhood. Knowledge that we don’t have in a convincing manner yet. Then there remains the not insignificant problem of lack of efficacy of vaccines in children, particularly under 2 years, as shown in a Cochrane review published in Lancet in 2005 (3). These results, together with the observation of cases and deaths also in vaccinated children (4), lead us to believe that we need to make innovative tools through new technologies which could perhaps derive from research in progress from several drug industries to face the possible pandemic. We must not forget that the techniques to make actual influenza vaccine date back to the first half of the last century and they are unchanged. To have more effective products is much more important for children and all persons at increased risk of complications for influenza, apart from the duty to study their immune response to vaccine stimulation, and strive for better vaccines. To conclude, among the many stimuli offered by the analysis of Jefferson, I would like to underline some that I have at heart. Above all, his recall to rigour of scientific logic and to defend its supremacy as regards on other logic, including vaccination strategies. Otherwise we risk to act without possibility of knowing the results of our actions. In the second place, we need (desperately, he says) to know efficacy of influenza vaccine with studies more adequate than those that we have now: studies that produce evidence. For the elderly, for the children and for all persons at higher risk. In the end, we need to modify radically the ways and the choices of research and of production of new vaccines. Public health should not run after, same time breathlessly, the choices and the decisions already taken by industry. It would be better to coordinate the timelines of industry with the timelines of public health, to allow the time and the way to identify priority of intervention in the delicate matter of prevention and to allow evaluation of health impact and appropriate use of vaccines in different contexts. Before or at the same time as availability of new products. Luisella Grandori,
1) Jefferson T. Influenza vaccination: policy versus evidence. BMJ 2006; 333: 912-915. 2) Influenza-related mortality in the Italian elderly: no decline associated with increasing vaccination coverage. Vaccine 2006; 24: 6468- 6475. 3) Jefferson T, Smith S, Demicheli V et al. Assessment of the efficacy and effectiveness of influenza vaccine in healthy children; systematic review. Lancet 2005; 365: 773-780. 4) Influenza associated deaths among children in the United States, 2003- 2004. N Engl J Med 2005; 353: 2559-2567. Competing interests: None declared |
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Sergio Mariotti, Senior Researcher Istituto Superiore di Sanità (National Institute of Health), 00161 Rome, Italy
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