Influenza vaccination: policy versus evidence
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.38995.531701.80 (Published 26 October 2006) Cite this as: BMJ 2006;333:912
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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,
Cultural Paediatrics Association, Italy
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
Competing interests: No competing interests
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="coverage" among="among" over-65s="over-65s" and="and" under-65s="under-65s" regardless="regardless" of="of" underlying="underlying" chronic="chronic" disease="disease" was="was" _63="_63" _19="_19" _30="_30" _52="_52" _32="_32" _62="_62" respectively.="respectively." p="p"/>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)
Competing interests: Table: Distribution of pilgrims according to addresses and ethnicities with their vaccination rates.Number of participants Vaccinated Not at Risk At Risk Not at riskn(%) At Riskn(%) 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)
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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:
(i) Autism counts were based on inpatient records in the first cohort and
then changed in the middle of the study period (1995) to include
outpatient records. Outpatients exceeded the inpatients by a ratio of 13.5.
(ii) After 1992, the registry added inpatients, , from a Copenhagen clinic
who had been excluded prior to 1992; this accounted for 20% of the
caseload in Denmark.
Therefore the increase of autism may be caused solely by a tremendous
increase in the study population.
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Coordinator
Cochrane Vaccines Field
jefferson.tom@gmail.com
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).
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
Influenza seasonal vaccination: is it enough?
Tom Jefferson’s paper (1) is a provoking and stimulating one. The
article should be read in parallel with a previous systematic review paper
on the same influenza vaccination subject by Jefferson and colleagues of
Cochrane Center, which appeared on “The Lancet” (2) one year before, and a
group of systematic review papers belonging to the Cochrane database (3-
6), to gain more insight on the original material upon which Jefferson
bases his considerations.
Jefferson states that for most of the declared objectives of the
vaccination campaign there is limited evidence of efficacy, and indeed
looking at Table 2 of the paper, it is difficult not to agree with him,
since significance is lacking very often and, when significant, the
Vaccine efficacy has a modest value for preventing Influenza-like Illness
(ILI) or Hospital admission for influenza and pneumonia. In view of this
fact, if one finds significance and a higher value for vaccine efficacy in
predicting death from all causes, one should be very cautious, especially
if a comparable efficacy for predicting death from more specific causes
like all respiratory diseases is missing. In this case, one should suspect
a possible selection bias, as Jefferson warns, since the vaccinated cohort
could be more healthy and wealthy than the non-vaccinated one. The
alternative possibility that frailer people are more likely to be
vaccinated is probable only in presence of high compliance of the
population. In a recent study, conducted in Seattle, USA, in 2006 (7) , on
a cohort of 72527 people 65 years old or more, followed for 8 years, the
relative risk of death for vaccinated persons, compared with non
vaccinated persons was 0.39 (95% CI 0.33-0.47) before influenza season,
0.56 (95% CI 0.52-0.61) during influenza season, and 0.74 (95% CI 0.67-
0.80) after influenza season, indicating preferential receipt of vaccine
by relatively healthy seniors.
In general, there are also reasons to doubt conventional estimates of the
mortality burden of influenza, as remarked previously by Doshi (8) on this
same journal.
Jefferson points out that one of the reasons for the gap between policy
and evidence is the potential confusion between influenza and ILI, in view
of the fact that very rarely these diseases are laboratory confirmed. The
“confusion” is not a small one, since it is well known that in non-
pandemic years, the forms of ILI due to agents different from influenza
are overall more frequent than true influenza during most of the year,
except for the peak period of the influenza epidemic, as documented in a
well-done monography distributed on-line by the Health Protection Agency
(HPA) of the U.K. (9). In fact, in the Communicable Disease Report on
influenza by the same Agency relative to the period October 2004 to May
2005 (10), virological surveillance on positive respiratory virus
specimens routinely reported to the Centre for Infection of HPA and of
National Health Service identified 1190 confirmed influenza A infections,
246 confirmed influenza B infections, and 5113 confirmed respiratory
syncytial virus (RSV) infections. Parainfluenza activity was not reported
in detail.
The presence of forms of illness that can be misunderstood as influenza,
but on which the vaccine has no effect, “dilutes” the efficacy of the
vaccination, as can be seen from Table 2 comparing the outcomes Influenza
and Influenza-like Illness, when they are both available. For instance
vaccine efficacy (VE) in a population of children 6 years or more is 69%
in preventing influenza, but only 28% in preventing ILI, while in a
population of healthy adults the same quantities are 67% and 22%.
From a Public Health point of view, the really important achievement would
be to prevent the complications of whatever form of ILI, and not only the
complications of influenza, and it is not demonstrated that in non-
pandemic years the complications due to other forms of ILI would
necessarily be milder than the complications of influenza, first of all
because this demonstration is a very difficult one, since in most cases it
is not possible to distinguish the illnesses, and also because several
recent papers pointed out the importance of the RSV virus as a threat to
Public Health (11-13).
The “confusion” caused by the presence of not-distinguishable illnesses
increases the perception of scarce efficacy of the vaccination among the
target population, thus potentially decreasing its compliance to the
recommendations of the campaign.
It would be wise to promote an information campaign aimed at increasing
the knowledge about influenza and the ILI in the general population. The
diffusion among General Practitioners of a pamphlet like the one mentioned
previously (9), and the involvement of the GPs in spreading the main
concepts and information about the different respiratory viruses
circulating normally during the different seasons of the year, could help
in decreasing the “confusion”.
It would also be useful to improve greatly the etiological assessment of
the viruses in the existing Surveillance systems. The aim should be to
detect not only the circulating strains of influenza, but also those of
the most common among the other ILI (RSV, Parainfluenza virus).
With the current situation of multiple agents, for some of which no
vaccines exist, and no perfect immunization on the horizon anyway, since a
limited overall efficacy of the vaccination should be expected, it would
be also wise to promote among the general population those old-forgotten
conventional preventive measures concerning personal hygiene and person-to
-person contacts, to prevent spread of ILI infections.
At the same time, stronger efforts, not only in identifying next year’s
influenza strains, but also in developing those much needed new vaccines
should be spent. After all, the Pharmaceutical industry should be able to
see its own interest in this enterprise, since a recent paper estimated
the economic burden of non-influenza-Related viral respiratory tract
infections in the United States in about 40 billions US$ (14).
The views expressed in this article reflect the personal opinions of
the author and not necessarily the views of the Istituto Superiore di
Sanità (Italian National Institute of Health).
References
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systematic review. Lancet 2005;366: 1165-74.
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Competing interests:
None declared
Competing interests: No competing interests