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.
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).
Rapid Response:
Author’s response
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