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Wed Oct 17, 2007 at 12:47:02 PM EDT
( - promoted by SusanC)
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Reading the fine print, on the safety profile of adjuvanted flu vaccines.
The equivalent of "read the fine print" for a scientific paper is "read the data". The interpretation of the data can be skewed by an author to support a larger agenda Or an author can make mistakes.
Gary Matsumoto, Vaccine A, published by Basic Books 2004, p 134.
| SusanC :: Adjuvants, Autoimmunity, and Vaccine Safety in a Pandemic III - The Story of Fluad
In reviewing this whole issue of safety around MF59 and the influenza vaccine, I've come to realize that the biggest challenge, and the commonest pattern that I've come across, is the difficulty of trying to pin down the truth. In part II, I gave a few examples of statements made or written by scientists and authorities that, on closer scrutiny, do not always support the point they are trying to make, like here and here.
Because of this, I'm now going to focus on finding out whether and where any discrepancies or misrepresentations might lie, in all the 'evidence' that have been used to support the case that there is no cause for concern.
Maybe there isn't, but I believe we owe it to our children to exercise due diligence, and scrutinize this to the best of our ability.
In this diary, I'm going to cover the adjuvanted influenza vaccines specifically, both the licensed seasonal flu one, and the pandemic vaccines under clinical trials. Again because of the length, I will have to save the rest of the discussion for another diary!
- Fluad is the licensed MF59-adjuvanted vaccine for seasonal flu. First some basic facts:
- This vaccine was first licensed in 1997 in Italy.
- In 2000 it was licensed in the rest of the EU via a European Mutual Recognition Approval mechanism, ie it did not have to go through more regulatory barriers in other countries once it was approved in Italy.
- It is licensed for those aged 65 and over only.
- The company claims variously that between 22 to 30 million doses of the vaccine have been 'distributed'. That's not the same as the number of doses given, nor the number of people who have received it. Still, suffice it to say that it's been given to millions by now.
- First let's look at the safety profile. Yes, there is a series of clinical trials for subjects over 65, and the results generally show that the vaccine provides better immune response and protection. The vaccine tends to cause more local reactions but generally these are considered mild and transient.
- As always, the devil is in the detail. Let me just show one example. This particular paper appears at first look to include a very large patient sample, which should give us a sense of comfort, right?
Podda, The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine, Vaccine. 2001 Mar 21;19(17-19):2673-80.
from the abstract:
Data from a clinical database of over 10 000 elderly subjects immunised with this adjuvanted vaccine (Fluad®, Chiron Vaccines, Siena, Italy) demonstrate that, although common postimmunisation reactions are more frequent in recipients of the adjuvanted vaccine, this vaccine is well tolerated, also after re-immunisation in subsequent influenza seasons.
How exactly was the safety profile determined?
All adverse events and specific post-immunisation reactions were recorded during the first 7 days, as well as the adverse events requiring physician consultation during days 7 through 28 post-immunisation.
- I think we can agree that if we are worried about autoimmune disorders, they may not manifest within this timeframe.
- These disorders do not tend to have severe acute onset, but as generalized non-specific symptoms such as 'aching all over', which are so common in the elderly it is very likely they would not seek medical advice for them.
- Whether one seeks physician consultation is also often dependent on socio-economic status as well, and the elderly is hardly the group that can afford to spend money except when absolutely necessary.
- But here's the killer phrase:
There was no difference in the incidence of adverse events possibly related to vaccination occurring between day-0 and day-28.
COMMENT: It would appear that the investigators have exercised some pre-conceived judgment as to what might or might not be 'possibly related to vaccination'.
Remember that such adjuvants are a completely different class of substance than vaccines. We do NOT have extensive clinical experience on their effects in humans. That being the case, would you not agree that the expecting the investigators to know what symptoms might possibly be related to vaccination is a bit like putting the cart before the horse?
- Let's get back to the "10,000 patient" sample question.
A large phase IV trial was not included in the safety meta-analysis because the safety follow-up did not include the assessment of common post-immunisation reactions, but only that of adverse events leading to a physician visit within 7 days of immunisation.
So how many people were ACTUALLY included for "the assessment of common post-immunisation reactions" on days 0-7? 2112 for first immunization, 492 for second, 150 for the third immunization. Now, I don't know how exactly these numbers work, but I can't see how someone can take part in the 2nd and 3rd immunizations without having been in the first.
Which means this study evaluated about 2000 patients for the immediate period after vaccination. Which is still a fairly large number, but hardly the 10,000 shown in the abstract.
- So what EXACTLY were the rest of the patients assessed for? The rest of the 9171-2112=7059 subjects were only assessed for (see above) adverse events leading to a physician visit within 7 days of immunisation.
In other words, unless you are desperately ill within the first week of vaccination, AND your symptoms pass the test of whether they are 'possibly due to vaccination', any other reaction would not be counted!
Is this enough to make you feel comfortable about giving such adjuvanted vaccine to your child? I don't know. Suffice it to say that autoimmune conditions as well as other syndromes such as GWS or chronic fatigue don't tend to have acute onset, but they can be just as crippling as many other severe illnesses.
- Studies in non-elderly subjects. In comparison, the data on non-elderly subjects is even more scarce, irrespective of how they try to portray the issue.
The most important one is the one on Fluad, the seasonal vaccine:
Comparison of the safety, tolerability, and immunogenicity of a MF59-adjuvanted influenza vaccine and a non-adjuvanted influenza vaccine in non-elderly adults, Frey S, Poland G, Percell S, Podda A. Vaccine. 2003 Oct 1;21(27-30):4234-7.
The adjuvanted influenza vaccine FLUAD is composed of subunit influenza antigens combined with the MF59-adjuvant emulsion. The vaccine was developed primarily for use in elderly populations, but non-elderly individuals might also benefit. To evaluate this hypothesis, 301 healthy adults were assigned randomly to receive two intramuscular injections of either FLUAD (150 subjects) or a non-adjuvanted vaccine, Fluzone (151 subjects), in two trials conducted at a 1-year interval. Injections consisted of 15 micrograms per 0.5 ml dose. Vaccine composition was A/Texas/36/91 (H1N1), A/Johannesburg/33/94 (H3N2), and B/Harbin/7/94 for the first injection and A/Texas/36/91 (H1N1), A/Nanchang/933/95 (H3N2), and B/Harbin/7/94 for the second injection. Immunogenicity was evaluated at 28 and 180 days post-immunization. FLUAD was generally well tolerated in healthy adults when compared with Fluzone. FLUAD was associated with increased pain at the injection site after immunization. A statistically significant increase in the incidence of injection-site warmth, chills, myalgia, and analgesic/antipyretic use occurred in the FLUAD group after the first injection but not after the second injection. In both groups, most of these local and systemic reactions were classified as mild. FLUAD was more immunogenic than Fluzone following both injections. After the first injection, statistically significant differences were found in the percentage of subjects with four-fold rises in hemagglutinin inhibition (HI) titers at 28 days post-immunization for the B antigen. After the second injection, the FLUAD group had significantly higher HI titers, a significantly higher percentage with a four-fold increase in titer, and a significantly greater percentage of subjects with titers >/=160 for the H3N2 antigen at 28 days. Only minor immunogenicity differences between the two groups were seen at 180 days. Compared with Fluzone, FLUAD was associated with increased immunogenicity and mild post-immunization reactions in healthy adults. The magnitude of increased immunogenicity in healthy adults was less than that seen in elderly populations.
This looks pretty straight forward, they injected 150 people aged 18-64 with the regular flu vaccine, and 150 people with the adjuvanted one, fluad. Fluad appears to cause more mild reactions but also more immunogenic, but this increased immunogenicity is not as marked as in the elderly group, and not sustained at 180 days. In this and the rest of the studies quoted here, the subjects were followed up in similar ways as the studies on elderly subjects described above, so I'm not going to repeat myself.
However, given that the purpose of this study is to evaluate safety as well as efficacy in a younger age group, the single most important piece of information missing from the data is the mean or median age of the subjects! I mean 18-64 is a pretty wide range. For example, there is a big difference if the mean age is 28 or 58! But apart from stating this is a study for those aged 18-64, the only other mention of age in the whole paper is this one single sentence:
The mean age and sex distribution were similar in the two groups.
- Other studies on non-elderly subjects that I can find include the following. I'm including the ages given and the number of people vaccinated, to give you an idea for comparison. The safety follow-up is pretty similar.
Safety and Immunogenicity of Nonadjuvanted and MF59-Adjuvanted Influenza A/H9N2 Vaccine Preparations
age 18-34, total 96 subjects, 48 each group.
MF59-adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18-60 years of age) with chronic diseases who are at risk of post-influenza complications
Mean age 51, 120 given subunit vax with MF59, 118 subunit vax only.
Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza
Mean age around 28 years. 32 MF59, non-adjuvanted 33.
The rest of this series can be found via these links here part I, part II, part IV, and part V.
swine flu vaccine safety,