Effect Measure

Flu vaccine safety

Any concerns about the current swine flu vaccine inevitably bring up the swine flu episode of 1976. This is not 1976. For starters, this year we have a bona fide pandemic and in 1976 the virus never got out of Fort Dix, NJ. That in itself is a game changer. If there are any risks from a vaccine (and there are usually some risks, even though they are much safer than most over the counter drugs) and they are for a disease no one is at risk for, the risk – benefit equation has nothing on one side and if there is anything, no matter how rare, on the other, it makes it unfavorable for the vaccine. But this year people are getting seriously ill by the tens of thousands and dying by the thousands from the virus and even if the vaccine were only 50% effective (and it is likely better than that), there is no contest. Vaccination wins.

Pandemic aside, 2009 does not seem to be like 1976 in the side effects area, either. The big issue in 1976 was the rare neurological problem, Guillain-Barré Syndrome (GBS):

Named after two French physicians who described it in 1916, Guillain-Barré syndrome causes weakness and tingling that starts in the legs, but over weeks can affect most of the body’s muscles. The symptoms occur because the insulation on the outside of nerve fibers breaks down, damaging the normal conduction of impulses.

In normal times, GBS occurs at a rate of roughly 2 cases per 100,000 people per year. Although only about 5 percent die, up to a third spend time in an intensive care unit on a ventilator before they get better. Nearly a third still have some weakness three years later.

After the 1976 vaccination campaign was halted on Dec. 16 of that year, much work went into figuring out whether the increase in GBS cases was real, or just a random upward blip.

Careful counting in defined populations — most important, the entire states of Minnesota and Michigan — proved beyond doubt that it was real: The risk of developing the condition rose four- to seven-fold in the six weeks after getting the swine flu shot. The number of cases attributable to the vaccine ranged from 5 to 12 per million people vaccinated. (David Brown, Blue Cross Blue Shield Newsletter)

Any disease that strikes on the order of 10 in a million is too rare for any pre-deployment testing (think about how big a clinical trial that would take). So the idea that the current vaccine is indeed safe is based on two main arguments. First, it is made by the same process and same manufacturers as the seasonal vaccine, which years of experience has shown to have an acceptable safety record. That process and the quality control for vaccines has changed since 1976. It’s better. And as for that routine seasonal vaccine, the swine flu version amounts to the kind of strain change we have seen many times as the seasonal vaccine is adjusted each year or two to account for the antigenic drift this virus undergoes routinely. There are no adjuvants or other changes that make this vaccine different.

The second argument is that current surveillance for adverse events suggests there is no unusual spike in serious adverse events in comparison to seasonal vaccines:

To assess the safety profile of H1N1 vaccines in the United States, CDC reviewed vaccine safety results for the H1N1 vaccines from 3,783 reports received through the U.S. Vaccine Adverse Event Reporting System (VAERS) and electronic data from 438,376 persons vaccinated in managed-care organizations in the Vaccine Safety Datalink (VSD), a large, population-based database with administrative and diagnostic data, in the first 2 months of reporting (as of November 24). VAERS data indicated 82 adverse event reports per 1 million H1N1 vaccine doses distributed, compared with 47 reports per 1 million seasonal influenza vaccine doses distributed. However, no substantial differences between H1N1 and seasonal influenza vaccines were noted in the proportion or types of serious adverse events reported. No increase in any adverse events under surveillance has been seen in VSD data. (CDC, Morbidity and Mortality Weekly Reports)

We are neither reassured or alarmed. There is insufficient data at the moment to make any judgement about rare events. If we saw something now it would have to be a very strong signal, the epidemiological equivalent to being whacked over the head with a two-by-four. The risks of the virus itself are two-by-four in size, so if you believe, as we do, that this vaccine works, even partially (and the evidence from trials is that the match is good and antibody response is robust), the risk – benefit equation is a no-brainer.

Having said that, we still don’t really know about adverse events. We have a pretty primitive reporting system that almost certainly under reports serious adverse events. It can take many weeks for GBS to show up post vaccination and we are just getting people vaccinated now, so it may be well after the campaign is over that we have a decent answer to this question — if then. We know so little about what causes GBS, which usually comes after some infection, that figuring out whether there still might be something different about a strain that comes from pigs that makes GBS more likely is a question that remains to be answered.

I do have another concern, which I voice with reluctance. I am looking very hard at whatever evidence and data are available, but it isn’t much. However the reassuring noises coming from CDC and WHO don’t make me feel any better. For too long there has been a cozy relationship between vaccine makers and both agencies and I sometimes worry that they are so deeply invested in the success of flu vaccines (not in the monetary sense but in the unshakeable belief sense) that it colors the way they report things.

I don’t automatically discount what they say because of this. Both CDC and WHO remain some of the best and most reliable sources of information on the vaccine program and the vaccines themselves. But I don’t automatically and uncritically accept everything they say about flu vaccines either. Right now we don’t know about the true rate of adverse events. I do feel confident — quite confident, in fact — that getting vaccinated for influenza makes rational sense for anyone. The imbalance of risks for the vaccine and the virus is so great — huge, in fact — that nothing else seems like rational behavior.

But I wish I had more confidence there’s no spinning going on. Given the facts, there’s no need to spin. Distancing themselves from the vaccine companies wouldn’t hurt. In fact it would help. A lot.

Comments

  1. #1 K
    December 7, 2009

    Revere can you comment on this story posed by Crof at H5N1 that experts in Canada are calling for an end to the vaccine at 30% vaccinated
    http://crofsblogs.typepad.com/h5n1/2009/12/canada-experts-call-for-end-of-vaccination-program.html

    Also can you comment on the adjuvants in the swine flu vaccine. Much is made of this by the anti-vaccine camp. They contend that those used in the swine flu vaccine may cause auto-immune disorders later in life

    One such article here http://vran.org/in-the-news/swine-flu-vaccine-a-public-health-experiment/

  2. #2 JJackson
    December 7, 2009

    I am not going to thank all those in the chain that bought this to my attention as it is long. You know how you are. I like this a lot but you should remember it is based on incomplete data.

    Is the H1N1 Swine Flu Vaccine Safe?
    http://www.informationisbeautiful.net/2009/is-the-h1n1-swine-flu-vaccine-safe/

  3. #3 SusanC
    December 7, 2009

    K and revere,

    Any discussion about the safety and risks/benefits of flu vaccines really should specify which vaccines we are talking about. The unadjuvanted seasonal formulations have good safety track records, and I agree with revere about all the reasons to believe there shouldn’t be significant (ie order of magnitude) difference in safety, in principle.

    The use of adjuvants turn these vaccines into a whole new category for risks (see ongoing discussions on Flu Wiki). Just as Vioxx did not have the same safety profile as ibuprofen, even though both are/were NSAIDs. Note that 80 million people were given vioxx before it was pulled off the market (read this excellent OpEd from JAMA Failing the Public Health — Rofecoxib, Merck, and the FDA), many of whom would have done just as well on ibuprofen or other NSAIDs, and it would have cost less, in terms as lives as well as dollars…

  4. #4 Tsu Dho Nimh
    December 7, 2009

    @1 – You can discount the information at vran.org because they are still claiming that anthrax vaccine had squalene in it, and linking it to “Gulf War Syndrome”. It did not, and the original reports of squalene have been traced to contaminated glassware.

    Many older persons – vaccinated or not- develop anti-squalene antibodies. Presence or absence of the antibodies doesn’t correlate with any illness.

    Europe has been using some vaccines with squalene as the adjuvant for over a decade.

  5. #5 Lisa the GP
    December 7, 2009

    Revere it must be hard to remain as patient and understanding when you have to keep debunking the same arguments of the vaccine fear-mongers year after year after year.

    They seem to be following the faith model of decision-making:

    http://miscellanea.wellingtongrey.net/comics/2007-01-15-science-vs-faith.png

  6. #6 davidp
    December 7, 2009

    I was going to ask whether the 1976 vaccine that triggered the increase in Guillain-Barré syndrome an attenuated live virus or an inactivated split virus (or something else). I’m not sure if justthevax answered it:

    The increased risk of GBS associated with the 1976 swine influenza vaccine appeared consistent for vaccine from the four different manufacturers, for the monovalent and bivalent vaccines, and for the whole- and split-virus vaccines

    The 1976 whole virus vaccine’s can’t have been recombinant DNA technology like the current one, so I am still unsure.

  7. #7 melbren
    December 7, 2009

    Hi Revere-

    I am sure you are familiar with the article that was released today regarding the autopsies of some of New York’s early swine flu victims. I have a couple of questions about the report, but I also have a comment. I think I get the gist of the article, but I have a couple of questions and one very passionate comment to make.

    My comment is wrapped in a lot of frustration. Public Health professionals travel in public health professional circles. They assume they are regular folk, or at least have contact with regular folk. But, if you are on a first-name basis with a person who has an MD, you are not regular folk. And I think people like me are not effectively communicating to those in the higher ranks of the public health field that our experience with health care professionals is different from theirs in one very important way. They have access to antibiotics; we don’t. And I do not think you (your profession—not you, personally, Revere) know the extent to which this is true.

    Relatives of doctors, friends of doctors, patients of concierge doctors are able to talk themselves into scripts for antibiotics. (Probably just because it’s harder to say no to someone you know.) My former husband’s father was a doctor. The perk in being related to him was not him, specifically—it was that our doctors knew him. Once or twice year, we could pick up the phone and ask for an antibiotic without an office visit. And if we had an office visit the doctor would often write a prescription for an antibiotic “just in case.” That sort of access to antibiotics is only for the privileged.

    The article I referenced above discusses what you have said all along—the bacterial infection is usually what gets these people in the end. And I suspect that those who did this study do not understand how ridiculously difficult it has become—for people who obviously need them—to get antibiotics on the front end of such an illness. I am begging for someone to listen to me.

    I understand the concept of herd immunity. But we need to weigh risk of antibiotic resistance to the risk of not giving antibiotics to those who need them—when they need them. Could someone please bother to ask the question—at what point would a script for Cipro have made the difference between life and death for these people who died? Please don’t assume they were prescribed an antibiotic early on in their illness.

    One last thing. Can anyone tell me if it is apparent from the report whether or not many of these victims presented with an elevated white blood cell count? My daughter and niece both presented with significantly-elevated white blood cell counts (over 15,000), and were initially refused antibiotics. They had to get sicker first. But an elevated white blood cell count might be a potential marker for determining who is most-likely to need the help of an antibiotic to keep this illness from “going pulmonary.” I remember that there were some victims who presented with leukocytosis in the early cases in California.

    Thank you for providing a forum where someone like me can voice a concern to someone like you. And please protect me from the “acute care physician from a large city in Massachusetts” should he again accuse me of suggesting that doctors “hand out antibiotics like candy.” He hurt my feelings.

    I know. There’s no crying on Effect Measure.

  8. #8 revere
    December 7, 2009

    melbren: I don’t really know what to say. I have my own PCP and he is the one who prescribes antibiotics for me if he thinks it is indicated. I trust him and follow his advice. I myself can write prescriptions but have never done so for myself or any member of my family. Never. I don’t have a stash of Tamiflu. I take antibiotics seriously and I take their misuse seriously. I don’t ask for it, I only take it when it is prescribed for me by the person who is in charge of my medical care (whom I see infrequently because I’m stupid and don’t like to go to doctors). I rarely take them except if told to. Doctors who hand them out will nilly are not practicing good medicine, IMO. My doctor does it rarely and I think he’s a good doctor. That’s about all I can say.

  9. #9 Lisa the GP
    December 8, 2009

    I guess I’m a bad doc. I’ve prescribed myself albuterol while having an asthma attack in WalMart when I had no inhaler with me.

    Melbren it may comfort you to know that white blood cells come in subtypes and as an imperfect rule of thumb, the white count of one type goes up for viral infections and for another type goes up for bacterial ones.

    I would guess that the high white counts in your daughter and niece fit the profile for what usually (but not 100%) is a viral infection rather than bacterial. That is probably why antibiotics were not immediately prescribed.

  10. #10 Epifreek
    December 8, 2009

    None of the H1N1 licensed for use in the United States contain adjuvants.

  11. #11 Mathematician
    December 8, 2009

    epifreek, what do you think the first two Ws in WWW stand for? Revere has enough readers outside the US that he really shouldn’t be talking about “the” vaccine. (Even _if_ a very similar argument can be made for all the various vaccines, neither of the actual arguments made here apply world-wide, since the first is based on a claim that isn’t true world-wide and the second is based on US-only data.)

  12. #12 Quinn O
    December 8, 2009

    A few questions:

    An article published in Nature recently suggested that authorities have no real idea what percentage of the population is or has been affected by the H1N1 virus. It could be 5%, it could be 20%, they don’t know. (http://www.nature.com/news/2009/091124/full/462398a.html)

    According to WHO estimates, influenza epidemics annually affect 5-15% of the global population and cause over 250,000 deaths. Currently, there have been fewer than 10,000 H1N1 deaths worldwide. The virus doesn’t seem especially lethal, and it isn’t clear that the number of people affected by the flu this year differs from that of previous years. So why is this is a pandemic if previous years’ flus were not?

    An estimated 10,000 people die of starvation every day (over 3,400,000 so far this year). From a global public health perspective, how can the WHO justify a multibillion dollar effort to counter such a relatively small and self-limiting problem?

    The package insert (this from CSL) says this: “Neither Influenza A (H1N1) 2009 Monovalent Vaccine nor AFLURIA has been evaluated for carcinogenic or mutagenic potential or for impairment of fertility.” And this: “Animal reproduction studies have not been conducted with Influenza A (H1N1) 2009 Monovalent Vaccine or AFLURIA. It is also not known whether these vaccines can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.” Particularly when it comes to pregnant women, how can we say that the risks outweigh the benefits if the risks aren’t known?

  13. #13 revere
    December 8, 2009

    Lisa: Albuterol isn’t an antibiotic last time I looked. So you’re still OK.

    epifreek, Mathematician: You are both right. My post was more about the CDC announcement about the US monovalent vaccine than the vaccine in general. SusanCC and I differ on the adjuvant but I noted that I wasn’t talking about adjuvanted vaccines. I consider that an open question scientifically but one I’ve decided in my own mind. I wouldn’t hesitate to get an adjuvanted vaccine for myself. I might hesitate for someone with immune systems that weren’t behaving as usual (e.g., someone with autoimmune disease). I’ve thought plenty about that as I have personal family experience with this problem.

    Quinn:We’ve discussed the problem of estimating infection prevalence quite a bit here. It is a difficult problem but it isn’t that we have no idea, only we don’t have good enough for certain purposes. As for why it’s a pandemic, it’s a novel version that most of the world has no natural background immunity for and it has spread worldwide and is highly transmissible. That’s the definition of a flu pandemic. We don’t know how many people die as a result or are affected but it is very large and novel viruses of a serious disease like flu (and flu is always a serious disease) are unpredictable and have the potential to get out of control if you don;t take some action (and in many cases, even if you do). As for other diseases that are as or more important from that standpoint, yes, we should be investing heavily in them. Write your congressthing about it or whoever runs your government. WHO does a great deal of work in things like River Blindness and malaria which they don’t get much public credit for but have been doing for half a century. The CSL package insert is required by law, but there is no way to assure it has no carcinogenic effects but also no reason, based on what we know of the biology, to think it does. The same thing is true of every vaccine, so unless you are an antivaxer, then the package insert is irrelevant. We also don’t know if it causes baldness.

  14. #14 Quinn O
    December 8, 2009

    “but it isn’t that we have no idea”. From the mentioned article:

    “I’m very struck that we don’t have even an idea of the magnitude of infection,” says Xavier de Lamballerie, a virologist at the University of the Mediterranean Aix-Marseille II in Marseilles, France. “Epidemiologists haven’t a clue if it is 5%, 10% or 20% of the population.”

    In other words, we don’t know that this year’s flu (H1N1, or all circulating flus collectively) is affecting more of the population (local or global) than typical seasonal flus.

    it’s a novel version that most of the world has no natural background immunity for and it has spread worldwide and is highly transmissible.

    Novelty and lack of background immunity seem to be poor distinguishing features of H1N1, when one considers that a new seasonal flu vaccination is recommended every year. The H1N1 virus is not highly transmissible. It is less transmissible than other flu viruses. Researchers at MIT published a genetic explanation for this in Nature: http://web.mit.edu/newsoffice/2009/h1n1-0702.html

    If we can’t establish that the flu (H1N1 and/or seasonal strains) has affected more people (locally or globally) than annual flu epidemics, and we know that the virus is less transmissible, we have little justification for this year’s exceptional mass vaccination efforts.

    As for other diseases that are as or more important from that standpoint, yes, we should be investing heavily in them.

    Is starvation a disease? The WHO considers hunger to be the single greatest threat to the world’s public health. More people die of starvation every day than have died from H1N1 all year. Most of these starvation deaths occur in developing countries. This year, the WHO and developed countries donated many millions of dollars worth of expensive vaccines to these countries. This is shamefully inappropriate and the WHO knows better.

    Mutagenic potential can be assessed. Formaldehyde is considered to be a known or probable human carcinogen (depending on the source of material safety info). Though it is present only in small amounts in the vaccines, suggested safe exposure levels are also small. Thimerosal is also mutagenic according to MSDS info, and mutagenic capacity has been demonstrated in live virus vaccines (in animals). http://www.ncbi.nlm.nih.gov/pubmed/12126897?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=10
    Flu vaccines are recommended every year and many people this year will be getting more than one shot. This, and the fact that mutagenicity has been demonstrated in more than one vaccine ingredient, indicate that assessment for mutagenicity and carcinogenicity is warranted.

    Of great concern is the potential for teratogenic effects and spontaneous abortion, since vaccination is being strongly encouraged for pregnant women. Animal reproductive studies have been conducted with an adjuvanted seasonal flu vaccine. The Canadian vaccine package insert says this:

    Although no definite conclusion could be reached, regarding a possible relation to treatment with the H5N1 vaccine and/or the adjuvant AS03, and other findings were considered normal, the following observations deserve to be mentioned: In the first study, there was an increased incidence of fetal malformations with markedly medially thickened/kinked ribs and bent scapula as well as an increased incidence of dilated ureter and delayed neurobehavioral maturation. In the second study, there was an increased incidence of post-implantation loss, and the fetal variation of dilated ureter.

    From Eli Lilly’s Material Safety Data Sheet for thimerosal:

    Reproduction: Thimerosal – decreased offspring survival. Mercury – Changes in sperm production, decreased offspring survival, and offspring nervous system effects, including mild to severe mental retardation and motor coordination impairment.”

    It’s also mutagenic.
    http://www.scribd.com/doc/23383798/Eli-Lilly-Material-Data-Safety-Sheet-for-Thimerosal

    Testing for carcinogenicity, mutagenicity, and teratogenicity is clearly warranted. I am not anti-vax, I am pro-safety testing. Some serious potential risks have not been adequately investigated.

  15. #15 CCW
    December 9, 2009

    Quinn, did you even bother to read the papers you cited? Swine fever virus is mutagenic; I only gave the reference a quick glance, but it’s mentioned right at the top of the discussion section. It’s not a vaccine-specific effect.

  16. #16 revere
    December 9, 2009

    Quinn, CCW (I can’t figure out who is saying what here): The virus is mutagenic? I don’t think so. Mutagenic means it mutations. As for thimerosol, I hope you don’t eat fish because there is more mercury in many single fish meals than in one vaccine load of thimerosol (and there is thimerosol-free vaccine available in the US). Formaldehyde? Carcinogenic when breathed (nasophyaryngeal CA). In your body at very small amounts? You better hope not as it is part of the body’s normal metabolic economy.

  17. #17 hope
    December 9, 2009

    I must say i am very obsessed with the swine flu and very worried ,and this article has surly expressed my feelings in some way but i can’t say that calmed me down in another way.
    I also found a swine flu update that talks about the reasons and statistics that should make us all feel more peaceful . You can find it at the micro-blog and news at http://www.isrameds.com
    Thank you a worried mom

  18. #18 Quinn O
    December 10, 2009

    CCW, my point was that a vaccine can be mutagenic. But you’re quite right, the effect isn’t specific to the vaccine. Mutagenicity has also been demonstrated in A-influenza viruses.
    http://www.springerlink.com/content/v120k26359537880/
    http://www.ncbi.nlm.nih.gov/pubmed/10366773?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=19
    My argument is not that flu vaccines *are* mutagenic, it’s that testing for such effects is warranted.

    Revere, the presence of mercury in fish doesn’t support its use in vaccines. PCBs and arsenic can also be found in fish. It’s not clear, at least to me, that the same amounts of mercury via parenteral and oral routes are exactly equivalent; I haven’t seen any literature on this. Exposure to mercury at certain levels can cause serious adverse health effects, whether the source is fish, vaccines, or both. Efforts to reduce exposure from all sources would be prudent, especially in pregnancy. But again, my argument is not that thimerosal in vaccines is unsafe, it’s that the vaccine formulations should be evaluated for serious possible risks. It’s not unreasonable to suppose that exposure to thimerosal may carry some risk, particularly in pregnancy.

    Failure to investigate vaccine formulations for mutagenic, carcinogenic, and teratogenic potential prior to mass vaccination is irresponsible.

  19. #19 revere
    December 10, 2009

    Quinn: Thanks. Hadn’t been aware of this prior to this cite. Of course there are many things that will cause DNA damage and in this case it is a live virus. Most of the vaccines are not live virus and the ones that are are attenuated so that would be another factor to test. This seems to me to be another argument in favor of the vaccine: it prevents DNA damage from the virus. As for mercury, I agree with what you say and we have argued to get it out of vaccines, period, and in the US it isn’t in single vial vaccines for pregnant women and children. But like everything else in public health it’s a balancing act, and in the developing world there is the problem of single vial vaccines and feasibility and cost. There are data on parental bioavailability from vaccines (thimerosl is ethyl mercury not methyl mercury) and the kinetics are very different. Not only is there less ethyl mercury but it is elminated much faster than methyl mercury. If I get time I’ll write a post about it.

  20. #20 Quinn O
    December 10, 2009

    Revere,

    “This seems to me to be another argument in favor of the vaccine: it prevents DNA damage from the virus.”
    This is presumptuous.

    In the previously mentioned study, the virus was attenuated. From the paper:
    “Our results agree with those of a preceding study allowing us to infer that the virus does not lose, after the attenuation process, the mutagenic capacity observed in CSF diseased pigs.”

    “But like everything else in public health it’s a balancing act, and in the developing world there is the problem of single vial vaccines and feasibility and cost.”
    Deaths worldwide this year from starvation: over 3 million. Deaths worldwide this year from H1N1: less than 10,000. In the developing world, from a public health perspective, H1N1 is of negligible concern.

  21. #21 revere
    December 10, 2009

    Quinn: Explain to me what is presumptuous about it if it is not a live virus vaccine. As for the rest, you assume a zero sum game, which this isn’t, nor is it likely that money spent on flu will be spent to feed starving people. Indeed we spend much much more money killing people via the military. Let’s feed people from that instead. Then we can do flu (which always has the potential to kill) and feed people.

  22. #22 Quinn O
    December 10, 2009

    “This seems to me to be another argument in favor of the vaccine: it prevents DNA damage from the virus.”

    This assumes that a) the H1N1 virus is mutagenic, and b) the vaccine is not. Neither is a safe assumption. The effect of the inactivation process on viral mutagenic potential hasn’t been well studied. One study suggested that inactivation (using thiophosphamide and formalin) reduced the mutagenic activity of HSV 1.5-2-fold. It’s unclear if the process would have the same effect (and to the same extent) on other viruses.

    “Indeed we spend much much more money killing people via the military. Let’s feed people from that instead.” That’s a great idea, but it misses my point. In developing countries, starvation is a much greater threat than the flu. Why spend all kinds of money vaccinating people who are more likely to starve to death?

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