Effect Measure

The latest study on flu vaccine effectiveness in children has been well discussed in the MSM and the flu blogs, so I’ll point you to those excellent pieces (Branswell, crof, Mike Coston at Avian Flu Diary) and just add some things not covered elsewhere. The full text of the article is available for free at JAMA and it’s a pretty good read, so if you want to see for yourself what is involved I urge you to read it, too. First, let me back up a bit and connect this to the controversy about observational and randomized clinical trials we’ve been discussing here of late (before my grant writing interfered, anyway).

There is ample evidence, both biological and observational, that immunization for seasonal influenza “works.” But how well does it work? And what is the best way to do it? This is not just a scientific question (although it is a scientific question) but also a policy question. If it doesn’t work at all or only minimally, then the policy of many national health departments is misguided and possibly dangerous. The question of whether flu vaccination works has been raised by (in our view) misguided zealots who demand standards of proof difficult to obtain (blinded and randomized trials) under the guise this is the only acceptable kind of evidence. We have previously registered our disagreement with this view (here, here), not least because even the availability of this evidence won’t answer the questions. In fact reading some of the literature and commentary about this makes us wonder if the RCT zealots even understand why randomization is useful (and when possible, it is; see here, here, here, here, here, here). Just as importantly, the JAMA study illustrates why RCTs won’t answer the question. More about that in a moment.

A quick synopsis of the JAMA study (you can read more details in the paper itself or in the linked articles, above). Suppose you wanted to do a randomized trial of whether vaccinating children protects unvaccinated older adults (on the theory that the children are good spreaders of the virus). How would you do a randomized trial of a community, not of the people in it? The beauty of the JAMA paper is that the authors found a way to do that, using fairly isolated and self-contained colonies of an Anabaptist fundamentalist sect in Canada, the Hutterites (I guess it shows that religious extremism is good for something). Instead of randomizing people, they randomized the colonies, vaccinating the children in some against flu, in others against hepatitis A. Not every Hutterite colony wanted to participate and many refused or dropped out after initially agreeing (but before allocation to either vaccine). Look at Figure 1 in the paper for the reasons why some colonies were included or not. It’s a little lesson in how difficult these things are to do. Moreover this is a highly unusual situation and would simply not be feasible in almost any other set of communities. So good for these researchers for taking advantage of this opportunity. It’s one of the things that makes epidemiology as much an art as a science.

The idea was to vaccinate a large proportion (in excess of 80% as it turns out) of the healthy children between 3 and 15 years old in each of the study colonies (each colony had from 60 to 120 people of all ages) to see if vaccination against flu, as opposed to hepatitis, protected the older, unvaccinated members of the colony against flu. And because this is part of the mantra of the RCT crowd, it was done “blinded” to the vaccine status. This is not as easy as it sounds because the flu vaccine came in a multidose vial and the hepatitis vaccine in a single dose vial, so the nurses who gave it knew which was which. To remedy this the nurses who gave the vaccine where then switched out of the study for new nurses who didn’t know which vaccine was used. The new nurses did the assessment of outcomes. There were some other details related to blinding, too, that are worth reading (middle column on p. 945 of the .pdf), just to get a flavor of what you have to do to do a conventional double-blinded RCT. You might think about it next time someone says, “Why didn’t they just do an RCT? How stupid are they?”

There are a lot of these pesky details in this paper. It’s a non-trivial task. In our view they did an excellent job. I wasn’t sure it was even possible to do something like this and they showed it was. You can read the results in all the other accounts but in sum it was that if you vaccinate 80% of the healthy school aged children you obtain a very significant herd immunity effect: you protect the older unvaccinated population to the same extent as if they had themselves been vaccinated. Unfortunately there weren’t many in the usual target group of over 65, so we don’t know what would have happened if the vaccine campaign had been extended even further for the target group, or, for that matter how generalizable this result is to the more complex setting of crowded, non-isolated urban populations. In other words, this is a valid and highly important result, but it doesn’t bullet proof the controversy over flu.

Indeed the controversy continues. CDC has had a policy of targeting high risk groups, particularly the over 65. This group (to which I belong) may or may not benefit as much because our immune systems may be getting like our memories — senescent. So that’s the second question this study addresses. Is there a benefit to the over 65s if we instead target the under 15s? Yes. But this study doesn’t completely answer the policy question because the over 65s weren’t targeted. Maybe the result would have been even more dramatic. It is this age group that is most at risk, so maybe it would save more lives to target them.

Bottom line: flu vaccines work to significantly reduce outbreaks when school aged children are vaccinated in isolated populations. Although we knew that already, now the nay sayers will have to find another objection. And they will be able to do so, as I just demonstrated. Because just doing an RCT isn’t a definitive answer. It just produces more questions.

Science is like that.

Comments

  1. #1 iayork
    March 11, 2010

    As a quick comparison, considering vaccination and prior infection levels (as described by the CDC), probably at least 60% of children in the US are now immune to the swine-origin H1N1 (http://www.iayork.com/MysteryRays/2010/02/13 for references etc). The JAMA study tells us that 80% immunity is enough to stop spread, and they say their models suggest that 70% or more would be sufficient.

    I would wonder if the 60% level is enough to drastically slow down the virus, and that may be why we never saw a winter wave of H1N1 this year.

  2. #2 iayork
    March 11, 2010

    … and following up now I’ve skimmed their references, given that the swine-origin H1N1 is believed to have a relatively low R0 in the 1.3 range, a couple of recent models estimate that 50% or lower vaccination levels should dramatically reduce flu spread.

  3. #3 Sili
    March 11, 2010

    Off-topic(ish), but I’ve been wondering this for a biI wasn’t targeted for the swineflu vaccine at the time (unemployed, not much contact to others), but since it sorta petered out now the state has lots of vaccine leftover, so they offer it for free to anyone wanting it (I still have to pay the GP to administer the shot, though).

    Will it be worthwhile to get the vaccine now? I assume the effect lasts and a strain akin to the current one might return decades down the line. What I guess I’m asking is will it do any good to get jabbed, or is it just a question of not doing any harm? (Much like multivitamins in ordinary doses I s’pose.)

  4. #4 revere
    March 11, 2010

    Sili: Yes, get vaccinated. It will likely be back next year. Whether there will be much antigenic shift no one knows but it’ll provide you with some protection no matter what (statistically speaking; your mileage might vary).

  5. #5 phytosleuth
    March 11, 2010

    Now the question is, does vaccinating children for chicken pox affect the rate of shingles in those over 50?

  6. #6 Phillip Gross
    March 11, 2010

    It’s funny how back in the days real journalists researched their work before publishing it.
    Here the author goes on to write that Hutterites are religious extremist and a sect, when the author clearly knows nothing about Hutterites.

  7. #7 revere
    March 11, 2010

    Phillip: Obviously it is a subjective judgment on each of our parts. But on the merits, what is there about Hutterites that does not qualify them as a sect? And what is there about their lifestyle, based on religion, that is not an extreme outlier in the 21st century?

  8. #8 Sili
    March 11, 2010

    Thanks. I’ll talk to the GP one of these days when I go to renew the ADs and have my vasectomy checked.

  9. #9 Jimmy
    March 12, 2010

    I’ve known Hutterites and typically the colonies have lots of chickens and pigs as well as child and adult humans. Members have mentioned to me that there were simultaneous flu inflections in pigs and humans at their colony and implied that possibly humans caught what the pigs had from time to time, something not necessarily reported to any authorities. To me this leads to an assumption that Hutterite colonies are a possible source of coinfection and development of avian swine human hybrid flus.

    Is there any evidence this research is tied to a study testing the effect of these mass vaccinations on pig human co-infections in Hutterite colonies? I see swine mentioned only in the references to that paper. It’s an odd coincidence to me that the researchers would choose Hutterite colonies in particular without further using the opportunity.

  10. #10 anon
    March 13, 2010

    bottom line of the bottom line:
    avoid RCTs

  11. #11 Paula
    March 18, 2010

    This is anecdotal and local or perhaps regional, perhaps a simple cluster but–today I’d an email saying 2 of the 10 persons I’d met with on Sunday are sick with respiratory etc., then I went to teach and 1/2 the students were out, the other 1/2 sick and coughing, then I turned on the Portland PBS station on the drive home and one of the 2 announcers was out ill, then I got home and opened email and the book publicist I’m supposed to meet with (in Portland) has a virus. . . Am wondering if anyone has heard any indications of other flus/viruses now happening (certainly possible) or any indications “it’s back” for the 3rd wave, or—? Possibly just a sudden and quite extensive cluster, though.

  12. #12 revere
    March 18, 2010

    Paula: We’ll get a CDC update tomorrow and might see if there is an uptick. Wouldn’t surprise me either way.

  13. #13 Ron Law
    April 3, 2010

    This study has many problems. One is that a number of other people were vaccinated in the study but these were excluded from analysis. Another is that 15 cases of 2009 H1N1 influenza were mentioned in the text but excluded from the graphs and analysis. Given that the clinical trial registration took place after the study started should also have disqualified it from publication in JAMA in line with its publication policy.

  14. #14 anonymous
    April 18, 2010

    Ron Law is incorrect – all participants vaccinated were accounted for in the analysis (this is what the authors refer to as adjusted analysis). He is also incorrect about trial registration – the trial was registered with the International Standard Randomised Controlled Trial Number Register before the study started. With respect to 2009 H1N1, the outcomes described specified seasonal influenza a priori.