The Weird History of Vaccine Adjuvants

WellcomeWitch.jpg

Last week the Times ran a story by Andrew Pollack, , that covered some of the ground I trod in my Slate story, “. Pollack also had the room to explore something I lacked room for — the fascinating history of adjuvants, and the strange mystery of how they work.

Like so many things that work in medicine, adjuvants were discovered more or less by accident — and were in fact a “dirty little secret” in a fairly literal sense. As the puts it, summarizing neatly some materials from a paywalled a couple years back:

“Adjuvants have been whimsically called the dirty little secret of vaccines [4] in the scientific community. This dates from the early days of commercial vaccine manufacture, when significant variations in the effectiveness of different batches of the same vaccine were observed, correctly assumed to be due to contamination of the reaction vessels. However, it was soon found that more scrupulous attention to cleanliness actually seemed to reduce the effectiveness of the vaccines, and that the contaminants – “dirt” – actually enhanced the immune response.”

At that point, vaccine geeks started trying various additives to see (in animals) how to boost vaccine effectiveness — and had fair luck, which they didn’t quite understand. As a fine account of this work by Iayork, of the fabulous blog Mystery Rays from Outer Space, puts it:

no one knew how adjuvants worked. They just … worked. There were a myriad of choices (for animals; in the US and Canada there’s only one adjuvant, alum, that’s licensed for humans), and they all mostly worked, and sometimes one worked better and sometimes another worked better, or differently; but there was no understanding of how, or why. Sometimes toe of newt was the best choice, and sometimes you were better off with eye of toad, and it depended on the phase of the moon and on which malign vapours were influencing your system.

Sounds scary, and I suppose it is — but then again, a lot of things in medicine work this way. But don’t get skeered; we use not the eye of newt. Early on in that run of adjuvant experimentation, immunologists recognzied that one adjuvant in particular, the above-mentioned alum (or alum salts), dissolved in mineral oil, was both effective and safe to use in humans. While a few new adjuvants are coming online (most notably MF59, the adjuvant used in seasonal flu vaccines in the EU, as well as in many of the swine-flu vaccines now being made), the most common adjuvant for human vaccines remains alum, and alum is, at this point, the only adjuvant approved for use in the U.S.

Now we get to the “Eureka” part of the tale. In 1989, Yale immunologist , and one of a long line of distinguished physicians in his family (his dad was a noted pediatrician), gave a startling lecture at at the Cold Spring Harbor in which he proposed a solution to the adjuvant mystery — and to the larger mystery of vaccines. Asked by Cold Spring Harbor director James Watson, of double helix fame, to write the introductory essay to a summer symposium, Janeway “agreed,” he later recalled, “with the proviso that [I] could write about anything [I] wanted to.”

What he wrote was “Approaching the Asymptote: Revolution and Evolution in Immunology,” which laid out the ‘pattern recognition’ theory, now dominant, by which the immune system mobilizes when it recognizes conserved features (that is, typical features that are conserved through evolutionary time because they work well) of pathogens. Accordingly, as Iayork puts it,

adjuvants work because they mimic these conserved pathogen-assocaited molecular patterns. (Polly Matzinger [another giant of immunology] also proposed a related model, in which immune responses start because cells are damaged — the danger-signal hypothesis.) Since then, many of the pathogen-associated patterns have been identified, and many of the pattern receptors have been identified; adjuvants are no longer magic, they’re science.

In rough terms, the pattern-recognition and danger-signal theories can make room for each other. (Though people argue about this.) They describe two different triggers for the immune system. One, pattern recognition, is a threat-detection alarm that mobilizes the immune system simply because a stranger enters the house. The other, the danger-signal response, rallies the troops because the stranger — someone who didn’t look nasty, apparently — has begun breaking up the furniture.

These seemed to explain how many adjuvants worked, and they have helped (and are helping) scientists design new adjuvants now. But as Iayork notes, there remains a weird exception to this understanding y. These theories account for all adjuvants …

except for one: Alum, the most important one of all (because it’s the main adjuvant jused for human vaccines).

It alone remains unexplained. Which is why, as Vincent Raceniello recently told me, “We still don’t really understand how most adjuvants work.”

As Iayork notes, a argued that alum’s activity comes from uric acid, which is released by dying or damaged cells (and is a ), and that alum thus works along the lines proposed by Metzinger’s danger hypothesis: alum, mimicking uric acid, sends a danger signal that accelerates the body’s immune response. Jury’s still out on that one, though, so alum’s action still remains unexplained. (Oct 2, 2009: Alert reader passionlessdrone notes another paper, this one from Nature, argues that alum sets off the danger signal via another route.)

This puts me in mind of two things: that (as every ER doctor knows): that kids who spend more time on floors develop stronger immune systems; and that — as every ER doc and surgeon knows — a ragged incision (a tear) will heal faster (if not prettier) than a clean, straight incision made by a scalpel.

A little sloppiness can draw a stronger response. And we often don’t know why something that works, works.

Public Plan as Inoculation Against Mandate Backlash | Gooznews

But every version of reform fails to deal with the root cause the uninsurance problem: millions of employers in our “employer-based” system do not provide their workers with health insurance. Why isn’t there more discussion about the free rider distortions in that state of affairs? 

Instead putting the mandate on employer free riders, the bills now before Congress put it on people with minimal penalties for employers who refuse to provide coverage. 

Then, on the subsidy side, the bills offer help only to the poorer of the poor (working, but not on Medicaid). They do nothing for two-earner households working at two, three or four crap jobs without insurance, who earn a modest household income of $60,000 to $100,000 a year. Subsidizing them, they’re told, would cost too much.

The greatest fear Democrats should have at this point is what will happen when millions of hard-working, lower-middle-class American families without health insurance are told they’re about to be slapped with a $500 to $1000-a-month bill to buy a plan most don’t use (most people don’t get sick). On top of that, they are going to be told that their employers and the government aren’t going to help out.

Is there any reason why these hard-working members of the lower middle class shouldn’t conclude that they are being taxed to help those even less fortunate than themselves? You don’t have to be a political genius to realize Glen Beck, Rush Limbaugh and Lou Dobbs will have a field day.

via gooznews.com

Public plan? Mandate? Goozner tests the sharp double-edges of these provisions.

Posted via web from David Dobbs’s Somatic Marker

Public health surveillance: America the backward (from Effect Measure)

Every other industrialized country has a national health care system that makes keeping track of these elementary facts possible. The US doesn’t. We have a lot of electronic medical records, all right, but they are mostly devoted to billing and insurance. And there are a lot of different proprietary software systems that can’t be easily adapted, altered or modified and can’t talk to each other. One of Obama’s initiatives to control costs is Electronic Medical Records (EMR), but the economic benefits he touts are almost certainly being oversold. It won’t save us that much money.

But what a decent system could do — and the system that we might get might be very, very far from a decent one from the provider and patient perspective — is provide the kind of surveillance information that would make assuring the safety and efficacy of vaccine programs and a myriad of other things possible.

via scienceblogs.com

Revere notes just one of the many drawbacks of our lack of healthcare statistical information at a national level.

Posted via web from David Dobbs’s Somatic Marker

Morning dip: Obama on fascistic healthcare, Razib on religion, & other notables

At Gene Expression, Razib casts a skeptical eye on a study of the neuroanatomical variability of religiosity.

The brain areas identified in this and the parallel fMRI studies are
not unique to processing religion [the study states], but play major roles in social
cognition. This implies that religious beliefs and behavior emerged not as sui generis evolutionary adaptations, but as an extension (some would say “by product”) of social cognition and behavior.

May
be something to that, Razib says — but it would be nice “get in on the
game of normal human variation in religious orientation
(as opposed to studies of mystical brain states which seem focused on
outliers).”

The Atlantic Wire rounds up reactions to Obama’s case for more and longer school days. TAPPED, meanwhile, opines that Obama is winning on education.
One reason? States are passing reform tweaks in order to compete in the
$4.3 billion “Race to the Top” competition. Money talks.

Dawdy notes a BMJ study linking (again) antidepressants to raised (but still low) rates of birth defects in women taking some antidepressants in the first trimester. An extremely tricky issue. 

The President describes the puzzlement of other world leaders that trying to give everyone healthcare comes off as a fascism. (H/T TPM)

“One of the [G20] leaders, I won’t mention who it was, he comes up to
me and … he says, ‘Barack, explain to me this health care debate.’ He
says, ‘We don’t understand it. You’re trying to make sure everyone has
health care and they’re putting a Hitler moustache on you. That doesn’t
make sense to me, explain that to me,'” Obama said. “He didn’t
understand.”

Swine flu spreads, and confusion with it

Updates from the flu front:

Confusion grows over the still-unreleased study
that apparently finds, contrary to other studies, that getting this
year’s seasonal flu shot may raise your risk of getting swine flu. Peter Sandman, meanwhile, argues that since the swine flu seems
to have largely displaced the seasonal flu, getting vaccinated for the
latter doesn’t make much sense. (I’m doing so this afternoon anyway.)

WaPo notes that the swine flu’s second wave is starting to really make itself felt in the U.S., with over half the states reporting widespread flu activity.

Low stocks of Tamiflu (how long have we had to stock up?) seem to have contributed to the swine-flu death of an otherwise healthy 14-year-old girl on Sunday. Painful reading.

A timely Times article reminds us not to blame flu shots for every ailment that shows up afterwards. (Review correlation does not imply causation 101.) The CDC, meanwhile, will be doing its own close tracking of post-vaccination effects.

And Crof wonders whether it’s too early to worry about the different hospitalization:death ratios in various countries.
One of his readers did a study that found the hospitalization fatality
rate (the percentage of those hospitalized who die) is 5.43% in Canada
but 9.42% in the U.S. (This is since the ‘new’ flu season officially
began on August 30, 2009.) Writes Crof,

I’m
hesitant to accept this ratio as a way of gaining an understanding of
H1N1. It may make me feel good as a Canadian to see that our public
health insurance may be saving lives while the uninsured Americans die
at almost twice our rate.

[He should included underinsured Americans in there too.] Then, after
outlining several caveats about such a study, he expresses feelings I
share:

Maybe
the hospitalization:death ratio is a useful tool in the hands of a
competent epidemiologist. Or not. I’d appreciate some advice from the
experts on this.

Embargo? Embargo? The case of the missing swine flu paper

[Note: An update from 25 Sept 09 is at bottom]

Here’s a sad mess. It seems a
potentially important finding — that getting a seasonal flu shot might
increase risk of contracting the swine flu — is being sat on by a
journal, with the authors forbidden from talking about it, until they
get through the slo-mo publishing process.

The finding may or
may not be accurate. But as it regards an important issue, it needs to
be vetted and discussed openly, with the data at hand, as soon as
possible. But it’s not.

This is a tricky situation, to be
sure. There are, at least theoretically, both good and bad reasons to
withhold this information. But it seems to me the bad outweigh the good
here, and both science and the public interest would benefit from a
full airing of this study asap. At minimum, the journal holding the paper (which journal’s id we don’t even know) should state its reasons for doing so. I hope they’re good ones.

The good argument for
withholding this information is that the journal’s peer reviewers need
time to finish their review. Okay as far as it goes — only in this case, I don’t think it goes very far. For many subjects, three peer reviewers is about all you’re going to muster to vet a paper. But in a case this
urgent and high-profile, you’d get a much more thorough airing if you released the thing, for  scores of epidemiologists — whole armies of them, actually, all over the world — would be eager to help out. Unless there’s something we’re missing here, it woulud seem much more helpful to let these
findings get vetted out in the open, by the entire epidemiological
community, by publishing the study and the underlying data online asap so that
a little open science can be done. Let the hivemind at it.

Instead, we get rumors of an unsettling finding — and a process that just flat looks bad.

And this gets us to the bad reasons for sitting on a paper like this: the proprietary embargo disguised as careful review.  As a
journalist, I run into this all the time. Findings — non-peer-reviewed so far,
yes, but still of interest and often based on substantial work, and
very often already aired in public at conferences and meeting — can’t be
discussed “on the record” because … well, because the journal
wants to be the one to break the story. Particularly
upsetting is that the authors aren’t allowed to talk to the press about
their findings, having been forbidden to do so by the journals. This gag practice is
not so much in the interest of ensuring accuracy as it is of ensuring a
splash when the journal publishes the paper.

I find it hard to fault
the scientists in these cases; they know well that if they break a
journal’s gag order, their chances of publishing again at that journal
are quite slim. This is questionable enough in any case, and especially
given that science is ultimately a collaborative endeavor. But when
issues of public health are clearly and directly at stake, it’s
particularly hard to defend.

Here’s the thread; see what you make of it yourself.

Here’s the main news kernal, from the ever-alert ace flu reporter Helen Branswell:

Flu shots increase risk of H1N1: Unpublished study
September 24, 2009

The Canadian Press
Unpublished Canadian data are raising concerns about whether it’s a good idea to get a seasonal flu shot this season.

Drawn
from a series of studies from British Columbia, Quebec and Ontario, the
data appear to suggest that people who got a seasonal flu shot last
year are about twice as likely to catch swine flu as people who didn’t.


A
scientific paper has been submitted to a journal and the lead authors –
Dr. Danuta Skowronski of the British Columbia Centre for Disease
Control and Dr. Gaston De Serres of Laval University – won’t speak to
the media. Journals bar would-be authors from discussing their results
publicly before they go through peer review.


While
few people appear to have actually seen or read the study, the puzzling
findings have been a poorly kept secret and many in the public health
community in Canada have heard about them.


In
fact, concern about the unconfirmed findings is playing into calls from
Quebec and possibly other jurisdictions to delay or even cancel this
year’s seasonal flu shot campaigns across the country.


The
findings are causing consternation abroad as well, with officials at
public health agencies and even at the World Health Organization
worried the alleged link will deter people from getting vaccinated in a
fall when many people are being asked to get both seasonal and pandemic
flu shots.


The
Public Health Agency of Canada knows of the findings and has been
seeking help here and internationally to try to figure out if the
effect is real or if the studies are flawed.


“An
arms-length review of the various methods is currently underway to
assess the validity of the studies relative to that observation,” Dr.
David Butler-Jones, Canada’s chief public health officer, said by email.


“We
are also examining other data that will help to understand what if any
association there is. We look forward to the results of the review and
other data to inform our recommendations as we go forward.”


The
U.S. Centers for Disease Control also knows of the work. It said it has
looked for similar evidence in the United States but sees none.


“It
is difficult to speak about a study that has yet to be published,
however, as this is an important issue involving the subject of
seasonal influenza and the fast moving global pandemic of 2009 H1N1
influenza it is important to note the scientists at the Centers for
Disease Control and Prevention have not seen this effect in systems we
have reviewed in the United States,” spokesperson Joe Quimby said by
email.


A number of influenza and infectious diseases
experts know of but are unwilling to speak publicly about the paper.
But several were quick to note that British and Australian researchers
haven’t seen the phenomenon either. The lack of corroboration in other
jurisdictions is “a red flag,” said one expert, who does not believe
the findings are true.

This
shouldn’t be something that flu experts feel compelled to discuss sotto
voce. If the journal has good reasons to sit on the paper for now, it
should declare them. If not, it should get the paper out in the open so
the data and findings can be examined and vetted openly.

Update 9/25/09, 9:25 am EST: Two things:

  1. As per my comment below, I was glad to read this morning a thread at FluTrackers
    that the CDC and Health Canada will be discussing this whole flap this
    afternoon — apparently at 1:30 pm EST by the CDC and 2:00pm EST by
    Health Canada (though I can’t find those at the CDC and Health Canda
    sites!). Not clear whether they’ll make the paper public or whether the journal will step up.

  2. Helen Branswell reports this morning that the (rumored/unconfirmed) small f findings have led Canadian officials to decide to delay seasonal flu shots for most people until after the H1N1 shots become available in November, so that the latter, being given earlier, can work without any possibility of, ah, influence from the former, now to be given later.

Nobody said this would be simple. I’ll say this: I’m glad I’m writing about this and not calling the shots.

Clay Shirky’s bracing dystopianism

Even with that experimentation, he added, the ongoing shrinkage of newspapers is likely to create a “giant hole” that will not be filled for some time. He said he has a vision of communities of 10,000 people or fewer becoming rife with “casual endemic corruption,” as newspapers are no longer able to fulfill their traditional watchdog roles.

via dankennedy.net

I live in a town of 8,500, and I’m not sure I buy this. I see Shirky’s point. But I think he misses how porous and connected the lines of communication in a town of this size are, and how they can curb casual endemic corruption — not by directly exposing people (though that can happen) but the close (often too close) intimacy of such a place gives people a sense of oversight at least as powerful as that in the paper.

The paper in this town runs only the most exceptional scandal/corruption stories; most of the reporters lack that investigative impulse, and the paper tends to go soft on things in general anyway; it’s not, I would guess, much a check on even casual corruption — and far less a check than the disdain or anger of neighbors and people you all too reliably run into on the street.

Posted via web from David Dobbs’s Somatic Marker