The Weird History of Vaccine Adjuvants


Last week the Times ran a story by Andrew Pollack, Benefit and Doubt in Vaccine Additive, that covered some of the ground I trod in my Slate story, "To Boost or Not to Boost: The United States' swine flu vaccines will leave millions worldwide unprotected. 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 Wikipedia entry puts it, summarizing neatly some materials from a paywalled The Scientist article 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 Charles Janeway, and one of a long line of distinguished physicians in his family (his dad was a noted pediatrician), gave a startling lecture at an annual symposium 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 recent paper argued that alum's activity comes from uric acid, which is released by dying or damaged cells (and is a powerful natural adjuvant), 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.

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Hi David Dobbs -

Along the lines of figuring out what is going on, you might consider these papers.

This paper seems to argue that alum is bypassing the pattern recognition (i.e., TLRS) all together, and initiating a signal further down the chain.

I've also read that this could be the result of a frustruated phagocytosis attempt, and the resultant debris signals an immune response; but cannot find the reference now. It was compared to the reason why asbestos creates an immune response.

- pD

David, thank you so much for posting this today of all days. I started talking about antibody development for ELISAs and a student just asked me about adjuvants. This is a lot more interesting than what I had proposed to present.

On a related topic, I understand that the anti-vax movement is starting to froth at the mouth about squalene being a component of MF-59 adjuvant because people appear to develop antibodies to it - little do they realize is that squalene is already a normally-occurring biochemical precursor in the body for numerous endogenous compounds including bile salts, cholesterol, and steroids, and some people already have antibodies to it. It's simply a condensation produce of the branched 5-carbon isoprenoid pathway. Of course, no one knows exactly how squalene acts as an adjuvant either.

Nice post, David. You've hit on some great topics, including the need for BETTER adjuvants that bias the immune response to be most effective for the individual vaccine antigen.

Some companies are in development of such adjuvants; TH1- or TH2-biased immune responses can induce a significantly different physiological effect. The drug my company is developing utilizes the 'danger-signal' response, you've rightly mentioned, which is TH1 (cellular) biasing. What we've found is an incredible effect in the arena of cancer vaccines, where a cell mediated response is most effective. We think we're on to something grand. Other companies are developing similar adjuvants.

P.S. - the mechanism of action of Alum's adjuvant effect has been described recently as being mediated by NALP3 inflammasomes - something entirely unique compared to 2nd and 3rd generation adjuvants... though there is some debate on this.

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In regards to squalene, yes, the body does contain it naturally, the problem is, in a vaccine, you are introducing it directly into the bloodstream, initiating an immune response to something occuring naturally, which is exactly what happens in autoimmune diseases. Its not "frothing at the mouth" for nothing, this can potentially have serious consequences to the health of those receiving squalene in a vaccine. Its also important to note, it has not been approved by the FDA, yet is is in the newest vaccine. Autoimmune diseases are on the rise, if components in a vaccine are contributing to the problem, don't you think it important to research it? Especially since this article notes that something works, but science doesn't understand how/why?

Sharon K,

When is the last time you had a vaccine injected directly into your vein? While you might have a point, vaccines are not injected directly into the bloodstream.

Also, squalene is not in the "newest vaccine" in the US. Only in the EU, where it is approved for human use.

As for researching squalene and the immune response to it, you are correct. It's being done. As the link Abel Pharmboy posted said, which you probably should have clicked on: "More importantly, vaccination with a subunit influenza vaccine with the MF59 adjuvant neither induced antisqualene antibodies nor enhanced preexisting antisqualene antibody titers."

Hi David,

I found your post while I was looking for information on the history of adjuvants for a vaccine course I'm teaching. Thanks of the information. Do you know of a good review article about the history of adjuvants? I was hoping to find an overview of the first experiments showing adjuvant effects.