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The Mess Francis Made
Decoding the illusion behind "OAS."
A Failure to Communicate
Carolyn Johnson’s Washington Post article on “Original Antigenic Sin,” published yesterday, turns out to be… not that bad.
I had expected a lazy send-up of the flimsy paper by Reynolds, et al. Instead Johnson synthesizes those findings with others, including Quandt, et al. and another paper I missed on my summer hiatus, leading to a productive discussion of the relevance of B Cell “imprinting” in the context of SARS-CoV-2.
The quote below condenses the virtue and two of the primary flaws of her article:
“Essentially, original antigenic sin is often a very good thing,” said Laura Walker, chief scientific officer of Adagio Therapeutics, a biotechnology company focused on developing monoclonal antibody drugs [flaw 1]. Walker recently published a paper
This burst of antibodies capable of recognizing a new variant is not surprising to experts.
“It’s not a sin. It’s a natural progression of our immune response,” said Ali Ellebedy, an immunologist at Washington University School of Medicine in St. Louis. “We should not think of it as a glitch.”
Flaw 1 is that Johnson apparently doesn’t consider a critical outlook as one available in interpretation of a scientific topic, defaulting to absolute deference. Why is a “sin” “good”? This begs for meta-criticism and confrontation from a supposed representative of the lay public. If Science is divining and ordaining reality for the public at large, why are its priests speaking in deceptive and emotionally charged language? But at least Johnson is offering a lucid view of the contradiction and incoherence to begin with. Even if unintentionally, she has brought sunlight into the fetid swamp.
Flaw 2 is the embedding (hyperlinking) of sources, which obscures the actual structure of the evidence-presentation. This mires what is otherwise a thorough and concise collection of very pertinent sources, never a given in Science Journalism.
Additional flaws are her description of Francis’s original formulation and her turn, in the final stretch, to a worrying tone over potential harms as the key takeaway. For the former:
More than 60 years ago, a virologist named Thomas Francis Jr., observed that influenza infections in childhood had lifelong repercussions. For decades after, people’s immune systems carry an imprint from their first flu, activating defenses primarily against the original version of the virus they encountered. He called it “the doctrine of original antigenic sin.”
Besides the contextual incompatibility with his observations - in an era where only new variants of a single influenza A subtype prevailed - and modern human experiences with flu - where multiple subtypes prevail - there is the subtle difference of “primarily against,” where Francis said “of a character largely determined by.” Both these inaccuracies serve to anachronistically translate Francis’s actual thoughts into the modern understanding of flu. A bit like saying, “Thomas Jefferson was pro-abortion.” Whatever Jefferson actually said obviously wouldn’t be describing modern abortion. Had Johnson left, “of a character largely determined by” in her depiction, the reader might understand that relaying Francis’s thoughts to a modern understanding begs for additional translation.
Still, her work compares favorably to your average Substack Original Antigenic Sin Fearmongering Engagement Generation Vehicle (SOASFEGV), which typically consists of a bit of performative handwringing over the hazard of reading too much into a single data point quickly chased with the announcement that the latest paper clearly shows the immune systems of half the world are now 100% nonfunctional.
Johnson’s article does a good job reviewing the research on “imprinting;” and regarding OAS, is valuable in that it reveals the contradictions in the concept. I have been arguing for close to a year that “Original Antigenic Sin is not real.” Johnson consults a roundtable of Science insiders who variously tell her that “Original Antigenic Sin is good” and “Original Antigenic Sin is bad” (the actual phrase invokes a “dog’s dinner”), as if she is a protagonist in some children’s book stopping at houses along a wooden path, receiving a different description of the Snark at each one. “The Snark is good.” “The Snark is bad.” What is at least certain is that half of the folk in this forest have poor powers of perception.
A reader of moderate intelligence, consuming yesterday’s article, would get the gist that this whole “OAS thing” is just some sort of diffuse communication failure within Science. Which is exactly what it is.
Isn’t It Ironic
Johnson’s article arrives as I crystalize my thoughts on the dynamics, or behavior, of OAS as an idea over time.
If human thought and communication - here, in the realm of Science - are a program whose alleged function is to align thoughts with reality, certain strings of words can, on their own, if introduced into the system, degrade the same function. They break the collective brain. Such word-strings are further naturally selected by those for whom the successful function of the program - identification of reality - is against their interests. They become akin to the eyes in the feathers of the peacock - they serve those who speak them by confusing predators. OAS is such a linguistic construct; however, I refer to it as an “idea” because it also exists in individual minds and because me like simple talk.
Much of my work on OAS refers to it as a “distributed motte-and-bailey argument,”with some writers intimating or outright proposing immune sabotage only for another wing of writers to use a definition that is neutral with regard to infection outcomes. If the former definition of OAS is attacked, the latter rescues the phrase from that defeat.
Humans, upon infection with a novel influenza strain, produce [antibodies] against older viral strains at the expense of responses to novel, protective antigenic determinants. This exacerbates the severity of the current infection. This blind spot of the immune system and the redirection of responses to the “original Ag” rather than to novel epitopes were described fifty years ago.
Thus, the conclusion drawn, when OAS was first conceptualized, was that the first infection experience in life “orients” immunologic memory. When discussing the implications, the public health concern at the time was related not to any diminished response to contemporary viruses in different age groups
I intended to conduct my review of the modern research without litigating which definition was the "original," and instead to insist on a strict evaluation according to the extreme definition. I had considered it likely that Francis had the extreme definition in mind at first (though in the context of vaccination); but by the time I was beginning my review it was clear that early usages were more ambiguous.
My attempt to just sideline the issue at all events failed utterly. I had to know what the phrase’s “framers” - Francis included, obviously - meant when they used it.
The second of the above quotes belongs to Monto, et al., a paper which gets the original meaning correct (and happened to be cited in Johnson’s article, helpfully).
The reason the paper was written, in fact, was in reaction to modern misuse of the word in published research (emphasis added).
At this point, >60 years after the first description of OAS, most would expect that the debate about what it is and whether it exists would be settled. Yet the doctrine is still invoked to explain observations that may but often may not relate to its original description, such [may or may-not things] as reductions in the response to antigens encountered in sequence later, namely in annual influenza vaccination. […] The underlying immune mechanisms involved may be similar to that of OAS, but reductions in the response to a second antigen should not be termed OAS without evidence of a birth cohort effect [so “original” only means “original,” thank you!] […]
The classic description of OAS did not report any “impaired” response to subsequent vaccination, only a strong anamnestic response to the original infecting strain, which was absent [I would say diminished, when discussing similar-enough antique strains] in younger individuals not so infected. […]
And regarding the “Hoskins paradox,” which in modern times is misunderstood as falling in the OAS umbrella:
However, it is also clear that, since most of the boys in question were born in and therefore had their first influenza infections during the A(H2N2) era, the observations cannot be attributed to OAS as originally defined.
The authors are essentially complaining that the common modern use of the word is wrong; akin to those who would describe modern use of “ironic” as wrong. They wish to propose that almost everything currently being described as “OAS” be assigned new or different terms. But absent aggressive language-standards-enforcement by scientific journals, the phrase must by definition “mean” whatever the present writers and readers have in mind when it is used; and anyway the horse is out of the barn.
And how was it supposed to happen any other way? Were new minds somehow not going to emerge from schools and reencounter the old phrase, have it instantly conjure up a meaning akin to “exacerbates the severity of the current infection,” and launch into using it that way? How was the field supposed to be future-proofed against this mistake? There is a reason for speaking precisely and plainly; biology routinely turns itself into a secret code at the peril of the exact thing that has been realized here.
And so at best “OAS” was a time-bomb, waiting to go off. As the framers and those who were steeped in their understanding of flu, the immune system, and the current linguistic framework around the same left the field, new minds would misinterpret their writing in the context of modern understandings and linguistic frameworks. Where no technical meaning obtained for a given phrase, plain-speak would be used to interpret the framers’ intention. And while the tendency for science writing to indulge in dad-joke whimsy hasn’t died out completely, modern researchers are surely more accustomed to poetic flourishes being kept to a minimum. The only natural understanding a new mind can have when being told there is a thing called “original antigenic sin” and it has been “totally known and proven for like, decades,” is that:
No one with one tenth of a corgi’s brain-cell in their skull would use the word “sin” to describe a materially neutral phenomenon; that’s not what the word means.
So while Monto, et al.’s review is stellar, their “leave OAS alone” plea is beyond quixotic. It’s idiotic. Original Antigenic Sin needs to either stop being accepted as a concept at all - replaced by as many discrete, non-deceptive, and future-proof terms as are required - or be accepted as describing a detriment, just as “ironic” describes a death row pardon two minutes too late.
The farce of scientists having to explain to journalists that “Essentially, original antigenic sin is often a very good thing” demonstrates that the phrase has broken the collective brain of the field.
Imagine instead if Francis’s observations - made before an understanding of cellular immunity was even available, I must point out again - had instead been kept specific and grounded in plain speech. If he had simply said, the highest antibody levels to a given strain are usually found in those who were children when that strain circulated? Or, I find that in many cases all antibodies against new strains cross-react with old strains? Would anyone still care about these two statements? Would any researchers use them to imply to each other and to the lay public that immunity is not truly adaptive?
But that is not what happened. The linguistic construct entered the program; the program eventually stopped functioning. In using the construct, those with a self-interest in the system not functioning - I can get funding, I can get clicks - benefit over those whose interest is opposite.
For modern researchers, there’s simply no excuse in general for not routinely updating standards of language just as is done for our machines which communicate electronically, so that the language matches the reality as understood. In such a context it should not matter what a scientist who was around before the discovery of cellular immunity called “having more antibodies to childhood strains.” “Having more antibodies to childhood strains” should be referred to as “having more antibodies to childhood strains,” and nothing else.
Monto, et al., in the first quote from them, go on to provide the context for Francis's "childhood antibodies" observation that accords with his 1960 presentation, in exactly the way described here previously: Francis dreamed of mapping all the possible antigens that flu was “cycling” through, past and future alike, to make a universal vaccine. Not only does this lack any application in the present understanding of flu as deriving from avian reservoirs with multiple different "species" (subtypes) of spike glycoprotein genes, it leads to no deterministic justification for fretting over whether novel adult antibody responses were always “childhood-strain-forward.” So what? Why not just make the universal vaccine first, see if it prevents infection in adults, and then worry about what to do next?
The second observation - “cross-reaction to older strains” - is what was meant by “largely determines” (the word which Johnson substitutes with “primary”). Again Monto, et al. convey the original context correctly, though they slightly mis-report the findings on the “serum absorption” paperand leave out mention of the even further mis-reporting committed by Francis and co.
Monto, et al. have an advantage in understanding OAS in an originalist fashion since they hail from Francis’s citadel, the University of Michigan. His papers are still physically at hand; the local dialect of the school in the 60s still influences the dialect today. Meanwhile, my partially published audit of the papers on the topic from the 60s and 70s affirms the same interpretation for “largely determines.”
It would seem, therefore, that Francis could be exonerated for the extreme definition. Or at least issued a sentence of involuntary mind-slaughter. But were his intentions really so pure?
Again, the framing of OAS as relevant to a universal vaccine is forced, and even more-so on the second point. The question of whether early responses “largely determine” future responses (in that immunity to future strains is cross-reactive to prior ones, which today when phrased in terms of B Cell memory pools can be called “imprinting”) has nothing to do with how “childhood antibodies are the highest” is relevant to a hypothetical universal flu vaccine.
The antibody-forming mechanisms have been highly conditioned by the first stimulus, so that later infections with strains of the same type successively enhance the original antibody to maintain it at the highest level at all times in that age group. The imprint established by the original virus infection governs the response thereafter. This we have called the doctrine of original antigenic sin.
So he has gone out of his way to stress to his audience substantial limitation on the response to new variants (which was extremely poorly substantiated by his own research). They are "governed" by the original infection (meaning, "new" responses must be cross-reactive). This may be explained in part, and I think not at all unfairly, as an effort to recapitulate the even more flawed original claims that led eventually to OAS - that exposure to new variants invariably results in a higher antibody reaction to childhood variants. This was, simply, a false claim, based on limited observations for the first "FM1" vaccine trials and then litigated by almost hilariously faulty methods using pooled sera.
The actual fact was that whether after infection or vaccination, antibodies often react to new strains more than old strains. This has been found repeatedly in modern efforts to “prove” OAS (though as Monto, et al., complain, almost never with correct reference to the childhood strain). And so Francis would rather move the goalpost so that his original claim - redefined - can still be included, rather than simply admit error. Yes, antibodies react to new strains more than old strains - but ah-ha, they are all still cross-reactive (as in, none fail to be absorbed by the old virus). Except even this was already falsified by his own results.
Francis OAS “definition” timeline
Observes poor variant antibody response in FM1 vax → proposes OAS as “can’t make antibodies to new variants” privately → “can’t make antibodies to new variants,” including after vaccination, totally falsified → redefines OAS publicly as “high childhood antibodies” and “new antibodies cross-react” to dodge falsification of “can’t make antibodies to new variants” → audience and all future readers apprehend OAS to mean “can’t make antibodies to new variants” → legend
What seems more likely is that Francis, having created the linguistic construct that broke the functioning of the program, almost immediately also found his interests aligned with the nonfunctioning of the program.
He was an old, fading star. He had failed to attach his name to a vaccine that would endure. All he had, was a phrase that provoked the imagination of those who didn’t yet know what he meant by it.
And so of course, he couldn’t just come out and say what that meaning was. He had to leave room for the misunderstanding. He had to break the collective brain.
If you derived value from this post, please drop a few coins in your fact-barista’s tip jar.
Cover image: Still from “Cool Hand Luke (1967) - Failure To Communicate Scene (7/8)”, uploaded by MovieClips. youtube.com
Johnson, Carolyn. “Your first brush with coronavirus could affect how a fall booster works.” (2022, August 23.) The Washington Post Democracy Dies in Darkness.
Kaku, C. et al. “Recall of preexisting cross-reactive B cell memory after Omicron BA.1 breakthrough infection.” Sci Immunol. 2022 Jul 29;7(73):eabq3511.
“Not surprising”? Then why do they run so many cross-neutralization tests whenever there is a new variant?
Behold this egregious example:
Oh, wait. That’s not OAS (also note the lack of performative handwringing).
Kim, JH. et al. “Original Antigenic Sin Responses to Influenza Viruses.” J Immunol. 2009 Sep 1; 183(5): 3294–3301.
Monto, AS. et al. “The Doctrine of Original Antigenic Sin: Separating Good From Evil.” J Infect Dis. 2017 Jun 15; 215(12): 1782–1788.
Originally unintentionally written and published as “barn is out the door.” I would have left it in, but since this is a very meta essay it might have been interpreted as somehow significant to the thesis.
Monto et al. report that for kids given non-FM1 vaccines, “the (pooled) titer was higher against more-recent strains [meaning FM1].” This is an outright misreading; anti-PR8 levels were higher following PR8 vaccination in kids, totally refuting OAS:
Not linking to it.
Francis, T Jr. (1960.) “On the Doctrine of Original Antigenic Sin.” Proceedings of the American Philosophical Society. Vol. 104, No. 6 (Dec. 15, 1960), pp. 572-578.