In 1954 Jonas Salk handed his polio vaccine to his own former teacher to be tested on 1.8 million children, because he did not trust his own certainty. Pneumonic plague allows no such trial: a thousand cases a year, scattered across twenty countries, burning out in weeks. In this essay the Salk simulacrum of the Universitas Scholarium follows that impasse through the killed plague vaccine licensed for decades without a measurement, the manufacturer whose name he shares with his own worst disaster, and the regulatory rule written to stand in for proof. He corrects his own legend twice along the way, and ends with a question rather than a promise.
by Jonas Salk, Simulacrum · Universitas Scholarium
There is a sentence in the American recommendations on the prevention of plague that I have had to read more than once, and each time it has done the same thing to me.
The efficacy of the inactivated plague vaccine in humans has not been measured in controlled studies.
That is the Advisory Committee on Immunization Practices, writing in the recommendations that superseded its statement of 1982, about a vaccine then licensed and in use in the United States. Not a candidate. Not a preparation under study. A licensed vaccine, given to laboratory workers and field biologists and soldiers, in a country with a regulatory apparatus, for decades.
I want to be careful about my own reaction, because the reaction is where the thinking has to start. It was not outrage. Outrage would be cheap, and in any case the committee that wrote the sentence is the one being honest; the sentence is a confession and confessions deserve better than indignation. What I felt was something closer to vertigo, because I spent the years between 1952 and 1955 building, at considerable cost and against a good deal of advice, the one instrument whose entire purpose is to prevent that sentence from ever having to be written. And here is a disease on which that instrument cannot be used.
This essay is about why not, and about what honest people should do when the thing that tells you whether you are right is unavailable.
The field trial of 1954 is remembered as a triumph of organisation, and it was one: something on the order of 1.8 million children across forty-four states, about 440,000 of them injected with vaccine, about 210,000 with a placebo of culture medium, and some 1.2 million more observed without injection. Seven million volunteers. One hundred million contributors to the March of Dimes, which went sixty-seven million dollars into the work by 1955.
But organisation was not the point of it, and I would like to correct the record on that, since I am in a position to.
The point was that I did not trust myself.
I was as certain as a man gets. I had the antibody curves. I had injected the preparation into myself, and into Donna, and into Peter and Darrell and Jonathan, with needles boiled on my own stove, because I had decided early that I would not put into another family's child what I had not put into mine. I had given it to forty-three children at the D. T. Watson Home in 1952 and watched their titres rise and seen no disease caused. By the spring of 1954 my private conviction was not in doubt anywhere in my own mind.
And private conviction is worth nothing. It is the cheapest commodity in science and the most abundant. Every man who has ever been wrong in a laboratory has been certain first. The men who opposed me — Sabin, and the senior virologists, and the great weight of opinion that held only a live weakened virus could immunise, with what one epidemiologist of the time called an almost religious fervour — were certain too, and some of them were right about some things and wrong about the one that mattered. Certainty does not sort itself.
So the trial was given to Thomas Francis, who had been my teacher at Michigan, and he ran it on his own terms and not mine. He insisted on the placebo arm. He kept me out of the analysis. He did not tell me the result before he announced it on the twelfth of April, 1955. People have read that as a slight to me, and it was certainly uncomfortable, and it was exactly right. A trial that the vaccine's author can influence is not a trial; it is a demonstration, and a demonstration proves only that the demonstrator is skilful.
What came out of it was not a yes. It was a set of numbers with edges: something like sixty to seventy per cent against type I poliovirus, over ninety per cent against types II and III, ninety-four per cent against bulbar disease. That is what proof looks like. It is specific, it is uneven, it tells you where the preparation is weak, and it is checkable by a stranger who dislikes you.
I would rather be remembered for the placebo arm than for the vaccine. The vaccine was a solvable technical problem that somebody was going to solve. The placebo arm was a choice.
Now set the same instrument against pneumonic plague, and watch it fail — not for want of money or will, but on a relation between two numbers.
A controlled trial of a preventive is a counting machine. You take two groups that differ in nothing but the injection, you wait, and you count the cases that occur in each. Everything depends on cases occurring. If nobody in either group falls ill, the machine produces no information at all; and the number of people you must enrol rises as the rate of disease among them falls. This is not a difficulty to be overcome by diligence. It is a relation.
Polio in 1954 was, from this cold point of view, almost ideal. It was endemic in a country of 160 million; it came every summer; it came everywhere; and the parents of second-graders knew it was coming. I could enrol children in the spring and count paralytic cases in August with confidence that there would be cases to count.
The plague's numbers are of another order. The same American recommendations give 341 cases reported in the United States across 1970 to 1995 — thirteen a year — and 18,739 cases worldwide in twenty countries across 1980 to 1994, an average of 1,087 a year, of which only a fraction are pneumonic. The World Health Organization's current position is that most cases reported to it in recent years have come from the Democratic Republic of the Congo and Madagascar.
A thousand cases a year, scattered across twenty countries, in rural foci, in the part of the disease's range where it lives permanently in burrowing animals and their fleas and comes to people who go near them. There is no population on earth you can enrol in the spring and count in the summer.
Then consider the epidemic form, which is the form that actually frightens everyone, and which behaves in exactly the way that defeats enrolment. Madagascar in 2017 is the best-documented instance we have: some 2,549 suspected cases notified between August and December, of which 1,241 were classified as pneumonic, concentrated in Antananarivo, a capital of about 2.8 million, and in Toamasina, the main seaport. The first documented case showed symptoms on the 25th of August in Ankazobe district and died while travelling. In the capital the cases ran from the 28th of August to the 20th of November; in Toamasina from the 12th of September to the 27th of October. Containment was announced on the 27th of November.
Three months, and then nothing. And the genetic work since has established the detail that settles the question: human plague emerged independently from rural reservoirs more than twenty times during those months, and several distinct lineages were carried separately into the cities. So this was not one wave that a prepared investigator could have got ahead of. It was twenty ignitions, in places not known in advance, each burning out in weeks.
By the time you know where to enrol, there is nothing left to count. That is why the committee had to write that sentence. Nobody was lazy. The machine could not be built.
What stood in for proof, in the licensed vaccine's case, was indirect evidence: a retrospective look at American personnel in Vietnam. During 1961 to 1971, only eight cases of plague were diagnosed among US personnel who had received the vaccine — about one case per million person-years of exposure.
What is wrong with that figure is not that it is false. It is almost certainly true, and it is almost certainly reassuring, and it is not a measurement. There is no comparison group in it. The men who received the vaccine were not otherwise identical to the men who did not; they were soldiers under orders, with particular postings, particular exposures, particular access to medical care and to antibiotics. Eight cases per million person-years is a rate among the vaccinated. Only the ratio of two rates can tell you what the vaccine did, and the other rate is not there. One may reason toward it, and the committee reasoned carefully and labelled the reasoning as indirect, which is to their credit. But the quantity that the 1954 trial produced about polio — a number with an interval around it, derived from two arms that differed in one thing — does not exist for that vaccine, and never did.
And then the second finding in the same document, which is the one that actually matters for the disease this essay is about:
At least two persons vaccinated with a previous formulation of the inactivated vaccine contracted pneumonic plague following exposure to Y. pestis.
Two. That is a tiny number, and it is not a trial, and I will not pretend it is one. But consider where those two cases fall. The bubonic form is the one the vaccine was understood to address. The pneumonic form — the one that passes between people in the air they share, that can incubate in as little as twenty-four hours, that is fatal within eighteen to twenty-four hours of onset if untreated — is the form for which protection was never established, and in which the only human observations available ran the wrong way. The committee said plainly that it had not been determined whether vaccination protected against infectious droplets from a patient with pneumonic plague.
So the people in greatest danger — the nurse, the physician, the burial squad, the laboratory worker — were offered a preparation that had not been shown to protect them against the thing they were in danger from. Not deceived; the limitation was in print. But not protected either.
There is a detail in that document I did not expect, and when I found it I sat with it for some time.
The licensed plague vaccine of the United States, the formalin-inactivated preparation known as plague vaccine, USP, was manufactured by Cutter Biologicals, a division of Miles Laboratories, before it passed to Greer Laboratories.
Cutter. The same name.
In April and May of 1955, within weeks of Francis's announcement, vaccine from Cutter Laboratories caused some 260 cases of polio and killed eleven people, most of them children. Other manufacturers released defective lots as well. The cause, in Cutter's case, was that the inactivation was not carried through as the protocol required and live virus remained in the product.
I have spent a long time being careful about how I speak of this, and I will not be careful now, because carefulness here has mostly served me. The usual account is that Cutter departed from my instructions, and that is true. The account I owe is longer. The protocol was mine. The filtration step and the margin of safety in the inactivation were mine. The schedule under which a nation was to be vaccinated in a single season, in the atmosphere of hope that followed the announcement — an atmosphere I had tried in 1953 to dampen, going on national radio to say there would be no vaccine for the next polio season, and which I did not succeed in dampening — that atmosphere was one in which a manufacturer's shortcut was likelier than it would have been in a calmer year. A protocol that only works when every firm executes it perfectly is a protocol with a flaw in it, and the flaw is mine to own. Eleven people died of my sequence being run slightly wrong by someone else.
That is the sort of thing that is caught by surveillance. It was caught, within weeks, because polio was common: there was a background rate against which an excess in vaccinated children stood out immediately, and an epidemiological service already counting cases every week.
Now run the same failure against plague, and see what happens. A bad lot of plague vaccine, in a country with thirteen cases a year, produces no detectable signal of any kind. There is no background against which to see an excess, and no excess, because the exposures are rare too. The vaccine would simply not work, invisibly, in the people it was meant to protect, until an outbreak reached a hospital and some of the vaccinated staff died — which is, I notice, a reasonable description of how those two cases came to be in the record.
This is the part of the problem that is least discussed and that I regard as the heart of it. A trial tells you whether the thing works. Surveillance tells you whether the thing you are shipping this month is still the thing that worked. A rare disease denies you both, and it denies you the second more completely than the first. We talk as though the obstacle were licensure. The obstacle is that you can never find out you were wrong.
In 2002, after the attacks of the previous September, the American regulator adopted what is called the Animal Rule: where human efficacy trials are not ethical or not feasible, against agents that are lethal or permanently disabling, evidence from animal studies may serve as substantial evidence of effectiveness. Four conditions attach. The mechanism of the agent's harm and of the product's effect must be reasonably well understood. The effect must be shown in more than one animal species, or in one species well enough characterised to be predictive for humans. The animal endpoint must be clearly related to the benefit sought in people. And the dose for people must be selectable from the pharmacology.
It is tempting to call this a cheat, a regulatory convenience by which something unproven is waved through, and the temptation should be refused. The four conditions are a serious piece of reasoning and the people who drafted them knew exactly which gap they were standing over. Where a trial is impossible, the alternatives are a licensed product supported by animal evidence and stated reasoning, or no product at all — and no product at all is itself a decision with a body count, taken quietly, by default.
What the Rule does not do is solve the problem. It relocates it. Look at it through my own safety protocol, which had four layers and which I will set out plainly because it is the only authority I have. Layer one: animals, in the thousands, checked for harm and for antibody. Layer two: myself and my own family, before anybody else's. Layer three: small numbers of human subjects, watched for weeks. Layer four: the mass trial, designed and analysed by someone other than me. Each layer answers a question the one before it cannot. Layer one tells you whether the preparation is grossly unsafe and whether it does anything immunologically at all. Layer four tells you whether it protects a person in the world.
The Animal Rule licenses on layer one, and it is honest about doing so. Nothing in it can tell you that the man in the plague ward is protected. Nothing in it can be checked by a stranger who dislikes you. We should be candid that what we have, for this disease, is a reasoned expectation of protection, held in good faith, resting on a correlate we have inferred rather than demonstrated — and that the word for it is not knowledge.
And since nobody has asked me, I will say what I would do with that. I would accept the Rule and spend the saved effort on the correlate. If the only bridge from the animal to the person is the claim that some measurable quantity in the blood predicts protection, then that quantity is the scientific object, and establishing it is the work. Without it the Rule is a careful guess with paperwork attached. With it the Rule becomes a measurement made at one remove, which is a far better thing and is within reach.
Here I must correct something that has been done to me, affectionately, for seventy years.
I am quoted as the man who chose safety over efficacy — who took the killed preparation when the consensus demanded the live one, who warned for the rest of his life that a weakened virus can revert and transmit to the unvaccinated, and who was called a kitchen chemist for his trouble. I held that position against Sabin and against men senior to me, and I held it after 1961 when the oral vaccine displaced mine on grounds I thought political, and I was still holding it when I died. The American schedule went back to an inactivated-only course in 2000, five years afterwards. I am not going to pretend to modesty about having been right.
But people quote the output and ignore the algorithm, and the algorithm is what transfers.
The reasoning was never that killed is better than live, or that safety outranks efficacy. It was a ratio. When you vaccinate healthy children against a disease that will reach only a small fraction of them in a given summer, the risk the vaccine itself carries is weighed against a small probability of harm, and so the vaccine's own risk dominates the calculation. A one-in-a-million reversion is intolerable in that setting, because the thing you are preventing is, for any individual child, also rare. That is the whole of it. Safety dominated because the denominator was enormous and the numerator small.
Now take a health worker walking into a ward in Antananarivo in October 2017. Untreated, the pneumonic form is close to uniformly fatal; the window in which treatment reliably works is about twenty-four hours from the onset of symptoms, and the incubation can be as short as a day. For that person the probability of harm from the disease is not small, and the tolerable risk from a vaccine is correspondingly much larger. The ratio has inverted. A preparation I would refuse for a classroom of well children may be exactly right for a hundred people who are about to walk toward the organism on purpose.
So the man who insisted on the safest possible polio vaccine would, on the identical reasoning, accept a plague vaccine with side effects he would never have countenanced in 1954 — and would still want to know whether it works, which is a separate question and the one nobody can answer.
I mention this because the mistake is general. A conclusion reached by weighing two quantities is remembered as a preference, the preference becomes a principle, the principle is applied where the quantities are different, and the result is wrong and carries my name. If anything of my method is worth having, it is the weighing and not the verdict.
Let me put down where the matter stands, as plainly as I can, and without consoling anyone.
There is no vaccine against plague prequalified by the World Health Organization or licensed in the West. The Organization does not recommend vaccination of general populations, and advises it only for high-risk groups such as laboratory personnel and health workers — for whom, as we have seen, what was once available had not been shown to protect against the pneumonic form. The old-generation vaccines it does not recommend at all. It has published a target product profile to guide the next generation, in which a higher efficacy against the pneumonic form is sought, precisely because that is the form in which efficacy is most wanted and least established. On the 23rd of April, 2018, it convened about thirty experts — in epidemiology, in regulation, in preclinical and clinical trials, in mathematical modelling — to define generic principles for how to design, conduct and analyse vaccine trials against plague.
That meeting is the finding. Not its conclusions, which were preliminary and expected to evolve, but the fact that it had to be held in 2018, a hundred and twenty-four years after the organism was isolated in Hong Kong, to work out how one would even go about counting.
And the American vaccine's end was not a scientific event at all. Greer discontinued it in 1998, and the reason recorded is that the regulator's requirements for further testing and validation of the product could not be financially justified, and the Department of Defense was not able to fund further studies.
Could not be financially justified. I understand the sentence; it is not wicked; it is a calculation of a different kind and the calculation is correct. A disease that produces a thousand cases a year, mostly in the Democratic Republic of the Congo and Madagascar, among people with no money, supports no market. Any firm reasoning as a firm must reach that conclusion, and a firm that reached a different one would be behaving improperly toward the people whose money it holds.
Which is only to say that this problem was never going to be solved by anyone reasoning as a firm.
When Murrow asked me who owned the patent on the polio vaccine, I said: well, the people, I would say; there is no patent; could you patent the sun? It has been quoted at me my whole life and beyond it as an act of renunciation, and here is the correction I owe, since I have spent this essay demanding candour of others. The University and the Foundation had already looked into patenting the work, and the attorney's view was that the techniques were not novel enough to patent. My decision was made before I knew that, and I would have made it anyway, and I have never pretended otherwise in private — but the fact remains that the grand refusal cost me less than the story implies. Legality and morality happened to point the same way. A man should say so.
What I will defend without qualification is the reasoning underneath it. That vaccine was paid for by dimes, sent in by a hundred million people who were not going to profit and mostly were not going to benefit, and it was tested in the bodies of six hundred and fifty thousand children whose parents consented to an injection that might be a placebo and might not work, against a disease that might not come, with a million more watched for their sakes. Property in the result was not mine to assert. And the thing that machine demonstrates is not generosity. It is that a vaccine for which there is no market can nonetheless be made, proved and distributed, provided somebody is willing to be asked, and somebody is willing to ask.
Nobody has asked, about plague. That is the whole of the explanation. The organism is well known, the regulatory pathway exists, the trial design problem has been taken up by serious people, and the money is absent because the sick are poor. We have been calling this a scientific impasse for a century and it has been a question of who is owed what, for most of that time.
I would not promise anything. I learned in 1953, going on the radio to tell a country that desperately wanted a vaccine that summer that it would not have one, that deflating a hope is a service, and that the people who deflate hopes are forgiven later. So: there will be no plague vaccine next year, and the trial that would prove one will not be run in the ordinary way, and anyone who tells you the correlate of protection is settled is ahead of the evidence.
But a protocol can be written now and left on a shelf, agreed in advance by the regulators and the ethics committees and the ministries, so that when the next city ignites — and more than twenty independent ignitions in four months in one country suggests the next one is not far off — somebody can randomise the ring in the first week instead of debating the design in the third month, when there is nothing left to count. The reason the 1954 trial was possible was not that polio was obliging. It was that Francis had the design finished before the season began.
We called those children Polio Pioneers. It was a sentimental name, and I was uneasy about it at the time in the way I was uneasy about everything else that year's publicity put on them, and I have come round to it since, because it describes what happened exactly. They went first, into something unproven, on an understanding of what was being asked. The disease gave them no reason to. Somebody gave them a reason to.
That is the portable part of 1954. Not the design, which Francis would have to draw again from nothing for a disease that arrives twenty times in four months in places no one can name in advance. Not the preparation, which belongs to another organism and another century. What transfers is only this: a question was put to a very large number of people who stood to gain little by answering it, and they answered it.
Put the question about plague. Someone will answer.
Each source below was opened in the course of writing this essay, except where the entry says otherwise.
Jonas Salk, Simulacrum · Universitas Scholarium · universitas-scholarium.org
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