The Immunes

The new blood antibody tests will change everything — and start to bring back the economy.

In one of the first papers out of China, the Novel Coronavirus Investigating and Research Team included a detail that would be easy to miss.

In a long list of facts about one Wuhan patient, the Coronavirus Team reported that “IgM and IgG antiviral antibodies were detected” in his blood.

We’re going to hear a great deal about IgM and IgG in the next few months.

The serological tests for Covid-19 antibodies will be our best hope for breaking the pandemic. And for rebooting a new, if different, version of the economy.

If we can make enough of them, and use them wisely.

This is not to offer cheap hope, or make light of the pandemic. The pandemic is bad, and going to get worse. Last week’s 538 “consensus of experts” estimates for the final death toll were all over the place, but they centered around 200,000 for the U.S. alone.

That’s a lot of death. It approaches the 215,000 combat deaths on both sides in the American Civil War, and well exceeds U.S. combat deaths in Vietnam (47,000) and World War I (53,000).

And that doesn’t include the rest of the world.

Looking at the near-term future in wartime can be difficult and unpleasant. It can be hard to focus when the death count is going up before your eyes.

But it’s vital to remember that modern wars are won by planning and logistics. We rightfully honor front-line heroes. But front-line heroes die if they are provided with inadequate weapons, or no weapons at all.

Antibodies

IgM and IgG are antibodies.

The idea that there was something protective in the blood was first put forward by Japanese bacteriologist Kitasato Shibasaburō in 1890. He was then working with legendary German microbiologist Robert Koch at the University of Berlin.

Blood serum therapies had just been discovered, and these held promise for a list of late Victorian diseases, including diphtheria and tetanus.

There was a conception at the time that an infectious agent was something like a toxin — a little bit of poison.

Whatever these mysteriously good things in the blood were, they were functioning like an antitoxin. Paul Ehrlich coined the German word Antikörper for them October 1891.

(Kitasato went on to identify the bacterium Yersinia pestis as the cause of bubonic plague. He was apparently a few days ahead of Alexandre Yersin, the Swiss/French bacteriologist from the Pasteur Institut who got the credit. Ehrlich went on to discover a cure for syphilis, his so-called “magic bullet.”)

We now know a lot more about antibodies. They are created by the body’s immune system to ward off infection.

When it encounters an unknown pathogen, the immune system starts a chemical version of artificial learning. It has a built-in library of protein building blocks at the ready and, using them, attempts to evolve a matching template.

This evolution, if successful, finds a protein that fits to the outside of the new pathogen. It fits that one and only that one, or another very, very similar. Antibodies are typically highly specific.

In a recovered patient, antibodies sit on the surface of white blood cells and acts like early warning proximity sensors. If the — now-familiar — pathogen comes back and binds to them, they wake up the immune system in time to fight off a new infection .

The presence of antibodies in the blood specific to a particular virus is solid evidence that someone has either (a) recovered from a viral disease; (b) at some time been exposed to the virus, perhaps without developing symptoms; or ( c ) had a vaccination for for the virus that “took.”

We use blood antibody tests all the time. The blood test for HIV is an antibody test. There is an test for antibodies to the varicella zoster virus, in case you can’t remember if you had chickenpox as a child. There is a blood test for HAV-specific IgM antibodies for hepatitis A to reassure you that a vaccination took before you travel to an undeveloped part of the world.

An blood antibody test does not detect the presence of live virus.

That it worth repeating, because failing to understand it may lead to the new blood antibody tests being wasted and misapplied, compounding the previous testing blunder with a new one.

The current test — the PCR test — detects the virus itself. It looks for Covid-19’s signature RNA in a mucus sample. It reveals one thing: if the coronavirus got onto the swab at the time the swab was taken.

As a tool to confirm a Covid-19 infection, it’s a very good test.

Tests are judged by false positives and false negatives. On positives, the PCR test is great. A positive result is conclusive.

(On false negatives, the PCR test is not quite as great. False negatives appear to run about 2 in 10. The New York state department of health finds it necessary to warn, “A negative result does not rule out COVID-19.” A subject who has recently been infected may get tested too early, or things can go awry with the swab or test mechanics.)

The serological test, the blood test, is doing something different.

It is looking for antibodies to the virus in the blood, not for live virus in the nose.

Antibodies show up around day 3 after the onset of symptoms, so it is possible to use the blood antibody test in clinical diagnosis.

But the first and best use of new tests, as they become available, will not be on incoming patients with symptoms.

The PCR test is remains the right test for them.

The correct fix for testing delays are the new rapid PCR machines and old-fashioned organization and logistics.

We have high-throughput batch testing machines that can run hundreds of tests at a time, but take several hours. Cepheid, a Sunnyvale, Calif. company, has 5,000 of its automated GeneXpert Systems installed in the U.S., and has announced a kit to detect of SARS-CoV-2 that can be operated at bedside and produce results in 45 minutes.

Ironically, the FDA, perhaps in atonement for its role in the original testing blunder, may save us from another. Its guidance for the new serological tests is:

▪ Negative results do not rule out SARS-CoV-2 infection, particularly in those who have been in contact with the virus. Follow-up testing with a molecular diagnostic should be considered to rule out infection in these individuals.
▪ Results from antibody testing should not be used as the sole basis to diagnose or exclude SARS-CoV-2 infection or to inform infection status.
▪ Positive results may be due to past or present infection with non-SARS-CoV-2 coronavirus strains, such as coronavirus HKU1, NL63, OC43, or 229E.

The key phrase is “infection status.”

The antibody test isn’t for that. A positive blood antibody test will reveal if there was an infection in the past, but doesn’t say when it that past was. And it says nothing about whether the test subject is currently infectious.

If you want to know if someone is has the virus now, somebody has to gear up and take live virus from the nose.

Given how notorious doctors were — in peacetime — about ordering more tests, the best public health policy for the blood antibody tests may be to — literally — keep them out of their hands.

Most of the serological tests can be self-administered, and involve a simple finger stick that produces a drop of blood.

Amazon has discussed delivering them to at-home Amazon employees via the company’s Amazon Care program.

A key point is that there is no live virus in the air with a blood test. That’s why we see the hazmat suits on the people taking swabs.

PPE is already being rationed, and needed elsewhere. We need to design a blood antibody testing program that takes advantage of its far lower risk.

If it’s just another test, but the FDA says it really shouldn’t be used for clinical diagnosis, what good is it?

If one assumption is true, the blood tests will be absolutely vital to stopping the pandemic.

The assumption is: among the recovered, immediate re-infection is unlikely.

It’s an assumption, but a very reasonable one. Its similarity to “SARS classic” suggests at least a few years , possibly long enough to find a vaccine.

Your annual flu shot is good all season. It doesn’t wear off; the flu virus mutates year to year. SARS-Cov-2 does not appear to mutate like flu does.

This assumption should, of course, be tested. This would involve a longitudinal study to see if effective antibody levels are maintained over time.

As Siddhartha Mukherjee points out in current issue of The New Yorker, we know something now about the path of Covid-19 between people; we don’t know nearly enough about the course of Covid-19 inside people.

That said, the blood antibody test will, in time, reveal to us who is immune.

And that will change everything.

At the current pace, blood antibody tests may be ubiquitous by summer.

Designing a new blood antibody test is a challenge, but several dozen labs around the world, public and private, have already done it.

As early as January, the Wuhan Institute of Virology was using an in-house serological test to confirm infections.

By February, the Duke-NUS Medical School in Singapore had a blood test, which public authorities used to solved a cold case. They had a missing link in a transmission chain radiating from the Life Church. The blood test allowed them to track down a couple that had not been given the PCR test in January, because of their symptoms had been too mild. That version of test had about 90% accuracy. A new version is more reliable.

The private sector has stepped up quickly. EUROIMMUN, a Lübeck, Germany company owned by PerkinElmer, was the first company to offer diagnostic tests for SARS-CoV in 2002/2003, MERS-CoV in 2012/2013 and Zika virus in 2015/2016. On February 21, it announced that it had two tests for ready for Covid-19 and was seeking approvals.

In March, virologist Florian Krammer and a team of the Icahn School of Medicine in New York City not only developed a working test, they posted their lab notes and the recipes on the internet. Krammer reported that the test could pick up antibodies “as early as three days post symptom onset.”

On March 19, the U.S. CDC announced that it was working to develop a serology test that will look for the presence of antibodies.

South Korea, as is well known, moved quickly on testing. There, SD BioSensor developed a blood antigen test that will be distributed in the U.S. by New York–based Henry Schein, Inc. It promises results in 15 minutes from a pinprick.

On March 24, the UK’s health minister announced that it had ordered 3.5 million antibody test kits from two British firms, Mologic and SureScreen. SureScreen has a finger-prick test that takes 10 minutes and claims 98% per cent accuracy. Both look something like home pregnancy tests.

More of the tests are being announced all the time. Indeed, with peacetime regulation in hiatus, there is some danger of the market turning into a Wild West. The FDA’s current position is that it “does not intend to object” to serology tests to identify antibodies to SARS-CoV-2.

One Chinese firm that rushed out a kit has already caused trouble. Bioeasy had its tests returned by Spain and Turkey, whose health ministers called them “defective” and “wildly inaccurate.”

There will be snafus, delays, glitches, and bugs to work out.

That said, the U.S. government needs to be placing orders for millions of the tests. Now.

Because there is a vital, national interest use for the blood antigen tests that will not get much public understanding or sympathy.

A large number of the tests need to be used to test people at random — more precisely, in a “stochastic process random probability sample.”

Think of it like taking a nationwide opinion poll.

This means testing people who have never had symptoms, or live in an area that appears to be low-risk.

With waiting lines at emergency rooms on TV every night, the optics will not be appealing.

But it must be done, and the sooner the better.

Since the blunders that put the U.S. behind the curve on testing, the country has been flying blind.

We need to know if the side of a mountain is coming up in the fog. Or not.

Despite the early problems, PCR testing has at long last ramped up pretty well. The COVID Tracking Project is about to top 1 million test results, which does not include tests in progress. That’s a number undreamed of several weeks ago.

But the ramp is linear. The threatened infection curve is exponential.

While the early testing fiasco may be coming to a close. But with PCR testing dedicated to symptomatic patients, we have yet to address what Professor John Ioannidis of Stanford calls the “evidence fiasco.”

We need to test the general population at random. And use the blood antibody tests to do it.

No, we don’t know what we’ll find.

That’s why you do it.

There are a few hints from other countries.

Iceland tested 3.2% of its population by offering free screening to all, including the non-symptomatic. It found “the virus had a much, much wider spread in the community than we would have assumed, based on the screening of high-risk people,” according to deCODE Genetics CEO Kári Stefánsson. Iceland has had some hospitalizations, but no deaths.

In a dense urban area like New York, the epidemic is deeply entrenched. The sledgehammers of lockdown and social distancing are the only tools available to slow it down.

Today’s gigantic “unknown unknown” is what’s going on in the rest of the country, outside the known hot spots.

That information is absolutely vital to develop a rational — national — strategy.

New York Governor Andrew Cuomo told the rest of the country that it may be New York in matter of weeks.

He said it for the right reasons, as a warning, but we actually need to put that rhetorical point to scientific test.

To repeat, we don’t know what we’ll find when we test the general population at random.

What we find could make a major difference in fighting the epidemic.

These are all just “ifs.”

If a national antibody survey shows there has already been vast, hidden exposure, it would point to urgent research on why some individuals stayed asymptomatic, while others were hit so hard.

If it shows small, relatively isolated clusters of infection outside the hotspots, these might be manageable by classic public health techniques, such as aggressive contact tracing and isolation.

The experience of Vò, Italy, is instructive. Vò, a town of 3,000 inhabitants near Venice, was involved in a project led by the University of Padua. By the time the first symptomatic case was diagnosed, it was later calculated that a significant proportion of the population, about 3%, had already been infected, yet most of them were completely asymptomatic.

Vò was put into quarantine and every inhabitant tested. In the first round of testing, 89 people tested positive. In the second round, the number had dropped to six, who remained in isolation. Within 14 days, there was a 100% recovery rate for those previously infected, and no further cases of transmission.

Perhaps after there is a vaccine, life will return to the Old Normal.

In the meantime, we need to think.

The blood antibody tests will start to change the economy on a timescale of months.

It’s instructive to start with doctors, nurses and other heath care workers.

There was an interesting detail in the UK’s announcement about buying 3.5 million antibody blood tests for the NHS.

They were prioritized for testing people working at the NHS — not testing patients coming into the NHS.

A negative PCR test is still the right precaution for those working with the unexposed.

But the NHS has a lot medical staff that’s in limbo. They may have been exposed and gone home and put themselves in isolation, yet not developed symptoms. The blood antibody test may give them quick first answer about whether they can return to work.

Here’s where we enter the topsy-turvy New Normal.

The best blood antibody test result for a healthcare worker is a positive.

Without symptoms or live virus, of course.

Like a visit from the ghost of Christmas Future, the plight of the NHS workers gives us a glimpse of what may come to pass in the economy at large.

For health-care workers, it’s simple. The immune will be able to care for Covid-19 patients without themselves worrying about getting sick. Great day! Their PPE, in such short supply, can go to non-immune caregivers who need it.

Immunity to the virus is going to be a job qualification.

Just as vaccination will be, after that happens.

There are a number of other jobs that should, by all rights, start being performed by the immune.

Begin with those who, like health care providers, have jobs where contact with infected members of the public is unavoidable, even if that public is locked down.

These would include EMTs, police officers, public health contract tracers, possibly firefighters, and some delivery drivers.

On a positive note, in certain trades, being an immune with present a golden opportunity.

Any occupation requiring close, one-on-one physical contact is a candidate here: barbers, hair and nail stylists, massage therapists, personal trainers, and, yes, sex workers.

Physical contact brings up sports. The commercial incentive to bring them back will be irresistible. Television is waiting. It takes 5 immunes to make a basketball team, 10 to make a game.

As other sectors of the economy sputter back to life, immunity will be highly desirable, if not an absolute necessity, in jobs that require routine, close-proximity with the public: TSA agents, flight attendants, prison guards, hotel and retail clerks.

And school teachers. I didn’t want to mix them in with the prison guards.

Masks, gloves, and keep-your-distance might work in these occupations for a time. But an immune employee will appear to have superpowers.

Will it be legal to discriminate by hiring an immune?

Should the immune be conscripted to perform essential jobs?

The social obligations of the immune take us to the root of the word.

In ancient Rome, the munus were a range of social practices and obligations of the Roman citizen. They were expected to do a lot: the munus involved services, public functions, duties, gifts, favors, taxes, tributes to the dead, rites, sacrifices, public office.

Over time, certain classes and individuals — the Emperor, for one — were exempted from these duties: they were immunis, the prefix im- denoting that someone have received a dispensation.

The Roman army had a category of soldiers known as the immunes. These were excused from ditch-digging and the Roman equivalent of peeling potatoes (potatoes are a New World plant). But they were expected to be in the front ranks in a battle.

Will the fault line of immunity add another crack in our already fractured country?

As a demographic, we can guess that the immunes will be younger than the non-immune.

This is not because the elderly will die off, but because the elderly are sensibly doing everything they can to avoid getting the virus.

The immunes will, perhaps proudly, be in work. They will be makers, not takers.

They will also be “normal,” as memories of what that was like fade into the rear-view mirror.

The immunes, being young and normal, will want to gather, socialize, and have sex.

The distinction between “safe” and “unsafe” sex will add a new dimension. No doubt some cautionary song will rhyme “undressed” with “blood test.”

Touch-deprived non-immunes, unwilling to wait until the vaccine is ready, may seek out immunes. It may be small consolation to those who got the disease that it’s now easier to get lucky.

So there will be incentives to being immune. You can get a job, go out and about, run around with practically anybody, and maybe even get laid. What’s not to like?

It’s time to have the talk about variolation.

Which is the correct term for deliberate exposure to a virus.

The social-distance shamers would probably like to make this a taboo topic.

It shouldn’t be.

Variolation is the oldest method humans have used to prevent viral infection.

It is known to have been used against smallpox around 1100 in China, and from there it spread west along the trade routes to India and the Islamic world.

In 1715, in Turkey, the practice was observed by Lady Mary Wortley Montagu, the wife of the British Ambassador to Constantinople. She herself had been stricken by smallpox, and had a disfigured face.

Techniques for variolation varied, but typically a powder containing a small amount of live smallpox virus was introduced to a scratch on a healthy person’s arm. Lady Montagu called the process ingrafting.

Lady Montagu’s advocacy of the Turkish practice went viral, so to speak, upon her return to London in 1717.

To demonstrate her confidence in the procedure, she had both of her children variolated, with no ill effect.

In 1721, yet another smallpox scare in Britain prompted the so-called Royal Experiment. This test inoculated three male and three female prisoners. (The King did not need to appear before an ethics review board in those days.) The prisoners survived the procedure and did not subsequently contract smallpox. The Royal Experiment has the dubious distinction of being the first clinical trial.

Inoculation by variolation came to America that same year. On April 22, 1721, HMS Seahorse docked in Boston harbor, out of the West Indies. By flag, it reported smallpox onboard. Despite the ship being put into quarantine, smallpox cases began to appear in town.

Puritan minister Cotton Mather, who was well aware of the London theories, urged his doctor, Zabdiel Boylston, to inoculate people. This Boylston did with success.

In a prefiguration of our century, there was vicious counter-reaction. Mather and Boylston were the subject of “furious Obloquies and Invectives” by those claiming they were spreading the disease. Boston’s Selectmen prohibited inoculation. A lighted grenade was thrown into Mather’s home.

All that, and they weren’t even on Twitter.

Variolation is a tricky business, since it depends on getting the dose of live virus just right. Several 18th century physicians ran successful clinics where they specialized in the procedure. They closely guarded their recipes as trade secrets. The key to “Sutton’s method,” it was later revealed, “lay in a shallow scratch and careful selection of only mildly affected donors.” And, something of a heretic for his time, Sutton believed there was no need to bleed his patients before the procedure.

The advance from variolation to vaccination is credited to Gloucestershire doctor Edward Jenner, who was aware of a common observation that local milkmaids were immune to smallpox.

Jenner theorized that variolation using material from a cowpox vesicle might transfer smallpox immunity with less risk. It worked.

The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), Jenner’s Latin term for cowpox.

We now know what Jenner had come across in cowpox was an attenuated virus — a weakened relative of smallpox, but sufficiently similar to provoke an immune response that worked. In the years since, attenuated virus vaccines have become a mainstay of modern medicine.

A virus was traditionally attenuated by “passing” it through a species in which it does not replicate well (for example, by infecting an animal with a human virus), or by forcing the virus to replicate repeatedly in tissue culture.

Modern molecular methods allow some shortcuts.

While the virulence of the attenuated virus is reduced, it is technically still viable, or “live.” This fact gives anti-vaxxers the heebie-jeebies. But most people have had live attenuated vaccines for measles, mumps, rubella, and possibly chicken pox. The Sabin oral polio vaccine was a live virus, as was the 2009 H1N1 flu nasal spray.

Finding a proper vaccine is hard, but attenuating a virus is not.

In the race for a polio vaccine in the 1950s, many doctors, some with dubious motives and credentials, passaged polio virus.

We can imagine a doctor doing it today with Covid-19.

For variolation, the goal is have a somewhat weakened wild virus, not a vaccine with no side effects at all. The people who take it plan to get a little bit sick; they just don’t want to die.

Speaking strictly scientifically, Covid-19 is not the worse candidate for variolation with a weakened strain. It’s not polio, or AIDS, and certainly not smallpox.

If widespread blood antibody testing turns up large numbers of once-infected but never symptomatic, we may have a path to our milkmaids right there. We may want the strain of virus that infected them

This is not be be confused with convalescent serum therapy, which attempts to mitigate an infected person’s disease by transferring antibodies in the blood serum of a recovered patient.

Let’s say our modern-day Dr. Jenner, or Dr. Sutton, has worked out his special attenuated Covid-19 formula.

What would be the circumstances for a safe-and-sane coronavirus party?

I picture La Clínica as a beach resort, with good wi-fi and high-speed internet.

You, the client, are young, healthy, and have none of the risk factors that lead to coronavirus complications. Sorry, no smoking, no asthma.

Your blood antigen test is a negative, as is your nasal PCR test. Test positive, on either of these and you get your deposit back. You don’t need to go to the clinic.

You arrive and meet the other members of your incoming class. You, like them, are prepared for a stay of three weeks, maybe four.

It sounds like a long time. But you tell yourself that once you get through it, you will get yourlife back.

At Day One orientation you get a little lecture, sign yet another release, and finally snort a hit of the Doctor’s special nasal spray.

That’s it for the Day One. You’re free to socialize and get to know your classmates. After months of social distancing, it’s exciting to be close in a group of people again. What’s the worse thing that can happen if you kiss? You’re trying to get sick, remember?

The first few days, nothing happens. The beach is great, the food is okay, your classmates are interesting, and you can study or do a little work online if you feel like it.

On Day 3, your antibody test goes positive. That’s good news. The variolation worked.

On Day 5, your temperature is up and you and your classmates are feeling things. You talk about them in group. It’s not fun, but the attenuation seems to be working.

Week Two, as you have been warned, is the worst. If it’s needed, the clinic has a few oxygen machines and a low-cost ventilator.

A devilish finding in full-blown Covid-19 infections is that some patients suddenly turn for the worse, going into respiratory distress. Thus, the clinic prudently has a last-ditch contingency plan for your evacuation to an (overcrowded) nearby hospital with an small ICU.

As a practical matter, however, being taken care of at the clinic is much simpler. Everyone who works there has already had the disease. To the extent you can, you take care of each other.

In this, La Clínic is not unlike one of the plague hospitals of the 16th century.

In Week Three, you are starting to feel better. The PCR tests begin. You grdaduate if you get two negatives, two days in a row. Some of your classmates have obligations and have to rush off as soon as they cleared. Others stay on to see everyone else through.

When you’re done, you get a certificate. Back in the time of plague, you had to have one to go from town to town. You also get the special stamp on your passport.

You’ve gotten close to your classmates; all but a few of you decide to get the tattoo, whose design you spent idle days working on together. And you opt for the the microchip in your hand, so you can wave it like a magic wand and walk into one of those clubs you’ve heard about, but never been able to get in.

At the airport, you kiss that special classmate goodbye, and shake hands with the others. You group get dirty looks. You dig around in your Exit kit find the little green ribbon, and pin it on your shirt.

You’re immune.

I write this on March 31, 2020 at 6 p.m. Eastern Time.

I turn on CNN to add another kind of timestamp.

The scoreboard the cable channels put on right-hand side of the screen, in red, shows 185,00 confirmed cases in the U.S., with 3,746 dead.

When I read this in the future, will those numbers seem laughably small?

The cable channels take their numbers from the Johns Hopkins dashboard, a reliable source.

But they leave one Johns Hopkins number out. The one in green.

This number, too, is going up, although slower than anyone would like.

But it should give us a sliver of hope. It’s the number under “Total Recovered.”

There they are.

The immunes.