Must we wait for the perfect COVID immunity test? — What 225 years of trying to make the perfect Kilogram can teach us about unlocking our nations.

Dr Jack Kreindler is a Physician, Technologist and Policy Advisor @drjackUK. Founding contributor to Project COV-CLEAR

A Weighted Question

Let’s start at the end: How much does one kilogram weigh? How heavy is ‘one thousand small weights’. Obvious, no? A thousand grams. But, what’s a gram then? (“Hey Siri. Play, Infinite Regress”). We decided in 1795 that one cubic centimetre (a ‘cc’) of water weighed a gram so 1000 cc’s weighed one ‘kg’. Good. But wait, what if you need to know you have one kg of water, really, really accurately? Perfectly, in fact. You’d need a perfect container holding 1,000 cc’s of perfect water - a box measuring 10 x 10 x 10 cm or equivalent cylinder. How you measure out and build that container is another tough one, but made easier by ‘constants’ like wavelengths of lasers instead of relying on tape measures [1].

This has suddenly gotten rather scary, hasn’t it.

Beaker, the perpetually panicked lab scientist from the Muppet Show

More tiresome perfectionism: How much does the perfect 1,000cc container itself weigh? Won’t that make your kilo of water weigh more than a kilo? It’s okay: The kg is just the water inside the container. Just pour the litre into a set of scales then the container doesn’t matter, does it? All we need is… the PERFECTLY accurate container that’s EXACTLY 10x10x10 cm filled PRECISELY to the brim with IMMACULATELY pure water and SPECIFICALLY only those molecules [2] in an ABSOLUTELY stable physical environment, all poured out INFALLIBLY. Your scales, of course, then have to be UNFAILINGLY reliable and INFINITELY sensitive. When you pour out the Litre of water onto your (magically perfect) set of scales it will excerpt 1 kg of force, at rest, on Earth (Gravitational Waves permitting).

Bored yet? I am.

The 22 Karet Gold World Cup weighs in 6.1kg — “That’ll be $303,030, Sir.”

Let’s Get Practical: On one side of the scales you’ve got a perfect kilogram, on the other side you can chuck on a bunch of something else, like gold say. If it balances then I know that you’re handing over the expected kilo of bullion you lifted from the bank heist before I hand over the dollar bills.

In the real world, you don’t need balancing scales, you can calibrate a reasonable electronic scale with a reasonable kg so you can weigh yourself each morning in the bathroom, weigh the amount of sugar you need for your kid’s birthday cake in the kitchen, or get into a fight about your luggage allowance just as you’re about to board your flight at Heathrow. You may, however, need a damn-near perfect kg or perfectly calibrated scales for the amount of Thorium-229 you need to buy for the atomic clock in your GPS satellite.

The bottom line is this: We don’t need kilograms, scales or any measuring system to be perfect to do most things that matter in daily life. What do the best bakers need to make great cakes? How accurate do the scales at Heathrow need to be sure planes can safely take off? Not very.

Immunity. Embracing the Imperfect

Moving swiftly on, to the beginning: What the f*kg has any of this got to do with COVID-19 and immune testing. EVERYTHING. Why? Because our measures of immunity do not need to be perfect to be powerful.

Platinum-Iriduim cylinders that define the kg. Photograph: National Institute of Standards

It’s taken 225 years to get to sufficiently precise, accurate and stable measure of the kg for today’s most demanding scientific needs. From a Litre of water we progressed to a machined platinum cylinder, leaped forward in 1889 adding a splash of iridium, we’ve had diamond cutters and lasers to craft ever more perfect reference kilos. Dozens of incredibly bright people are employed full time to do this stuff. Their kg’s are are still all called ‘prototypes’, two centuries in the making! Now they’ve given up and created a silicon ball and the something-out-of-StarTrek, ‘Kibble Balance’, and some esoteric physics to ‘describe’ a kilogram by how much spacetime it bends or something. [3]

Frankly, writing about all this pursuit of perfection is killing me.

Meanwhile, COVID is really killing people. And not just those we expected. Yes, far too many of my patients older and some surprisingly young have ended very sick. Far too many in ICU. And far too many of those have lost their lives. And not even had the right to proper funeral. But, there will be even more non-COVID mortality and morbidity too. One of my cancer patients, a young parent of two had potentially curative surgery cancelled. COVID does not cause Cancer, but Cancer as well as many other critical medical services have been crippled by COVID and our inevitable response. Time is of the essence.

The Phantom Menace

Succumbing to the military COVID verbiage, today’s Battle of Britain is on the front line where ventilators are our weapons and PPE our shields. But this is not the War. The War against the Germs, that’s just Episode I. The true War is against the most insidious, but necessary evil in all this: The meltdown-causing lockdown of every other part of healthcare and welfare, and moreover the world’s economy. Critical to winning the World War is estimating our immunity, not just as individuals, but as Nations. It’s non-binary. The fact is, even if you do get a confirmatory IgG Antibody line on a ‘pregnancy test style’ home kit or better still a fancy looking official report from a certified serology lab, it doesn’t guarantee lasting immunity to SARS-COV-2 (or version 2.x).

An Antibody test today might, if sensitive enough for someone who’s just had a bit of a cough, indicate that you’ve got some antibodies and so have had COVID, probably. But it does NOT give you a yes/no answer on immunity. It does not tell you if your infection has been reactivated (looking likely for some). It does not tell you that someone later confirmed infected was sat on the no. 82 bus with you last week or that you forgot to wash your hands before eating that burger. It quite definitely does not give you the authority to print a ‘Hey, Trust me, I’m Immune’ passport or T-Shirts with QR Codes to be stolen and forged, prized and feared.

Not cool! Don’t try this at home.

But data-driven, ‘Probabilistic Exposure / Immunity Estimates’ for each of us to work hard towards improving, unlocking opportunities to volunteer and work, and unlocking the doors to our elders and most vulnerable? Yes.

Open standards for weights and measures were good enough for the creation of human civilisation. Fair trade — knowing the amount of something I’d get for giving you an amount of something else was the cornerstone of bartering, market trading, eventually, the invention of money and economies. It’s not perfect. It is powerful.

We certainly cannot wait for perfect. We cannot even wait for the traditional requirements by regulatory bodies demanding sufficient precision, accuracy and stability of tests for reliable individual diagnosis. We must not throw away any opportunity for data. Tracing and truly reliable diagnostics including rtPCR for virus testing, and alternatives like rapid antigen testing also for viral infection must all be scaled to understand who is infected. For who was infected and to map and surveil our nations’ immunity we also need immune Antibody testing. On a vast scale.

Patient 00000001: IgG Antibody kits will be less sensitive and need 2–3 weeks post infection for community cases. Even highly exposed household members may not show symptoms or test positive, so should then be selected for Lab Serology. Despite the limitations, such kits promise ultra high specificity — meaning if positive it’s very likely you’ve got antibodies post COVID-19 and nothing else. These would be valuable data.

COVXIT

Some 3.5 million cheap (and cheerful) home pin-prick antibody tests were mis-sold to the UK Government. GOOD! 3.5 million reliably unreliable tests sampling volunteers in households once a week for a month, covering Recovered PCR confirmed Infected patients sick enough to come to hospital, clinically likely community cases of COVID pneumonia now Recovered, and those with mild or no symptoms too, would give us a vital piece of the ‘how, when and where to unlock’ data the world is waiting for. And every country can share theirs.

Of course, cheap antibody test kits are not the holy grail. We need a combination of many tests and technologies. But it is only with cumulating all learnings from different kinds of test strategies, trading off sensitivity, specificity, reliability, scalability, practicality, utility and speed can we get to the answers we need. By combining data from all test programmes we can, within weeks, deliver a data foundation for smart probabilistic passporting and wise exit trade-off decisions:-

From COV-CLEAR Proposed Protocol and Utility for Community Diagnostic & Antibody Testing illustrative process flow and risk stratification only.

1. Deliver the real-world performance analysis of all tests using Bayesian Inference.
2. Deliver exposure and immunity ‘estimates’ for individuals, households and neighbourhoods combined with contact tracing.
3. Deliver a National (Herd) Immunity Mapping for unlock policy decision support.
4. Deliver a Registry of potential volunteers for a Convalescent Plasma Biobanks.

We don’t need to hone the perfect test, prototype after prototype. Imperfect tests may not give YOU or ME the answer we are looking for today. We just need to test, test, test. And trace, trace, trace. Time and time again. And learn from it all, assuring identity, preserving privacy. This does not mean Gattaca.

Clever tech and maths, (thankfully not for going into now), has already pretty well figured all this stuff out. The thing that’s missing is to get our top scientists and medicines regulators to speak to the global tech community, especially our statistics and machine learning gurus woven into our behavioural scientists who can help us sew much needed seeds of hope, and chance to contribute through citizen science, in these disenfranchising times. As quick as our front-line clinicians have had to draft ventilation protocols we have to radically rethink what’s fit for purpose in diagnostics devices for the coming weeks and months ahead, and flex those requirements in real-time with the prevailing conditions. Forget PERFECTLY, EXACTLY, PRECISELY, IMMACULATELY, SPECIFICALLY, ABSOLUTELY, INFALLIBLY, UNFAILINGLY, INFINITELY SENSITIVELY. The purpose is not only for diagnosis. It is for data. And all data is good.

Must we wait for the perfect COVID Immunity Test? At no time in my career has the old phrase been more apt: “Perfect is the enemy of Good”.

Dr Jack Kreindler
@drjackuk

Wishing you all a Happy Easter, Passover, Nothing and Everything. Please stay home (for as long as it takes) and keep well.

Disclosures: No current or potential conflict of interest was reported by the author

Acknowledgements: A very special thanks for the extraordinary contributions of the many people working on Project COV-CLEAR and the exceptionally kind support throughout my COVID war effort and volunteering: Mosaic Ventures, CHHP, Havas Lynx / Havas Health & You. None of our progress would have be possible without all of your generosity. 🙏

[1] 10cm is 157980.0298728 wavelengths of a Helium-Neon laser in a vacuum, or thereabouts.

[2] A Litre is 3.345*10²⁵ molecules of H2O, under atmospheric pressure and at the temperature of its maximum density, which is approximately 4 °C, or thereabouts.

[3] The Kilogram is now is defined by taking the fixed numerical value of the Planck constant h to be 6.626 070 15*10-³⁴ when expressed in the unit J s, which is equal to kg m2 s -1 , where the meter and the second are defined in terms of c and ∆νCs, or thereabouts.