I want to visit an interesting point featured in Michael Yeadon’s interview. This is the question about levels of pre-existing immunity to #SARSCoV2 in the population due to exposure to other endemic coronaviruses, resulting in T cell 'cross immunity'.

This is an open question, so this isn’t an ‘I’m right, he’s wrong’, but rather my take after looking into it. I hope that voices from all sides will accept that this is an ongoing debate. If we were to meet, we would discuss it. We're both scientists. They often disagree.

This thread is me thinking out loud, addressing this fascinating immunological question. Please maintain etiquette as we explore it. I aim to represent @MichaelYeadon3 accurately. I respect his opinion & those who agree with him.

Dr. Yeadon has a hypothesis: previous exposure to common cold CoVs (CCC) has significantly reduced population-level susceptibility to SARS-CoV-2

“People exposed to CCC are now immune to SARS-CoV-2. 30% were protected before we started.”

Listen again. That is an *enormous* claim

“Quite a lot would have been exposed to CCC, so we would perhaps expect protective immunity”.

I will explore the opposing side for the sake of argument. My position will be “previous exposure to CCC does not provide substantial protection from SARS-CoV-2”

Some findings to kick us off:
Gorse et al - >90% of adults are seropositive for multiple HCoVs
Grifoni et al - healthy people are seropositive for anti-RBD IgG against two CoVs.
Stan Perlman (CoV godfather) supports this number.

An elegant experiment to nail this would be testing seropositivity of COVID-19 patients for anti-CCC Abs. If positive, this would confirm previous infection, established cellular & humoral memory and suggest no definitive protection conferred by recent CCC exposure.

Was it done?

It seems that we don’t develop very effective cross immunity, even among endemic CoVs.

If we are continually reinfected with highly homologous viruses, or if immunity is short lived to the *same* CCC, can we confidently anticipate significant pre-existing immunity to a new one?

So it's higher than the 30% proposed in the video clip, in fact. Upwards of 90% of people have evidence of recent CCC infection, assuming rapidly waning antibody titers. Both T and B cell immune responses will have occurred. That's a fair assumption after viral infection.

He discusses SARS, which is "80% similar to SARS-CoV-2". There is significant sequence overlap in multiple proteins. Some significantly higher than 99% (PMID: 32447571). I’m sure significant sequence homology exists between various proteins across CCC, SARS-CoV, MERS etc

So the scene is set: the majority of people have been exposed to multiple CCC. Foreign peptides from CCC have created T cell memory. Abs are circulating. The population is primed, protected by substantial cross-immunity against SARS-CoV-2.

This is where it gets tricky.

How then, if effective cross-immunity exists, can an nCoV rapidly spread across continents in which >90% have been continually reinfected with multiple highly homologous CCC, with demonstrable immune responses to them?

These positions seem mutually exclusive, so let's explore

See my gripe? It may appear niche to some.

We've all been infected multiple times with a diverse repertoire of CCC. We are continually reinfected with symptomatic outcomes.

We can't yet say that if you've had a CCC you're immune to SARS-CoV-2.

At least I can't. I'm not alone.

The reason is perhaps that SARS-CoV-2 is indeed “novel”. Established immunity at a population level would preclude viral spread like we are observing. What happened in Feb-Apr and now again in Sep-Nov speaks to limited immunity in the population.

A robust T cell response is important to fight off SARS-CoV-2. This is not in question. We agree.
a) COVID-induced death and lymphopenia are linked (image below) PMID: 32296069
b) Clonally expanded T cells are a hallmark of mild disease PMID: 32398875

... but effective pre-existing T cell immunity remains a hypothesis for the time being.

I stand by this opinion: whatever mechanisms are in play, however they affect severity and/or transmission, the current NPIs are surely warranted. https://twitter.com/andrew_croxford/status/1330883200193884163?s=20

A confounding factor in all of this are the diverse NPI in place internationally, which (fortunately) suppress the spread of this virus. But that surely hampers determining the potential of an unmitigated outbreak. We will *never* know how it that scenario would have played out.

In defence of SAGE:

“SAGE said it was 0% (immunity to SARS-CoV-2), and I don’t see how they could have justified that”

It’s justified because it was 0%. Nobody had SARS-CoV-2. Too many unknowns to make policy based on an untestable hypothesis faced with a new infectious agent.

Even if a ‘card-carrying immunologists’ (as he puts it) were present on SAGE from the outset, I disagree profoundly with Dr. Yeadon that this would have been an open/shut case. I am surrounded by them and haven’t heard one say that we should return to normal.

I will continue to learn (it’s fascinating). The jury is still out. But my personal take is that the majority of the population is still susceptible to SARS-CoV-2, which means it has potential to cause serious harm. Do we need more evidence? We're about to get some from the USA.

So, I’m moving on. I would like continue to make threads on COVID, but also new therapeutics.

And remember… STAY HEALTHY (watch the vid! It's cool. If you’ve made it this far, you probably don’t need convincing that masks stop you infecting others) https://www.nejm.org/doi/full/10.1056/nejmc2007800

I see how these threads could go on forever. I had fun making it. Please chime in with your thoughts, your papers, your articles, your rebuttals.