Thread by @profshanecrotty

How much immunity do you need to stop COVID? And what about the variants?
Here's the way I am currently thinking about it. Please imagine these models written in crayon. They are not formal, just where my head is at. 🧵

Immunology is complicated, and scientifically proving all mechanisms of protection in humans is somewhere between hard and impossible. But not to say we know nothing. I summarized the scientific knowledge on immunity to SARS2 in this review last month.
doi.org/10.1016/j.cell…

What I have said for the past 20 years (in almost every scientific seminar I give) is: 

The best vaccine is one that elicits high concentrations of neutralizing antibodies and maintains those high amounts forever.
For any antibody neutralization sensitive pathogen.

That vaccinology principle has held true for almost all human vaccines, and the data for COVID vaccines is definitely consistent with that: high concentrations of neutralizing antibodies are clearly protective. And they stop the virus at the front door.

But, if you cannot do that, are there other things the immune system can do to protect you from COVID?
Yes! Probably. My perspective has been and still is:  hospitalization-level COVID is probably prevented by any decent combination of antibody, CD4 T cells, and CD8 T cells.

And preventing COVID hospitalizations/death is obviously a primary goal of COVID vaccines, and natural immunity. I summarized that, from various lines of evidence, in the review of COVID immunity last month.

There is a pretty good chance that circulating T cells from a vaccine don't respond fast enough to prevent symptomatic COVID, but that the T cells respond fast enough to prevent COVID pneumonia, and thus severe disease, hospitalizations, and deaths.

We discussed the general principles in this article. Highlighted in the "Model 1" panel.
nature.com/articles/s4157…

One important aspect of all of this is speed. SARS2 grows really fast in the nose, but causes serious disease in the lungs rather slowly.

Therefore, stopping the virus in the nose has to be done fast, but it appears that there is a lot more time for the immune system to stop the virus in the lungs (or on the way to the lungs) and prevent severe disease.

But what about variants?

The 1-dose J&J vaccine trial results seems consistent with T cell providing significant protection against variants. 1-dose J&J had almost equivalent protection against 'regular' SARS2 and B1351 (72%-->64%) (see other thread for definition of illness in that trial), even though

B1351 has mutations creating a high degree of antibody escape. Unfortunately, no direct measurements there of T cells and neutralizing antibodies against B1351. But 1-dose J&J elicits a substantial T cell response (CD4 & CD8) and an ok antibody response against regular SARS2.

But the AZ vaccine ChadOx South Africa trial results appear to tell an opposite story. That vaccine has ~75% efficacy against mild cases with 'regular' SARS2 but ~10% against B1351. If the AZ vaccine T cells were highly protective against mild cases, that shouldn't have happened.

So, the puzzle pieces we have for COVID vaccines and protection from B1351 don't fit together yet, indicating that we are missing information. And I am sure many groups are working very hard to generate that knowledge now.

A working model based on available data. The vaccines work great against reg SARS2 & B117. But there is a substantial dropoff for B1351-like variants. That could be due to a combination of antibody escape plus the T cells being a bit too slow to keep infections asymptomatic.

It is reasonable to project a high level of protection against hospitalization-level COVID, but modest protection against infection, transmission, and symptomatic COVID.

To be clear: that model is what I have floating around in my head to integrate the data I know. It is not a formal model. I would draw it in crayon if I knew how to do that.🙂

More re-infections with variants like B1351 and P.1 is consistent with imperfect immunity. There still isn't clear data on this topic, but the fact that the B1351 variant is maintaining these mutations

--and other variants are gaining similar mutations--indicates a selective advantage for spreading through the population, and the simplest interpretation is that the amount of antibody escape by B1351 is sufficient to allow for re-infection of a meaningful number of people.

A functional level of escape of natural immunity at miminum allowing for continuing transmission.

This is my working model for natural immunity. Most of the neutralizing antibody data indicate natural infection has narrower antibody breadth than seen for the RNA vaccines. But there are broader and stronger CD4 & CD8 T cell responses in natural immunity.

And, also importantly, our data on immune memory in people after COVID-19 shows a huge amount of heterogeneity from person to person. Most people have a substantial about of immune memory, but not everyone, which results in more uncertainty.
science.sciencemag.org/content/371/65…

once you have to factor in unknowns surrounding B1351 and similar variants. I think the available laboratory data and vaccine data warrant real caution on that point. So...the same schematic.

Do T cells still recognize the variants?
Yes. Extensive data here doi.org/10.1016/j.xcrm…
And direct experiments here and here.
doi.org/10.21203/rs.3.…
biorxiv.org/content/10.110…

As concluded in the LJI paper, "While it is not anticipated that circulating memory T cells would be effective in preventing Sars-CoV-2 infection, it is plausible that they can reduce Covid-19 severity.”

(Also, I am completely skipping over the fact that you have to get a CD4 T cell response to generate good neutralizing antibodies, which is a major focus of my lab. Vaccines have to elicit those T cells to get good antibodies. But, not the central topic for this thread.)

In summary
🔵 we have to take B1351 seriously, and any variant of concern (VOC) similar to B1351
🔵 several of the vaccines provide ok immunity against those VOCs
🔵 most of the vaccines *probably* provide excellent immunity against hospitalizations/deaths from those VOCs

🔵 that does impact public health policies, which are decisions outside of my expertise.
🔵 A booster vaccine against those VOCs makes sense, and is likely to be highly effective, and those efforts are hurtling forwards

I get asked, Am I optimistic or pessimistic?
I am optimistic that 2021 looks good, but not great. If there weren't any VOCs, I think the projections would be great. But, there are VOCs. Unfortunate, but still probably ok. An optimistic scenario for America is:

(i) we get enough people vaccinated to blunt a B117 surge in coming months (hi Texas, get it together),
(ii) current vaccines work well enough against more challenging VOCs in the interim,
and
(iii) a booster vaccine is likely to be quite successful against B1351-like variants