So I have a few hours with unexpectedly not much to do. And to no surprise to anyone who knows me, my mind wanders into geeky immunology thought exercises.

Say you have 2 or more circulating variants with some non-overlapping changes-> partial immune evasion. In a vaccinated/
recovered population, would you:

1) Boost with two separate spike mRNAs/proteins, each identical to the different variants

2) Design a greatest hits version carrying a composite of key changes

And for option 2, what experimental evidence would you need to see first?
a) Alphafold/Rosetta predictions
b) SPR/BLI of binding to ACE2 + thermostability
c) Successful pseudotyping/infection
d) something else
e) nothing, it is a terrible idea
Just continuing to think about this issue of original antigenic sin, and that the more times we have to boost, the greater the chance that it will get worse each time.

@victora_lab @TheBcellArtist @PepperMarion @vcluca1

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More from @deeptabhattacha

12 Jan
In this piece by @rddysum, I am on record (again) stating that the vaccines will substantially reduce overall infections. I know some of my immunology colleagues think I am being premature, but I really think I am on solid footing here. So let me explain.…
The question is whether the vaccines only reduce symptoms, but not infections. Let's see if the math is consistent with that, as explained per @JoannaMasel. In the Moderna placebo group, there were 185 symptomatic infections vs. 11 in the vaccine group.
Let's then add in ~20% asymptomatic infections to the placebo (or choose whatever number you prefer here).

Placebo: 185 symptomatic + 46 asympt = 231 total

For the vaccines to match:

Vaccine: 11 symptomatic + *220* asymptomatic = 231
Read 9 tweets
19 Dec 20
Those who follow me know that alarmism isn't my style. But the new UK variant does have me a bit concerned. I'm not qualified to critically assess changes in transmissibility, but deletions of H69/V70 do seem to partially evade Abs. So it's worth a primer on how the immune system
handles such changes, and how memory T and B cells become really important. First, some evidence that these variants may matter. In an immunocompromised COVID patient treated with convalescent plasma, the delta 69-70 variant (+ D796H) was selected for.…
It also partially evaded other convalescent plasma samples. The evasion wasn't complete, but one can imagine how this could take hold in someone who didn't mount a great Ab response. Thankfully, immune memory is multilayered. If a pathogen gets past the first line of defense...
Read 9 tweets
10 Dec 20
Kept meaning to do this thread on the duration of vaccine immunity, but got paralyzed b/c of length. So instead I'll break it up into 3 pieces, becoming increasingly geekier and wonkier. TLDR, I think it's likely that vaccine immunity against symptomatic disease will be >1yr.
I’ll focus only on antibodies, as the thread is long enough as is even w/o memory cells. Today, I’ll speculate on antibody levels that are protective. In part 2 later next wk, I’ll talk about the cell biology/immunology, and then in part 3 I’ll try to link the mechanisms of the
vaccines back to the cell biology and predictions on durability.

Based on a lot of metrics, it doesn’t seem to take much to protect against symptomatic disease (preventing all infections will be harder as per this article by @apoorva_nyc…).
Read 12 tweets
6 Dec 20
K, it's Saturday evening and I am tired of working. So how about a little light history. I've seen some speculation as to the origin of Moderna's name. People have gotten close, but I haven't seen anyone quite get it right. On this, I admit to a bit of insider info.
My friend Derrick Rossi is the original founder of the company, and his wife was the one who came up with the name--it is a play on 'modified RNA.' Derrick (who exited from Moderna years ago) is a stem cell biologist, not an immunologist. This began when his lab wanted to find a
better way to make induced pluripotent stem cells. These are somatic cells that are reprogrammed with transcription factors to become like an embryonic stem cell. At the time, people were doing this with retroviruses, which integrate into host DNA. He explicitly wanted to avoid
Read 7 tweets
23 Nov 20
Two questions on vaccine efficacy keep coming up: 1) How long will immunity last? 2) Will it limit overall infections/transmission, and not just symptomatic disease? Q1 is exactly what my lab works on, but is tough to know (thread later). So on to Q2…
In macaque challenges pneumonia was prevented, but infections still occurred. I am going to pretend I'm a Vegas oddsmaker and take you through my (possibly incorrect) logic on why the macaque data likely underestimates efficacy against overall infections.…
This article by @KatherineJWu explains the issue nicely. Infections start in the upper respiratory tract, which is protected by a mucus and epithelial cell layer. The barrier goes both ways--it limits things from getting….
Read 13 tweets
1 Nov 20
I received this email from someone last week that I can't stop thinking about. I probably received this since I have been openly optimistic about vaccine efforts. So I wanted to explain exactly why I am glass half-full.
Many of the grim posts about predicted efficacy (only 50%) have used the flu vaccine as a comparison. But as with many aspects of the pandemic (e.g. IFR, transmission), flu is not a very informative prior for vaccines without some major adjustments.
To be considered effective, the flu vaccine has to protect against symptomatic disease by *any* flu strain, whether it is in the vaccine or not. There are usually at least 4 circulating flu strains and sometimes the vaccine doesn't match one or more strains. That's a big ask...
Read 11 tweets

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