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. medrxiv.org/content/10.110…
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...
which are pre-existing antibodies made by plasma cells, then memory B and T cells can kick in. Memory T cells recognize a bunch of different parts (peptides) of viral proteins, and the virus can't escape them all. There have been many nice studies on T cell memory after infection
e.g. by @profshanecrotty, @PepperMarion, @marcus_buggert, many others. Looks pretty good--much better than the cross-reactive T cells that exist prior to COVID in some people. For vaccines it is less comprehensive, but when examined, it also looks decent nature.com/articles/s4158…
These memory T cells can rapidly respond and clear infected cells before things get out of hand. There are also memory B cells, which produce a lot more antibodies if the pathogen slips past those that are already there. Work by our group in collaboration with Mike Diamond's
showed that these cells are well-positioned to deal with viral escape mutants. These memory B cells are in fact selected to be diverse, presumably for exactly these circumstances. cell.com/immunity/fullt… pubmed.ncbi.nlm.nih.gov/22162833/
The upshot is that for at least common coronaviruses, even if the virus slips past the antibodies and productively infects, there is a short duration of viral shedding and few symptoms. ncbi.nlm.nih.gov/pmc/articles/P…
All this to say that I don't think we should be in panic mode. But I do think we need to be thinking about how/when to update the vaccines, and really thinking about the regulatory framework to do so.

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More from @deeptabhattacha

10 Dec
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 nytimes.com/2020/12/08/hea…).
Read 12 tweets
6 Dec
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
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. biorxiv.org/content/10.110…
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 in...nytimes.com/2020/07/14/hea….
Read 13 tweets
1 Nov
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
27 Oct
Brief explanation of the difference between methods of the ICL/REACT study and the many longitudinal studies I have cited before. These studies below, including ours, followed individuals over time to quantify antibody levels and decay
The ICL work is a yes/no population study to check the frequency of people with antibodies. For these types of tests, a strict cutoff is used to minimize the number of false positives (telling someone they have antibodies when they don't). This comes at a cost of telling...
some people they don't have antibodies when they do. Lesser of two evils. But for this reason, seroprevalence studies aren't ideal for quantifying the duration
of antibody production. Consider the graph below of a stereotypical antibody response, with range of outcomes in gray Image
Read 5 tweets
31 Aug
I've been reading the discussion on re-infection events, with some now arguing that this is not rare. This is being interpreted at the extremes that protective immunity is not possible. In this thread, I am going to argue that re-infections are rare based on data so far.
First, let's look at our toolbox on how re-infections can be measured w/o sequencing everyone. This Herculean paper on common coronas medrxiv.org/content/10.110… uses Ab responses as surrogates for re-infection. You will see that in the top row, there are periodic spikes in Abs... Image
This means that a person has been productively infected by a same or similar virus, and the immune system revs up again with new Abs. Keep in mind that these data are for common cold-causing coronaviruses, not SARS-CoV-2. However, we now have a dozen+ reports on serology...
Read 9 tweets

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