🧵We discussed how mucosal antibodies function to block SARSCoV2 infection. A study on this just posted from my Stanford colleague Michal Tal and UToronto collaborator Jennifer Gommerman.

Interesting: RNA and J&J make Abs in saliva, but neutralizing levels only detected with RNA
2) First, as a reminder, the role of mucosal antibodies (thought mostly to be IgA, but we'll revisit that in a moment) is to block viruses, once they land on your mucous membranes, from entering your cells.
3) Second, here's the link to Dr. Tal's paper. Let's begin...
medrxiv.org/content/10.110…
4) First they looked at plasma levels of neutralizing antibodies in J&J vs convalescent (previously infected) plasma. The assay uses VSV (a harmless virus we also work with) expressing the SARSCoV2 spike protein to mediate cell attachment and entry into cells in culture.
5) You mix some human plasma into it and see if it blocks entry. If it blocks, it means there are neutralizing antibodies in the plasma. You know it's specific to vaccination because you have control plasma that doesn't block.
6) You then dilute the plasma further to see what dilution stops blocking. If there are high levels of antibodies, you can dilute a lot and still block. If there are low levels of antibodies, you lose blocking with a lower dilution. Hope that makes sense.
7) What do we expect? Well you may recall this paper I keep citing. It says plasma Ab levels in J&J (Ad26CoV2S) trial participants were about 0.5x of convalescent plasma. So we expect J&J neutralization to end at ~half the dilution of convalescent plasma
nature.com/articles/s4159…
8) Indeed this is what the Tal lab observed (I moved panels around). Plasma was >50% neutralizing up to 1:400 in J&J vs 1:800 convalescent. Always nice to see the same thing in the real world as seen in clinical trials.

Notice the variability. These assays are not easy to do.
9) Having established the neutralization assay works, they then looked at neutralization by saliva. Note there's some mild neutralization activity in saliva without vaccination. But 1 and 2 months after J&J vaccine, there's no detectable additional neutralizing activity in saliva
10) In contrast, in previously infected (convalescent) people, there was detectable neutralizing activity in saliva beyond control levels.
11) Also, after vaccination by a RNA vaccine (Pfizer and Moderna samples grouped together for analysis, but split into 1-dose, 2-dose with low plasma abs, or 2-dose with high plasma abs) there is detectable neutralizing activity in saliva beyond non-vax controls.
12) A caveat is that saliva from RNA-vaccinated were collected using a different kit than from convalescent and J&J, so RNA neutralizing titers may not be compared directly with convalescent or J&J titers. But each can be compared to their similarly collected controls.
13) So are the saliva antibodies seen in RNA IgA? Surprisingly there was both IgG and IgA. IgG isn't supposed to be there, but the authors speculate that high levels of IgG in the blood and interstitial tissues can leak out into mucous or saliva.
14) They were also able to detect a little bit of IgG in J&J saliva, but not IgA (asterisks mean statistically significant difference, ns means non-significant)
15) So J&J elicits neutralizing antibodies in saliva lower than previous infection (undetectable neutralization in this study). They may be there though, as IgG can be detected.

RNA vax elicit neutralizing Abs in saliva, and these are both IgG and IgA.

Nice work by @ImmunoFever

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More from @michaelzlin

15 Sep
1) The news has been reporting on this "expert" editorial opposing boosters.

Just read it. Shocked that anyone would use pre-Delta studies to argue against boosters now.

Plus blatant data destruction that I'll try to explain.

A complete Lancet fail.

thelancet.com/journals/lance…
2) The editorial takes the form of a metaanalysis of vaccine efficacy, but it's the worst statistical malpractice I've ever seen. Fortunately it's short (one figure of 4 panels), so hopefully we can get through it quickly and point out the major issues.
Panel A: What is this??? Studies are grouped by efficacy ranges of 50-80, 80-90, and 90-100 for disease, then their average efficacy for all disease and severe disease are plotted. Why??? I'll try to be polite but I'm upset by this. It's an insult to human intelligence.
Read 19 tweets
10 Sep
And there you go

New CDC stuy shows best estimate of J&J efficacy vs Delta hospitalization is 60%

This is worse than 80% for Pfizer and 95% for Moderna

cdc.gov/mmwr/volumes/7… Image
And before anyone complains the CIs are overlapping, that's a sophomoric complaint. Remember that's the 95% CI, and 95% is an arbitrary bar. Also there are other data that show J&J's lower effectiveness on hospitalization, such as below (pre-Delta)

Or the finding that J&J is only 71% effective vs hospitalization due to Delta, from South Africa

Read 15 tweets
8 Sep
The South African trial has finally revealed something about J&J effectiveness against Delta disease, and it is "about half".

No precise #, just a response to an interview question

Low protection and lack of clarity by trial organizers not surprising

bloomberg.com/news/articles/…
You may recall on August 6 the SA trial announced 71% effectiveness against Delta hospitalization, but didn't say anything about effectiveness against disease, which is the default metric and the one used if you are gonig to report only one number.
Some surmised that effectiveness against Delta disease must be very unimpressive, or else it would have been reported alongside the hospitalization numbers on 8/6 (which were already unimpressive).

This has been proven correct.
Read 15 tweets
30 Aug
1) There was an ACIP meeting today, but nothing newsworthy happened. CDC briefing materials (as posted at cdc.gov/vaccines/acip/…) are limiting the ability of ACIP to independently and intelligently assess data.
2) Most concerning, CDC continues to withhold J&J data by omitting it entirely or lumping it together with the 10x larger Pfizer+Moderna data so it becomes a rounding error. No wonder ACIP is not able to make any recommendations specifically for J&J
cdc.gov/vaccines/acip/…
3) But the data exist, and is becoming increasingly in plain sight, showing higher case and hospitalization rates for J&J than for Pfizer and Moderna in the real world against Delta
Read 4 tweets
29 Aug
In a recent thread I posited that mechanisms of antibody production, viral resistance, and somatic hypermutation can explain why pre-Delta vaccines block most Delta infections but not peak virus levels once infected, yet still limit late disease.

Here I present the explanation…
Most neutralization of SARSCoV2 infection is performed by antibodies against the spike (S) protein, and the vaccines used in the US include only S and no other parts of SARSCoV2, so we'll concentrate on S as the antigen, i.e. the protein targeted by antibodies or T cell receptors
Your body has millions to billions of resting/naive B cells, each with an unique surface-bound antibody or immunoglobulin (Ig), just waiting to find their match to foreign particles. You also have T cells with unique T cell receptors (TCRs)
ncbi.nlm.nih.gov/pmc/articles/P…
Read 27 tweets
29 Aug
In our @nytimes opinion piece, Dr. Paul Sax (Brigham and Women's Hospital) and I present why the data support RNA boosters for immunocompromised J&J patients, now possible off-label.

And when boosters kick in for everyone, we hope #JnJers are given good options at the same time.
@nytimes From available breakthrough numbers, J&J has consistently shown higher rates than the other two vaccines, as I discuss in the thread below.

This week's DC numbers suggest in that population J&J vaccine efficacy against infection is about 50%

And that's why we think the data we have sitting in databases on J&J VE need to be openly discussed, and why boosters for #JnJers are needed at least at the same time as boosters for everyone else.
Read 20 tweets

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