OT: Covid-19 Neck Sharpies Part I: Hello, Antibodies
Finally got around to this. Footnotes are formatted as (fnX). Apologies for the length, but I didn't have time to write something shorter.
YES THANK YOU I KNOW THIS IS TOO LONG FOR A BOARD POST AND SHOULD BE A DIARY BUT I'M POSTING TO THE BOARD BECAUSE EVEN LOCKED DOWN PEOPLE DON'T READ MGOBLOG DIARIES. Since I'm breaking this up into multiple posts maybe I'll put it all back together and slap into the Diaries for convenience later.
Live fast and die young, post.
TL;DR Version:
1. Antibodies are useful for remaining alive, and you want some
2. There are different antibody tests being described in the media and they're not all answering the same question
3. The results of antibody tests for exposure/infection don't necessarily tell you if you're immune, but it's better to know something than nothing
4. Please do not hookup intravenous Lysol
Ok then.
For reference, this post follows up on a comment I made in a thread last week (fn1) about the Stanford study estimating the percentage of the local population here (I live nearby) has been exposed/infected with SARS-CoV-2, the underlying virus of COVID-19 (fn2).
The high-level summary is that the authors estimated between 2.5-4% of the Santa Clara County population had been infected with SARS-CoV-2, or roughly 50-85x more than the number of confirmed cases in the region.(fn3)
So, I noted in the thread that testing for exposure or infection* does not mean you're testing for immunity. I suggested I'd do some kind of neck sharpie post soon on how testing works, and why that last statement is true.
This is that.
*(not the same thing but just treat them as the same thing for now, and we'll talk later. K thanks)
I'm never going to get the balance between keeping it simple and giving the whole picture completely right. But my goal here is to be a more informed consumer of the news, which often confuse similar-sounding tests and say words like "immune" when they don't really mean "immune."
Here's what I'm trying to cover for now:
TODAY: Part I. Hello: Antibodies
TOMORROW: Part II. The Tests, The Tests, The Tests: How do the various COVID-19 tests work, and what do the results tell you?
MONDAY-ISH: Part III. "Immune." You keep using that word. I do not think you know what it means.
LATER: Part IV. Treatment Pipeline: Ye Olde and New
Maybe others but that fulfills my mission to make your Covid-19 readings a bit more discerning. It was either hammer this out now or join my girlfriend binging "Love is Blind" on Netflix, which, kill me please.
Here we go. Sharpies out.
________________________________________________________________________
I. HELLO: ANTIBODIES
Also Known As: Immunoglobulins (Ig) meaning "immune proteins", Ab, mAb, "the Y-things"
You May Remember Me From Such Films As: Fantastic Voyage (1966) starring Raquel Welch (fn4a) and some dudes you ignored because Raquel Welch was in a tight bodysuit (but none of them were Coolio, whose ride was a '65 Chevy Impala, not a '66 Miniaturized Spaceship/Submarine so you decide which is more fantastic)(fn4b). Antibodies were portrayed as the enemy but they were just doing their job, man. Seriously you can't be flying spaceships around in people's veins up in here.
You May Remember Me From Such FDA Approved Drugs As: adalimumab (Humira), infliximab (Remicade), golilumab (Stelara), rituximab (Rituxan), trastuzumab (Herceptin), and over the next year you may be hearing a lot about drugs like tocilizumab (Actemra) and sarilumab (Kevzara).
Q. Because I am not blind, I noticed a pattern. What's up with the "mabs"?
This is short for "monoclonal antibody." Think "Y" shape. They fall into the bigger class of drugs known as "biologics" or "large molecule" drugs which look like proteins you see in the body. Monoclonals will get some attention in Part IV.
When you see a drug name ending in "vir" (e.g., Remdesivir) that's an antiviral but a more traditional small-molecule drug you can draw as a chemical formula. These are not antibodies or other proteins.
Don't worry about what "monoclonal" means for now. It means "I am very expensive, bring insurance" is what it means.
Available Flavors: IgM, IgA, IgD, IgG, IgE BUT PRETEND ITS JUST IgM and IgG, OK? The goal of this process is to get to IgG as fast as you can, but IgM holds down the fort while the big IgG guns are coming.
IgM vs. IgG 
FINALLY SOME SHARPIES. Forgive me because trying to draw on a free iPad whiteboard app is like trying to draw on a free iPad whiteboard app. All art is passed through an "toddlerization" filter.
IgM is to IgG as Paul Blart, Mall Cop is to Robocop. Eventually. After Robocop gets some upgrades to watch his background and not kill a bunch of civvies, hopefully. Paul Blart can get some stuff done, but... let's just say he's limited. If you're lucky, Blart punches above his weight and if you're at Foot Locker or Jamba Juice you weren't even aware there was a security problem in the mall.
Q. Yeah but what makes one antibody better than the next?
So, before we get to the next childishly drawn illustration, these are qualities of antibodies worth knowing. These qualities are PICKY and STICKY. The tips of the Y shape (not the stem) are what determine both.
1. Specificity: This is how PICKY the antibody is. Does the antibody have laser-focused eyes for only one specific target, or does it "cross-react"? In other words, monogamous or kinda the "ethical slut" of the immune system? This is important because you don't want it so specific that the slightest variation in the target will throw it off, but you don't want it so slutty that it binds to a different target every night, which is probably going to be you sooner or later. Cross-reactive antibodies are often where "autoimmune" (immunity to self) diseases come from. But generally, the more specific the better.
Maybe instead of slut-shaming antibodies, I should have just said pit bull. No, not MGoBlog banner Pitbull, because nobody is having a good time. I mean a guard dog that keeps your property safe. Better analogy.
2. Affinity: Refers to how STICKY the antibody is. This is how tightly your pit bull will hang on to an intruder's appendage and make them reconsider his career choice. The higher the affinity the better. But if you're going to be high-affinity, you better hope you got the specificity right. If your dog is going to lock its jaws, it would be good if its not on the FedEx guy's leg. Or yours.
Q. Up at the top it says "variety of antigens." Guh?
That means all the varieties of badness that shows up at your door and confronts the immune system. "Antigen" comes from "Antibody-generating", typically microbe proteins but not always. If your immune system doesn't learn dangerous from non-dangerous, peanuts and shellfish and pollen and cat hair can look a lot like a microbial invader.
When you see "antigen" think "something that sets off the immune alarms." Like, I don't know, a pandemic-causing virus that threatens death, economic depression, and some half-assed 2020 edition of HTTV this year, perhaps? JUST WRITE IT LIKE EVERYTHING IS GOING TO BE FINE, BRIAN COOK, THAT IS WHY SUSPENSION OF DISBELIEF WAS INVENTED.
Q. You have convinced me antibodies are useful. Where do they come from?
They are produced by "B-cells" which are little antibody factories that come from bone marrow. You would think the B stands for bone. It should, but it doesn't.
Q. OK, I'll bite. What does the "B" stand for?
For our purposes, B stands for "Beilein." (fn5) Because Beilein takes underrated 3-star talent in the rough and produces first-round NBA players. His players develop and mature (but not in Cleveland, amirite MGrowOld?). Improvement and refinement over time is the hallmark of the B-cell/antibody response. It is the immune system's Beilein Effect. Please remember this for later.
OK, it's now later. Still with me? Let's look at player development. Recall the goal is to get from lower-affinity (but hopefully still specific) primary response IgG (3-stars, insert FIRE BEILEIN post) to high-affinity, high-specificity IgG (Final Four runs, 1st Round NBA picks, KEEP BEILEIN)
IgG from primary exposure to the viral antigen is like freshman Caris or freshman Stauskas. Good but need polish. A little sluggish. I SAID SLUGGISH NOT THUGGISH.
IgG from secondary exposure is Sophomore Not-Just-A-Shooter Stauskas or NBA Caris. Not slugs.
IgM never gets better. Weird guys stay weird. Paul Blart stays Paul Blart.
The faster response time after second exposure is due to immune memory. We'll talk more about that in Part III.
Q. I see something something something about vaccines and therapy. 'Splain.
Plasma (aka "Convalescent" or "Serum") Therapy is an old-timey method involving passive transfer of antibodies (mostly IgG) from recovered patients to sick patients who are sick enough to require hospitalization. It doesn't substitute for your own immune response, but it gives you a much needed boost while your own troops are trying to get organized. We'll look at pros and cons in Part IV.
Vaccine: pretends to be a first infection so when you hit the virus in the real world, you jump right to the higher-efficiency secondary response. It's like skipping low-efficiency freshman year.
Stuff that if explained would turn this into a textbook but some wiseguy is going to point out like it's something I'm hiding from you: The mechanisms of improving the quality of the IgG the second time around owes to processes like clonal expansion and hypermutation. It's long enough as it is. And then Helper T-Cells actually assist the B-cells to start improving so some will say these are the real Beilein cells, but that screws up my mnemonic device ok? And if you mention Helper T Cells you have to talk Killer T cells and Natural Killer cells and Macrophages and Neutrophils and god forbid Basophils and Dendritic cells and blah blah blah you see how viral things spiral.
NEXT UP: Part II: The Tests, The Tests, The Tests.
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Footnotes:
(1) Link to MGoBlog post: "CV: Stanford Antibody study results are out ..."
(2) Link to Stanford paper: "COVID-19 Antibody Seroprevalence in Santa Clara County, CA" (April 11)
(3) A couple of caveats about the Stanford publication:
(i) Not peer reviewed yet, but published online as many COVID-19 papers are these days given the time-sensitivity. This is understandable. Peer review in biomedical journals can take upwards of 6 months between the date of submission and publication.
(ii) The Stanford study used an antibody kit from China (Hangzhou Biotest Biotech Ltd, distributed in US via Premier Biotech, Inc. of Minnesota) that the Chinese version of the FDA says has reliability issues, and has subsequently stopped export of the kit.
Our FDA had relaxed its usual guidelines on test verification to allow more testing kits into the country and Stanford obtained it's kit during that window of time.
For what it's worth, I read the materials and methods section of the paper and I believe the authors used adequate internal controls to test the Chinese kit itself and think their study is generally reliable.
(4a) It will not surprise you to know I spent a good chunk of years in the scientific arena and never saw anyone who looked remotely like Raquel Welch.
(4b) '65 Impala vs. '66 Proteus Spaceship Thingie, who ya got?
vs. 
(5) "B" actually stands for "Bursa of Fabricius" which is a lymphoid (immune) organ in birds where B cells were first identified, but that doesn't exist in humans, so usually people just think of it as "B is for bone marrow," which, really, ought to make everyone happy but you know how orinthologists get, amirite?
Your author holds a PhD in Immunology and Microbial Pathogenesis from Northwestern University. Informing you of this may or may not have been the real motivation of this series of posts.
This is awesome. The question I have is, Modernas core technology is mRNA, and likely using this to make their vaccine. On that assumption are they encoding for pieces of the virus (to activate an immune response) or going directly to B cells or IgG? Or something else?
Vaccines almost ubiquitously work by targeting antigen-presenting cells (APCs), which is a fancy term for cells that can take up antigens. The most specialized of these cells are dendritic cells, but B cells are also APCs, among others.
In the case of mRNA vaccines, the mRNA encodes for immunogenic proteins (in the case of COVID-19, viral surface proteins), and is typically formulated in such a way to promote uptake by APCs. Once consumed by APCs, the viral proteins are expressed, processed, and then little parts of them are externally presented to other immune cells, including T and B cells, which stimulates the immune response again them.
Everyone loves to talk about T and B cells, including myself, but professional APCs are also superstars (but harder to study, for reasons I won't get into). Long time reader, new poster. Hope this answers your question.
yeah, i always find myself talking about T and B cells...
you guys are great. good stuff all the way around.
I can't really add anything to this. APCs (not Armored Personnel Carriers) serve things up to the glamorous B and T cells, but nothing works without antigen presentation. They're like the analog to digital converters of the system.
Agreed, great piece. To me worthy of a Bolivia-mab for you (lifetime of course).
April 25th, 2020 at 10:23 AM ^
Pretty funny.
Yes. Informative and written in a digestible way (but definitely a slow read - there is a fair amount to digest/think about/understand. And if I’m being honest, does not make me regret in the least never considering a degree/career in something biologically related.
Thanks for writing this post. If you don’t teach or write biology for dummies type books, you have a couple more career options if you ever get bored doing what you are doing,
This is definitely the mgoblog difference. Some of the folks who claim to be experts on shit they are talking about actually are. Presumably you are here because you went to U of M as an undergrad?
I spent my early years in A2 and was attending band practices in the Big House when I was in diapers, but I didn't put a ring on it until I left the lab life and attended the law school. As they say, all roads lead to the Law Quad. But mostly it's South U, State, Tappan, and Monroe. It just doesn't really roll off the tongue when you say it like that.
I was tempted to stop at Raquel Welch. But glad I didn’t.
OP, here's a question for you.
How long are those antibodies that we manufacture going to protect us? If the answer is quite a while, herd immunity is very relevant; if it's a short time, aren't we basically screwed until we get a vaccine or a therapy that is effective.
Sopwith May disagree, but everything I've read on the subject to date suggests the answer is a collective ¯\_(ツ)_/¯
Well, it’s really more that there not enough data yet. As countries reopen we will get a much better look at reinfection rate, but a realistic time line to know if developing antibodies works will be 9-18 months.
we will know pretty quickly (like 3 months) if previously infected people get reinfected at a high rate though.
Absolutely true, and the reason for much uncertainty. Data takes time to gather, and sample size matters a LOT.
Yeah, this is mostly right for lack of data about this particular virus, but I'll get into more general discussions of long-term implications in Part III.
April 25th, 2020 at 12:02 PM ^
Key takeaway for me is that it doesn't really matter how long those antibodies from the first infection last. For conservatism, assume it's only a year like other highly infectious coronaviruses. But once it's happened for people, and they've built immune memory, they're in the same spot as if they had been given an effective vaccine because even if IgG have faded, they have B-cell factories ready to churn out more of that NBA talent. That's the key.
So the bigger questions are how long until we have an effective vaccine and what should we do until then? I think the medical community is being way too optimistic when they're talking about a year to a vaccine. The record time for a vaccine is four years and we've never produced a vaccine successfully for a coronavirus (albeit without the effort and technology we're throwing at this).
And given that there is more and more evidence that a lot more people have had this than we originally thought (which means hospitalization rates and deaths from those initial infections are lower than previously thought), I think we need to work towards low risk people that initial infection in a steady stream that won't overload the health system.
OP: Sorry, I don't read long egghead posts like yours. I also don't trust scientists. Anyway, this is just the flu.
Aside: I sprayed Lysol on my custard launcher yesterday. Had never tried that before. It cleared up a longstanding issue pretty quickly. YMMV.
April 25th, 2020 at 10:42 AM ^
Is this some attempt at humor?
Yep. Sometimes the jokes don't land. :)
The Stanford study test kits being shit Chinese ripoffs makes sense given the results of 85x infected being discordant with reality in New York
Do we know the kits that nyc used? Their results are more realistic
A doc from Mt Sinai in NYC went apeshit on Gov Cuomo in a tweet for not including the Mt Sinai team in either the design and execution of the test, nor the production of the tests themselves. Evidently, that team has a "best-in-class" test protocol. I haven't heard of anyone else completely dismissing the results of NY's testing, other than to point out that randomly sampling people walking into grocery stores, while better than the Stanford method of using Facebook ads, may have skewed the data.
A study just published by U-Miami (YTM) using 1,400 randomized subjects chosen with the help of Florida Power & Light's database of customers, suggests that Miami-Dade County has a 6% rate of infection in the population. The error is fairly wide, and a great story published by the Miami Herald explains a lot about the test method and it's possible sources of error.
OUTSTANDING!!! Very well written, and the mnemonic devices are top notch. As mentioned in a different post, this should be turned into a 'immunology for dummies' book. The Paul Blart and Beilein references are absolutely perfect!
Thank you for the information, I love reading stuff like this even if I want nothing to do with molecular biology as a field of study.
Need the Cliff Notes version.
This is the Cliff Notes version, and a very well done version at that. It wasn’t that long if you skip the footnotes.
Spot on. This is the Cliffs Notes to the Cliffs Notes to the Cliff Notes. I mean, it's Cliffs Notes all the way down.
Really good job! Thank you for doing this. I'm looking forward to the next one. Discernment...highly under rated.
a.) great post. and now as i've had time to go over it more, this is probably the start of a four-part HOF post, in it's own 'virus' wing of the HOF, as revered as the original 'wife day' post and the 'outing of roll damn tide'.
b.) you're not really a flying dog, are you. dogs can't go to northwestern, i mean, they're cats there so definitely no dogs.
c.) i'll take the chevy
d.) if you live in cal, that means you posted this at 0513 hrs, PDST. you cra-cra.
take care
April 25th, 2020 at 10:38 AM ^
Time is meaningless now. I don't even know what day it is.
Outstanding post OP, and this coming from a guy that passed any science related classes by the skin of his teeth.
I keep farm hours on Saturday ;)
Actually I did try to time it so that the post would land on Eastern time zone people's doorsteps like the weekend paper so they could enjoy it with coffee. Then I went right back to bed.
this is really cool, and yes, you are a maniac. not kidding that this is the first of a 4 part HOF post. no pressure.....
hope you got some sleep b/w posts.
Thank you for this --very informative. And you weren't kidding when you said
Don't worry about what "monoclonal" means for now. It means "I am very expensive, bring insurance" is what it means.
I get Entyvio (vedolizumab) infusions every eight weeks for ulcerative colitis. When I first started several years ago the price listed on my paper work before insurance was around $15,000 and my out of pocket was $1,500. Fortunately, by my third treatment I had met my deductible. Now, between insurance and a plan by the drug manufacturer, my out of pocket costs are negligible, but the price before insurance has gone up to just over $20,000, and as I mentioned, that's every eight weeks.
The only alternative that works for me is prednisone, an inexpensive corticosteroid, but I had to take a fairly high dose (eight times what is recommended for long term use) that created its own problems.
I've worked with several of the producers of biologics. They're super expensive for several reasons, including the difficulty in manufacturing the drugs. Many are not very stable, which means the time from production to patient can sometimes be measured in minutes. That puts a huge burden on the supply chain (that's actually my current profession, although I spent the first 8 years as an aerospace engineer) to not only concern itself with getting a product from points A to B, but also keeping the environmental condition highly regulated.
April 25th, 2020 at 10:11 AM ^
Good points. And one of the problems with our health care system is that we often do not see the price broken down. With a little online research, it looks like the price for the Entyvio that is sent in powder form is about 1/3 of the $20,000 total cost that I see (and I'm never too sure about the accuracy of those prices anyway--a lot of those costs seem grossly inflated). Then it has to be shipped to the place I go, where it is mixed to become a fluid, then administered by IV. It only takes about 30 minutes once the IV is started, but given the expense, they never start mixing it until I arrive, so the whole process usually takes an hour to hour and a half. I'm just thankful that there is a medication that works for me (and that I have health insurance).
April 25th, 2020 at 10:17 AM ^
Yep. When I worked with several of the biologics manufacturers, we used to joke that their products had the half-life of an ice cube.
April 25th, 2020 at 11:50 AM ^
Just the shipping can run more than $1000 if it had to be shipped refrigerated or frozen. Which fuses usually have to be. And consider that it is shipped at least 4 times before it gets to you. API manufacturer (site) to DP manufacturer (site) to distribution entity to clinical site where you get infused.
100%. Companies like Cardinal Health and others can manufacture/mix the product in their DCs before sending it via courier to the healthcare provider. That reduces the number of touches, but it is still a big challenge.
Thank you, Sopwith.
I am going to read each part as it appears. Then putting Parts 1-4 in a file to read as one continuum next week.
Note: I used to show Fantastic Voyage to my class(es) after studying the circulatory system. Those insidious white cells.
Awesome read! I sent the link to my physician and his response was "excellent explanation of immunity." Naturally, he is also a U-M grad.
And just to be clear, Windex is okay, but not Lysol, right?
409 is okay, jury still out on Windex
Note to self: Costco run.
April 25th, 2020 at 10:12 AM ^
My Big Fat Greek Wedding - Windex cures everything but it is a topical solution.
April 25th, 2020 at 10:16 AM ^
That way the light has a clear path.
April 25th, 2020 at 10:26 AM ^
I remember Raquel, those white blood cells, not so much.
April 25th, 2020 at 11:03 AM ^
Blessed Clorox wipes cut into pepperoni size pieces and given as communion wafers at the Vatican? No
Clorox IV, Chewables or bath? No
Irish Spring suppository? Hmmmmmm Hit this bugger from behind. It will never see it coming.
April 25th, 2020 at 11:47 AM ^
Ninja,
Any cleaner is fine except Lifebouy... you'll go blind if you ingest that
Soap poisoning is only a problem if you didn’t get a Red Ryder BB gun from Santa Claus.
Great post. Have neen following your posts for weeks now. Glad you took the time and sat down to crank this/these out!
April 25th, 2020 at 10:10 AM ^
Doctor Sopwith, I just wanted to thank you by calling you DOCTOR because what better reason to get a PhD than to have people call you DOCTOR.
Thank you for taking the time. Much appreciated.
I also like your sense of humor and the last line of your post.
April 25th, 2020 at 10:23 AM ^
Thanks for doing this. Now I have some daily Coronavirus Calvary reading to look forward to, amirite?