Cliff's Notes for COVID 19 or Virilogy for Dummies

The Phantom has been told his blogs are too long, digressive and require too much of the reader.
So here's his boiled down version of TWiV #645:

Michael Mina, MD, PhD

We can get out of this pandemic thing before the vaccines become available if we believe certain assertions which are likely true, but are as yet unproved:

#1 SARS COV-2 is only infectious briefly.  Michale Mina, MD PhD has said this on a couple of TWiV episodes:  He tells us who have the virus in their noses, throats and lungs are likely infectious to others for only a few days, like 3-7 days. 
During this infectious period they can be super spreaders or just ordinary spreaders and they make millions upon millions of infectious virus units (virions).
But once they pass through this phase, they are no risk to anyone else. They may make virions but only in the thousands which is not enough to infect most contacts.

#2. Detecting the patient who is breathing out millions of virions is best done with a low sensitivity test, which is sensitive enough to catch the big load of virus in the saliva but will miss the patient who only has thousands of virions in his mouth.  You really don't want to know about the non infectious patient: He can go to school or to the bar or fly on the airplane. You only want to know about the infectious guy who spreads the disease.

Why would you not care about the asymptomatic or pre-symptomatic person? Because if he does not become sick, it doesn't matter to him or to the rest of us, as long as he doesn't spread virus.  If he becomes sick, then you can use other more sensitive tests to confirm he is sick with COVID 19 if he seeks medical attention.

#3 We have on the shelf different versions of a test strip which can be used at home like a pregnancy test with results from saliva in 10 minutes.
According to  Mina, you could print these strips by the millions almost as easily as photocopying. 
Imagine if you could test kids at home or when they arrive at school each day with a cheap, 10 minute test and you send home or keep home the kids who are infectious but then move on with your day without masks, without contact tracing. 
You don't need contact tracing if you can test virtually everyone daily at home.

If all these things are true, then Mina is talking about a game changing approach.
If he is right, he should be talking to the powers that be.

So far Democratic Senators and Congressmen and Republican governors have ignored him or simply not heard of him.  

The system for making the bureaucracy aware of scientific advances or changes in thinking is apparently imperfect. 

The science and details are summarized by the excellent Medcram youtube:
https://www.youtube.com/watch?v=h7Sv_pS8MgQ&t=9s

There is a long form version now in the Atlantic:
https://www.theatlantic.com/health/archive/2020/08/how-to-test-every-american-for-covid-19-every-day/615217/?utm_source=newsletter&utm_medium=email&utm_campaign=atlantic-daily-newsletter&utm_content=20200814&silverid-ref=NjYzNDQ4NjU4MDY2S0

This Week's Truth

"It's the Infectivity, Stooopid."

Having listened assiduously to every "This Week In Virology" (TWiV) podcast since February, the Phantom has noticed that he has become, to his surprise, to some degree more educated than even his colleagues who are specialized and board certified in Infectious Disease (ID), in this one small niche of virology.

At a Journal Club, where a very learned ID doctor spoke, the Phantom was surprised to hear this specialist embrace the idea that SARS CO-v-2 (the virus that causes COVID 19) is a blood borne virus--i.e. it has a significant viremic phase. The Phantom had heard the virologists of TWiV discuss this point on many occasions, the studies of trying to culture (with plaque assays) the virus from blood so he "knew the literature" as the ID doc did not. 

The fact is, you could, too, if you had the time, because we are all learning it together now.

The thing about whether SARS COv-2 is blood borne is important because, typically, blood borne viruses elicit long term immunity if you survive them--measles being the classic example. But viruses which are not blood borne, like corona viruses, typically do not elicit long term immunity.

A small point but one which makes a larger point: Even the doctors who normally are up to date about infections are not up to date on COVID 19 because the news and concepts are changing too fast, and ID doctors are too busy to be listening to 4 hours of TWiV every week. But the Phantom can listen to every minute, because he has a smart phone and a bicycle and he goes for 2 hour bicycle rides four times a week and listens.

This does not make the Phantom an expert in virology, or immunology (although he does listen to the "Immune" podcast by the same crew.) But it does mean he has kept up with the shifting sands of what we know more than most doctors who are busier than the Phantom is right now.

So where are we now?
The latest TWiV episode (#645) begins with an update by the physician who sees lots of COVID 19 patients, Daniel Griffin. 
Dr. Griffin is important for the very reason he himself has disparaged in other doctors: He has seen a lot of patients with the disease and so his experience, his anecdotes are illuminating.  
Griffin managed to annoy a lot of docs by saying that he is purer than they are because he will not act based on "experience" but only on the basis of controlled, prospective, double blind studies--the gold standard of medical care or "evidence based medicine," as Griffin calls it. 
But as Dr. Siddhartha Murhurjee (author of "The Emperor of Disease") observed, there are never enough of these elegant, rigorous studies to guide thinking on the ward where daily a myriad of problems arise for which there are no studies yet published. You are always learning as you go along, as Griffin did when he "proned" his patients whose blood oxygen levels fell--rumor had it that if you turned them on their abdomens or sides,  lung blood flow improved, and, it worked, so Griffin recommended it, despite the lack of rigorous studies.

So we are all feeling our way along, gathering data not always systematically and what is true today may be disproved tomorrow.  But from his broad and intense experience with COVID patients, Griffin has described a disease which looks very different in different people but usually begins with a short phase, just after the virus finds its way into the naso pharynx. The fate of the patient  and the course of the illness, likely depends on how many virions get in--the dose--and the host's defenses, which depend on his immune system, his age, his general state of health, other diseases he may harbor which make him more vulnerable.

This "pre-symptomatic" phase, before the patient develops fatigue, headache, cough or fever, may last 3-7 days, our best guess. 

And at some point during this phase--when the patient is either not feeling sick at all or just mildly off his game--the virus is stoking up its takeover of host cells and pumping out billions of replicas of itself--infectious virus. This is the "infectious stage" and even the more insensitive (saliva/ monoclonal antibody/instant ) tests will be positive and turn colors and ring bells. 
The more sensitive PCR tests from nasal swabs which detect virus particles in the thousands will, of course, not miss the disease incubating at this point, but they take days to weeks to come back from the lab.
The idea that you're only infectious and a risk to others during this brief window when you're making millions to billions of virions, is one pushed by Michael Mina, MD, PhD at the Harvard School of Public Health.  And it is or should be central to our response to this pandemic, because if this is true, it means we can reopen schools, factories and much more. 

The test  Dr. Mina prefers misses virus levels below the level of infectivity, but catches the infectious patient, who is the only patient a public health official cares about, the only person who places the public at risk: You want to test everyone daily, catch these guys and keep them isolated until they are no longer infectious.

Once they are infected, the patients may not get seriously ill, but if they do they become the problem of the hospital doctors, not the public health folks.

So there is a way to prevent the virus from spreading, to stop it in its tracks, with daily home testing with little cardboard strips  available now, and only awaiting ramp up of manufacturing and distribution. (Assuming the anti science/anti-vax/anti-think crowed at 1600 PA Ave in WDC allow.)

If the patient gets really ill, that is usually not because the virus kills his cells--although it can do that--but because the virus elicits an explosion from the patient's immune system, like an ammo dump getting hit by a grenade, so called cytokine storm, usually 7-21 days after the virus has established a beach head and pushed inland. During this time, glucocorticoids (dexamethasone, prednisone) can douse this explosion and save the patient. Anti-virals, like remdesevir are of no use during this cytokine storm--the virus is long gone. It's the immune rampage that's killing the patient.

Antivirals only really help when the patient is incubating, pumping out millions of viral replicants from inside the cells it has infected. 

Then there are the much feared sequelae. Weeks to months later, profound fatigue and breathlessness with exertion may linger. (The "long haulers.) But worst of all, clots in arteries in the brain or the fingers, legs or toes may cost patients their digits and limbs or parts of their brains.

Anti body tests were once promoted as identifying immune people who could be issued passports to go back to normal life, but the antibody tests may be of little value owing to  certain new concepts: Antibodies (made by B cells) rise during the initial illness 3-7 days (IgM) but then, after a couple of weeks, the next phase of antibodies (IgG) may peak and then fall to low levels, making tests go negative. 

That has been typical of other coronaviruses, the ones that cause the common cold. This may mean the patient is no longer protected against reinfection. Or it may simply mean the immune system realizes there is not much virus to fight and it brings its troops back into the barracks and awaits a second attack.  
It may be the T cells are now programmed and they will be the cells roused from the forts and barracks to meet the next attack. 

This is all what's called the "correlate of protection" by Brianne Barker, an immunologist from Drew University. It may be antibody (B cell products) testing is irrelevant to the question of who is immune. We might be better informed with T cell tests, but these are less widely available. 

As for vaccines: The big worries here are:
1/ Most vaccines are assessed in two basic ways for efficacy: 
--Measurement of antibody levels in response to the vaccine doses. 
If we are measuring antibodies but antibodies are not actually what's protecting us, this may be misleading. (Antibody titers at best tell if the vaccine is likely to work.)
--Assessment of how many people who received the vaccine get the disease they were vaccinated against, vs how many in the control group (not vaccinated) get it.  
(This tells us if the vaccine actually does work.)

2/ Coronaviruses have been notoriously unfazed by vaccines or prior explosure to the native virus--people get re infected with the same coronaviruses over and over in the case of the common cold and even when some immunity is attained through vaccine or infection, it wanes rapidly.

3/ Most vaccines under development have been made against the spike protein on the virus, which is the hook which attaches to the normal cells--but if that does not work, then all the scores of vaccine candidates under trial will fail for the same reason. Vincent Raccaniello, of Columbia, has complained that we have put all our eggs in one basket with the spike protein as our target. We ought to be making vaccines which target other parts of the virus as well.

In order to know whether the vaccine protects, you have 2 options:  
1/ challenge the patient with the virus or 
2/ vaccinate a large number (30,000) of people and let them go out into the COVID infected world and see how many of them get the disease and how many are protected compared to those who did not get the vaccine.  
The problem with the "challenge" is you are giving patients disease which might kill them and there is no such thing as truly informed consent here.
The problem with the double blind prospective controlled study is that it can take months to years to get the data.

Obadiah Youngblood, Little Boar's Head, North Hampton

So that's where the Phantom thinks we are now with COVID 19.
Here's a link to TWiV #645

https://www.microbe.tv/twiv/twiv-645/

Next month, some of what has just been said will be proved wrong and there may be new concepts. 

COVID 19 Breakthrough Idea: Do Not Make the Perfect the Enemy of the Good

The Phantom has been trying to get the attention of his elected representatives from his state senator to his state reps to his US Senators and Representative about the idea from Michael Mina, MD, PhD from the Harvard School of Public Health, a simple idea with enormous implications.

Michael Mina, MD, PhD

The idea is that you can do an "instant" test, on saliva, at home, or at school or at an airport and it can tell you, for about $1, whether you are carrying the SARS CO-2 virus in enough viral load to make you infectious to others.

Apparently, the test is like a home pregnancy kit test in its practical execution, but it can be made much more cheaply and it could be made as a "paper test" a cardboard strip coated with monoclonal antibodies to detect antigens (virus particles). 

This may not be useful in trying to manage an individual patient in the Emergency Room who has fever, cough and you are trying to decide if he has COVID19, because it's not a very sensitive test, it will miss some people who have the virus, but that doesn't matter at all if you are simply trying to figure out if a school kid has enough virus to be infectious to others.

This "insensitive" test is potentially enormously useful in public health, where all you care about is if a patient at a given moment infectious to others.  

Patients are likely infectious for only a few days or even hours, when the virus load is very high and all you need is a test that tells you if the student is infectious that day, or if the airline passenger is infectious for that plane ride.

All this depends on a new understanding of COVID19: When you first get the virus, it takes 24-72 hours for the virus to replicate in your nose or throat and around day 3-7 you finally make millions of virus particles and for that brief interval, you can, unknowingly in many cases of presymptomatic or asymptomatic people, be infectious to others. But after that, although you may "shed" virus particles for weeks to even months, these are just the wreckage of virus, bits and pieces, which cannot infect anyone else.

So it's good the test misses those viral particles. This is a test for infectivity (infectiousness) not infection.

This test can be made at local universities, local companies and it could be produced in the millions.

The test actually gives you results in 10 minutes.

As some have noted, getting people to do home testing when you cannot get people to even wear masks may limit the usefulness of this test.

But let us not make the perfect the enemy of the good.

It's good enough if we have all students checked at home and spot checked at school, and it's good enough, maybe to make airplane rides or to eat in a restaurants or to go to work at the factory or the office.

Here is Medcram's version of the This Week in Virology #642 podcast where it's discussed:

https://www.youtube.com/watch?v=h7Sv_pS8MgQ&feature=youtu.be

In this age of Twitter and ascendant marketing, we need a good slogan so people who are all worried about who has the infection, how many people may be undiagnosed, we might roll out a simple Clinton-esque phrase:

"IT'S INFECTIOUSNESS, STUPID!"

Vaccines for COVID19: TWiV Just Keeps Getting Better

Okay, I admit it: I have the luxury of a 2 hour bike ride, which is just enough time to listen to a TWiV episode end to end, and most people cannot or will not do that and I understand.

But this latest episode #642 is a gem.
Everything you ever wanted to know about how vaccines can and are being developed, the problems which have to be overcome, how vaccines are shown to be safe and to be effective.

Brianne Barker, that stellar immunologist from Drew University in New Jersey, explains the nuts and bolts of which cells are involved and Rich Condit leads her interrogation asking just the  question which floats up before my eyes after each of her sentences and so she then goes to explain the why.

Vince Raccaniello and Alan Dove and Dickson Despommier chime in to elucidate anything Rich missed.

For those of you who will not schedule in, here forthwith is my humble attempt to offer a synopsis. But really, nobody can adequately do justice to this lovely panel.
Here is the link:

https://www.microbe.tv/twiv/twiv-642/


Here's the nub:

1/ Vaccines come as different models: There are SUVs and sports cars. There are trains and planes. They all transport but they do it in different ways. Most vaccines under development depend on going after the spike protein, which is putting a lot of eggs in one basket.  All have risks.

2/ A paper detailing the mRNA vaccine from Moderna is discussed.
 The vaccine works by going after the spike protein on the virus which attaches it to the cell it wants to attack and take over.
There is a  lot of talk about changing an amino acid in nucleic acids which the Phantom cannot recall well enough. He will listen a second time.
This is a "phase one study" which is meant to test the safety of the vaccine and to take the first step in assessing potential efficacy: measuring antibody levels.

3/ When any vaccine is given into a deltoid muscle, it attracts B cells which make antibodies. There are different sorts of antibodies, including neutralizing antibodies and its various type of antibody levels which researchers look for to infer how much protection a patient receiving the vaccine might get from the vaccine. But antibodies are not protection; they are an indicator of something which happens which might confer protection. It's like seeing the troops armed on the border and what kind of weapons they carry, but you don't know how well they will fight until you attack, until you test. 

Angela Merkel, a Scientist

4/ Other things then happen, after the antibodies get made. T cells get programmed, alerted, set up to swing into action.  There are at least two types of T cells which swing into action and Type1 may  protect the patient by identifying the infected cells while Type 2 may do that but may release a kind of cytokine which actually makes the patient worse.  So far, the Moderna vaccine seems to program the right type of T cell.
This is important because most patients die not from the virus but because of the immune system's explosive reaction to the virus--a sort of Dr. Strangelove scenario, a doomsday machine.

American Response

5/ Weeks to months after the antibody levels rise, they fall. 
This has caused a Twitter storm because people assumed falling antibodies were a bad thing. Like withdrawing troops from the border--you'd be unprotected.
But, as Brianne Barker points out, falling antibody levels are not necessarily a bad thing with respect to protection.  You don't want to have millions of cells and tons of antibody after every infection with every virus which never regress "or you'd be nothing but one big lymph node."  What you want is a well trained army which can be mobilized quickly at the next attack. 

American Leadership

6/ The current trial is encouraging and now they are recruiting 30,000 patients for the next phase of the study, which is done by vaccinating people and then sending them out into communities where they will likely be exposed and tracking how many get sick and how many appeared to be infected.  You do not "challenge" them by giving  them virus because its considered unethical to give a study subject something which might kill them or which may leave them without their fingers or legs (an outcome seen after clotting complications in some patients.)

Listen to this and you re enter planet Earth, where science and inquiry thrive.
It  restores your faith in humanity.