Sept. 25, 2020 -- Since the beginning of the COVID-19 pandemic, scientists have struggled to find out why some people who get COVID-19 develop severe disease, and others are infected but don't notice symptoms.

Now, new research from the National Institutes of Health and other institutions suggests that some people have antibodies that are misguided, called autoantibodies, that attack the immune system instead of attacking the virus that causes COVID-19. Others may have a genetic mutation that makes their immune system less able to fight the virus.

Coronavirus in Context: Do Antibodies Provide Protection?WebMD's Chief Medical Officer, John Whyte, speaks with Alexander Greninger, MD, PhD, Assistant Director of the UW Medicine Clinical Virology Laboratory, University of Washington, about the effectiveness of antibodies for COVID-19 immunity and transmission.673

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JOHN WHYTE: You're watching

Coronavirus in Context.

I'm Dr. John Whyte,

chief medical officer at WebMD.

What's the role of antibodies

against coronavirus infection?

It's one of the biggest

questions

that we've had over the past six

months.



To provide some insight,

I've asked Dr. Alexander

Greninger, a virologist

from the University

of Washington, to join me.

Dr. Greninger, thanks for taking

time to speak today.



ALEXANDER GRENINGER: Thanks

for-- thanks for having me.

It's great to be here.



JOHN WHYTE: Now there was a very

interesting study from a fishing

vessel that leads us to believe

that perhaps antibodies can

provide protection

against COVID infection.

Can you tell us

about this study?



ALEXANDER GRENINGER: Sure.

So, uh, we're the Clinical

Virology Lab at the University

of Washington Medical Center.

We've done about 600,000,

620,000 tests so

far for PCR tests for COVID

as well as about 50,000

serology tests.



JOHN WHYTE: Wow.



ALEXANDER GRENINGER: Serology

doesn't have much

of a penetration, uh,

compared to the PCR tests.

People are much more interested

in ac--

testing for active infection.



Um, and so we do a lot

of testing for different groups,

um, and we were doing testing

for the fisheries,

uh, trying to prevent outbreaks

on boats.

Uh, and on a couple

of the-- the-- the fishery

boats, there-- there were

outbreaks.

In this one in particular,

there was, uh, an outbreak that

affected 85% of the individuals

on board.

Then with that high attack

rate-- this was in May.

And with that higher attack

rate, that allows you to get

statistical significance

with not a lot of people

if you're looking at protection.



And since we had blood

from individuals before they got

on the boat

and we had follow up over,

you know, 30 days after they got

off the boat,

we were able to look

at correlates of protection

before they got on the boat.



And, um, sure enough we saw that

the three individuals who had

neutralizing antibodies-- now we

don't necessarily know they had

prior infection, but presumably

they had prior infection--

that neutralizing antibody

titers that weren't super high,

they did not get infected

on the boat.

And they are the only three

people who had those-- uh,

those antibodies,

based on our algorithm.



JOHN WHYTE: What does this tell

us about the presence

of antibodies and infection?

This has been one of the biggest

debates for the past six months.



ALEXANDER GRENINGER: Well, it

says that they're a correlative

of protection, which means

that they are a correlative.

So you're not actually proving

that the antibodies are-- are--

doing-- are doing the work.

But, uh, you know, basically

from sort of analogy,

we sort of use different,

uh, levels of evidence

and causality here based um,

uh, on [? some ?] analogy as

well as our prior experience,

we think that antibodies are

going to have a role here.



And here we show that they were

statistically, uh, significant

and associated with protection

from the virus.

So, yeah, I think that, based

on the overall evidence,

I'd be pretty comfortable saying

the antibodies are definitely

associated and probably

protective.

And then the next questions

become, like, how long, right?

How long [INAUDIBLE]?



JOHN WHYTE: We don't know

that yet, do we?



ALEXANDER GRENINGER: Yeah.

That takes time--



JOHN WHYTE: Yeah.



ALEXANDER GRENINGER: --right?

So--



JOHN WHYTE: What's your best

guess as a virologist?



ALEXANDER GRENINGER: Woo.

That's a tough one, I mean,

right?

So people-- so it's going--

the-- the-- the hedge,

right, is it depends.

Um, and the reason it depends is

because we see, you know,

somewhere between a 50-

to 100-fold difference

in the titers in--

of antibodies that people

generate after infection.

Uh, so you see

that big diversity of response.

And so if you're going to see

some declining titers over time,

you would expect it really

depends on how high you started,

and so it's going depend

on different individuals.



So, you know, we're starting

to see-- we've seen some reports

out of Europe and Hong Kong

and I think we've seen

a few cases too, uh, potentially

of reinfection.

Those are individuals probably

infected, you know, at least,

uh--



JOHN WHYTE: Well, I want to ask

you about that--



ALEXANDER GRENINGER: Yeah.



JOHN WHYTE: --reinfection.

Those were people

with moderate disease, right?

In your study that you looked

at, these were people with low

to moderate titers, that

measurement for-- for--



ALEXANDER GRENINGER: Yeah.



JOHN WHYTE: --people in terms

of how many antibodies, yet they

still were protected.

So what-- what are you thinking

about reinfection?

Do you think

it's-- it's possible?

And I'm still going to push back

on you in terms of how long

you think--



ALEXANDER GRENINGER: Oh,

of course.



JOHN WHYTE: --antibodies may

provide protection for [? us. ?]



ALEXANDER GRENINGER: So I think,

you know,

if I had to throw a number

on it, I'd say probably

about six months you should be

able to get, um, out

of protection.

And then, you know,

basically the coronavirus

is, especially

for significant infections

where you drive those titers

quite high, uh, you're looking--

you would be looking at year--

a couple years.

Um, and so--



JOHN WHYTE: So more antibodies

probably means more protection,

for those folks that--



ALEXANDER GRENINGER: I-- I think

I'm--



JOHN WHYTE: [INAUDIBLE]

virology.



ALEXANDER GRENINGER: Yeah,

that's what we'd see

from other viruses, that titer

matters.

And so the higher titer

you start, then the longer

you're going to be protected.



JOHN WHYTE: Do you think

reinfection occurs?



ALEXANDER GRENINGER: Uh, yeah.

I'm-- I-- I'd bet it does.

I mean, it's-- we have

individuals who, on mild

infections-- we even 10% people

sometimes-- this is not our work

but other people's work showing

that 10% of people don't really

show a very strong immune

response at all in mild

infection.

And so those people would be

at a much higher risk

for, uh, for reinfection.

Now, typically

those reinfections are milder.

They're asymptomatic usually.

There's some memory response

that gets-- gets-- gets jolted,

and there's also some antibody,

and there's some T cells.

So, you know, it's all--

it's all--

that's all good news.



It's just really going to be

how high can we drive the titers

in these vaccine studies,

and how long lived are they?

And so I feel pretty

confident and optimistic

in the vaccines,

especially because we're not

having to fight against much

genetic diversity,

uh, of the virus,

really just having to fight

against--



JOHN WHYTE: In terms of mutate--

what about-- is the virus

mutating?

And that's not necessarily

a bad thing, correctly?



ALEXANDER GRENINGER: Oh, it's

always mutating.

I mean, so it throws down--

it throws down two mutations

a month, but the big-- the key

here is the month, right?

So it's-- it's only-- we've only

been around for 10 months

in people.



You look

at the other coronaviruses.

You look at, you know,

influenza, RSV,

other respiratory viruses,

and they've been circulating

in people for--

for hundreds of years

or in different animal hosts

that can infect people.

So there's incredible amount

of diversity.

They evolve-- some of them

evolve faster.

But even just

the other coronaviruses have

been circulating for tens

to hundreds of years in people,

and so there's a lot

of diversity.

You're having to fight

against a lot

of different strains.



JOHN WHYTE: Now help us break

this down because this can be

confusing to a lot of people.

What if the vaccine is only 50%

effective versus, say, 70%

effective?



ALEXANDER GRENINGER: The reason

people anchor on the 50% number

is because that's what the FDA

has said that's the sort

of minimal threshold, the bar

that has to be crossed for them

to authorize or approve

a vaccine,

and I think

that's a reasonable floor.



I think with six or seven shots

on goal, we'll attain that.

And it allows these companies

to move forward and invest,

and it's also

a reasonable-- like,

OK, if-- if something's not

50% effective, you know,

we probably can find another one

that's going to be

50% effective.



Let's be honest.

We've never really done this

for the coronavirus viruses.

You know, we barely made

some early candidate vaccine

for SARS and MERS.

We really haven't done it

for the other coronaviruses.

They weren't high on the list,

and, um, now we're putting all

of our attention to it,

and we're using a lot

of new modalities.



I mean, I think the--

the other silver lining

to this cloud

is that we're going to be

able to test

these different platforms,

and hopefully one or two of them

really, you know, shine through.

We're testing

some new hypotheses

around prefusion, uh, protein,

so new ways to make

these proteins, new ways

to deliver them.

New adjuvants are on board.

And hopefully one of these

will work well

and we'll be able to continue

the momentum into the rest

of the respiratory viruses.



JOHN WHYTE: When do you think

we're going to see a vaccine

that's approved

as safe and effective?



ALEXANDER GRENINGER: Yeah, uh,

that's a good question.

I think, you know--

I mean, I-- I'm-- the guy who

knows the most amount about it

is Tony Fauci, and so he says

to some [INAUDIBLE].

So why-- why would you-- why

would you go against that,

I mean, right?

You know, he's basically

practically designing

the trials.



So, you know, it's, uh, I think

that's a reasonable answer.

I think, you know, I do--

I do want to say that, you know,

compared to other viruses

such as Ebola or Zika

where there have been

recent vaccine initiatives

for sort of emerging viruses

is they sort of tailed away.

We don't talk about Zika virus

right now, right?

There aren't a ton of cases.



Uh, and, you know, that actually

complicated the vaccine trials.

By the time you rolled out

the vaccine trial, the cases

were diminishing.

Makes it harder to show that you

can prevent cases.



If we still have 30,000

to 40,000 cases or 50,000 cases

a day in the United States,

in Brazil, in South Africa,

you know, adjusted

for population, that makes--

that means that there's

a lot of cases to prevent, um,

and that makes the trials

a little easier to open, enroll,

achieve significance maybe

that first time you look

at the data.

And so it could be-- it

could be-- it could be a lot

quicker

than-- than the average vaccine

trial.



JOHN WHYTE: And in the meantime,

we'll continue to learn

about the role of antibodies,

um, and, you know,

whether or not that provides

protection.

One other quick question-- a lot

of this-- the current labs

that measure antibodies right

now, they're not measuring

neutralizing antibodies.



ALEXANDER GRENINGER: Nope.



JOHN WHYTE: Is that correct?

And that's what you looked at it

as-- as the real measure

to know, uh, about

the effectiveness of--

of, uh, antibodies.



ALEXANDER GRENINGER: Well--

well, so--

I mean, for full disclosure

here, I mean, basically we have

a clinical lab and also

Jesse's--

Jesse's lab at Fred Hutch.

And so, you know, clinical labs,

um, don't often run

neutralizing antibody tests.

Most places don't, actually.

The--



JOHN WHYTE: Is that what we

really need, though?



ALEXANDER GRENINGER: So if you

look at all

across the whole

antibody-clinical-lab spectrum,

you have two different antigens.

You have the nucleocapsid, which

wraps the genome, and you have

the spike protein, which is what

binds the cells.



Actually, most of the tests that

are done the United States

are done

against the nucleocapsid

because it's the most sensitive

assay and it's better at telling

you were you infected?



JOHN WHYTE: All right.



ALEXANDER GRENINGER: But really

what we want are antibody tests

that show that [? argon ?]

spike, the outside glycoprotein

from the virus that's involved

in attachment and entry.

And if you can get antibodies

against that, you can say more

about can you prevent infection?



JOHN WHYTE: But that's not what

current labs typically are

doing, right?



ALEXANDER GRENINGER: Yeah.

There's a mix of them.

I'd say it's like maybe--

the market is probably,

like, 75%, 80% nucleocapsid,

20% spike.

And then there's--



JOHN WHYTE: But I really want

the spike.

Is that what I [INAUDIBLE].



ALEXANDER GRENINGER: Yeah.



JOHN WHYTE: OK.



ALEXANDER GRENINGER: I mean,

I think that

for the receptor-binding domain,

uh, you want to look

at the outside of the spike,

the part that binds

the receptor.

That's what you'd like.

Um, that I think is a-- is

a-- is what's most--

most-- you're most likely going

to see in a clinical lab that

could be achievable

and will be the best, uh,

potential correlative

protection.



JOHN WHYTE: You've given us

a whole virology lesson today.

I want to-- I want to thank you,

you know,

for taking the time today,

helping us understand what is

the role of antibodies in terms

of preventing infection?

what's the risk of reinfection?

where are we on the vaccines?

We've covered a lot, uh,

and I appreciate you taking

your time.



ALEXANDER GRENINGER: All right,

thanks for taking the time

to talk to me.

Appreciate it.

Thanks for doing all this.

This is really-- the media

is so important when it comes

to this-- this pandemic.



JOHN WHYTE: And I want to thank

you for watching Coronavirus

in Context.



[MUSIC PLAYING]

John Whyte, MD, MPH. Chief Medical Officer, WebMD, <br>Alexander Greninger, MD, PhD, Assistant Director of the UW Medicine Clinical Virology Laboratory, University of Washington/delivery/aws/72/6a/726a5a3d-5caa-37c3-b60c-9307d375cdef/Greninger_082720_2_,4500k,2500k,1000k,750k,400k,.mp408/31/2020 10:41:0018001200Greninger_082720_1800x1200/webmd/consumer_assets/site_images/article_thumbnails/video/covid19-images/Greninger_082720_1800x1200.jpg091e9c5e81fbe04b

Both groups fall short in mounting effective immune responses that rely on what’s called type I interferon, a group of proteins needed to protect cells and the body from viruses.

In one study, researchers found that among nearly 660 people with severe COVID-19, many had variations in 13 genes linked with the body's defense against the virus that causes influenza. More than 3.5% completely lacked a functioning gene. When the researchers looked further, they found that immune cells taken from those 3.5% could not produce any detectable type I interferons when exposed to the coronavirus that causes COVID-19.

The innate immune system, sometimes called the general immune system, is the body's first line of defense against germs and other foreign invaders. The adaptive immune system, sometimes referred to as the specialized immune system, takes over if the innate immune system can't do the job and attacks the specific germ causing the trouble.

In research that looked at about 1,000 patients who had severe COVID-19 pneumonia, more than 10% had autoantibodies against interferon when they first became infected. And 95% of these were men, who have been found in other research to be more likely to get a severe infection.

Expert Perspective

"The most shocking thing [about the research] is that that many people are making autoantibodies that block type 1 interferon," says Shane Crotty, PhD, a professor at the Center for Infectious Disease and Vaccine Research at the La Jolla Institute for Immunology in California. He was not involved in the new research but has published recently on COVID.

"What this is showing is that there are people, almost all men, for unclear reasons, who have these autoantibodies against their own antiviral proteins, the type 1 interferon. Then when these people get coughed on [by infected people], they really run into trouble. Their own body is preventing an innate immune response."

Much of the research published on COVID has dealt with the innate immune response, he says. He compares the innate response to a kind of burglar alarm that is set off before the adaptive immune system kicks in. "An early response by our innate immune system is important to stop this virus."

People can be tested for these autoantibodies, Crotty says. Of the research, he says: "This is really valuable information to have. The more you can potentially categorize patients, the more likely you come up with treatments [that are tailored]."

Show Sources

Shane Crotty, PhD, professor, Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA.

Science: "Auto-antibodies against type I IFNs in patients with life-threatening COVID-19."

Science: "Inborn errors of type I IFN immunity in patients with life-threatening COVID-19."
News release, National Institutes of Health: "Scientists discover genetic and immunologic underpinnings of some cases of severe COVID-19."

NCBI Bookshelf: "The innate and adaptive immune systems." 

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