Oct. 23, 2020 -- People who have recovered from COVID-19 may worry about lingering health effects, but some may also focus on what they see as the good news: Now they are immune.

Or are they?

It's true that the number of reinfections has been small -- about two dozen reported from more than 41 million cases globally. While scientists are learning more about how the immune system responds to the novel coronavirus, SARS-CoV-2, that causes COVID-19, many questions remain.

Getting more specific answers about how the immune system responds to the virus, including whether recovery is likely permanent, is crucial not only to those who have recovered. These answers can help inform vaccine makers to make the most effective vaccines as well.

To get the answers, scientists are studying immune responses of infected people. They are also looking back at other serious viral diseases, such as Ebola, to see if they can apply the knowledge about immunity from those conditions to COVID.

Immune System: The Basics

Scientists talk about the innate immune system and the adaptive immune system. Both play a crucial role in helping to fight off viruses and other invaders. "The innate immune system is the evolutionary, older part of your immune response," says Santosha Vardhana, MD, PhD, assistant professor of medicine and attending physician at Memorial Sloan Kettering Cancer Center in New York. "It's what we describe as the 'first wave of defense.''' This reaction is often what drives the initial symptoms of fever seen with COVID-19, he says.

"That is followed by what is called the adaptive immune response," he says. "Your adaptive immune response is much more specific." When your adaptive immune system kicks in, certain types of white blood cells, or lymphocytes, mount a defense. This includes B and T lymphocyte cells.

B lymphocyte cells make antibodies, which attach to a specific invading antigen or protein and help the immune cells destroy it.

T lymphocyte cells come in two forms: helper cells and killer cells. The killer cells attack the antigens directly and help control the immune system, releasing chemicals known as cytokines.

The helper cells assist the B cells in making protective antibodies.

Immunity to COVID: What Is Known

"Most people infected, 90% of people, develop antibodies," says Joel Ernst, MD, an immunology expert who is professor of medicine and chief of the division of experimental medicine at UCSF School of Medicine.

People who are infected with COVID-19 but don't have symptoms have less robust antibodies, perhaps undetectable, Ernst says. However, ''most with proven infection do develop an immune response, including neutralizing antibodies."

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

Neutralizing antibodies, as the name implies, defend a cell by neutralizing the harmful effect the virus (or other pathogen) has on it.

"These so-called neutralizing antibodies are associated with protective immunity," Ernst says. "If you get a sufficient level, you are protected against infection at least from that strain. From the very beginning, it seemed pretty likely that a goal of vaccine development and a goal of natural immunity after infection would involve neutralizing antibodies."

Researchers have found that how someone’s T cells respond to a COVID-19 infection varies greatly, Ernst says. Factors include the severity of the illness and the person’s gender -- women have higher responses than men.

In a recent study, researchers from the La Jolla Institute for Immunology and other institutions found that the immune system must launch a ''multi-layered" and virus-specific approach to control how severe the infection becomes. In the study, they collected blood samples from 50 COVID-19 patients and analyzed the antibodies specific to the coronavirus, the helper T cells and the killer T cells.

They found that people who had a strong specific T cell response to the infection tended to have milder disease. People who had a less-coordinated response or weak T cell response did poorly.

The findings may explain why people over age 65, who were more likely to have a poor T cell response, are at higher risk of severe infection or death, the researchers say. Immunity weakens as we age.

What else is known? "The virus generally does not mutate very quickly," Vardhana says, so that's good news for a vaccine being effective. If a virus changes quickly, a vaccine may no longer work against it.

Immunity to COVID-19: Unanswered Questions

One of the biggest unknowns about COVID-19 immunity is how long it lasts.

Canadian researchers analyzed blood samples from 31 people who were recovering from COVID-19. They measured antibodies at 1-month intervals, finding they dropped about 6-10 weeks after symptoms began. Another recent study found that people who had severe cases of COVID-19 produced antibodies for up to 4 months after they had symptoms.

Researchers also aren’t sure about what level of antibodies you need in your blood to protect you, Ernst says.

The Truth About Face MasksSince the COVID-19 pandemic began, there’s been lots of buzz about covering your face. Here’s the truth about face masks.120

SPEAKER: Since the COVID-19

pandemic began,

there's been lots of buzz

about covering your face.

Here's the truth about face

masks.

I'm not sick.

Should I have to wear a face

mask?

Yes.

COVID-19 can be spread by people

with no symptoms, who don't even

know they're sick.

And as many as 35%

of COVID-19 cases

are asymptomatic.

Wearing a mask goes a long way

to protect people around you.



Doesn't wearing a mask cause

carbon dioxide poisoning?

No.

Wearing a mask

won't cause carbon dioxide

poisoning.

Although an airtight mask might

make it a little harder

to breathe, that doesn't include

cloth masks or N95 respirators.



Do masks actually help protect

the person who wears them?

Yes.

Masks can help block

infectious particles in the air

and reduce the amount you

breathe in.

One study found that wearing

a mask

can reduce the risk of infection

by 79%.



Does wearing a mask cause a drop

in blood oxygen levels?

No.

Doctors wear masks for very long

periods of time, even all day,

in lots of cases.

Masks are designed to be

breathable, and there's

no evidence that suggest wearing

masks will cause

a drop in oxygen levels.



Will wearing a mask weaken

your immune system?

No.

There's zero evidence that

wearing a face mask will lower

or weaken your immune system.



Do you still need

to social distance with a mask

on?

Yes.

You still need to practice

social distancing when you're

wearing a mask.

Every step you take,

like distancing

and good handwashing,

lowers your risk further.

The CDC recommends wearing

a face mask and staying at least

six feet apart from others

to best stop the spread

of COVID-19.



The bottom line?

Face masks are most

likely to reduce the spread

of COVID

when you wear them in public.

Researchers have predicted

that if 80% of us wear masks,

we could do more to suppress

the spread of coronavirus

than a strict lockdown.

So do your part and mask up.

Hartford Healthcare: “Killer COVID-19 Masks? The Truth About Trapped Carbon Dioxide.” University of California San Francisco: “Still Confused About Masks? Here’s the Science Behind How Face Masks Prevent Coronavirus.” American Lung Association: “From the Frontlines: The Truth About Masks and COVID-19.” CDC: “Considerations for Wearing Cloth Face Coverings.” Poynter: “Can the government legally force you to wear a mask?”/delivery/aws/2a/da/2ada2b02-95ef-3bf7-8875-300d91503992/091e9c5e81f8ad71_truth-about-face-masks_,4500k,2500k,1000k,750k,400k,.mp408/10/2020 10:04:0018001200black girl putting on mask/webmd/consumer_assets/site_images/article_thumbnails/video/truth-about-face-masks-1800x1200.jpg091e9c5e81f8ad71

Nicolas Vabret, PhD, assistant professor of medicine at the Icahn School of Medicine at Mt. Sinai, agrees. "One thing we don't know yet is the minimal immune response that is necessary to prevent infection." That's important for vaccine development.

Ernst says data from ongoing vaccine trials may provide insight into that question. It will be important to monitor immune responses to the vaccine, especially in older people and others more vulnerable to severe infection, Ernst says.

Another unknown: How often reinfection will occur and why it occurs. Researchers recently took a closer look at four reinfection cases. According to their report in The Lancet Infectious Diseases, none had known immune deficiencies. Two had worse infections the second time than the first.

Researchers also found one person in the study was infected by a different strain from the first case to the second. This suggests being infected might not guarantee total immunity.

Looking back at other coronavirus outbreaks, such as the MERS-CoV, the Middle East respiratory syndrome outbreak first reported in 2012, ''have provided a foundation for our understanding" of COVID-19 in general, Vabret says.

Researchers studied 117 survivors of the Ebola virus, a deadly viral disease that caused international alarm in 2013-2016. They compared the survivors' blood samples to those of their 66 contacts and 23 negative control subjects, finding that many of the survivors had the capacity to fight off reinfection due to their ability to produce T cells, even without antibodies.

But experts don’t agree yet on which is more important: antibody or T-cell response. In general, the vaccines now in development have produced a response in neutralizing antibodies, although some have been reported to have T cell responses, Ernst said.

According to the La Jolla investigators, it may be that T cells are more important in fighting a ''natural" infection with SARS-CoV-2, while antibodies may be more important in a vaccine. Or the researchers say, the T-cell response may be important in both for the vaccine and for someone who gets infected naturally.

Finding out the minimal immune response needed that allows people infected naturally to fight off the infection will be valuable information to vaccine developers, Vabret says. That can then be a target to aim for in the vaccine development and trials.

WebMD Health News

Sources

Joel Ernst, MD, professor of medicine and chief of the division of experimental medicine, UCSF School of Medicine, San Francisco.

Santosha Vardhana, MD, PhD, assistant professor of medicine and attending physician, Memorial Sloan Kettering Cancer Center, New York.

Nicolas Vabret, PhD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York.

Medline Plus: "Immune response." 

Journal of Experimental Medicine: "The many faces of the anti-COVID immune response."

UCSF: "Ask the Expert: Seeking Immunity Against COVID-19."

La Jolla Institute for Immunology: "T Cells Take the Lead in Controlling SARS-COV-2 and Reducing Covid-19 Severity."

Cell: "Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity."

Immunity: "Immunology of COVID-19: Current State of the Science."

The Lancet Infectious Diseases: "Genomic evidence for reinfection with SARS-CoV-2: a case study," and "What reinfections mean for COVI-19."

Johns Hopkins Coronavirus Resource Center.

The Lancet Infectious Disease: "Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study."

mBio: "Decline of Humoral Responses against SARS-CoV-2 Spike in Convalescent Individuals."

Science Immunology: “Persistence and decay of human antibody response to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients.”

BRO News: “COVID-19 reinfection tracker.”

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