The Wall Street Journal - 07.04.2020

A12| Tuesday, April 7, 2020 THE WALL STREET JOURNAL.

THE CORONAVIRUS PANDEMIC

Recovery

Orders Sow

Confusion

progress that is remarkable by
usual standards remains far
behind the racing virus.
Health officials are warning
Americans to brace for the
most difficult days this week,
with the number of infections
in the nation’s hardest hit cit-
ies expected to peak. In the
U.S., more than 10,000 people
have died from Covid-19.
It usually takes years to de-
velop a new drug treatment or
vaccine. The compounds must
be tested in the lab, in animals
and extensively in humans. If
they succeed, more time is
needed to manufacture large
numbers of doses.
The urgent, high-speed
search is moving on three
fronts. One is to get a vaccine
that could provide immunity,
allowing a return to normalcy.
Among the farthest along is
a vaccine hatched by govern-
ment researchers and Mod-
erna Inc., a biotechnology
company in Cambridge, Mass.,
for which safety testing in hu-
mans has begun. If clinical
studies succeed, it could be
ready for use as soon as early
next year, researchers say.
In addition, Inovio Pharma-
ceuticals Inc. of Plymouth
Meeting, Pa., said human trials
were starting Monday for an
experimental coronavirus vac-
cine it is developing. Chinese
company CanSino Biologics
Inc. and a research arm of the
Chinese military have started
human testing of a vaccine,
according to the World Health
Organization. In Europe, Ger-
man company CureVac AG and
the University of Oxford are
developing vaccines.
Scientists also are exploring
whether existing drugs such
as hydroxychloroquine for ma-
laria or HIV treatments might
work against the coronavirus,
and some doctors are already
treating patients with hy-
droxychloroquine. Results of
two Chinese studies of Gilead
Sciences Inc.’s antiviral rem-
desivir, previously tested in
Ebola, are expected this
month. Regeneron Pharmaceu-
ticals Inc. and partner Sanofi
SA are testing a rheumatoid
arthritis drug against the cor-
onavirus.
On the third front, re-
searchers are hunting for en-
tirely new drugs. Among these
efforts, which take longer, are
programs to mine the blood of
recovered patients for infec-
tion-fighting soldiers known
as antibodies that can be con-
verted into drugs.
“I think we can find some-
thing that, at least, helps peo-
ple out,” said Derek Lowe, a
veteran drug researcher.
“Whether any of these things
work well enough to get peo-
ple out of their houses, that’s
another question. Maybe it
works well enough to reduce
the number of people who go
on ventilators.”
Johnson & Johnson said it
and a division of the Depart-
ment of Health and Human
Services together have com-
mitted more than $1 billion of
investment to co-fund vaccine
research, development, and
clinical testing. Other govern-
ment agencies and universities
are also spending on research.
Unlike many drug quests,
there’s not necessarily a big
payoff at the finish. Some
companies have indicated
they’ll provide drugs free or at

Continued from Page One

chief scientific officer at Re-

generon in Tarrytown, N.Y.,

texted his head of infectious

disease research. “Good luck

today,” he wrote. “The world

is sort of maybe depending on

you ;).”

It was 8:41 a.m. on Satur-

day, March 14, the latest in a

string of weekends consumed

by the company’s hunt for a

medicine that could knock out

the virus. Spearheading the ef-

forts was Christos Kyratsous,

drug-discovery chief for infec-

tious diseases, who used a

rapid-response platform

formed after the 2014 Ebola

epidemic in West Africa.

His team collaborated with

colleagues who tended some

special mice with immune sys-

tems genetically engineered to

have a human-like response to

viruses. Because the mice

make antibodies indistinguish-

able from people’s, research-

ers working with them can

have a compound ready to test

in people in months rather

than the years it takes to birth

a traditional drug from

scratch.

The teams had spent weeks

collecting antibodies from

mice exposed to the coronavi-

rus’s spike protein, in hopes

that two of the antibody mole-

cules could be combined into a

drug able to stop an infection.

They also gathered antibodies

from the blood of recovered

coronavirus patients.

Experiments to see whether

these killed the virus in test

tubes were being finished up

that March Saturday.

“You can come now,” Dr.

Kyratsous texted Dr. Yanco-

poulos at 2:45 p.m. Dr. Yanco-

poulos got off a conference

call and walked to the lab. As

he entered the lab and saw Dr.

Kyratsous smiling, he texted a

colleague to bring a bottle of

champagne.

Data showed they had

found hundreds of antibodies

that blocked the virus from

entering cells. If it couldn’t en-

ter cells, it couldn’t replicate.

A treatment was still far

away—but now was in sight.

The champagne popped open.

“My head was in a rush:

‘We’ve got it,’ ” Regeneron

Chief Executive Leonard Schle-

ifer recalls thinking after his

chief scientific officer gave

him the details. “The world is

starting to fall apart, and if we

can just hold on, in that lab, in

those tubes, is a cure.”

Regeneron said it would

choose the best two antibod-

ies for a drug in April and

start clinical trials by early

summer. It is preparing to

make hundreds of thousands

of doses a month by the sum-

mer’s end.

Getting the drug on the

market isn’t assured. Clinical

trials showing the treatment

is both effective and safe

could take months. These are

the stages where so many

low cost. Gilead said it won’t

charge for 1.5 million doses it

has manufactured.

Scenes from labs show the

quest from the inside.

One weekend in January,

Kizzmekia Corbett rushed to

Building 40 on the National

Institutes of Health campus in

Bethesda, Md.

Dr. Corbett is a researcher

at the National Institute of Al-

lergy and Infectious Diseases,

or NIAID. For years, she and

colleagues have braced for a

pandemic, studying bacteria

and viruses that popped up

around the world to gain a

better understanding when a

bad one finally came.

Around Jan. 10, she got a

cellphone alert with a vital

piece of information about a

mysterious virus emerging in

China. A consortium of re-

searchers including Chinese

scientists had published online

the virus’s genetic sequence.

That provided its molecular

makeup, information needed

to craft a vaccine. It also indi-

cated the new virus belonged

to a well-known family, the

coronaviruses. Named for the

crown-like spikes protruding

from their surface, coronavi-

ruses had caused two deadly

outbreaks since 2002: severe

acute respiratory syndrome,

or SARS, and Middle East re-

spiratory syndrome, MERS.

Dr. Corbett and a colleague

studied the genetic code—

seemingly endless combina-

tions of the letters A, G, C and

T, each standing for the chem-

icals making up DNA. The se-

quence looked similar to that

of the SARS virus. This meant

researchers who had investi-

gated a SARS vaccine, which

didn’t advance after the epi-

demic waned, could pursue a

similar tack against the new

coronavirus.

A vaccine would deliver a

disabled spike protein, or the

genetic instructions to make a

close copy, into the human

body. This wouldn’t infect a

person but would train the im-

mune system to recognize and

attack the virus. If a vacci-

nated person encountered the

virus, antibodies would spring

into action and neutralize it.

“We’re lucky that this is a

coronavirus because we know

what to do,” said Barney Gra-

ham, deputy director of the

Vaccine Research Center at NI-

AID.

As the virus spread in Wu-

han, China, and then in other

countries, U.S. government

researchers searched for a

partner to help design and

make a vaccine. Dr. Graham

reached out to Moderna,

which is pioneering a new

technology for making vac-

cines. It uses “messenger”

RNA, genetic material that can

instruct cells to make proteins

able to trigger immune re-

sponses.

Like the NIH, Moderna re-

searchers studied the new vi-

rus’s genetic sequence and

concluded the spike protein

would be the part to target. By

Monday, Jan. 13, the NIAID

and Moderna agreed on a vac-

cine design. Moderna made a

small batch for testing. Dr.

Corbett and colleagues started

testing it in mice on Feb. 4.

Two weeks later, initial results

showed it elicited antibodies

to coronavirus in the blood.

Months of testing in hu-

mans would be necessary..

Moderna retrofitted equip-

ment at its plant outside Bos-

ton, and by Feb. 25 the NIAID

was ready to recruit healthy

volunteers.

Champagne moment

One morning the following

month, George Yancopoulos,

medicines fail even after they

show promising test-tube and

animal results.

Testing

Neal Browning was scroll-

ing through his Facebook feed

in early March when a friend’s

post caught his eye.

Mr. Browning is a network

engineer at Microsoft Corp.

living in the Seattle suburb of

Bothell, Wash., not far from

one of the country’s earliest

and worst coronavirus out-

breaks. He also lives close to

the research center doing a

human study of the vaccine

that Moderna and the NIAID

are developing.

The research center, Kaiser

Permanente Washington

Health Research Institute, was

urgently seeking healthy vol-

unteers to test the experimen-

tal vaccine’s safety. Mr.

Browning’s Facebook friend

knew of the recruitment ef-

fort. After Mr. Browning ex-

pressed concern about the vi-

rus, the friend texted him

details of the trial.

Many medical facilities

across the U.S. are seeking

people to test the safety of po-

tential coronavirus drugs or

vaccines. To make way, they

are suspending trials of other

medicines, clearing space for

coronavirus study subjects

and assigning data-entry

workers, pharmacists and

other staff to deal with the pa-

perwork.

Massachusetts General Hos-

pital, one day after agreeing to

test Gilead’s remdesivir,

walked federal health officials

through how it planned to

conduct the trial. It did so by

phone for safety reasons and

because time was short, said

Libby Hohmann, who oversees

the hospital’s clinical-trial ef-

fort.

That evening, Dr. Hohmann

assembled about a dozen

pharmacists, researchers and

physicians in a conference

room to parcel out trial’s

tasks, such as collecting blood

samples and tracking patients

once discharged.

To save time, they skipped

typical pretrial exercises such

as training the staff in show-

ing hospital doctors and

nurses the way to administer

the drug. “We’re sort of doing

those on the fly,” Dr. Hohmann

said.

Since the trial began March

15, Mass General has enrolled

35 subjects. Among them is a

man in his 40s who agreed to

be in the study just before

nurses inserted a breathing

tube down his throat because

of respiratory problems from

the virus, Dr. Hohmann said.

He is now stable, she said.

For the test of Moderna’s

vaccine, Mr. Browning, the Mi-

crosoft engineer, showed up at

the Kaiser research institute in

downtown Seattle on March

16, becoming only the second

volunteer.

It had been just nine weeks

since researchers selected a

section of the virus’s genetic

sequence to target, an unusu-

ally short period. Even so, the

trial is unlikely to have pre-

liminary results until summer,

followed by more testing re-

quired that would push the

vaccine’s availability out about

12 to 18 months, according to

the NIAID.

After his shot, Mr. Brown-

ing stayed for about an hour

so the staff could make sure

he didn’t have any side effects.

He drove home and worked

that afternoon helping Micro-

soft configure network fire-

walls to accommodate a surge

in employees working re-

motely, until the threat posed

by the virus can be quashed.

Antibody

secreted

Ribosome

Vaccine Administration VirusInactivation

mRNA Vaccine

How Vaccines Work

Vaccinesaredesignedtoteachyourimmunesystemhowtofightoffcertainkinds

ofgerms—andtheseriousdiseasestheycause

Some types of vaccines and their groups

Whole-Pathogen

Workbyintroducinga'messenger'RNAsequence (themoleculethattellscellswhattobuild)

whichiscodedforadiseasespecificantigen.Onceproducedwithinthebody,theantigenis

recognisedbytheimmunesystem.

Covid-19candidatevaccines

as20ofMarch

Monthsfromviralsequenceselection

tophase1studyofvaccine

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SARSCoronavirus(200)

InluenzaAIndonesia(2006)

InluenzaACalifornia(200)

Zikavirus(206)

Covid-19 (2020)

mRNAisencasedinalipid

nanoparticle.Afterinjection,

getsintothebody'scells.

ThemRNAtheninstructsthe

cellstostartmakingaprotein

thatcanbefoundonthevirus.

Theseproteinsresemblethevirus.

Theyinducethebody'simmune

systemtomakeantibodies.

Live-attenuated

Usesa

weakened

(orattenuated)

formofthegerm

thatcauses

adisease

Inactivated

Usesthe

killed

versionof

thegerm

thatcauses

adisease.

Toxoid

Usesatoxin

thatcreates

immunityto

thepartsofthe

germthatcause

adisease.

DNA

SyntheticDNA

instructsthecellsto

makeproteinsthat

resembleapathogen.

Thebodyreactsby

producingantibodies.

Recombinant

UsesDNAfromthe

targetedpathogen

andinsertsitintoa

differentvirusthat

hasbeenrendered

non-infectious.

Subunit NucleicAcid

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Sources: Vacinnes (National Institute of Allergy and Infectious Diseases; World Health Organization; U.S. Department of Health and Human Services;

CureVac) Drugs ( the companies) Note: Companies’ estimates for projected start dates. *July to September. † Early summer

Alberto Cervantes/THE WALL STREET JOURNAL

Remdesivir

Maker:GileadSciences

Kevzara

Regeneron

Pharmaceuticals/Sanoi

Actemra

Roche

StartdatesofclinicaltrialsforexperimentalCovid-19drugs

DrugsinthePipeline

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Of Vaccine

Moves Fast

old baker, a former laboratory
scientist, said she is battling a
cough that makes it difficult to
talk. Drinking fluids and cough
medicine has helped, she said,
but her heart races whenever
she stands up.
“It’s just frustrating to not
be able to have the testing and
the knowledge we need to ade-
quately combat this,” she said.
Ms. Edwards, a 38-year-old
venture capitalist, started feel-
ing on March 12 like she
couldn’t breathe. She called
her doctor, who told her she
likely had Covid-19 and should
self-quarantine.
“I’d never felt like that,” she
said.

Continued from Page One

She stayed home but con-

tinued working. Six days later,

she went to the emergency

room after her shortness of

breath worsened. It felt like

drowning, she said.

The ER physician advised

self-isolation, plus rest and hy-

dration. She followed that ad-

vice more closely this time,

taking vitamins and drinking

fresh juices and water.

Her symptoms evolved: She

started coughing up phlegm,

the fevers let up, and slowly

her energy and ability to

breathe normally returned.

March 26, the day her 14-

day isolation ended, “was the

first morning where I felt like

I could take a deep breath,”

Ms. Edwards said.

There was some confusion

about what her release date

should be. She said her doctor

had told her that her 14-day

clock started on March 11. She

decided it would start on

March 12, the day she had first

felt shortness of breath.

Even physicians have said it

can be difficult to know for

certain when the countdown

should begin. “This is really

hard because I’m not sure any-

one knows,” said Alicia Fernan-

dez, a professor of medicine at

the University of California,

San Francisco and a primary-

care doctor at Zuckerberg San

Francisco General Hospital.

Part of the problem is that

scientists don’t yet fully under-

stand when patients begin to

be infectious, or when they

cease to be.

Many of the guidelines focus

on symptoms, but some pa-

tients have symptoms so mild

they may be imperceptible.

And as many as 25% of infected

people in the U.S. might be as-

ymptomatic, federal Centers

for Disease Control and Preven-

tion director Robert Redfield

said. Whether they are infec-

tious is unknown, experts said.

Asymptomatic patients can test

positive for the virus almost a

month after the initial expo-

sure, some case reports from

China and the U.S. suggest.

CDC guidelines say Covid-

patients can discontinue home

isolation if they meet these

three criteria: They have been

fever-free for at least 72 hours

without taking fever-reducing

drugs, respiratory symptoms

like cough and shortness of

breath have improved, and at

least seven days have passed

since symptoms first appeared.

When Ms. McKenzie, a 30-

year-old mother of three in

Australia, tested positive, she

said local health authorities

initially told her to prepare to

self-isolate for 14 days. But Ms.

McKenzie, a mental-health co-

ordinator at a health-care pro-

vider, soon realized her isola-

tion could last longer.

Ms. McKenzie said because

of her job there are more strin-

gent requirements for when

she can cease home isolation.

After her symptoms are gone,

she will have to return two

negative tests for the coronavi-

rus, taken 24 hours apart, be-

fore she can be released.

“People are thinking it’s just

14 days. It’s not,” Ms. McKen-

zie said. “You could be in isola-

tion for a long time.”

Ms. McKenzie is isolating at

home with her boyfriend, and

her children are staying with

other family.

More than a week after her

positive test result, Ms.

McKenzie said she felt her

symptoms were improving.

Daily chores can still be a chal-

lenge. She recently took a hot

shower but had trouble breath-

ing. She felt better after using

an inhaler.

In the Netherlands, Mr.

Toms, a 62-year-old software

developer, also felt perplexed

about when he could end his

quarantine.

“It’s clear that if you get

symptoms, you’ve got to iso-

late yourself and wait 14 days,”

he said. “But if you’ve got it,

how long do you wait? That’s

not quite consistent.”

On March 11, Mr. Toms felt

hot flashes while watching

television. By the next day, he

developed a dry cough. The

following day, he felt like his

lungs were getting smaller, he

said.

Over a telemedicine consul-

tation, his doctor told him he

probably had Covid-19 and he

should stay home for 14 days.

Over three days, tension in

his chest worsened. He took fe-

ver reducers and rested. By the

fourth day, his symptoms

seemed to have stabilized, but

it took another six days to

“feel normal again...and it got

steadily better after that,” he

said.

Now, he has resumed riding

his bike. “My energy levels are

definitely lower at the mo-

ment,” he said.

Some patients have

symptoms so mild

that they may be

imperceptible.