Friday6 March 2020 ★ FINANCIAL TIMES 7

F T B I G R E A D. CORONAVIRUS

A lossmaking start-up is leading the fight to immunise people against Covid-19. But any vaccine will need

state backing and big pharma to become a reality. Even then it could take 18 months to succeed.

By Hannah Kuchler, Clive Cookson and Sarah Neville

successfully from clinical trials, says

Roger Connor, president of global vac-

cines at GSK. “Everybody will want it

immediately. It may then take a period

of time to create the supply organisation

after that,” he warns.

GSK, the world’s largestvaccine

maker, hasannounced a partnership

with Clover Biopharmaceuticals of

China, which runs one ofthe country’s

largest in-house biopharmaceutical

manufacturing operations.GSK has also

madeits “adjuvant” technology, which

proved effective in the H1N1 flu pan-

demic,available free to any company

that it judges can make use of it.

When added to a vaccine an adjuvant

agent can trigger a stronger immune

response. “The dose that you have to

give of the vaccine can be smaller, which

means you can get it to more people

faster,” he says. GSK has had “lots” of

approaches since announcing it would

make the technology available, and is

running a “structuredassessment”

processto determine who receives it.

Not all vaccines will benefit from an

adjuvant. First, experts scan the andi-c

date vaccine. “We want to understand

how capable they are and what’s their

probability of success to bring it

through,” he adds.

For now anycommercial gain from

involvement n creating a successfuli

vaccine is a secondary concern to the

drive to find a treatment, Mr Connor

says. “At the minute we’re completely

focused on the science and focused on

who to partner with... to bring together

vaccine fast.”a

Negotiations over commercial terms

can wait, he says: “We think the priority

is to get the scientific collaboration

together, get the product to them free,

get it tested pre-clinically and let’s see if

this thing can work.”

Accessforall

In the US, where politicians and patients

are railing against high drug prices,

more than 40 members of Congress

wrote toDonald Trump in February to

demand that the president ensure that

any governmentfunding of a vaccine or

treatment came with an important

string attached:everyone will be able to

access it.

“If we manage to find, at taxpayer

expense, some treatment or cure

through a vaccine, we need to be able to

afford it everywhere,” says Jan Scha-

kowsky, a Democratic congresswoman

from Illinois, who led the initiative. “It

should not be turned over to private

pharma companies.”

“We are very concerned about

access,” saysCepi’s Dr Hatchett. “With

H1N1 flu in 2009, the wealthiest coun-

tries put contracts in place and monopo-

lised vaccine supplies.”

Cepi has done a lot of scenario plan-

ning, including asking whether a Cov-

id-19 vaccine will be needed when it is

ready next year. “I don’t think it is plau-

sible any longer that containment will

be a success and the disease knocked

out,” he says. “There is a business case

that there will be a long-term commer-

cial niche for these vaccines.”

Back at the Moderna headquarters,

Mr Bancel says Covid-19 proved the

company’stechnology was faster than

anyone imagined. And next time he

thinks it could be even faster still.

Yet asthe death toll rises, his col-

league Stephen Hoge, the company’s

president,worries thatevenquicker is

not quick enough. Just when he thought

Moderna would have time to breathe

after the first batch of itspotential vac-

cine was out the door, he watched the

outbreak spreading to South Korea,

Europe and beyond.

Like Mr Andres, he has had his own

sleepless nights. “I’m going to bed think-

ing we made some progress,” he says,

“and waking up every morning feeling

further and further behind.”

The $2bn race to find a vaccine

J

uan Andres woke up three

times during the night after

putting his precious vials of

vaccine on the back of a

d e l i v e r y l o r r y. I n l a t e

February,Moderna, a biotech group

based outside Boston, smashed the

record for the fastest time between

identifying a virus — in this case Cov-

id-19 coronavirus — and creating a vac-

cine ready to test on humans:42 days.

In the lab, the team had been excited

but in the early hours Mr Andres, a 30-

year pharma veteran in charge of manu-

facturing, was nervously checking his

phone totrack he lorry carrying thet

potential vaccine o a discreet location.t

There the US National Institutes of

Health would start the trial to test

whetherit works.

“The pride comes from this [being] a

race,” he says. “Doing this as fast as

possible is something that is a duty.”

Once they were sure the vaccine had

arrived safely, the team celebrated with

ice cream.At least 100Moderna staff

worked on the projectbut Mr Andres

says everyone isexcited to be involved,

evenpeople’s families.

“I can’t remember the last time my

15-year-old thought I did something

cool,” he laughs.

Moderna is one of more than 20 com-

panies and public sector organisations

worldwideracing to develop a vaccine

against Covid-19, which in little more

than two months has exploded from a

few people suffering from respiratory

disease in theChinese city of Wuhan o at

near-pandemic with more than 97,

cases and 3,300 eaths worldwide so fard.

The Coalition for Epidemic Prepared-

ness Innovations — a partnershipof gov-

ernments, industry and charities,cre-

atedthree years ago to fight emerging

diseases that threaten global health — is

already sponsoring four Covid-19 vac-

cine projects, including Moderna’s. It is

alsoon the point of signing contracts for

four more, saysRichard Hatchett, CEPI

chief executive. He estimates that devel-

oping Covid-19 vaccines at the speed

required will costabout $2bn over the

next 12-18 months.

Moderna is off to the fastest start, Dr

Hatchett believes, but several others are

close behind. “We received 48 applica-

tions from all over the world following

our call for proposals in February,” he

adds. “There is a real sense of urgency

.. because the threat we are facing is.

unprecedented in the last 100 years in

terms of its speed and potential sever-

ity,” he says, referring to the 1918 Span-

ish flu pandemic.

The trigger for Moderna came when

Stéphane Bancel, itschief executive —

who hadworked on the 2009H1N

swine flupandemic which came from

Mexico — alled ac contact at the

National Institutes of Health. In the

autumn, the two organisationshad

agreedto run atest at the company’s

manufacturing plant to see how quickly

they could respond to a pandemic. But

beforeany dry run was possible,

coronavirus —part of a family of viruses

that cause respiratory diseases ranging

from mild colds to fatal pneumonia —

provided a real test.

Crackingthegeneticcode

Nestled on a hill outside Boston, Mod-

erna’s Norwood factory is smaller than a

standard pharmaceuticals plant. It was

built to be quickly adaptable, as some of

its potential products are personalised

for each patient.Work at the Massachu-

setts facilityand atother early entrants

in the Covid-19 vaccine race beganin

earnest as soon as Chinese scientists

published online the genome ofcorona-

virus — all 30,000 biochemical “letters”

of its genetic code —on January 10.

“With the genomic sequence, we were

off to the races,” says Anthony Fauci,

head of the US National Institute of

Allergy and Infectious Diseases.

Ahead of an outbreak, it is impossible

to predict what virus is coming next.

“Instead of trying to develop a vaccine

for a pathogen [virus], which is kind of

tough... you have to try to develop

platform technology to facilitate rapid

development of vaccines,” Dr Fauci

says.

One such platform isModerna’spro-

ductionof vaccines based on viral genet-

ics. By February 7, the company’s scien-

tists had manufactured dozens of doses

of clinical grade vaccine, enough for the

NIH’s early trial in healthy volunteers,

scheduled for April.Researchers then

had to wait to see if the batch was sterile,

giving any bacteria two weeks to grow.

Staff uickly completed other necessaryq

tests in case they needed to start again.

Fortunately everything went right,

every step of the way.

Despite the rush, vaccine experts say

that it will be at least a year to 18 months

before one is available for widespread

use — typically the process takes several

years. After aninitial safety trial, there

must now be larger clinical studies to

test efficacy. Meanwhile, the epidemic is

likely to spreadacross the world, killing

many more thousands or even millions

of people.

The work of Moderna and its compet-

itors may only be useful ifcoronavirus

comes back again in another outbreak

next year or becomes an endemic infec-

tion like seasonal flu. With commercial

returns uncertain, industry’s response

to epidemics carries elements of corpo-

rate social responsibility and excite-

ment in meeting a scientific challenge —

though sometimes there is a big pay-off,

as Wellcome, later part ofGlaxoSmithK-

line, found with its pioneering zidovu-

dine Aids drug in the 1980s.

Moderna may be the first to test on

humans but many more aretrying to

create a vaccine, from big pharma com-

panies such asJohnson & Johnson nda

Sanofi o academics including those att

the University of Queensland. Genetic

sequencing and new structural biology

tools are transforming vaccine develop-

ment, allowing scientists to create their

own synthetic versions of viruses —

rather than waiting for someone to

FedEx a specimen.

This is opening the field to new play-

ers, says Paul Duprex, director of the

Center for Vaccine Research at the Uni-

versity of Pittsburgh. “You have more

people thinking aboutthe problems in

different ways, not limited by having to

grow the virus in a particular lab,” he

adds.

Shane Crotty, a professor atLa Jolla

Institute for Immunology in California,

says one approach being pursued is to

search for the best immune response in

a patient with the disease — and try to

copy it so the vaccine can elicit a more

robust defence. “That’s been the big-

gest, most exciting advance in the past

five years. Several of those have gone

into human trials looking good. It’s a

much more sophisticated way to make a

vaccine,” he adds.

Payingthebill

Mr Bancel signed the Cepi contract that

helped fundModerna’svaccine n Janu-i

ary on an iPhone at the World Economic

Forum in Davos, where the coalition had

been foundedin 2017 tohelp quash

epidemics quickly. Hetold Dr Hatchett

that in this case “quickly” meant now —

and the agreement was signed two days

after their first conversation about the

outbreak.

As a nine-year-old lossmaking com-

pany with several candidate vaccines

and treatments in trials but none on

sale, Moderna could not shoulderthe

costs of creating a new Covid-19 vaccine

on its own. Even profitable big pharma

groupshave shied away from investing

in vaccines for outbreaks withoutpublic

funding, because the chances of cashing

in are small. Several companies have

lost money over vaccines developed for

past outbreaks, such as Ebola and Sars,

which were almost over before any

products were ready.

NowModerna is over the first hurdle,

it must start preparing to scale up. The

Norwood facility could producea larger

batch for the next trial but not create a

vaccine for all those who might need it.

Mr Bancel is in talks with governments

about how they would manufacture

millions or even billions of doses.

Inevitably Moderna will have little

option but to strike a deal with a larger

manufacturer.

Productioncapacity will be key if

and when licensed products emerge

FT visual journalism: Ian Bott Sources: Moderna; CEPI; The College of Physicians of Philadelphia; FT research

Vaccine A weakened form of a virus or part of it

Antigen-

presenting

cells (APCs)

Activated T

helper cells

Memory

cells

Killer T cells Cells

invaded by

vaccine virus

Plasma B

cells

Antibodies

Activated B cells

How a vaccine works











New vaccine technology RNA vaccines

In cells, RNA strands

carry coded genetic

information from nucleus

DNA to ribosomes ...

... where they dictate the

production of specific

proteins, the building blocks

for all organs and tissues

By introducing RNA coded

to create the antigens of a

specific virus ...

... an APC can be induced to

produce those antigens and

display them on its surface.

The body’s immune system

will then recognise the

antigens and remember them

in the same way that it would

Antigen- with a more traditional vaccine

presenting cell (APC)

Virus A parasitic agent consisting of DNA or

RNA within a protein coating. Unable to replicate

on its own, it uses a host cell’s mechanisms to

replicate itself, taking over the host’s normal

functions and possibly damaging or destroying it

The vaccine is injected

Antigen-presenting cells (APCs)

absorb immunity-stimulating

components of the vaccine,

break them apart and present

these antigens externally

Antigens displayed by the APCs

activate T cells which alert other

cells

T helper cells or antigens

activate B cells, which recognise

the antigen as a threat

Some of the B cells mature into

plasma B cells ...

... producing antibodies, proteins

that can bind to the viral

(vaccine) antigens

Bound to the antigen,

antibodies can hinder or

prevent its operation

APCs and T helper cells also

activate killer T cells, which

destroy other cells invaded by

viruses

Memory cells retain recognition

of the vaccine antigens, so when

the host is infected by the real

virus, the response will be faster

and stronger – ie, the host is

immunised

        

Cell nucleus

Ribosomes

Antigen

‘Doing this as fast as

possible is a duty. I can’t

remember the last time

my 15-year-old thought I

did something cool’

JuanAndres,Moderna

Traditionally, vaccines contain a

weakened live virus, a dead virus or

proteins produced by the virus. The

vaccine is often grown inside living cells

such as bacteria or in eggs. Once

purified and injected, it primes the

body’s immune system, which then

recognises and attacks the virus the

next time it finds it.

Some Covid-19 vaccine candidates,

such as the oneproduced by China’s

Clover Biopharmaceuticals, are high-

tech versions of these approaches —

making viral proteins in genetically

engineered cells. A favourite is the

“spike protein” on the outside of the

virus, which coronavirus uses to grab

and enter human cells. The University

of Queensland uses“molecular clamp”

technology to hold the proteins in a

shape that antibodies are most likely to

recognise.Sanofi lans top engineer a

different, harmless virus o carry Covid-t

19 proteins into people.

Others, includingModerna, are

developing “nucleic acid vaccines”,

which contain the genetic recipe for

viral proteins in the form of DNA or

messenger RNA (mRNA). That leaves

the human recipients to produce the

proteins inside their body. No viral

vaccine made from nucleic acids has yet

been licensed for human use.

At Moderna, 40 scientists in the pre-

clinical lab created mRNA coding for

Covid-19 spike protein. The first batch

was created in days in a large white

room, wherecolour is a warningsign

and minirobots move trays of tiny vials.

The spike mRNA was then put into

microscopic bubbles of fat called lipid

nanoparticles — a delivery vehicle to

carrygenetic instructions into patients.

One concern was thatCovid-19 has

unusually large spikegenes which are

longer than those in most of Moderna’s

previous vaccines. When the scientists

had confirmed that both the tail and

the cap of the mRNA had made it into

the vaccine, the work moved

downstairs for completion in a ab thatl

makes personalised cancer vaccines.

The science

Variety of options pursued

to avoid risk of failure

‘We are very concerned

about access. With H1N

flu, the wealthiest

countries... monopolised

vaccine supplies’

Cepi is sponsoring four Covid-

projects, including Moderna’s, above

Sars-CoV-2 is the

virus that causes

Covid-19. This

scanning electron

microscope image

shows the virus

emerging from the

surface of cells

cultured in the lab

NIAID-RML

MARCH 6 2020 Section:Features Time: 3/20205/ - 18:20 User:charlotte.middlehurst Page Name:BIG PAGE, Part,Page,Edition:USA , 7, 1