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Since vaccine candidates started being
developed in January, a version approved for public use won’t be available
until the end of summer 2021, at the earliest. And that’s if nothing goes wrongPhotograph:
Maria Toutoudaki/Getty Images
As Covid-19 spreads, the pressure is on for drugmakers to get a vaccine to market. But it's not that easy.
It’s been fewer than three months since a novel coronavirus emerged in China, causing fever, coughing, and, in severe cases, pneumonia. Since then, the disease known as Covid-19 has swept into 72 countries, infecting nearly 93,000 people and killing more than 3,000.
What makes the coronavirus scary enough to cause a worldwide run on face masks and lead countries to lock down whole megacities and ban travelers isn’t that it’s super deadly. So far, the World Health Organization estimates
Covid-19’s fatality rate to be about 3.4 percent globally, which is
still lower than other recent coronavirus outbreaks, including SARS and
MERS. (That said, it appears to be more fatal than flu, which has a case fatality rate of around 0.1 percent.) And it’s very contagious.
Still, most people who get Covid-19 will recover in a week or two,
without need for hospitalization. What has people panicked is that it’s
new.
In
the US and other developed countries, particularly in the global north,
mystery illnesses don’t strike that often. People are used to having
answers and a plan for avoiding getting sick. In these places, vaccines have already eliminated infectious diseases that were once common, including polio, hepatitis, and the measles. If you get your flu shot every year, the worst thing you’ll usually pick up is a case of the common cold.
Which
is perhaps why Americans can’t seem to wait to get their hands on a
Covid-19 vaccine. President Donald Trump told pharmaceutical executives
and public health officials in a White House meeting on Monday that he wants one ready before the election in November.
For
the record, that would be impossible. Developing vaccines that are safe
and effective takes time, investment, and good science. Developing a
vaccine for a coronavirus like the one that causes Covid-19 comes with
even more challenges. But at least 30 companies and academic
institutions are trying. Here’s your guide to everything you need to
know about those efforts. Check back often—we’ll be keeping it updated
with any notable progress or setbacks.
What’s In a Vaccine?
Vaccines
all work on the same basic principle: Scientists try to make something
that closely resembles a pathogen, and then expose a person’s immune
system to it through a small dose administered as an injection. Ideally,
the immune system develops a strong memory
of the pathogen, so that the next time the person is exposed, their
body will mount an attack before the infection can take hold. The trick
is to do this without making the person seriously ill from the vaccine
itself. There are a few different methods for making vaccines, but they
all must strike this delicate balance.
One
way to make a vaccine is to weaken, or attenuate, the microorganism
while still keeping it alive. The most common method for doing this is
growing several generations of the pathogen in environments other than
human cells, so that it evolves away from causing disease in humans. By
repeatedly culturing live viruses or bacteria in animal cells,
scientists can essentially create a bunch of mutants. Then it’s a matter
of selecting the mutant strains that can replicate in human cells but
don’t cause disease like their wild ancestor. The trick is that these
imposters still have to look enough like the original virus to
accurately train the immune system to fend it off. Examples of
attenuated vaccines include those for measles, mumps, and tuberculosis.
Another
type is called an inactivated vaccine, which is made from a dead
version of the whole virus or bacteria after it’s been killed with heat
or chemicals. This type of vaccine can also be made using smaller pieces of the microbe, which by themselves are not considered alive.
One
common approach is to locate the protein that a virus uses like a key
to get into human cells, which is usually on its surface. Once
scientists know the genetic code for this protein, they can paste it
into bacteria or yeast and use these microbial factories
to produce huge quantities of it to be used as the basis of the
vaccine. The protein alone is often enough to be easily recognized by
the immune system and to trigger a defense on subsequent exposure.
Alternately, sometimes scientists will genetically modify the virus
instead, swapping bits of the disease-causing pathogen into a harmless
virus shell. These types of inactivated vaccines almost always require
multiple doses, because they’re not as good at stimulating the immune
system as a live microbe. But they come with a lower risk of severe
reactions. Examples of inactivated vaccines include those for polio,
rabies, and hepatitis A and B.
All the approved vaccines on the
market use one of these two techniques. But newer methods still in
development may get their debut with the Covid-19 outbreak. One such
promising technology is nucleotide-based vaccines. Nucleotides are the
chemical building blocks that make up genetic material, both DNA and
RNA. The virus that causes Covid-19, known as SARS-CoV-2, consists of a
strand of RNA enclosed in a spike-covered capsule. It uses these spikes
to invade human lung cells. Vaccine makers can copy the genetic
instructions for making these spikes and package them up into a shot.
Once inside the body, human cells will make the viral proteins, which
the immune system will then recognize as foreign. It will produce
antibodies against them and learn how to attack any future invaders
carrying these protein spikes.
When Will a Covid-19 Vaccine Be Ready?
On Tuesday, National Institute of Allergy and Infectious Diseases director Anthony Fauci told US senators,
“It will take at least a year and a half to have a vaccine we can use.”
That might seem like an eternity for public health officials staring
down a probable pandemic. But if true, it would actually set a record.
Most vaccines take between five and 15 years to come to market, says Jon
Andrus, an adjunct professor of global vaccinology and vaccine policy
at the Milken Institute of Public Health at George Washington
University.
The reason it usually takes so long comes down to a
combination of factors. The first is getting a candidate vaccine that’s
ready to test. This part of the vaccine development process, known as
discovery, used to take years of careful benchtop biology. Scientists
had to isolate and grow viruses in the lab. But now, with genetic
sequencing, new protein-visualizing microscopes, and other technology
advances, it’s possible to skip that step. Arriving at a vaccine
candidate can sometimes be done in weeks.
All those advances,
though, can’t speed up the time it takes to meticulously monitor how
well these candidate vaccines work in people. Clinical trials, a
prerequisite for bringing a vaccine to market, are the real bottleneck.
Each happens in three stages. Phase 1 involves just a few dozen healthy
volunteers, and is meant to evaluate whether the vaccine is safe. That
takes about three months. If the healthy volunteers don’t suffer any
adverse effects, it’s on to Phase 2. This time, several hundred people
will get the shot, ideally in an area experiencing a Covid-19 outbreak,
so scientists can gather data on how well it spurs the production of
antibodies and fends off the disease for these trial subjects. That’s
another six to eight months. If everything still looks good, Phase 3 is
to recruit a few thousand people in an outbreak zone and repeat the
experiment. That’s another six to eight months—if you don’t have any
problems recruiting patients or with your vaccine supply. Then a
regulatory agency, like the US Food and Drug Administration, has to
review all the data before making a decision about whether to approve
the vaccine. That can take months to a year.
If
you’ve been doing the math, this means that, since vaccine candidates
started being developed in January, a version approved for public use
won’t be available until the end of summer 2021, at the earliest. And
that’s if nothing goes wrong. “Constricting the whole timeline of going
from concept to a product that can be distributed into a year or two is
really a herculean endeavor,” Andrus says.
Only
a handful of companies have vaccine candidates ready to move into human
testing, but more than 30 have joined the race. Even if one of these
companies does pull off the Thirteenth Labor, they’re left with a novel
product that still requires manufacturing and distribution. “The first
question we should be asking is: Does this producer have the capacity to
scale it up?” asks Andrus. If not, a limited supply will force public
health officials to make tough decisions about rationing out a vaccine.
Isn’t There Any Way to Speed It Up?
In
general, these timelines are very difficult to compress. The last thing
drugmakers and regulators want is to rush out a subpar product and
create—rather than solve—a public health crisis. Making vaccines is so
cost-intensive and high risk that most pharmaceutical firms don’t do it
anymore. Today, the vaccine business is dominated by just four
companies: Pfizer, Merck, GlaxoSmithKline, and Sanofi. Since they’re the
ones with the kind of capacity required to fight a global pandemic,
they’re the ones that have to be convinced it’ll be worth it.
Covid-19
might seem like a sure bet now. But outbreaks are unpredictable. SARS
disappeared just four months after it caused a global panic. The
companies that had begun developing vaccines against it had to abandon
their trials because there just weren’t enough patients. Similar disease
cycles help explain why it took so long to get an Ebola vaccine,
which was only approved last December despite dozens of outbreaks since
it first emerged in 1976. Plus, government funding and pharmaceutical
industry interest tend to evaporate once the sense of emergency fades
away.
No one wants to make a product that’s not going to be used.
But
there are some things governments can do to encourage vaccine makers to
take up the challenge despite its riskiness, including providing grants
and other financial incentives to spur their involvement. In the US, a
division of the Department of Human & Health Services known as the
Biomedical Advanced Research and Development Authority often plays the
role of incentivizing medical countermeasures
against an outbreak. BARDA has so far funded four projects to address
Covid-19, including two vaccines, in partnership with Johnson &
Johnson and Sanofi. In recent years, an international nonprofit called
Coalition for Epidemic Preparedness Innovations, or CEPI, has also
raised money to invest in vaccine research. So far, it has committed
more than $66 million to vaccine development efforts against Covid-19.
The
fact that Big Pharma players have already taken an interest doesn’t
mean that a vaccine will arrive any faster. But it does suggest that
these companies believe Covid-19 will be around for the long term, and
may be willing to lend their manufacturing muscle to ensure that a
vaccine, when it arrives, can be produced en masse.
A Potential Wrinkle
There’s
another factor that makes developing a vaccine against coronavirus a
particularly tricky endeavor, says Peter Hotez, a vaccine researcher and
dean of the National School of Tropical Medicine at Baylor College of
Medicine. That’s something called “immune enhancement.” In the 1960s,
scientists at the National Institutes of Health were working on a
vaccine against respiratory syncytial virus, or RSV, a common, very
contagious virus responsible for most of the colds that infants and
toddlers get. During clinical trials, some children who received the
vaccine later went on to get terribly sick when they caught RSV in the
wild. The vaccine produced an exaggerated immune response, causing
extensive damage in their bodies. Two kids died.
Decades
later, when SARS hit, researchers including Hotez began working on a
vaccine. But in early tests with lab animals, they saw something that
raised a red flag. The animals’ immune cells were attacking their lungs,
causing damage like what had been described in the RSV trials. “That
alerted everyone in the coronavirus research community that there was
potential for immune enhancement,” says Hotez. His group, which includes
collaborators from the New York Blood Center, adapted its strategy.
Instead of producing the entire spike protein, they built just a tiny
piece of it—the piece that actually latches onto human cells, called the receptor binding domain.
With this approach, Hotez says, when they tested in animals they saw
immune protection but without the undesirable enhancement.
The
prototype vaccine they developed wasn’t able to attract any investment
after the SARS outbreak dissipated. But now, the group is currently
submitting proposals to fund human testing of the vaccine, which has
been sitting in a freezer in Texas since the mid-2000s. Because the
virus that causes Covid-19 uses the same receptor as SARS to attack
human lung cells, they believe it might offer some protection. But it
will be important to come up with a clinical trial design that includes
additional, longer-term monitoring of patients to watch out for
potential immune enhancement. Hotez says any vaccines designed to fend
off Covid-19 will likely have to do the same. “That’s going to really
complicate things and slow them down,” he says. “I don’t think anyone’s
going to have something ready in 12 to 18 months.”
Who’s Making a Covid-19 Vaccine?
Almost
everyone! Here’s a breakdown of the 30+ candidates in development (so
far), starting with those that are making nucleotide-based vaccines.
Moderna
Boston-based biotech unicorn Moderna is perhaps best known for working on personalized cancer vaccines. But the company has a history of responding to public health threats, including the 2015 Zika outbreak.
In collaboration with scientists at the National Institutes of Allergy
and Infectious Disease, and with funding from CEPI, Moderna has already
produced an RNA-based vaccine which codes for a stabilized form of the
SARS-CoV-2 spike protein. On February 24, the company shipped doses of
its candidate, mRNA-1273, to the NIAID Vaccine Research Center, where a
Phase I safety trial is set to begin as early as April.
CureVac
Like
Moderna, crosstown rival CureVac uses lab-made mRNA to spur the
production of coronavirus proteins, triggering immune cells to produce
antibodies against it. And, like Moderna, it got a grant from CEPI to
apply its technology to SARS-CoV-2. CureVac representatives have said
the company expects to have a candidate ready for human testing within a
few months.
Inovio
This Pennsylvania-based
biotech uses a slightly different technology, using DNA instead of RNA
to make medicines. It has also received funding from CEPI to develop a
DNA-based vaccine against Covid-19. In January, the company started
preclinical testing of its candidate, called INO-4800. It has so far
produced 3,000 doses for trials to be conducted in patients in the US,
China, and South Korea. The first of these is scheduled to begin in the
US at the end of April.
Applied DNA Sciences / Takis Biotech
Applied
DNA, a New York–based company, announced in March it is partnering with
Rome, Italy–based Takis Biotech to deliver its own DNA-based vaccine
candidates against Covid-19. The companies plan to have four versions
available to test in mice by later this month.
Zydus Cadlia
India-based
pharmaceutical firm Zydus Cadila announced in February it had initiated
two approaches for developing a Covid-19 vaccine. Like Inovio and
Applied DNA, the first involves using a ring of DNA designed to produce
coronavirus protein once inside the human body. The second deals with
genetically manipulating an attenuated recombinant measles virus so that
it will induce antibodies against Covid-19. Company officials have not
announced timelines for human testing.
Stermina Therapeutics
This
is another mRNA vaccine project, based at Shanghai East Hospital of
Tongji University. The CEO of Stermina told Chinese state media at the
end of January that manufacturing has already begun, and doses could be
ready for human testing sometime in March.
Imperial College London
A
team of British scientists are currently testing their own DNA-based
vaccine in mice at labs in Imperial College London. The researchers are
looking for funding partners to advance the candidate into human testing
later this year.
Several other companies are also developing protein-based vaccines. These include:
GlaxoSmithKline (GSK)
One
of the world’s leading vaccine manufacturers, GSK is lending its
technology to a Chinese firm called Clover Biopharmaceuticals to work on
a coronavirus vaccine. Through the partnership, Clover will be
producing viral proteins, and GSK will be providing its proprietary
effectiveness-boosting compounds, known as adjuvants. Neither company
has provided a testing timeline.
Novavax
Novavax
got a jump on the competition from its previous work developing
vaccines against SARS and MERS. The Maryland-based company announced in
February that it had generated several candidates comprised of
recombinant protein nanoparticles derived from the SARS-CoV-2 spike
protein. Company representatives said they expect to complete animal
testing soon and move to the first phase of human trials by the end of
spring 2020.
Altimmune
Unlike its
competitors, this Maryland-based company is developing a vaccine that
gets sprayed into patients’ noses, not injected into their arms. Best
known for its nasal-spray flu vaccine, Altimmune announced in February
that it had completed the design and prototyping of a vaccine against
Covid-19 and is now advancing it toward animal testing and manufacturing
for human trials.
Vaxart
This Bay Area
biotech is the only one so far developing an oral vaccine against
Covid-19. In January, the company announced plans to generate candidates
based on the published genome of SARS-CoV-2, but no further timelines
have been released.
Expres2ion
This
Denmark-based biotech firm is leading a European consortium of vaccine
developers to tackle Covid-19. It uses insect cells from fruit flies to
produce viral antigens. The company aims to test its candidate vaccine
in animal models later this year.
Generex Biotechnology
Four
companies in China have contracted with Florida-based Generex to
develop a vaccine using the company’s proprietary immune-activating
technology. Company representatives say it could have a candidate ready
for human trials as early as June.
Vaxil Bio
This
Israeli immunotherapy company normally specializes in cancer. But last
month representatives announced they had discovered a combination of
proteins they believe will be an effective vaccine against Covid-19. The
company plans to start manufacturing doses for initial testing and
looking for partners to scale up further if that goes well.
iBio
This
Texas-based biotech company uses modified relatives of the tobacco
plant to grow viral proteins for vaccines. The company is partnering
with a Chinese vaccine maker to put its “FastPharming” platform to work
on a Covid-19 vaccine. Company officials expect to have a candidate
ready for animal testing later this summer.
Baylor College of Medicine / New York Blood Center
Peter
Hotez’s group is pushing for funding to test their SARS vaccine against
the Covid-19. He says they already have about 20,000 doses ready to be
deployed for clinical trials. These researchers are simultaneously
working on developing a new vaccine from scratch, based on the binding
receptor domain of the new virus, SARS-Cov-2, but that will take several
years to develop.
University of Queensland
A
team of Australian researchers, with funding from CEPI, have developed a
vaccine candidate they say is ready to move forward into human testing.
It relies on a “molecular clamp” technology invented in the lab of
molecular virologist Keith Chappell, which helps stabilize viral
proteins so they have the same shape they’d have on the surface of the
virus. The group is now intending to ramp up production for clinical
trials.
University of Saskatchewan
Canadian health
authorities have given university researchers the green light to start
working on a vaccine against Covid-19. They’ve used the virus’s
published genome sequence to begin building protein-based candidates and
are now waiting for live versions of the virus to begin testing in
animal models.
University of Oxford / Advent Srl
A
team of researchers at the University of Oxford’s Jenner Institute had
been working on a vaccine against MERS, which they quickly tailored to
the new coronavirus, SARS-CoV-2. In February, the scientists signed an
agreement with Italian vaccine maker Srl to produce the first 1,000
doses of the new vaccine, ChAdOx1, to supply human trials.
And a few more are developing viral vector-based strategies:
Sanofi
One
of the so-called Big Four, Sanofi has been working with BARDA since
2004 on pandemic preparedness, including against SARS. The company has
expanded this arrangement to focus on a Covid-19 vaccine using the
company’s recombinant DNA platform, which involves swapping in parts of
the coronavirus’ RNA with genetic material from a harmless virus. Sanofi
expects to have a vaccine candidate to test in animals within six
months. Human testing could begin sometime in 2021.
Johnson & Johnson
Johnson
& Johnson is expanding on the company’s past work with BARDA to
develop an Ebola vaccine to pursue a vaccine against Covid-19. With
funding from the government agency, the company’s plan is to deactivate
the virus, producing a vaccine that triggers an immune response without
causing infection. The company has not released any information
regarding development timelines.
Geovax Labs / BravoVax
Atlanta-based
GeoVax signed an agreement in January to work with BravoVax, a private
company Wuhan, China, to jointly develop a vaccine against Covid-19.
Under the collaboration, GeoVax will be providing its proprietary
platform—a modified pox virus that can be designed to express viral
proteins from SARS-CoV-2.
Tonix
In
February, this New York–based biopharma startup announced it is
collaborating with the nonprofit Southern Research to develop a live,
modified horsepox virus modified to express protein fragments from
SARS-CoV-2. Company officials have not released any further timelines.
CanSino Biologics
Chinese
vaccine-maker CanSino is reportedly developing a viral vector-based
vaccine against Covid-2019 but no further information is available at
this time.
Greffex
The
CEO of this Houston-based genetic engineering company announced last
month that they have completed the design of a vaccine against Covid-19.
The company has not released any information about its lead candidate,
but Grefex reportedly makes adenovirus-based vector vaccines involving a
harmless virus that can be genetically tweaked to express foreign
genes, like one for the SARS-CoV-2 spike protein.
And last but not least, is the only company attempting to attenuate a live SARS-CoV-2 virus:
Codagenix
This
New York–based biotech firm is collaborating with the Serum Institute
of India to co-develop a live, attenuated vaccine against Covid-19.
Rather than using blunt forces like heat or chemicals to kill the virus,
Codagenix uses a “deoptimization” strategy to manipulate the virus into
a version that can still replicate but won’t cause disease. The Serum
Institute of India will be in charge of the scale-up. Codagenix
representatives expect to have a vaccine candidate ready for animal
testing this spring, with human testing progressing by this summer.
Source: https://www.wired.com/story/everything-you-need-to-know-about-coronavirus-vaccines/
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