[Ip-health] The Economist: So many candidates, so little time - Can the world find a good covid-19 vaccine quickly enough?

Thiru Balasubramaniam thiru at keionline.org
Fri Apr 17 22:23:22 PDT 2020


The Economist

So many candidates, so little time
Can the world find a good covid-19 vaccine quickly enough?
And can it mass produce it fairly if it does?

Apr 16th 2020 edition



There were no pre-existing vaccine candidates handily squirrelled away when
the genetic sequence of sars-cov-2, the virus which causes covid-19, was
published on January 10th. But science moves pretty quickly these days.
There are reports of some 86 candidate vaccines against sars-cov-2 being
developed around the world, taking a wide array of approaches (see chart).
Three have already started phase I trials. One of these, made by CanSino
Biologics, a Chinese biotechnology company, in collaboration with a unit of
China’s Academy of Military Medical Sciences run by Chen Wei, a
major-general feted in the media, has been approved for phase II trials,
which are designed to find out if a vaccine can provoke an immune response
that might fight off the virus. It is recruiting 500 volunteers in Wuhan.

That one or more of these many efforts will lead to a working vaccine seems
quite likely. Vets have been using vaccines to protect farm animals against
coronaviruses for years. In most people infected with sars-cov-2 the immune
system is quite capable of dealing with the virus; that is why they do not
get sick. Among those who do, in most cases the immune system eventually
rids the body of the virus. An immune system forewarned by a vaccine should
be able to do so better and quicker.

But it is not enough that a vaccine be feasible. The job of making it
available around the world will be just as taxing. A candidate which goes
on to become a practical vaccine may be identified before the end of
summer—perhaps more than one. But showing how well it works, finding any
rare problems it may encounter, and manufacturing it in quantities large
enough for the whole world will still take time. Melinda Gates, who with
her husband has spent tens of billions of dollars on vaccines through the
Bill and Melinda Gates Foundation, has suggested that getting a covid-19
vaccine ready and distributed could take 18 months.

In terms of human welfare, what matters is making that time as short as
safely possible. In terms of prestige and politics, though, who gets to do
it matters a lot, too. Producing an effective sars-cov-2 vaccine will be a
huge feather in the cap of the researchers, companies and nations
responsible. If the cap in question is Chinese, as it could well be, the
development will be presented as a triumph both of Chinese science and the
Chinese system; mutatis mutandis, something similar will be true for any
other country, too.

The identity of the successful team may not just matter in terms of
prestige. The demand for a vaccine that provides reliable and safe
protection to whole populations will be huge. The world currently makes
over 5bn doses of vaccine a year, of which roughly 1.5bn are seasonal-flu
vaccines. Some companies and governments are already adding capacity in
advance of a sars-cov-2 vaccine being developed. But without knowing which
vaccine approach will do best, there is a limit to how much capacity can be
readied beforehand.

If vaccine production capacity is constrained, the politics of vaccination may
get nasty. An optimum strategy for using limited stocks of vaccine in a way
that best benefits the world might see them devoted to populations at
particular risk. But a country with a lead in vaccine manufacture might
prefer to devote its limited stocks to universal coverage for its own
citizens, securing a narrow advantage for itself at the cost of a broader
loss to the world. As Richard Hatchett, who runs the Coalition for Epidemic
Preparedness Innovations (cepi), an ngo, puts it, “Countries are in a
real-world prisoner’s dilemma.”

At the heart of every vaccine is an antigen, so-called because it is the
thing which provokes the body to generate antibodies as well as other
immune responses. When a cell that has been infected by a virus is forced
to make viral proteins, it will display bits of those proteins as antigens
on its surface, waving them around like little flags to draw the attention
of the immune system.

This is not the only way antigens come to the system’s attention. Some of
its cells engulf virus particles, or just bits of them, without getting
infected, and process them into antigens. When those antigens are in turn
presented to other immune cells, the production of antibodies gets under

Antibodies are proteins that stick to the antigen wherever they may find
it. In so doing, they prevent virus particles from infecting other cells
and flag them up for destruction. Building up a full immune response
against a previously unencountered virus’s antigens in this way takes time.
Covid-19 patients typically do not start producing antibodies until they
are in their second week of symptoms.

Before the advent of genetic engineering, doctors had three ways to let the
immune system get acquainted with viral antigens it needed to know about.
They could present it with a strain of the virus, or a related virus, that
was capable of infecting cells but had been hobbled in some way so as not
to cause sickness—what is called a live-attenuated vaccine. This is the
approach taken with many of the more common established vaccines, such as
those against measles, mumps and rubella. Alternatively they could present
it with a virus that had been inactivated, and thus could not cause
infection. This was the path to the Salk polio vaccine, and is the
technique used for seasonal-flu jabs. Finally they could present it with
the antigen itself, harvested from the blood of those infected—the approach
originally taken to make the hepatitis b vaccine.

Two of these approaches are being investigated for use against sars-cov-2.
A live-attenuated vaccine in which the sars-cov-2 genome is “deoptimised”
is being developed by Codagenix, an American biotech company, in
collaboration with the Serum Institute of India. Sinovac Biotech, based in
Beijing, is following the inactivated route. During the sars outbreak of
2003, Sinovac created a vaccine against the coronavirus
responsible—sars-cov, which is closely related to sars-cov-2—which used
inactivated virus particles. The vaccine made it through a phase I trial,
but not before the outbreak had ended. Now Sinovac is taking the same
approach to sars-cov-2.

In the past few decades genetic engineering has increased the range of
possible vaccines considerably (see diagram). Today’s version of the
hepatitis b vaccine, for example, no longer consists of antigen harvested
from blood; it consists of antigen made by adding the gene for the protein
that forms the virus’s outer coat to cell cultures and thereby producing
the protein in a pure form. Many teams are looking at sars-cov-2 vaccines that
consist of a single protein mass produced in this way, including Clover
Biopharmaceuticals, a Chinese biotech company, Novavax, an American biotech
company, Sanofi Pasteur, a French firm which is one of the largest
established vaccine companies, the University of Queensland and the us
army. Most of these efforts are aimed at the conspicuous spike proteins
that stud the virus’s outer layer.


Whatever sort of trials are chosen, many seem likely to take place. That
suits Paul Hudson, the boss of Sanofi. He argues the world needs
alternative approaches to a covid-19 vaccine not just to cover all the
biological bases, but “because manufacturing capacity is a question-mark.”

Making vaccines is a lot more complicated than making ordinary pills. Those
which use whole viruses have to grow them up in some highly standardised
way and purify them exactingly. Those which just use proteins need other
forms of ultrafiltration and purification to ensure that only the desired
antigen gets into the patient’s body. Dozens of quality checks are done
every step of the way; they may add up to more than half of the production

Won’t get fooled again
Because profits in vaccine making are low, not many Western companies find
such capabilities worth the candle. Almost all the pharmaceutical
industry’s vaccine-manufacturing know-how is concentrated in just four
companies: GSK, Johnson & Johnson, Pfizer and Sanofi. And these four are
generally wary of developing vaccines for pandemics, not least because
developing vaccines for diseases that then vanish is even less profitable.
“Look at what happened with the excellent Zika vaccine as soon as it turned
out America wasn’t going to get slammed. Look at the 2009 flu pandemic
vaccine,” says Laurie Garrett, author of “The Coming Plague”, a prescient
book published in 1994. A decade ago, after the h1n1 influenza pandemic
fizzled out, the governments of America and various European countries
backed out of promised contracts, leaving pharmaceutical companies holding
the bag which contained hundreds of millions of dollars of development
costs. Nevertheless, all four are contributing to covid-19 vaccine efforts.
In an unusual collaboration, gsk is providing a particularly promising
adjuvant to Sanofi’s protein subunit programme.

In theory, manufacture of covid-19 vaccines using conventional approaches
could be scaled up quickly by the four big companies, and by some of the
Chinese and Indian companies that make vaccines for markets in the global
south. But doing so might mean fewer regular vaccines get made because, as
Paul Stoffels, the managing director of Johnson & Johnson, confirms, “there
is no excess capacity.” Indeed, the World Health Organisation (who) reports
that there are already unrelated shortages of vaccines for yellow fever and
measles. The seasonal nature of flu vaccinations means that those
production facilities have spare capacity at some points in the year. But
Sanofi reckons that, at best, that would allow it to make 600m doses a year
of a covid-19 vaccine before cutting into flu-vaccine production. If the
new vaccine turned out to require a lot of antigen, that figure might fall
to 100m.

All together now
This means that governments, charities and other potential vaccine buyers
do not just need to find ways to assure the industry that they will pay for
what it produces. According to Bill Gates, they need to spend billions of
dollars building manufacturing plants for the half dozen or so leading
vaccine candidates before vaccine trials have reached conclusive results
about what vaccine or vaccines are best. Some of those billions “will be
wasted”, Mr Gates acknowledges, and billions matter a lot in global public
health. Stacked up against trillions of dollars of lost economic output,
though, overspending on vaccine-production capacity is penny-ante stuff.

Governments have yet to co-ordinate their response in this way. Some in
industry are going it alone. The Serum Institute of India, one of the
largest volume manufacturers of vaccines for the poor world, says it is
ready to step into the breach. It estimates that responding to covid-19
will require building a bulk manufacturing and filling plant costing some
€150m ($164m). Johnson & Johnson has committed $1bn to expanding
manufacturing on a “very, very large scale,” says Mr Stoffels. He adds it
will sell its vaccines on a “not for profit basis.” Mr Hudson has also
committed Sanofi to scaling up “with no profit motive”.

Despite such efforts, though, the ability to make vaccines will not be as
widely distributed as the populations in need of them, triggering fears of
Dr Hatchett’s prisoners’ dilemma. To try to ensure that an optimal
strategy is pursued instead, he and Seth Berkley of GAVI, a public-private
partnership which supports vaccination efforts worldwide, have been urging
the G20 to try and reach some kind of consensus on vaccine production and
then fund it. The G20 has in turn asked the who to outline a plan for the
equitable distribution of the goods needed to fight covid-19. This will be
part of a broader who initiative, the details of which have yet to be
announced, which will be led by a former head of GSK.

Dr Hatchett says that uncertainty over which vaccine will actually work
provides an incentive for co-operation: no one is sure to lose out;
everyone stands to benefit. “As we become more and more certain about which
vaccines are going to win, that advantage may go away and national interest
may begin to assert [itself],” he adds. The science of vaccination may well
offer humankind a viable exit from the straits that the covid-19 pandemic
has stuck it in. Politics could still see some people trampled underfoot in
the rush to get out.

Thiru Balasubramaniam
Geneva Representative
Knowledge Ecology International
41 22 791 6727
thiru at keionline.org

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