64 Science & technology The Economist February 6th 2021
The former has the advantage of being well
established. Versions of it go back to vac-
cine-making’s origins. But keeping cultur-
ed animal cells alive and healthy is a tricky
business. A whole subfield of bioengineer-
ing is dedicated to this task. Vaccine-mak-
ers who rely on live cultures constantly
struggle with yields. Using this method to
make a lot of vaccine, fast, is hard.
It was difficulties of this sort that Pascal
Soriot, boss of AstraZeneca, cited on Janu-
ary 26th in defence of his firm’s failure to
provide vaccine supplies which the Eu-
ropean Union claimed it had been prom-
ised. AstraZeneca is an Anglo-Swedish
company that, in collaboration with Ox-
ford University, created one of the first vac-
cines to be approved. As Mr Soriot toldLa
Repubblica, an Italian newspaper, “You
have glitches, you have scale-up problems.
The best site we have produces three times
more vaccine out of a batch than the low-
est-producing site.”De-necking the bottles
Maximising a bioreactor’s yield is as much
an art as a science. The underlying health
of the cells involved matters. So do envi-
ronmental conditions at the manufactur-
ing site. That AstraZeneca has not been
able to meet its own production targets
shows how hard it is to predict when the
right balance of biology will be found. The
company says it can take six to nine
months to start a production site up from
scratch, and that even this timetable is
possible only by working with experienced
partners and at an accelerated pace. At the
moment, AstraZeneca is working with 25
manufacturing organisations in 15 coun-
tries to make its vaccine.
Producing mrnavaccines at scale has
problems, too. The biggest is how to pro-
tect the mrnamolecules both from the en-
vironment they must travel through in or-
der to reach the arm of their recipient, and
from the recipient’s own body, which will
attack them as they journey to the ribo-
somes which will transcribe them.
Protection from the environment is
mainly a matter of having a strategically lo-
cated set of refrigerators, known as a cold
chain. Protection from the body, though, is
where the fatty bubbles come in.
Production of these bubbles was a cot-
tage industry before the pandemic. A small
Austrian firm, Polymun Scientific, is one
of just a handful that can make them. Their
main previous use was in niche cancer
treatments. Scaling up their production,
which is happening right now, has never
been done before and adds uncertainty to
the continued supply of mrnavaccine.
There are other bottlenecks, too. In par-
ticular, the factories in which vaccines are
made must be built to a high standard,
known as gmp, for “Good Manufacturing
Practice”. There is currently a shortage ofgmp facilities. Andrey Zarur, boss of
GreenLight Biosciences, a firm in Boston
that is developing an mrna vaccine, says
his company has employees whose entire
job, at present, is to work the phones trying
to find gmpfacilities in which to make
their vaccine. There is, though, nothing
available. He is therefore looking to buy
firms whose vaccine candidates have turn-
ed out not to work, simply in order to ac-
quire the facilities in question.
Supplies of raw materials such as nu-
cleotides are also tight. According to Dr Za-
rur, Thermo Fisher, an American chem-
ical-supplies company, has spent $200m
on a new facility in Lithuania to make
these molecules, though the firm itself
would not confirm this.
On top of all this, the transport and dis-
tribution of vaccines once they have been
made presents yet further challenges, and
concomitant potential for hold ups. Vac-
cines must be stored in special non-reac-
tive glass vials. Some, such as the current
version of Pfizer’s mrnavaccine, must al-
so be kept at extremely low temperatures,
though that problem may go away soon.
Drew Weissman, one of the inventors of
mrna-vaccine technology, says producers
are now testing shots which are stable for
three months when kept at 4°C.
Once supply chains for both cell-cul-
ture and mrnavaccines have been scaled
up, and bottlenecks unblocked, the manu-
facturing processes may face a different
test—how quickly they can produce new
vaccines to deal with new viral variants as
these emerge. The continued efficacy of
approved vaccines against such variants is
not guaranteed, and it may be necessary to
make others (see following story).
Here, the mrnaapproach may have an
advantage. Its production systems will re-
quire a simple tweak—the dropping in at
the start of a dnatemplate describing the
new variant’s spike protein. Cell-culture
systems, by contrast, will have to be rebuilt
to some degree for every new variant they
aim to vaccinate against.Scale models
Producers, such as those in China, who use
older-fashioned cell-culture techniques,
will have to recalibrate their entire oper-
ations. Newer systems, like AstraZeneca’s,
which use cells specially designed so as
not to be influenced by the new version of
the spike gene in the viruses they are carry-
ing, should be able to get on track in the
time it takes to start a culture from
scratch—about a month. For mrnasys-
tems, Drs Weissman and Zarur say it would
take a couple of months to go from new
variant to large-scale vaccine production.
If variants resistant to the current crop of
vaccines do evolve, then that speed and
certainty in making new vaccines to com-
bat them will be essential. Viral variants and vaccinationEnigma variations
V
iruses evolvethrough natural selec-
tion. Whenever they replicate, changes
can creep into their genetic material. If ad-
vantageous, these will cause variants
sporting them to prosper. One conse-
quence is that such variants spread rapidly.
Predictably, then, new variants of sars-
cov-2, the virus that causes covid-19, have
started to appear around the world. Four
are particularly worrying. One, detected
first in Britain, in September, is believed to
be 30-50% more transmissible than the
original wild-type virus. A second, identi-
fied in South Africa a month later, has been
linked to higher viral loads in throat and
nasal swabs. That makes it easier for it to
spread. Two others emerged in America
(July) and Brazil (December). And this week
a variant of the British variant has also
been detected, now sporting a mutation al-
so found in the South African variant.
There is no strong evidence to suggest that
any of these new variants is more deadly
than the wild type, but researchers are wor-
ried about the risk of one or more of them
evading existing vaccines.
The particular causes of this concern
are mutations in the gene that encodes a
protein called spike, which is found on the
surfaces of sars-cov-2 virus particles. This
protein is the means by which the virus
gains entry to cells. b.1.1.7, the viral variant
first found in Britain, has more than 20
mutations, not all of them in the gene for
spike. But one which is helps lock spike on-
to its target on the cell surface, a receptorWill variants of sars-cov-2 make
vaccination harder?