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Science & technology Aug 7th 2021 edition

Combating future viruses

Predicting viral evolution may let vaccines

be prepared in advance
New techniques could programme people’s immune systems against future pathogens

Aug 5th 2021

G enerally, immune systems mount responses only against pathogens that

have already infected the bodies they are protecting. Science, though, can
shorten the path to immunity by vaccination. This involves presenting the
immune system with harmless or lookalike versions of dangerous pathogens so
that it may create antibodies and killer cells hostile to the real thing in advance
of any actual infection, thereby reducing its danger.
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Like immune responses themselves, however, vaccination generally has to wait

for the appearance of the pathogen in question before it can do its stuff. There is
therefore a delay between a pathogen’s arrival on the scene and the deployment
of a vaccine against it. That delay costs lives. Even in the case of covid-19, which
has prompted the fastest vaccine-development programme the world has ever
witnessed, millions are reckoned to have died by the time vaccinations began to
be given in the rich world at the end of 2020.

But, just as vaccination introduces immune systems to pathogens that are

remote from them in space, new techniques which have come to the fore during
the current pandemic offer the possibility of introducing them to pathogens
that are remote from them in time—pathogens, indeed, that have not yet
evolved, but which are likely to do so in the future. Thanks to a combination of
high-throughput dna-sequencing technologies and modern machine-learning
it is now possible not merely to observe which variants of a virus are circulating,
but also to suggest how they are likely to change. Understanding in this way
what a virus might look like in the months and years to come gives those
designing vaccines and therapies a leg up, enabling them to prime more
immune systems sooner, so that fewer people die.

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The starting point for these predictions is the sort of work going on in the
laboratory of Jesse Bloom a virologist at the Fred Hutchinson Cancer Research
laboratory of Jesse Bloom, a virologist at the Fred Hutchinson Cancer Research
Centre, in Seattle. Dr Bloom and his colleagues grow variants of coronavirus
spike protein (the molecule which such viruses use to attach themselves to cells
they are about to infect) in Petri dishes. They then scan through these to discern
which mutations have what effects.

They have named this technique deep mutational scanning. It uses an array of
yeast cells that have been genetically modified to express a part of the spike
protein called the receptor-binding domain (rbd). As the yeast cells churn out
their rbds, many emerge, thanks to errors inherent in their production, with
slight deviations in their structures from that of the original wild-type virus. Dr
Bloom’s team then test the rbds from each yeast cell to see how tightly they
bind to ace2, a receptor protein found on the surfaces of some human cells, to
which the coronavirus attaches itself before entering those cells. rbds that bind
tightly have their underlying genomes sequenced, to determine which
mutations are present.

When Dr Bloom’s team ran this scan in the summer of 2020, on spike from a
version of the virus then circulating, they spotted a mutation called n501y
which appeared to confer a binding advantage. A few months later, that
mutation appeared in the Alpha variant, which for several months was
dominant across much of the world. Dr Bloom says it would be “charitable” to
say that he and his colleagues had predicted the emergence of n501y. It was by
no means the only mutation of interest to turn up. But even so, having a limited
set of such mutations to focus on is useful for narrowing the field of research.

Getting the message across

One firm taking advantage of that narrowing is Flagship Labs 77, a company
based in Boston that has until recently been working in secret. fl77, as it is
known for short, is a spin out from Flagship Pioneering, a biotechnology
incubator run by Noubar Afeyan, a venture capitalist. Moderna, a trailblazer of
the messenger- rna-based technology that helped speed up the production of
coronavirus vaccines, was also a Flagship Pioneering company, and Mr Afeyan is
its chairman.

fl77’s researchers are trying to combine experimental data of the sort Dr Bloom
is collecting with computation, in order to predict how viruses may evolve. That
information could be used to develop vaccines and therapeutic antibodies pre-
emptively. Whereas Dr Bloom’s laboratory predicts only single mutational hops,
fl77 can currently manage five or six. The firm calls its system “Global Pathogen
 y g y g
Shield”. The details remain confidential, but in June it published a paper
outlining the project’s goals. This described the scale of the challenge involved
in keeping pace with viral evolution—namely that biology is so diverse that

even looking at a small slice of possible mutations leads to a problem which

rapidly grows beyond the plausible limits of observation, to one on the scale of
counting and categorising all of the atoms of which Earth is composed.

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The conventional response to such overwhelming odds has been observation

rather than experimentation. The World Health Organisation’s Global Influenza
Surveillance and Response System does this for flu. It monitors which viruses
are circulating in the southern hemisphere when it is winter there, in order to
focus attention on which strains will be relevant during the next northern-
hemisphere winter, and vice versa. During the coronavirus pandemic,
organisations such as Nextstrain and gisaid have kept track of variants of sars-
cov-2 in a similar way.

fl77 aims to take this much further—not only tracking which variants of a virus
are where, but also predicting how they will evolve. It does this by feeding into a
piece of software called Octavia data from a scaled-up version of Dr Bloom’s
deep mutational scanning that runs assays on between 1m and 10m variants.

Octavia’s job is to recognise patterns in the Petri-dish data—for example, which

of the millions of mutations tend to lead to tighter binding, and also which lead
to poorer neutralisation by antibodies—and then to extrapolate those across all
possible variants of spike. This leads to predictions about which mutations will
defeat antibodies, and which will spread more easily. That, says the paper,
“makes it possible to define a protective antibody repertoire”, whether through
vaccination or manufacturing of antibody proteins themselves. fl77 calls this
an “antibody net”.

Dr Bloom, who is advising fl77, and who holds patents on deep mutational
scanning, says the value of these kinds of predictions has become clear with the
development of messenger-rna vaccines. These are not just quick to make, but
quick to update. Their manufacturing process starts with the gene for the viral

protein that the immune system is desired to attack, and ends with a strand of
rna which encodes that specific protein.

In covid-19 vaccines, the protein in question is spike. Updating vaccines to take

account of predicted variants of spike is merely a matter of inserting the
relevant genetic code at the start of the manufacturing process. At the least, such
predictions would permit a library of candidate vaccines to be held ready, in
anticipation of rapid manufacturing. At its most ambitious, fl77 imagines
vaccinating people against variants of a pathogen that are not yet circulating,
but are likely to.

Deep mutational scanning may have other uses, too. Gabriel Victora, an
immunologist at Rockefeller University in New York, thinks predicting the
evolution of a pathogen in this way will be useful not just for designing
antibodies and vaccines, but also for detecting parts of the virus which change
only rarely, and aiming antibodies at what would thus be reliable targets.

This, though, is difficult. The shape of any given segment of a protein depends
on the rest of the molecule of which it is a part. Yet, for the immune system, the
shape of its target is a crucial feature that it needs to learn in order to recognise
its foe. So, though predictive approaches like fl77’s might spot segments of viral
proteins which are unlikely to change, getting the immune system to look at
them specifically is difficult, because expressing an isolated protein segment in
a way that makes it the same shape as it is when it is part of a bigger structure is
tricky.

A more brute-force approach is simply to show the immune system all of the
protein structures that are likely to emerge in future, so that it makes antibodies
against the lot. Dr Victora says that immune systems have no known limit to
their capacity to absorb information about pathogens. Instead, the problem with
this approach may come if the system preferentially makes antibodies to some
of the predicted variant proteins, but not others.

Strain gauge
 g g
Seasonal flu vaccines already grapple with this problem when updating immune
systems with information about the strain predicted to be circulating in the
coming winter. Even after vaccination, immune systems may tend to make

antibodies against the old virus instead. It is not clear whether the same thing
will happen with updated messenger-rna vaccines.

No programme will ever be able to predict the evolution of the entire array of
pathogens which can plausibly infect human beings. But for those already
known to pose a threat, systems like Octavia may be able to see far enough into
the future to offer benefits. “We don’t have to be able to predict arbitrarily,” says
Dr Bloom. “We don’t need to predict mutation in a decade. Just a radius of five to
six mutations from where we are now. That’s good enough.”

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fl77 is already doing this. The most radical version of the firm’s vision—
vaccinating against variants and strains of pathogens that are yet to emerge—is
some way off, if it ever happens. Protecting people by programming their
immune systems against future pathogens, not just those already circulating,
would be a fundamental shift in the meaning, purpose and ethics of
vaccination. But even in the absence of that, pathogen prediction should soon
serve to speed existing sorts of vaccination programmes. And every increase in
the speed of vaccine development means thousands of saved lives. 7

Dig deeper

All our stories relating to the pandemic and the vaccines can be found on our
coronavirus hub. You can also find trackers showing the global roll-out of vaccines,
excess deaths by country and the virus’s spread across Europe and America.

An early version of this article was published online on August 4th 2021
This article appeared in the Science & technology section of the print edition under the headline "Predict and
survive"

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