SCIENCE science.org 8 APRIL 2022 • VOL 376 ISSUE 6589 121NEWST
he $1.5 trillion spending bill enacted
last month did more than fund U.S.
government operations for the next
6 months. It also revived congressio-
nal earmarking—the controversial
practice of allowing legislators, often
at the behest of powerful constituents, to
allocate money for specific projects in their
district or state that federal agencies did
not request.
Earmarks, such as a new bridge or re-
furbished airport, have traditionally given
lawmakers a reason to vote for legislation
they otherwise might not support, making
the wheels of Congress turn more easily.
But the U.S. higher education community
is deeply divided over the practice.
Many academic institutions have
sought—and won—earmarks, seeing them
as a quick and easy route to growing their
research capacity. At the same time, the
higher education organizations to which
they belong have long argued that scarce
federal dollars should be allocated based
on peer review rather than the whims of a
single powerful legislator.
A crescendo of costly projects of dubi-
ous merit led Congress to ban earmarking
in 2010. But the itch never went away. And
last year, the Democratic majority in both
chambers of Congress adopted new rules
that require earmark requests to be posted
online, limit eligibility to nonprofit organi-
zations and projects in which the legislator
has no personal or financial interest, and
cap the total spending on earmarks at 1%
of overall discretionary spending.
Lawmakers welcomed their return, in-
serting more than 4000 projects totaling
$9 billion into this year’s spending bill.
Research-related activities make up about
10% of both totals, according to an analy-
sis by AAAS (which publishes Science). Re-Congress
restores
earmarking—
but with limits
One legislator simulates peer
review to make her selection
process more rigorous
U.S. FUNDINGBy Jeffrey Merviscompany official told Reuters in January
that Walvax can produce 400 million doses
a year.
In Thailand, a team lead by Kiat
Ruxrungtham at Chulalongkorn University
has developed an mRNA vaccine, produced
by the French-Thai company BioNet-Asia,
that has completed phase 1/2 studies. The
team followed a key step in the playbook
used by the Pfizer-BioNTech collaboration
and Moderna: replacing uridine—one of
the four basic building blocks of RNA—
with methylpseudouridine, a substitution
that reduces the toxicity of mRNA and in-
creases the amount of spike protein cells
produce. The substitution is “the most im-
portant thing that people have done with
mRNA vaccines,” says Philip Krause, a for-
mer top vaccine official at the U.S. Food
and Drug Administration (FDA). BioNet-
Asia can use the replacement
for free because the company
that licensed the technol-
ogy from the University of
Pennsylvania, where it was
invented, has not sought pro-
tection in Southeast Asia.
The vaccine differs from
the marketed ones in other
ways, however. Kiat’s team
did not introduce two muta-
tions in spike that stabilize the protein,
which would have required an expensive
IP license. They avoided another licens-
ing issue by having the code direct cells
to secrete the spike protein, rather than
leaving it bound to the membrane. Some
comparative studies have found this leads
to a weaker immune response, but Kiat’s
mouse studies saw no difference, and hu-
man data show the vaccine triggers robust
levels of antibodies that can neutralize the
virus, he says.
BioNet-Asia can make up to 100 mil-
lion doses a year, Kiat says, at a lower
price than the Pfizer-BioNTech collabora-
tion and Moderna. Japan’s Daiichi Sankyo
and Canada’s Providence Therapeutics
have mRNA vaccines at similar stages
of development.
About half of the new candidates are
“self-amplifying”: They include harmless
genes from an alphavirus that code for an
enzyme used in RNA replication, enabling
the spike mRNA to make additional cop-
ies of itself. Each dose can get by with less
mRNA, which could make it easier to vac-
cinate more people. A downside is that
self-amplifying mRNA vaccines can’t use
the methylpseudouridine substitution—
they need the natural uridine to replicate.
A phase 1 study of a self-amplifying
vaccine developed at Imperial College
London triggered such mediocre immune
responses that the researchers went back
to the drawing board. But a similar can-
didate from GlaxoSmithKline solidly
protected hamsters against SARS-CoV-
infection, a January paper in Molecular
Therapy showed. That vaccine is now be-
ing tested in a 10-person phase 1 trial.
Showing that the new vaccines work in
humans presents formidable challenges.
“I’m in trouble because I can’t find the
population right now for the phase 3 trial,”
Kiat says. Not only is it becoming more dif-
ficult to find people who have no immunity
at all against SARS-CoV-2, but enrolling
participants in a placebo-controlled study
is increasingly ethically fraught, because
proven COVID-19 vaccines are now widely
available. Producers of self-amplifying vac-
cines in India and Vietnam instead plan to
compare the vaccines with others already
in use.
Kiat hopes to judge his
candidate based on a proxy
measure: how well it boosts
antibody levels in people who
are fully vaccinated. Past stud-
ies of the marketed mRNA
vaccines have shown that spe-
cific levels of neutralizing anti-
bodies are correlated with
protection from disease, and
BioNet-Asia and other manufacturers hope
regulators will accept similar data to au-
thorize use of their vaccines. The European
Medicines Agency and regulators from sev-
eral countries have indicated they will ac-
cept such “immunobridging” data in some
circumstances, Krause says. FDA has yet to
issue guidelines. “I know from talking to
people at FDA that they are reluctant” to
rely on antibody data, says Stanley Plotkin,
a veteran vaccine researcher who consults
with Moderna and many other companies.
One problem is that antibodies are only
part of the immune response triggered by
mRNA vaccines. T cells—which are more
difficult to measure—play a role in prevent-
ing severe disease by eliminating infected
cells. They also offer better protection
against new virus variants than antibodies
and help ensure the durability of immunity.
Still, Plotkin and others say, antibody levels
are good enough surrogates to issue emer-
gency use authorizations. For full approval,
they say, vaccines will have to prove effec-
tive in real-world studies.
“We know that there are a lot of hurdles
ahead,” Kiat says. But even if their COVID-
vaccine fails, his team is building capacity
for the future, he says. “We can now manu-
facture new mRNA vaccines very quickly, so
that’s a way to solve the next pandemic—
and we can make the price lower than the
Big Pharmas.” j“We can make
the price lower
than the
Big Pharmas.”
Kiat Ruxrungtham,
Chulalongkorn University