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The most advanced clinical studies involve an
mRNA-based vaccine candidate for rabies being
developed by CureVac, a biotech based in Tübingen, Germany. But there are many other companies, big and small, also actively pursuing
mRNA-based therapies or vaccines. Another
German company, Mainz-based BioNTech, is
involved in mRNA platform research. Karikó is
now a vice president at BioNTech, leading the
company’s mRNA-based protein replacement
program. BioNTech recently engaged Weissman’s lab to run a preclinical research program
for mRNA vaccine candidates against infectious
diseases. There are also a handful of others now
in the field: Tiba, Translate Bio, eTheRNA, and
Moderna Therapeutics.
Moderna is running Phase I safety trials of
mRNA-based vaccine candidates against cytomegalovirus, chikungunya virus, Zika, and
metapneumovirus. Influenza virus is also drawing interest: the most recent flu season killed
80,000 people in the U.S. alone, the highest
death toll in more than 10 years, and researchers
are in pursuit of new formulations for a more
universal flu vaccine (see A Mean Flu Season
Swings a Spotlight on Vaccines, IAVI Report,
Vol 22, No. 1, 2018). “I’m very optimistic for flu
vaccine. I think it’s doable,” Pardi says. Weissman and Pardi are testing a nucleoside-modified
mRNA vaccine candidate targeting the hemagglutinin stalk of influenza, a less variable target
on the virus. So far they’ve been able to induce
immune responses in mice, rabbits, and ferrets
(Nat. Comms. 9, 3361, 2018). CureVac and
Moderna are both pursuing mRNA-based flu
candidates, as is BioNTech.
Larger pharmaceutical companies are also
becoming involved in mRNA research, mostly
through deals with biotechs. Earlier this year,
BioNTech announced a licensing and equity deal
potentially worth up to $425 million with Pfizer
to partner on the company’s flu vaccine development efforts. Eli Lilly is collaborating with CureVac on its cancer vaccine candidates targeting
tumor neoantigens, which are fragments of protein found on cancer cells. The Bill & Melinda
Gates Foundation is investing $52 million into
CureVac to support construction of a vaccine
manufacturing facility and will separately fund
the firm’s development efforts for vaccines
against infectious diseases.
This enthusiasm, as well as the money and brainpower being invested in this approach stem from
mRNA’s attractive qualities. “Since RNA is
injected into the host and the host makes the protein, you can be more certain that these proteins
will be functional and properly folded,” Pardi
says. “That is a really important thing.”
Another quality that makes mRNA advantageous
is its persistence. Weissman and Pardi worked on
a Zika mRNA candidate, giving a single dose in
an experiment with macaque monkeys, and found
that the neutralizing antibody levels induced by
the candidate remained steady after a year. Other
candidates required two or three shots to gain the
same level of neutralizing antibodies required to
protect against Zika virus, Weissman says. The
team first gave mice single-dose intradermal injections of an mRNA-based vaccine candidate
encapsulated in lipid nanoparticles. The mRNA
carried the code for pre-membrane and envelope
glycoproteins from a Zika strain isolated in the
2013 outbreak. The vaccine elicited Zika-specific
CD4+
T-helper cells and neutralizing antibody
responses. The team followed this experiment in
mice with a monkey study using the same candidate (Nature 543, 248, 2017).