By Peter Loftus, Jared S. Hopkins and Bojan Pancevski
The strong early results for two leading Covid-19 vaccines have
implications that go far beyond the current pandemic: They suggest
the time has come for a gene-based technology that could provide
new treatments for cancer, heart disease and other infectious
diseases.
The unproven technology, named messenger RNA after the molecular
couriers that deliver genetic instructions, has long eluded
researchers. An mRNA vaccine has never been cleared by regulators.
It is now the basis for Covid-19 vaccines from Moderna Inc. and
Pfizer Inc. and its partner BioNTech SE.
Both have shown in recent days to be more than 90% effective at
preventing symptomatic Covid-19. That performance is in line with
some older vaccines even though the new shots were developed in a
fraction of the time.
"It's 21st-century science," said William Schaffner, professor
of preventive medicine at Vanderbilt University School of Medicine.
The positive data for mRNA-based Covid-19 vaccines bodes well for
the technology's potential to combat future outbreaks of infectious
diseases, he said.
Since the new coronavirus emerged as a world-wide threat, health
authorities have eyed vaccines as the antidote needed for the world
to begin returning to normal. They are crucial to ensure that
enough people are protected against the virus so it can't spread
easily, even to those who aren't immune. Nearly 50 candidates,
based on different technologies, are in clinical trials.
Vaccines normally take years to bring to market. With older
technologies, researchers spend time developing and growing a virus
or proteins from the virus, which generate an immune response when
injected. Measles, shingles and other older vaccines use an
inactive or weakened virus to coax the body to build up
protection.
The manufacturing process, often in eggs or large bioreactors,
is laborious and time intensive. Successful shots typically take
more than a decade to develop, according to a 2013 study published
in the journal PLOSOne.
Messenger RNA promises to cut that time by taking advantage of
the body's own molecular machinery, essentially teaching cells how
to make a protein similar to one found on the virus, which then
triggers the body's immune response.
Messenger RNA, one type of RNA found in cells, is a naturally
occurring substance. It is a kind of molecular worker bee, carrying
instructions encoded in DNA for cells to follow. Given its role,
scientists had long theorized it could be repurposed to turn cells
into miniature drug or vaccine factories.
With mRNA, vaccine development becomes an engineering issue,
rather than a scientific challenge. Companies can design mRNA
vaccines relatively quickly once they know the genetic sequence of
the pathogen. Researchers use the genetic sequence of a targeted
virus to program the mRNA that can fight it.
In the journal Nature Reviews Immunology last November, the
National Institute of Allergy and Infectious Diseases' Anthony
Fauci and John Mascola wrote, "MRNA has the potential to be a rapid
and flexible vaccine platform. Starting from gene sequence, mRNA
vaccines can be produced in a few weeks."
Fast development
Moderna, founded in 2010 to focus on mRNA, made more than enough
doses for about 45 people to start the first human study of its
Covid-19 vaccine within two months of learning the sequence for the
so-called spike protein found on the surface of the
coronavirus.
With a platform in place, Moderna could quickly design new drugs
or vaccines by inserting the relevant snippet of mRNA, said Moderna
Chief Executive Stephane Bancel. He calls mRNA "the software of
life."
Ugur Sahin, co-founder of Germany's BioNTech, was able to sketch
out a version of 10 possible mRNA vaccines on his home computer on
Jan. 25, days before the illness was first seen in Germany, after
reviewing the freshly-decoded genome of the new coronavirus virus.
One served as the basis for the current Covid vaccine.
He turned to Pfizer, which had first joined with BioNTech in
2018 to work on an mRNA-based flu vaccine that's still in
development. Mr. Sahin and his wife, Özlem Türeci, started BioNTech
in 2008, and have spent more than 25 years studying mRNA.
Pfizer was drawn to mRNA for how quickly any vaccines using the
technology could be manufactured, and for its potential for
generating stronger immune responses than traditional vaccine
platforms, said Kathrin Jansen, who leads Pfizer's vaccine
research.
Dr. Jansen said RNA appears to provide more stimulation of the
immune system than other vaccine technologies both by generating
antibodies and by inducing responses from T-cells, white blood
cells that recognize and eliminate infected cells.
"The mRNA platform is essentially fully synthetic. It's a
defined molecule that can be made very, very quickly, so you don't
need anything live -- no live virus, no live cell culture, no eggs,
no anything," Dr. Jansen said.
Messenger RNA is one of a number of new technologies drug
companies are using in what is emerging as a once-in-a-generation
test of human ingenuity.
Vaccines from AstraZeneca PLC and from Johnson & Johnson are
based on a technology that uses a common-cold virus to deliver
genetic instructions that teach the human immune system to mount a
defense. The common-cold viruses are modified so they don't cause
infections.
This type of vaccine technology forms part of J&J's Ebola
vaccine regimen that was cleared by European regulators this year.
The J&J and AstraZeneca vaccines are in large, late-stage
clinical trials that could yield results in the coming weeks or
months.
Merck & Co. is taking a more traditional approach by
pursuing vaccines with proven technologies that employ a weakened
virus that multiplies to generate an immune response. Merck said
its vaccines could produce more lasting protection against the
coronavirus than other technologies, but its research takes longer
to develop than mRNA versions.
Despite the positive early results for the Pfizer and Moderna
vaccines, a lot remains unknown, including how long any apparent
protection from Covid-19 lasts and how effective the vaccines are
in certain high-risk populations such as the elderly.
Both Moderna and Pfizer are waiting for more safety data on the
shots. The U.S. Food and Drug Administration wants to see if any
serious side effects arise during the two months after a vaccine
was given.
The mRNA vaccines have other limitations that aren't common
among widely used vaccines for other diseases.
The vaccines must be stored at subzero temperatures, which has
sent some health authorities and hospitals racing to find special
freezers. Pfizer created a special container to keep shots cold
during distribution and set up its own supply chain for
distribution.
The vaccines require two doses three to four weeks apart to
create the right immune response, so subjects will need to be
tracked to make sure they get both doses.
New understanding
Efforts to engineer mRNA to fight diseases began decades ago,
pushed by rapid advances in genetics.
Drew Weissman, an immunologist, and Katalin Karikó, a molecular
biologist, started working on mRNA more than 20 years ago in
laboratories at the University of Pennsylvania.
Dr. Weissman said he was intrigued not only by RNA's potential
to trigger the production of disease-fighting proteins but also its
potential safety.
"It didn't integrate into the genome. There was no chance you
could have an adverse genomic event," Dr. Weissman said. In
contrast, he said, a different type of gene-based therapy was found
in a study in France in the early 2000s to cause leukemia-type
illnesses in patients who had immune system disorders.
Dr. Karikó, who started working on mRNA in her native Hungary in
the late 1970s, said peers were skeptical of her work for more than
three decades.
At her first research institute in the city of Szeged, then
behind the Iron Curtain, she had to frequent local abattoirs to
extract biological material from bovine brains because her agency
lacked funding.
"The technology has not had a chance to prove itself until now
-- but now it is proving itself," Dr. Karikó said.
Dr. Weissman got mRNA material from Dr. Karikó, who had been
testing it in tumor cells. He tested the samples in certain immune
cells. "The results were off the wall," he said.
Problems emerged when the researchers began testing mRNA in
animals, where injecting it triggered immune responses that in turn
caused inflammation. In testing, high doses would kill mice.
Drs. Weissman and Karikó set out to overcome the inflammation
problem by making modifications to mRNA.
They found that making a change to a nucleoside -- a building
block of RNA -- could help RNA injected into the body sidestep the
immune reaction that would cause inflammation, while still allowing
the RNA to get into human cells to deliver instructions to start
producing the desired protein.
Drs. Weissman and Karikó patented their work, and Penn later
licensed the technology to both Moderna and BioNTech, including
through intermediary companies. In 2014, Dr. Karikó joined BioNTech
and serves as a senior vice president.
Moderna spent several years honing its technology. A hurdle was
finding the right shell that could carry mRNA toward their target
in human cells without getting destroyed by the body's naturally
occurring enzymes during the journey.
The company encloses its mRNA into a protective envelope made of
fatty substances called lipid nanoparticles. The company began
testing mRNA in humans in 2015.
Moderna also started collaborating several years ago with
researchers at the National Institutes of Health on making shots
against certain infectious diseases. That collaboration paved the
way for teams at both organizations to quickly begin collaborating
in January on a Covid-19 vaccine.
The mRNA vaccines' early success "gives us some encouragement
for the technology for other vaccine targets in the future," said
Dr. Mark Mulligan, director of the Vaccine Center at NYU Langone
Health.
Moderna is testing several preventive mRNA vaccines in human
studies, including one against cytomegalovirus, a common virus that
can cause health problems in babies whose mothers caught it during
pregnancy. The vaccine was generally safe and induced the desired
immune responses in early studies. Testing continues.
Moderna is also testing with Merck whether an mRNA-based
therapeutic vaccine can treat cancer. The treatment is custom-made
for each patient based on mutations found in their tumor cells. The
shot, when given with Merck's cancer drug Keytruda, showed promise
in some patients with head and neck cancer in a small, early-stage
study, Moderna said this month.
BioNTech continues advancing potential mRNA vaccines to treat
cancer, including tumors for breast, skin and the pancreas. The
company has several cancer shots in development, including one for
a type of skin cancer in mid-stage testing.
One of the advantages of mRNA vaccines, Dr. Sahin said, is that
they can be quickly adjusted so vaccines can better respond to an
eventual decline in immunity or virus mutations, which could render
other vaccines less effective.
Dr. Sahin said that regulator authorization could potentially
lead to a "whole new category of medicines."
Write to Peter Loftus at peter.loftus@wsj.com, Jared S. Hopkins
at jared.hopkins@wsj.com and Bojan Pancevski at
bojan.pancevski@wsj.com
(END) Dow Jones Newswires
November 17, 2020 14:03 ET (19:03 GMT)
Copyright (c) 2020 Dow Jones & Company, Inc.
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