The
messenger RNA, or mRNA, platform may be new to the global public, but
it's a technology that researchers had been betting on for decades. Now
those bets are paying off, and not just by turning back a pandemic that
killed millions in just a year.
This
approach that led to remarkably safe and effective vaccines against a
new virus is also showing promise against old enemies such as HIV, and
infections that threaten babies and young children, such as respiratory
syncytial virus (RSV) and metapneumovirus. It's being tested as a
treatment for cancers, including melanoma and brain tumors. It might
offer a new way to treat autoimmune diseases. And it's also being
checked out as a possible alternative to gene therapy for intractable
conditions such as sickle cell disease.
The
story of mRNA vaccines dates back to the early 1990s, when
Hungarian-born researcher Katalin Kariko of the University of
Pennsylvania started testing mRNA technology as a form of gene therapy.
The idea is similar whether scientists want to use the mRNA molecule to cure disease or prevent it; send instructions to the cells of the body to make something specific.
Researchers
like to use a cookbook analogy. The body's DNA is the cookbook.
Messenger RNA is a copy of the recipe -- one that disappears quickly. In
the case of genetic disease, it can be used to instruct cells to make a
healthy copy of a protein. In the case of mRNA vaccines, it's used to
tell cells to make what looks like a piece of virus, so the body
produces antibodies and special immune system cells in response.
The recipe disappears while the cooked product -- the body's immune response -- lasts.
Kariko
was unable to drum up much interest in this idea for years. But for the
past 15 years or so, she's teamed up with Dr. Drew Weissman, an
infectious disease expert at Penn Medicine, to apply mRNA technology to
vaccines. Since scientists started focusing on the threat of a pandemic
caused by a new influenza or coronavirus, they've recognized the promise
of mRNA vaccines for quickly turning around a pandemic vaccine.
"If
you want to make a new influenza vaccine using the traditional methods,
you have to isolate the virus, learn how to grow it, learn how to
inactivate it, and purify it. That takes months. With RNA, you only need
the sequence," Weissman told CNN.
They did not even need a sample of the virus itself.
"When
the Chinese released the sequence of the SARS-CoV-2 virus, we started
the process of making RNA the next day. A couple weeks later, we were
injecting animals with the vaccine."
Although it sounded revolutionary, the idea was far from new to Weissman, Kariko and others.
"In
my lab, we have been working on vaccines for years. We have five Phase 1
clinical trials that we started before Covid hit," said Weissman, whose
work with Kariko helped lead to Pfizer/BioNTech's coronavirus vaccine.
"They been delayed because of the pandemic. The plan is to complete them next year."
Two
of these experimental vaccines target influenza, including one Weissman
hopes will be a so-called universal influenza vaccine -- one that will
protect against rapidly mutating strains of flu, and perhaps offer
people years of protection with a single shot, eliminating the need for
fresh immunizations each flu season.
They
are also working on two vaccines against the human immunodeficiency
virus, or HIV, that causes AIDS, and one to prevent genital herpes.
Researchers have also studied mRNA vaccines to fight Ebola, Zika, rabies and cytomegalovirus.
Another
possible target: respiratory syncytial virus. RSV infects most people
in babyhood, and it can put fragile infants into the neonatal intensive
care unit (NICU). It kills an estimated 100-500 children a year, the US
Centers for Disease Control and Prevention estimates -- but it kills an
estimated 14,000 adults, mostly over age 65.
"It
infects everyone by age 2," said Jason McLellan, a structural biologist
and Robert A. Welch Chair in Chemistry at The University of Texas at
Austin whose work underlies several coronavirus vaccines.
One
obstacle will be finding the best version of the viruses. McLellan
specializes in finding just the right conformation of the target viral
structures that will allow the human immune system to best recognize and
build defenses against them.
GlaxoSmithKline
and Pfizer are both working on that, he said. A different common cold
virus called human metapneumovirus, which can cause pneumonia in adults
and children alike, is another potential target for a vaccine, McLellan
said.
Again,
ongoing work helped speed development of coronavirus vaccines, McLellan
said. In this case, work on the original 2003-2004 severe acute
respiratory syndrome, or SARS, virus and Middle East respiratory, or
MERS, virus helped researchers understand which version of the knoblike
structure found on the outside of the virus, called the spike protein,
to use in making vaccines. "We figured out how to stabilize coronavirus
spikes back in 2016, so we had all the knowledge ready when Covid-19
emerged," McLellan said.
It was ready to go "within hours," he said.
Other
potential vaccines include malaria, tuberculosis and rare viruses such
as Nipah virus, Weissman said -- all made more possible by the mRNA
technology. Effective vaccines against these infections have eluded
scientists for various reasons.
Weissman's
lab is now working on a universal coronavirus vaccine that would
protect against Covid-19, SARS, MERS, coronavirus that cause the common
cold -- and future strains.
"We
started working on a pan-coronavirus vaccine last spring," Weissman
said. "There have been three coronavirus epidemics in the past 20 years.
There are going to be more."
And
the mRNA vaccines work very well. "We knew in mice and monkeys and
rabbits and pigs and chickens that it was very potent," Weissman said.
The Pfizer vaccine, he said, produces an antibody response that is five
time bigger than what's seen in people who have recovered from
infection.
Cancer
Another
obvious use for mRNA technology is to fight cancer. The human body
fights off cancer every day, and using mRNA could help it do so even
better.
"You can use it to have your body produce a beneficial molecule," McLellan said.
Different
tumor cell types have various, recognizable structures on the outside
that the immune system can recognize. "You can imagine being able to
inject someone with an mRNA that encodes an antibody that specifically
targets that receptor," McLellan said.
Moderna -- a company formed specially to develop mRNA technology -- is working on personalized cancer vaccines.
"We
identify mutations found on a patient's cancer cells," the company says
on its website. Computer algorithms predict the 20 most common
mutations. "We then create a vaccine that encodes for each of these
mutations and load them onto a single mRNA molecule,"
Moderna says. That's injected into the patient to try to help orchestrate a better immune response against the tumors.
This is early, Phase 1 clinical research.
BioNTech
founders Ugur Sahin and Ozlem Tureci also had cancer vaccines in mind
from the beginning. The company has eight potential cancer treatments in
human trials. "While we believe our approach is broadly applicable
across a number of therapeutic areas, our most advanced programs are
focused on oncology, where we have treated over 250 patients across 17
tumor types to date," the company
says on its website.
Autoimmune diseases
Using mRNA to fight autoimmune diseases is an "exciting area," McLellan said.
Current
treatments are crude and involve tamping down specific areas of the
mistaken immune response -- something that can leave patients with
autoimmune disease such as lupus or rheumatoid arthritis vulnerable to
infection.
BioNtech
has been working with academic researchers to use mRNA to treat mice
genetically engineered to develop a disease similar to multiple
sclerosis -- an autoimmune disease that starts when the immune system
mistakenly attacks the myelin, a fatty covering of the nerve cells.
In the mice, the treatment
appeared to help stop the attack, while keeping the rest of the immune system intact.
Gene therapy
The
idea behind gene therapy is to replace a defective gene with one that
works properly. Despite decades of work, researchers haven't had much
success, with the exception of certain immune deficiencies and some eye
diseases.
It's difficult to find a vector to carry the corrected gene into cells without causing side-effects, and in a way that lasts.
The
mRNA approach promises to send instructions for making the healthy
version of a protein, and Weissman sees special promise in treating
sickle cell disease, in particular.
In
sickle cell disease, red blood cells take on a folded shape and can
clog tiny blood vessels, causing pain and organ damage. Messenger RNA
could be used to change the instructions going to the bone marrow, where
red blood cells are made, telling them to make healthier shaped cells.
"Now
that we can target that cell, the hope is we can give people an
injection of RNA and it will target the bone marrow stem cells and fix
the disease," Weissman said.
"It's gene therapy without the half a million dollar price tag," he added. "It should be just an IV injection and that's it."
Tests in mice are showing promise -- the next step it to test the approach in monkeys, Weissman said.
In
2008, a company then called Shire Pharmaceuticals started to develop
mRNA treatments for cystic fibrosis -- a deadly genetic illness caused
by any one of a number of small mutations to a gene called CFTR.
That technology is now owned by Translate Bio, a company dedicated to making mRNA therapies and vaccines. It's
working to correct faulty CFTR in the lungs by delivering mRNA via a nebulizer. The treatment appears safe in early stage trials in people and has won
orphan drug status from the US Food and Drug Administration.
Tickborne diseases
The mRNA approach might also work against some tickborne diseases, Weissman said.
"The
idea there is if you are immune to tick saliva proteins, when the tick
bites you, the body produces inflammation and the tick falls off,"
Weissman said.
Lyme
disease is caused by the bacteria Borrelia burgdorferi, and the tick
generally has to stay attached 36 to 48 hours before it transmits the
bacteria to the host. If the tick falls off before that, it cannot
transmit the infection.
