Leading universal vaccine strategies
HA is likely a major target for universal flu vaccines, explained
Fauci. Influenza has two surface glycoproteins: HA, which
helps the virus enter host cells, and neuraminidase, which
helps the virus spread among cells. HA is commonly likened
to a mushroom, as it has a round head and a stalk.
“When you look at the structural biology of the hemagglu-
tinin, in the head region it is a highly mutational tending area,”
said Fauci. “This is a major target for protection, which is good
news, but the bad news is that it is highly specific for each strain,
because it mutates readily. Whereas the stem region does not do
that much at all. In other words, this is the part of hemagglutinin
that does not change much at all from season to season. So the
obvious approach is why not direct the immune response to that
part of the virus that doesn’t change from season to season from
strain to strain, and perhaps even from pandemic to pandemic?”
A number of research organizations are investigating this
approach. At the Icahn School of Medicine at Mount Sinai,
flu microbiologist, Peter Palese, PhD, is working to create
“chimeric” viruses where the HA head comes from bird flu
and the stem from common human flu viruses.
To create a chimeric vaccine, the HA head is removed from the
stalk of a currently circulating virus and swapped for the head of
a virus that doesn’t typically infect humans. Unfamiliar heads are
used because the body won’t have existing antibodies the vaccine
can build upon, which decreases the immunodominance of the
head region. Researchers hope this will force a stronger immune
response against the stalk region, while the head region is relatively
ignored and that it will prompt an immune response against the
portion of the virus that is similar across strains and across seasons—doing away with the need for annual vaccination.
The Chimeric HA approach is currently being tested in
a phase I trial in partnership with pharmaceutical company
GlaxoSmithKline, as well as NIAD.
NIAID is also studying various strategies to create a vaccine
that elicits antibodies targeting the HA stem. NIAID scientists designed an experimental vaccine featuring the protein
ferritin, which can self-assemble into microscopic nanoparticles. The vaccine showed promise in animal testing and is
being evaluated for future trials in humans.
NIAID scientists also developed a vaccine incorporating
four subtypes of the H protein into one vaccine. The vaccine
is made from non-infectious virus-like particles that stimulate
an immune response but cannot replicate or cause disease. Results have been promising in animal studies and may advance
to human trials.
Phase 1/2 studies of a universal flu vaccine strategies have
also been initiated by NIAID, including an investigational
DNA-based vaccine called a DNA prime, followed by a
licensed seasonal influenza vaccine boost to improve the potency and durability of seasonal influenza vaccines.
There is also one potential universal vaccine that is further
down the pipeline. In 2018, BiondVax Pharmaceuticals,
based in Israel, launched a pivotal clinical efficacy phase III
trial of the M-001 universal flu vaccine candidate, designed
to provide multi-season and multi-strain protection against
all human influenza virus strains, both seasonal and pandemic. The vaccine contains antigenic peptide sequences shared
among many different influenza strains.
“You get nine overlapping peptides that are in an area that
is invariant in the virus,” explained Fauci. “If you put them to-
gether and vaccinate, we are starting to see a good deal of, if not
universal, certainly a broader approach.”
In six completed clinical trials in Israel and Europe, M-001
has been shown to be safe, well-tolerated, and immunogenic to
a broad range of influenza strains. An additional Phase II trial
in the U.S., sponsored and conducted by NIAID, is ongoing.
Fauci is excited for what is to come.
“We’ve been talking about universal flu vaccines for several
years now and we finally have multiple candidates in various
clinical trials, including one in a phase III trial,” he said.
Nabel agrees that the future is promising, especially considering how far the field has come in recent years.
“Ten years ago, we would have no understanding of what determinants were being recognized on the virus, where the points
of vulnerability would go, what the proofs of concept would be to
move it forward and to even have a shot of thinking of universal
from a structural point of view,” said Nabel. “I do however think
we have to operate with a sense of urgency; we don’t know when
that next major outbreak will come, so the faster we can work, the
more we can be informed, particularly about the human immune
response and the potential for protection in humans, the quicker
we will get to our goal.”
Image showing different features of an influenza virus,
including the surface proteins hemagglutinin (HA) and
neuraminidase (NA). Credit CDC