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NASAL VACCINES FOR COVID AND FLU ARE COMING—NO NEEDLE NEEDED  
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Stephani Sutherland
October 15, 2024
Scientific American
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_ Gentle nasal spray vaccines against COVID, the flu and RSV are
coming. They may work better than shots in the arm _

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Alyson Velasquez hates needles. She never liked getting shots as a
kid, and her anxiety only grew as she got older. “It really
ballooned in my teens and early 20s,” she says. “It became a
full-blown phobia.” She would panic at the sight of a needle being
brought into an exam room; more than once she passed out. Velasquez
says that she took an antianxiety medication before one appointment
yet still ran around the room screaming inconsolably “like I was a
small child; I was 22.” After that episode Velasquez, now a
34-year-old financial planner in southern California, quit needles
completely. “No vaccinations, no bloodwork. For all of my 20s it was
a no-go for me,” she says.

Then COVID showed up. “It finally hit a point where it wasn’t just
about me,” Velasquez says. “It felt so selfish not to do this for
the greater public health and the safety of our global community.”
So she got vaccinated against the SARS-CoV-2 virus in 2021, although
she had to sit on her husband’s lap while he held her arms. “It
was a spectacle. The poor guy at CVS ... he did ask me, ‘Are you
sure you want to do this?’” She very much did. “I’m very
pro-vaccine. I am a rational human. I understand the necessity of
[getting] them,” she insists. But today she still struggles with
each injection.

Those struggles would end, however, if all her future vaccinations
could be delivered by a nasal spray. “Oh, my God, amazing!”
Velasquez says.

The amazing appears to be well on its way. Vaccines delivered through
the nose are now being tested for several diseases. In the U.S., early
clinical trials are showing success. Two of these vaccines have
generated multiple immune system responses against the COVID-causing
virus in people who received them through a puff up the nose; earlier
this year their makers received nearly $20 million from Project
NextGen, the Biden-Harris administration’s COVID medical initiative.
Researchers are optimistic that a nasal spray delivering a COVID
vaccine could be ready for the U.S. as soon as 2027. Although recent
efforts have focused on inoculations against SARS-CoV-2, nasal
vaccines could also protect us against the flu, respiratory syncytial
virus (RSV), and more.

A few nasal vaccines have been introduced in the past, but they’ve
been beset by problems. The flu inoculation FluMist has not gained
popularity because of debates about its effectiveness, and a different
vaccine was pulled from the market decades ago because some people had
serious side effects. In China and India, nasal vaccines for COVID
have been approved because those countries prioritized their
development during the pandemic, whereas the U.S. and other wealthy
nations opted to stick with arm injections. But this new crop of
vaccines takes advantage of technology that produces stronger immune
responses and is safer than preparations used in the past.

In fact, immunologists say these spritzes up the nose—or inhaled
puffs through the mouth—can provide faster, stronger protection
against respiratory viruses than a shot in the arm. That is because
the new vaccines activate a branch of the immune system that has
evolved for robust, rapid responses against airborne germs. “It may
be more likely to really prevent infection from getting
established,” says Fiona Smaill, an infectious disease researcher at
McMaster University in Ontario. Such inoculations may also help reduce
the enormous inequities in vaccine access revealed by the pandemic.
These formulations should be cheaper and easier to transport to poor
regions than current shots.

 

But nasal vaccines still face technical hurdles, such as how best to
deliver them into the body. And unlike injected vaccines, which
scientists can measure immune responses to with blood tests alone,
testing for immunity that starts in nose cells is more challenging.
But researchers working in this field agree that despite the hurdles,
nasal formulations are the next step in vaccine evolution.

Traditional vaccines injected through the skin and into an arm muscle
provide excellent protection against viruses. They coax immune cells
into making widely circulated antibodies—special proteins that
recognize specific structural features on viruses or other invading
pathogens, glom on to them and mark them for destruction. Other immune
cells retain a “memory” of that pathogen for future encounters.

Intramuscular injection vaccines are good at preventing a disease from
spreading, but they do not stop the initial infection. A nasal spray
does a much better job. That’s because sprays are aimed directly at
the spot where many viruses first enter the body: the nose and the
tissue that lines it, called the mucosa.

Mucosa makes up much of our bodies’ internal surfaces, stretching
from the nose, mouth and throat down the respiratory tract to the
lungs, through the gastrointestinal tract to the anus, and into the
urogenital tract. Mucosa is where our bodies encounter the vast
majority of pathogenic threats, Smaill says, be it flu, COVID, or
bacterial infections that attack the gut. This tough, triple-layered
tissue is specialized to fight off invaders with its thick coating of
secretory goo—mucus—and with a cadre of resident immune cells
waiting to attack. “Mucosa is really the first line of defense
against any infection we’re exposed to,” Smaill says.

“We’re expecting to see fewer breakthrough infections in people
who got the vaccine up the nose.” 
—Michael Egan_ Castlevax_

Mucosal immunity not only prepares the immune system for the fight
where it occurs but also offers three different types of
protection—at least one more than a shot does. Nasal vaccines and
shots both mobilize immune messenger cells, which gather the
interlopers’ proteins and display them on their surfaces. These
cells head to the lymph nodes, where they show off their captured
prize to B and T cells, which are members of another part of the
immune system called the adaptive arm. B cells, in turn, produce
antibodies, molecules that home in on the foreign proteins and flag
their owners—the invading microbes—for destruction. Killer T cells
directly attack infected cells, eliminating them and the microbes
inside. This provides broad protection, but it takes time, during
which the virus continues to replicate and spread.

That’s why a second type of protection, offered only by the mucosal
tissue, is so important. The mucosa holds cells of the innate immune
system, which are the body’s “first responders.” Some of these
cells, called macrophages, recognize invasive microbes as foreign and
swallow them up. They also trigger inflammation—an alarm sounded to
recruit more immune cells.

Another part of this localized response is called tissue-resident
immunity. These cells don’t have to detect telltale signs of a
pathogen and make a long journey to the infected tissue. They are more
like a Special Forces unit dropped behind enemy lines where a skirmish
is occurring rather than waiting for the proverbial cavalry to arrive.
This localized reaction can be quite potent. Its activation is
notoriously difficult to demonstrate, however, so historically it’s
been hard for vaccine makers to show they’ve hit the mark. But it
turns out that one type of antibody, called IgA, is a good indicator
of mucosal immunity because IgAs tend to predominate in the mucosa
rather than other parts of the body. In an early trial of CoviLiv, a
nasal COVID vaccine produced by Codagenix, about half of participants
had detectable IgA responses within several weeks after receiving two
doses. That trial also showed the vaccine was safe and led to NextGen
funding for a larger trial of the vaccine’s efficacy.

It’s possible an inhaled vaccine may provide yet one more layer of
protection, called trained innate immunity. This reaction is a bit of
a mystery: although immunologists know it exists and appears also to
be produced by intramuscular injections, they can’t quite explain
how it works. Immune cells associated with trained innate immunity
seem to have memorylike responses, reacting quickly against subsequent
infections. They also have been found to respond against pathogens
entirely unrelated to the intended vaccine target. Smaill and her
colleagues found that when they immunized mice with an inhaled
tuberculosis vaccine and then challenged them with pneumococcal
bacteria, the mice were protected. In children, there is some evidence
that a tuberculosis vaccine, in the arm, generates this type of broad
response against other diseases.

Akiko Iwasaki, an immunologist at Yale University who is working to
develop a nasal vaccination for COVID, sees two major potential
benefits to nasal immunity in addition to better, faster, more
localized protection. First, attacking the virus in the nose could
prevent the disease from being transmitted to others by reducing the
amount of virus that people breathe out. And second, Iwasaki says, the
spray may limit how deeply the infection moves into the body, so “we
believe that it will also prevent long COVID.” That debilitating
postinfection condition, sometimes marked by signs of entrenched viral
particles, disables people with extreme fatigue, chronic pain, a
variety of cognitive difficulties, and other symptoms.

Making a new vaccine is hard, regardless of how you administer it. It
needs to raise an immune response that’s strong enough to protect
against future invasions but not so strong that the components of that
response—such as inflammation and fever—harm the host.

The lining of the nose puts up its own barriers—literal, physical
ones. Because the nasal mucosa is exposed to so many irritants from
the air, ranging from pet hair to pollen, the nose has multiple lines
of defense against invading pathogens. Nostril hair, mucus, and
features called cilia that sweep the nasal surface all aim to trap
small foreign objects before they can get deeper into the body—and
that includes tiny droplets of vaccine.

And lots of small foreign particles—often harmless—still make it
through those defenses. So the nose has developed a way to become less
reactive to harmless objects. This dampened reactivity is called
immunological tolerance, and it may be the biggest hurdle to
successful development of a nasal vaccine. When foreign particles show
up in the bloodstream, a space that is ostensibly sterile, immune
cells immediately recognize them as invaders. But mucosal surfaces are
constantly bombarded by both pathogens and harmless materials. The
immune system uses tolerance—a complex series of decisions carried
out by specialized cells—to determine whether a substance is
harmful. “This is very important because we can’t have our lungs
or gastrointestinal tract always responding to nonharmful foreign
entities that they encounter,” says Yale infectious disease
researcher Benjamin Goldman-Israelow. For example, inflammation in the
lungs would make it hard to breathe; in the gut, it would prevent the
absorption of water and nutrients.

[Graphic compares needle-delivered intramuscular vaccination to nasal
vaccination. Both trigger an adaptive immunity response. Nasal
vaccines also trigger a resident immunity response.]

These barriers may hamper the effectiveness of a nasal flu vaccine
that’s been around for a while, called FluMist in the U.S. and
Fluenz in Europe. The inoculation is safe, says infectious disease
scientist Michael Diamond of Washington University in St. Louis, but
it faces a similar problem as do injected flu vaccines: it isn’t
very effective at warding off new seasonal flu strains. This might be
because flu strains are so common, and people are frequently infected
by the time they are adults. Their immune systems are already primed
to recognize and destroy familiar flu particles. FluMist is built from
a live flu virus, so immune cells probably treat the vaccine as an
invader and demolish it as soon as it shows up in the nose, before it
has a chance to do any good. This preexisting immunity isn’t such an
issue in children, who are less likely to have had multiple flu
infections. Nasal flu vaccines are routinely used to inoculate kids in
Europe.

In other vaccines, researchers often use adjuvants, special agents
that attract the attention of immune cells, to boost a response. Some
nasal vaccines use adjuvants to overcome tolerance, but in the nose,
adjuvants can pose unique dangers. In at least one case, a nasal
adjuvant led to disastrous consequences. An intranasal vaccine for
influenza, licensed in Switzerland for the 2000–2001 season, used a
toxin isolated from _Escherichia coli _bacteria as an adjuvant to
provoke a reaction to the inactivated virus. No serious side effects
were reported during the trial period, but once the vaccine was
released, Swiss officials saw a concerning uptick in cases of Bell’s
palsy, a disease that causes weakness or paralysis of the facial
muscles, often leading to a drooping or disfigured face. Researchers
at the University of Zurich estimated that the adjuvanted flu vaccine
had increased the risk of contracting Bell’s palsy by about 20
times, and the vaccine was discontinued. “We need to be cautious
about using adjuvants like that from known pathogens,” says
pharmaceutical formulations scientist Vicky Kett of Queen’s
University Belfast in Northern Ireland.

To get around the challenges posed by the nose, some researchers are
exploring vaccines inhaled through the mouth. Smaill is working on one
of them. She and her McMaster colleagues aerosolized their vaccine for
COVID into a fine mist delivered by a nebulizer, from which it rapidly
reaches the lungs. Experiments in mice have shown promising results,
with mucosal immunity established after administration of the vaccine.

Another vaccine strategy is to use a harmless virus to carry viral
genes or proteins. Researchers at the Icahn School of Medicine at
Mount Sinai in New York City selected a bird pathogen, Newcastle
disease virus (NDV). “It’s naturally a respiratory pathogen,” so
it infects nasal cells, says Michael Egan, CEO and chief scientific
officer of CastleVax, a company that formed to develop the NDV vaccine
for COVID. A small early clinical trial showed the CastleVax vaccine
was safe and caused robust immune responses in people. “Those
results were very promising,” Egan says. People who received the
vaccine also produced antibodies that indicated multitiered mucosal
immunity, not simply the adaptive immunity from a shot in the arm.

Following that trial, the CastleVax project received NextGen funding,
and results from a trial of 10,000 people are expected in 2026. Half
of those people will receive a messenger RNA (mRNA) injection, and
half will get the new NDV nasal spray. The data should show whether
the new nasal vaccine can do a better job of preventing infection than
the mRNA injections. Egan has high hopes. “We’re expecting to see
a lot fewer breakthrough infections in people who got the vaccine up
the nose by virtue of having those mucosal immune responses,” he
says.

Florian Krammer, one of the Mount Sinai researchers behind the
vaccine, engineered NDV particles to display a stabilized version of
the spike protein that’s so prominent in SARS-CoV-2. “You end up
with a particle that’s covered with spike,” he says. Spike protein
in the blood­stream can raise an immune response. But the NDV vaccine
works in another way, too. The virus particle can also get into cells,
where it can replicate enough times to cause virus particles to emerge
from the cells, provoking another immune reaction. Before moving into
human trials, however, researchers had to complete clinical trials to
establish that the Newcastle virus is truly harmless because the nose
is close to the central nervous system—it has neurons that connect
to the olfactory bulb, which is part of the brain. Those trials
confirmed that it is safe for this use.

Nasal sprays aim directly at the spot where most viruses first enter
the body: the nose.

This type of caution is one reason a COVID nasal vaccine approved in
India hasn’t been adopted by the U.S. or other countries. The
inoculation, called iNCOVACC, uses a harmless simian adenovirus to
carry the spike protein into the airway. The research originated in
the laboratories of Diamond and some of his colleagues at Washington
University at the start of the pandemic, when they tested the
formulation on rodents and nonhuman primates. “The preclinical data
were outstanding,” Diamond says. Around the time he and his
colleagues published initial animal results in _Cell _in 2020,
Bharat Biotech in India licensed the idea from the university. In a
2023 phase 3 clinical trial in India, the nasal vaccine produced
superior systemic immunity compared with a shot.

Diamond says American drug companies didn’t pursue this approach,
because “they wanted to use known quantities,” such as the mRNA
vaccines, which were already proving themselves in clinical trials in
2020. As the pandemic took hold, there was little appetite to develop
nasal vaccine technology to stimulate mucosal immunity while the
tried-and-true route of shots in the arm was available and working.
But now, four years later, an inhaled vaccine using technology similar
to iNCOVACC’s is being developed for approval in the U.S. by biotech
company Ocugen. Both inhaled and nasal forms of the vaccine are set to
undergo clinical trials as part of Project NextGen. These new vaccines
are using classical vaccine methods based on the virus rather than
using new, mRNA-based technology. The mRNA preparations were developed
specifically for intramuscular injections and would have to be
significantly modified.

Codagenix, which is developing CoviLiv, sidestepped the need for a new
viral vector or an adjuvant by disabling a live SARS-CoV-2 virus. To
make it safe, scientists engineered a version of the virus with 283
mutations, alterations to its genetic code that make it hard for the
virus to replicate and harm the body. Without all these genetic
changes, there would be a chance the virus could revert to a
dangerous, pathogenic form. But with hundreds of key mutations,
“statistically, it’s basically impossible that this will revert
back to a live virus in the population,” says Johanna Kaufmann, who
helped to develop the vaccine before leaving Codagenix for another
company earlier this year.

Because most people on the planet have now been exposed to
SARS-CoV-2—in the same way they’re regularly exposed to the
flu—some nasal vaccines are being designed as boosters for a
preexisting immune response that is starting to wane. For example,
Yale researchers Iwasaki and Goldman-Israelow are pursuing a strategy
in animals deemed “prime and spike.”

The idea is to start with a vaccine injection—the “prime” that
stimulates adaptive immunity—then follow it a few weeks later with a
nasal puff that “spikes” the system with more viral protein,
leading to mucosal immunity. In a study published in 2022
in _Science,_ Iwasaki and her colleagues reported that they primed
rodents with the mRNA vaccine developed by Pfizer and BioNTech, the
same shot so many of us have received. Two weeks later some of the
mice received an intranasal puff of saline containing a fragment of
the SARS-CoV-2 spike protein. Because the animals had some preexisting
immunity from the shot, the researchers didn’t add any adjuvants to
heighten the effects of the nasal puff. Two weeks later researchers
detected stronger signs of mucosal immunity in mice that had received
this treatment compared with mice that got only the shot.

“Not only can we establish tissue-resident memory T cells” to
fight off the virus in the nose, Iwasaki says, but the prime-and-spike
method also produces those vigorous IgA antibodies in the mucosal
layer. “And that’s much more advantageous because we can prevent
the virus from ever infecting the host,” she notes. The study
suggests that this approach might also lessen the chances of
transmitting the disease to others because of the lower overall viral
load. Experiments in hamsters demonstrated that vaccinated animals
shed less virus, and they were less likely to contract COVID from
infected cage mates that had not been vaccinated themselves.

Although most of the new vaccine strategies are aimed at COVID, nasal
vaccines for other diseases are already being planned. Kaufmann,
formerly of Codagenix, says the company currently has clinical trials
underway for nasal vaccines against flu and RSV. CastleVax’s Egan
says “we have plans to address other pathogens” such as RSV and
human metapneumovirus, another leading cause of respiratory disease in
kids.

Vaccines that don’t need to be injected could clear many barriers to
vaccine access worldwide. “We saw with COVID there was no vaccine
equity,” Smaill says. Many people in low-income countries never
received a shot; they are still going without one four years after the
vaccines debuted.

In part, this inequity is a consequence of the high cost of delivering
a vaccine that needs to stay frozen on a long journey from
manufacturing facilities in wealthy countries. Some of the nasal
sprays in development don’t need deep-cold storage, so they might be
easier to store and transport. And a nasal spray or an inhaled puff
would be much easier to administer than a shot. No health professional
is required, so people could spray it into their noses or mouths at
home.

For these reasons, needle-free delivery matters to the World Health
Organization. The WHO is using the Codagenix nasal spray in its
Solidarity Trial Vaccines program to improve vaccine equity. The
CoviLiv spray is now in phase 3 clinical trials around the world as
part of this effort. “The fact that the WHO was still interested in
a primary vaccination trial in the geographies it’s passionate
about—that’s indicative that there is still a gap,” Kaufmann
says. CoviLiv was co-developed with the Serum Institute of India, the
world’s largest maker of vaccines by dose. The partnership enabled
production at the high volume required for Solidarity.

The CastleVax vaccine with the NDV vector provides another layer of
equity because the facilities required to make it already exist in
many low- and middle-income countries. “The cool thing is that NDV
is a chicken virus, so it grows very well in embryonated
eggs—that’s exactly the system used for making flu vaccines,”
Krammer says. For example, for a clinical trial in Thailand, “we
just shipped them the seed virus, and then they produced the vaccine
and ran the clinical trials,” he says. Many countries around the
world have similar facilities, so they will not need to depend on
pharma companies based in richer places.

Even high-income countries face barriers to vaccination, although they
may be more personal than systemic. For very many people, the needle
itself is the problem. Extreme phobia such as Velasquez’s is
uncommon, but many people have a general fear of needles that makes
vaccinations stressful or even impossible for them. For about one in
10 people needle-related fear or pain is a barrier to vaccinations,
says C. Meghan McMurtry, a psychologist at the University of Guelph in
Ontario. Needle fear “is present in most young kids and in about
half of adolescents. And 20 to 30 percent of adults have some level of
fear.” A review of studies of children showed that “concern around
pain and needle fear are barriers to vaccination in about 8 percent of
the general population and about 18 percent in the vaccine-hesitant
population,” McMurtry adds.

Some people are wary of injected vaccines even if they’re not afraid
of needles, Kett says; they see injections as too invasive even if the
needle doesn’t bother them. “We’re hopeful that something
administered by the nasal route would be less likely to come across
some of those issues,” Kett says.

In the U.S., however, sprays and puffs won’t be available until they
are approved by the Food and Drug Administration, which requires clear
evidence of disease protection. As Diamond points out, standards for
such evidence are well established for injections, and vaccine makers
can follow the rule book: regulations point to particular antibodies
and specific ways to measure them with a simple blood test. But for
nasal vaccines, Iwasaki says, “we don’t have a standard way to
collect nasal mucus or measure antibody titers. All these practical
issues have not been worked out.”

Iwasaki is also frustrated with a restriction by the U.S. Centers for
Disease Control and Prevention that stops researchers from using
existing COVID vaccines in basic research to develop new nasal sprays.
The rule is a holdover from 2020, when COVID injections had just been
developed and were in short supply; people had to wait to get
vaccinated until they were eligible based on factors such as age and
preexisting conditions. “That made sense back then, but those
concerns are years old; things are different now,” Iwasaki says.
“Now we have excess vaccine being thrown out, and we cannot even get
access to the waste, the expired vaccine.”

Today scientists want to contrast the effectiveness of nasal
formulations with injections already in use. “Those comparisons are
really important for convincing the FDA that this is a worthy vaccine
to pursue,” Iwasaki says. But the restriction has held up studies by
her company, Xanadu, slowing down work. (The CDC did not respond to a
request for comment.)

Despite the bureaucratic and scientific hurdles, the sheer number of
nasal vaccines now in clinical trials encourages Iwasaki and other
scientists pursuing the needle-free route. They say it seems like only
a matter of time before getting vaccinated will be as simple as a
spritz up the nose.

Velasquez, for one, can’t wait for that day to arrive. The
circumstances that finally forced her to reckon with her fear of
needles (a global pandemic, the prospect of parenthood and the
numerous blood tests that accompanied her pregnancy) were so much
bigger than her. If not for them, she might still be avoiding shots.
“So having vaccines without needles—I would get every vaccine any
doctor wanted me to get, ever. It would be a complete game changer for
me.”

_STEPHANI SUTHERLAND
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neuroscientist and science journalist based in southern California.
She wrote about the causes of 
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COVID in our March 2023 issue. Follow her on X @SutherlandPhD
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