YSM Issue 96.3

FOCUS
Biomedical Engineering
Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-COV-2 virus.
IMAGE COURTESY OF DAVIAN HO
The Promise and Pitfalls of Respiratory
Delivery
Current intramuscular mRNA vaccines,
typically injected into the upper arm,
excel at activating immune defenses in
the bloodstream, but they are not as
effective in rallying protective responses
in the upper airway and lungs. Thus, for
a viral respiratory illness like COVID-19,
the allure of an inhalable mucosal vaccine
stems from its geographical advantage.
When a viruses enter the body through
the nasal route, the respiratory mucosa
(the lining of the respiratory tract)
becomes the primary battleground for
early encounters. Notably, the Omicron
variant has been recorded in higher
concentrations in the lungs than in the
rest of the body. According to Benjamin
Goldman-Israelow, an assistant professor
of internal medicine at the Yale School
of Medicine and one of the authors of
the paper, mucosal vaccines are better
designed to engage the immune system
precisely at this entry site, enhancing
the body’s ability to mount a swift and
targeted response there.
The effectiveness of the oral polio
vaccine, which played a significant role
in the global effort to eradicate polio,
is grounded in the same principle.
Following ingestion, the vaccine induces
a strengthening of immune defenses
within the virus’ favored environment—
the gastrointestinal tract. This localized
approach minimizes the delay associated
with the migration of immune defenses
from the bloodstream to the environment
of interest, thereby reducing the
window of vulnerability and bolstering
protection against invading pathogens.
While the promise of inhalable
vaccines is compelling, it is not without
its challenges. Only one mucosal vaccine
currently exists to combat pathogens
entering through the nasal route: a nasal
spray comprising of weakened flu viruses
known as FluMist. While this nasal spritz
proves reasonably effective in children—
occasionally even surpassing the
performance of its injected counterpart—
its potency wanes significantly in adults.
This may be because the pre-existing
immunity built up over a lifetime of
influenza exposure can inhibit the
vaccine’s effects before it can establish
new protection, according to Goldman-
Israelow. Thus, developing a mucosal
vaccine tailored for respiratory viruses
presents a unique challenge, and there is
no well-established template to follow.
Mark Saltzman, the Goizueta Foundation
professor of biomedical engineering at Yale
and a senior author of the paper, shared that
there were several fundamental challenges
in devising an effective mucosal vaccine.
The effectiveness of mucosal vaccines
relies heavily on how well they can reach
and activate immune cells in the mucosal
surfaces. To reach cells in the lungs, the
vaccine must be able to overcome physical
barriers, such as cilia and mucus, meant to
prevent debris and pathogens contained in
inhaled air from reaching the lungs’ small
air sacs, or alveoli. Phagocytic cells, which
actively participate in the body’s immune
surveillance by destroying microbes
and debris, introduce another obstacle.
These cells may engulf vaccine particles,
thwarting their intended journey to the site
of action and potentially compromising
the vaccine’s effectiveness.
Finally, respiratory mucosa is
especially prone to producing unwanted
immune reactions. While current
mRNA vaccines employ small fat-based
capsules called lipid nanoparticles
(LNPs) as their delivery vehicles, these
components have been noted to incite
inflammation when administered via
nasal routes. In the development of
nanoparticles tailored for inhalation, the
team would have to maximize mRNA
delivery efficiency while minimizing
detrimental inflammatory responses in
the respiratory tract.
Inhaling Nanoparticles
Polymers are molecules formed
from repeating smaller chemical units
known as monomers. Visualize them as
molecular chains built from identical
building blocks repeated in succession,
much like LEGO bricks assembling into
a chain. The Saltzman group designs and
tests incredibly tiny nanoparticles made
20 Yale Scientific Magazine September 2023 www.yalescientific.org