Scientists
report their phage-based inhaled vaccine delivery system elicited a robust
antibody response in both mice and non-human primates.
Researchers
demonstrate in a proof-of-concept study that a phage-based inhalation delivery
system for vaccines generates potent antibody responses in mice and non-human
primates, without causing lung damage. According to the team, this system could
be used to deliver vaccines and therapeutics against respiratory diseases.
“This
translational strategy potentially enables more effective delivery of
therapeutics or vaccines while reducing the chance of toxic side effects,” said
a co-senior author of the study, Wadih Arap, of Rutgers Cancer Institute of New
Jersey, US. “In ongoing research, we hope that this work will play a crucial
role in the development of targeted vaccines and treatments to block the spread
of respiratory infectious diseases, possibly for the current COVID-19 pandemic,
especially in the setting of underserved populations.”
The team explained that pulmonary delivery of vaccines and therapeutics is particularly beneficial for the treatment or prevention of against respiratory infections because they arrive directly at the site of the infection. Inhalation-based vaccination is needle free and minimally invasive, which is especially attractive for administrating multiple doses. Additionally, it improves therapeutic bioavailability, negating the risk of drugs being degraded by enzymes in the circulation, while also reducing potential side effects by achieving a more rapid onset of action than needle-based vaccination.
“The
very extensive and accessible layer of cell surfaces in the lungs is highly
vascularised, which allows rapid absorption of molecules throughout circulation
in much higher concentrations by avoiding the drug-metabolising enzymes of the
gastrointestinal tract and liver,” said the other co-senior study author,
Renata Pasqualini, also from Rutgers Cancer Institute of New Jersey. “Because
the lungs are constantly being exposed to pathogens from the air, they likely
have a high level of immune defence activity and therefore represent an
efficient site for immune protection against airborne pathogens.”
Despite
the potential of pulmonary delivery for protecting against airborne pathogens
like SARS-CoV-2, Ebola, influenza and measles, it has not been widely adopted.
In part, the researchers said, this is because the underlying physiological
mechanisms remain largely unknown – and need to be understood for scientists to
design a general pulmonary delivery system for widespread use.
In
the new study, Arap and Pasqualini devised and validated a safe, effective lung
delivery system that could be used for a broad range of translational
applications – and showed how it works. The approach involves the use of
phages-viruses which infect and replicate within bacterial cells. In certain
types of vaccines, phage particles that carry peptides are used to trigger
protective immune responses.
To
develop their intranasal system, the team first screened for a peptide that
could efficiently deliver phage particles across the pulmonary barrier and into
the bloodstream. They identified CAKSMGDIVC. According to the team, phage
particles expressing CAKSMGDIVC on their surface are absorbed into the body
when the peptide binds to and is internalised through its receptor, α3β1
integrin, on the surface of cells lining the lung airways.
In
the study, inhaled delivery of CAKSMGDIVC-displaying phage particles elicited a
robust antibody response against the phage particles in mice and non-human
primates, without damaging the lungs.
According
to the authors, the new lung delivery system is safe and effective and has
unique advantages for the development of vaccines and therapeutics against
airborne pathogens. In particular, the researchers said that because phage
particles do not replicate inside eukaryotic cells, they are thought to be
safer than other classic viral-based vaccination strategies and have been used
as antibiotics against multidrug-resistant bacteria and as vaccine carriers for
decades.
The team also said that phage particles are highly stable under harsh environmental conditions and their large-scale production is extremely cost-effective, when compared to traditional methods for vaccine production. Moreover, unlike conventional peptide-based vaccines that often become inactivated, the new lung delivery system has no cumbersome, stringent or expensive cold-chain requirements for field applications in the developing world. “In addition, phage particles are versatile and can be genetically engineered by standard molecular biology technology,” Arap said.
The
researchers concluded that they now plan to examine the kinetics of pulmonary
transport after multiple doses and investigate cell-based immune responses. “It
is important to note that all this work was in preclinical models, so we look
forward to the translation of our approach to clinical applications such as
lung-targeted drug delivery or pulmonary-based vaccination,” said Pasqualini.
The
study was published in Med.
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