Introduction
Respiratory tract infections (RTIs) are the third leading cause of morbidity and mortality
worldwide, accounting for ~4.25 million deaths in 2010, in either children, adults
or the elderlies. RTIs encompass acute infections of the upper (rhinosinusitis, …)
and lower airways (pneumonia, bronchiolitis, …) and are also inherently associated
with chronic diseases such as chronic obstructive pulmonary disease (COPD) and cystic
fibrosis (CF). In addition to premature mortality, RTIs result in a huge burden on
the society considering quality-adjusted life year loss and additional pressure on
the overwhelmed healthcare systems, thereby representing a major public health issue.
Antimicrobial chemotherapies (e.g., antibiotics, antivirals) are the standard interventions
to prevent and to treat respiratory infections. However, their effectiveness is declining
due to increased pathogen resistance, urging alternative or complementary strategies
to reinforce the anti-infectious arsenal to fight RTIs. Among those under evaluation,
immunomodulatory agents (immunopharmaceutics) like therapeutic antibodies (Ab) or
other therapeutic proteins and vaccines may offer novel opportunities for the prevention
and treatment of RTIs, by targeting pathogens and boosting the host immune system.
When used in a preventive way in patients at risk, or therapeutically to stop or to
limit the spread of infection, both immunopropylactics and immunotherapeutics are
administered through parenteral routes (including intravenous, subcutaneous, and intramuscular)
(Table 1). As demonstrated in preclinical studies, parenteral delivery may not be
optimal for large molecular weight entities to treat respiratory diseases (1, 2) since
they poorly reach the lung compartment. In contrast, inhalation, comprising the intranasal
and oral respiratory routes, targets drugs into the respiratory tract. Currently,
inhalation is used both for locally- and systemically-acting drugs as it allows a
straight delivery to the diseased organ and a portal to the blood circulation, considering
the extensive alveolus-capillary interface. By providing a better therapeutic index,
inhalation is the gold standard for small molecules, delivered topically as an aerosol,
like corticosteroids/steroids, decongestants or bronchodilators for the treatment
of asthma, rhinosinusitis or COPD. Besides, it is also indicated for antibiotics (nasal
and oral inhalation), a local-acting protein therapeutic—Dornase alpha (Pulmozyme®,
oral inhalation), a mucolytic agent for patients with CF and an influenza live vaccine
(FluMist® Quadrivalent, nasal inhalation).
Table 1
Marketed immunotherapeutics and immunoprophylactics for infectious diseases.
Target
Product
Category
Sponsors
Administration route
Date of approval
Indication
RSV
Synagis
Monoclonal antibody
MedImmune
IM
1998
Prophylaxis
Influenza
Afluria
Inactivated vaccine Quadrivalent
Seqirus
IM
2007
Prophylaxis
Fluad
Inactivated vaccineTrivalent
Seqirus
IM
2015
Prophylaxis
Fluarix
Inactivated vaccineQuadrivalent
GSK
IM
2012
Prophylaxis
Flublok
Recombinant vaccineQuadrivalent
Protein Sciences Corporation
IM
2013
Prophylaxis
Flucelvax
Inactivated vaccineQuadrivalent
Seqirus
IM
2012
Prophylaxis
Pandemic influenza vaccine H5N1
Recombinant vaccine
Medimmune
IN
2016
Prophylaxis
FluLaval
Inactivated vaccineQuadrivalent
ID Biomedical Corporation of Quebec
IM
2013
Prophylaxis
FluMist
Live-attenuated vaccineQuadrivalent
MedImmune
IN
2003
Prophylaxis
Fluzone High Dose
Inactivated vaccineQuadrivalent
Sanofi Pasteur
IM
2014
Prophylaxis
Fluzone
Inactivated vaccineQuadrivalent
Sanofi Pasteur
IM
2009
Prophylaxis
Fluvirin
Inactivated vaccineTrivalent
Seqirus
IM
1988
Prophylaxis
Measle
Proquad
Subunit vaccine
Merck
SC
2005
Prophylaxis
M-M-R II
Subunit vaccine
Merck
SC
2014
Prophylaxis
Smallpox
ACAM2000
Live vaccina virus
Emergent Product Development
Percutaneous
2007
Prophylaxis
Mycobacterium tuberculosis
BCG Vaccine
Live-attenuated vaccine
Organon
Percutaneous
2011
Prophylaxis
Streptococcus pneumoniae
Pneumovax 23
Subunit vaccine
Merck&Co
IM
1983
Prophylaxis
Prevenar 13
Subunit vaccine
Wyeth Pharmaceuticals
IM
2010
Prophylaxis
Bordetella pertussis
Daptacel
Subunit vaccine
Sanofi Pasteur
IM
2008
Prophylaxis
Pediarix
Subunit vaccine
GSK
IM
2002
Prophylaxis
Kinrix
Subunit vaccine
GSK
IM
2008
Prophylaxis
Quadracel
Subunit vaccine
Sanofi Pasteur
IM
2015
Prophylaxis
Pentacel
Subunit vaccine
Sanofi Pasteur
IM
2008
Prophylaxis
Haemophilus influenzae
Hiberix
Subunit vaccine
GSK
IM
2009
Prophylaxis
ActHIB
Subunit vaccine
Sanofi Pasteur
IM
1993
Prophylaxis
PedvaxHIB
Subunit vaccine
Merck
IM
1989
Prophylaxis
Bordetella pertussis
Haemophilus influenzae
Infanrix
Subunit vaccine
GSK
IM
1997
Prophylaxis
Vaxelis
Subunit vaccine
MCM Vaccine
IM
2018
Prophylaxis
Bacillus anthracis
Anthim
Monoclonal antibody
Elusys Therapeutics
IV
2016
Prophylaxis/Therapy
Abthrax
Monoclonal antibody
GSK
IV
2012
Prophylaxis/Therapy
Biothrax
Subunit vaccine
Emergent BioSolutions
IM
2016
Prophylaxis
IM, intramuscular; IN, inhalation (nasal); SC, subcutaneous.
Local-Acting Immunopharmaceutics Delivered by Inhalation
There are accumulating evidences that administration of anti-infectious Abs, protein
therapeutics (e.g., cytokines) and vaccines, to the upper and/or lower respiratory
tract by inhalation, with the purpose of inducing a local action, is effective (3).
Several preclinical studies showed the superiority of immunopharmaceutics administered
topically to the respiratory tract in RTI models, in both therapeutic and prophylactic
regimens. For instance, inhalation of anti-infectious Abs in models of pneumonia using
Pseudomonas aeruginosa or influenza virus conferred higher protection and greater
therapeutic response, respectively, compared to parenteral route administration (4,
5). Besides, other immunoprophylactics delivered through the respiratory route such
as immunocytokines (e.g., IL-7 Fc) (6) and live-attenuated vaccines (7) showed superior
performances over conventional routes against airborne viruses, in mice and non-human
primates, respectively. Conversely, restricting the response to the site of action
for pleiotropic molecules (e.g., IL-7 Fc), envisioned as adjuvant molecule, may reduce
systemic side-effects. As reported for anti-infectious Abs, the inhaled route may
also enable a higher efficacy with a lower dose (4). This means that the inhaled route
may allow, in the future, to alleviate the financial burden of immunopharmaceutics
(in particular Abs), which may exceed the ability of both individual patients and
the healthcare systems to sustain them. Additional benefit of the inhaled route includes
its non-invasiveness, offering a better comfort for patients, in particular those
with chronic respiratory infections, and thus preventing additional healthcare costs.
Besides, needle-free vaccination may prevent the risk of cross-contamination and facilitate
mass vaccination efforts.
However, beyond clear preclinical proofs of concept and obvious theoretical advantages
of the inhalation route for immunotherapeutics and -prophylactics, few of these benefits
have materialized in the clinic (Table 1). Except for Flumist® Quadrivalent (Astrazeneca),
an intranasal live attenuated influenza vaccine, other marketed immunoprophylactics
vaccines (including those against Streptococcus pneumoniae, Haemophilus influenza,
Mycobacterium tuberculosis, Bordetella pertussis or measles and Ab (anti-RSV Pavilizumab)—are
administered systemically. Similarly, none of the protein therapeutics is given by
inhalation. Recently, Ablynx developed an inhaled anti-RSV trimeric nanobody® (ALX-0171)
for therapeutic purposes. Despite promising results in several animal models, the
development has been interrupted due to insufficient evidences of efficacy during
Phase 2 trial in children (in Japan). In 2019, only one phase 2 trial with an inhaled
anti-infectious protein therapeutics is still ongoing (NCT03570359) assessing the
efficacy of topical lung delivery of IFN-β1a (SNG001, Synairgen/Astrazeneca), as an
immunostimulant to treat COPD exacerbations. Overall, this highlights the complexity
of developing inhaled biopharmaceuticals and points out the persisting hurdles (Figure
1).
Figure 1
The multifaceted features from the development of inhaled immunopharmaceutics.
Challenges for the Development of Inhaled Immune-Therapeutics/Prophylactics
The instability of immunopharmaceutics and vaccines often emerges as a challenge for
inhalation delivery. Therapeutic proteins and vaccines are sensitive to various conditions
which may alter their structure, thereby decrease their activity. Delivering a drug
through the inhalation route implies either spraying, drying or aerosolizing, which
is associated with multiple stresses (shearing, temperature, air/liquid interface,
…) potentially deleterious as widely discussed elsewhere (8, 9). To deal with this,
both the device used for the generation of the aerosol and the formulation must be
adapted, as successfully reported for Ab-based therapeutics (3, 10). However, the
excipients must be adapted for respiratory delivery. The choice of mucosal-licensed
adjuvants, which should be exempt of intrinsic immune-toxicity, and the instability
of the associated carrier [e.g., nanoparticles, liposomes, immune stimulating complexes
(ISCOMs)] is particularly challenging for the inhalation delivery of vaccines, especially
those of the latest generation (e.g., T, B-epitope-based vaccines). The drug and device
combination yields proper aerodynamical properties (particle size, flow rate, …) to
achieve the anticipated deposition in the appropriate area of the respiratory tract.
Indeed, appropriate deposition to the anatomical site is mandatory to ensure an optimal
efficacy. On one hand, this depends on the drug formulation (e.g., surface tension
and viscosity for liquid formulation) (11) and device performances to allow the therapeutic
agent to reach the site of infection (Figure 1), by this means the microbe. For lung
infections, most pneumonia consists of an aggregate of trachea-bronchitis and alveolar
infections. Theoretically, this clinical condition may benefit from a uniform distribution
all over the lungs, with a polydisperse aerosol (ranging 1–5 μm). However, several
pathogens are associated with specific anatomic localization, like S. pneumoniae,
which is mainly found in the alveolar spaces, thereby requiring low-size aerosols
(<2–3 μm) to be targeted. On the other hand, delivery to the mucosal-associated lymphoid
tissue (MALT), located in the tonsils, would be more adapted for vaccines to induce
an adaptive immune response, since MALT plays a central role in the primary respiratory
immune defense (Figure 1).
Biological barriers are additional hurdles to overcome and apply to all inhaled anti-infectious
agents (12). First, a pathogen can “hide” itself inside host cells like M. tuberculosis
in alveolar macrophages, thus being more difficult to be targeted by immunopharmaceutics.
Other pathogens may produce extracellular barriers like the biofilm matrix produced
by P. aeruginosa in the context of chronic lung infections. This biofilm acts as a
diffusion barrier, preventing inhaled immunopharmaceutics from reaching their molecular
target. Antibody-based fragments, such as fragment antigen-binding (Fab) and single-chain
variable fragments (scFv) might be more efficient in crossing over the biofilm, like
they penetrate better solid tumors (13), and eradicate P. aeruginosa. Secondly, the
host physical defenses, which prevent foreign particles from penetrating into the
respiratory tract, may limit the accessibility of inhaled immunopharmaceutics to their
target. Among them, the mucus and the mucociliary escalator are highly efficient clearance
mechanisms (14, 15). The development of mucoadhesive formulations may be helpful to
enhance the bioavailability of inhaled drugs (16). In contrast, anti-adhesive molecules,
such as polyethylene glycol may facilitate immunopharmaceutics translocation through
the mucus blanket, as shown in vitro (17) and in vivo (18) for other applications.
It is noteworthy that, in some pathological conditions (e.g., chronic sinusitis, CF
and COPD), the mucus gets thicker. In CF, the mucus exhibited an increased density
of disulfide cross-links, further tightening the mucus mesh space, thereby reinforcing
its steric barrier potency to immunopharmaceutics (19). To date, overcoming this physical
barrier has not been addressed in the design of inhaled immunopharmaceutics. Other
biological barriers include alveolar macrophages and the pulmonary surfactant layer
in the alveolar region. While the molecular interactions between inhaled particles
and the surfactant are largely unknown, some evidences indicate that surfactant proteins
may facilitate the uptake of inhaled particles by alveolar macrophages (20). Alveolar
macrophages patrol the airways and phagocytose inhaled organic (including pathogens)
and inorganic particles ranging between 0.5 and 5μm (21). Interestingly, the size-discriminating
property of their phagocytosis potency has led to the development of innovative approaches
for inhaled drugs, in which carrier entrapped-particles of smaller or larger size
are inhaled to escape the alveolar macrophage phagocytosis and to provide a better
controlled drug release [(22, 23); Figure 1]. This strategy is investigated for mucosal
vaccines to prevent the degradation or denaturation of the peptide/antigen, to sustain
its release and favor delivery and adjuvancy (24).
The lung mucosa is a metabolic active environment (25). The presence of proteases
[which is more prevalent in the nasal mucosa (26)] may degrade therapeutic proteins
before they reach their targets. In addition to host enzymes, bacterial pathogens,
like P. aeruginosa, release additional proteases, which may metabolize respiratory-delivered
drugs (27). In this context, the presence of protease inhibitors in the formulation
of inhaled protein therapeutics may improve their pharmacokinetics and efficacy, as
previously demonstrated for inhaled peptides such as insulin and calcitonin (28).
Furthermore, the encapsulation of protein therapeutics into liposomes may also improve
stability and reduce the frequency of dosing (29). This strategy has already been
clinically validated for the pulmonary delivery of antibiotics (30). Of note, respiratory
diseases are often associated with an impairment of the protease/anti-protease balance.
In CF, high levels of proteases are a result of the chronic infection and inflammation
induced by P. aeruginosa (31). This proteolytic environment self-perpetuates the intensity
of inflammation, induces mucus hypersecretion and respiratory tissue damage, which
may ultimately affect inhaled immunotherapeutics (Figure 1).
Conclusion
Compared to the expansion of biopharmaceutics (excluding non-recombinant vaccines)
in all medical areas, the field of inhaled protein therapeutics/vaccines has stagnated,
with only few drugs approved so far. Despite promising preclinical data and significant
advances on macromolecule inhalation, a definitive demonstration that effective and
intact inhaled immunopharmaceuticals could be delivered (topically) to humans is still
lacking.
Although, we cannot rule out that the recent failures of inhaled biopharmaceutics
(Exubera and ALX-0171) make it challenging, to our opinion, it may be time for thinking
carefully where inhalation may have the edge over other routes: “finding the right
use for this modality!” They may be many possibilities considering the unmet clinical
needs for respiratory diseases and the growing market of immunopharmaceutics. But
the inhalation route must be envisioned and integrated early taking into account the
disease/population, the target, the drug and the device (Figure 1), rather than adapting
an approved molecule for the inhalation route. RTIs are undoubtedly an appropriate
clinical situation for inhalation, if we consider the importance of matching the delivery
of immunoprophylatics or immunotherapeutics to their site of action. Anti-infectious
macromolecules may certainly benefit from the success of inhaled antibiotics, but
it is critical to remember their precise molecular nature associated with a unique
pharmacokinetics profile when considering their development for inhalation. Besides,
the recent report of a universal flu vaccine, comprised of Ab-based therapeutics (VHH)
produced by an adeno-associated virus delivered intranasally pushed further the boundaries
of the potential of the inhalation route for immunoprophylactics (32).
Author Contributions
TS, AM, and NH-V participated in the review of research. NH-V prepared figure. TS
and AM prepared table. All authors contributed to the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.