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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5400_Библиотеки_им_академика_М_И_Перельмана
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RNA synthesis regulatory protein M2-2, which led to an increase in
gene transcription and antigen expression, but a reduction in genome
replication. This vaccine candidate was administered in RSVseronegative children of age 6–24 months as a single intranasal dose.
At least 85% of vaccinated individuals demonstrated a fourfold
increase or more in serum neutralising antibodies [75–77]. In another
study, live-attenuated RSV lacking the G attachment protein (RSVΔG),
which involves viral binding to host cells, was administered
intranasally to healthy adults of age from 18 to 50 years [78]. The
vaccine was well-tolerated, but the extent of systemic immunogenicity
was limited, attributed in part to the fact that this cohort was already
seropositive at baseline before vaccination.
Despite the initial success of the injectable COVID-19 vaccinations,
enormous work has been dedicated to the development of mucosal
vaccines against SARS-CoV-2 to address the lack of mucosal immunity
induction in injectable vaccines. To illustrate, an intranasal subunit
vaccine based on freeze-dried spike protein formulated with a
liposomal stimulator of interferon gene (STING) agonist as an adjuvant
has been reported, with the goal to improve immunisation against
SARS-CoV-2 [79]. BALB/c mice receiving a single dose of intranasal
vaccine-induced IgA secretion in both the nasal cavity and the lung, as
well as serum anti-spike IgG. Intranasal administration of ChAdOx1
nCoV-19 vaccines (Oxford-AstraZeneca COVID-19 vaccine) was
demonstrated to reduce viral shedding upon challenge in both hamster
and rhesus macaque animal models [80]. Syrian hamsters were
protected from pulmonary damage when challenged by the alpha or
beta variants [81], and potent systemic and mucosal immunity was
induced in the murine model [82]. Contrary to these promising results
in preclinical studies, intranasal vaccination with ChAdOx1 nCoV-19 in
healthy adults was shown to be safe yet neither a profound systemic
response nor consistent mucosal immunity has been detected [83].
Adenovirus type-5 vector-based COVID-19 vaccines represent another
prospective candidate for mucosal vaccination. Preclinical studies
reported that macaques were protected against the SARS-CoV-2
challenge after receiving a single intranasal Ad5-nCoV vaccination [84],
and profound systemic and mucosal immune responses were elicited
when the vaccine was administered by nebulisation [85]. Similar
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immunogenicity was also observed in mice upon intranasal
vaccination of Ad5.SARS-CoV-2-S1 [86]. Preliminary report on a phase I
clinical trial on nebulised Ad5-nCoV vaccine showed that the vaccine
was generally well-tolerated, and two doses of nebulised vaccines
28 days apart could induce a humoral immune response similar to one
dose of intramuscular injection [87]. Remarkably, intranasal
immunisation as a booster dose to a primary intramuscular
vaccination strongly enhanced humoral immune responses. In a
separate study involving more than 700 participants naıve to SARSCoV-2 vaccination and infection, the vaccine candidate dNS1-RBD was
given in two intranasal doses 14 or 21 days apart [88]. dNS1-RBD was
generally well-tolerated, yet only a modest mucosal and humoral
immune response was recorded, with seroconversion observed and
local RBD-speciic sIgA detected in 10–22% and 12–13% of vaccine
recipients, respectively. The landscape of intranasal and inhaled
vaccines against SARS-CoV-2 is rapidly evolving. Readers interested in
a more thorough account of their latest development are referred to
review articles recently published [89–93].
3 Socialand Econo m icBen eitsofIntranasaland
InhaledVaccines
Apart from the broader protection provided through both mucosal and
systemic immune responses, inhaled and intranasal vaccines offer
several additional beneits over their injectable counterparts. Selfadministration using inhaler devices or nasal sprays is possible for
most healthy individuals. Training through videos [94, 95] or mobile
devices [96, 97] can be provided when social distancing is exercised or
access to health care services is limited. This clearly juxtaposes
injectables that require close contact with trained personnel for
vaccination. The route of administration is relevant especially when
the safe use of injectable vaccines relies on the correct injection
technique. To exemplify, the risks of acute myocarditis or
myopericarditis associated with mRNA vaccines against COVID-19 [98,
99] may further increase when they are inadvertently given
intravenously instead of the intended intramuscular injection, as
evident in an in vivo study using murine model [100]. Similarly, risks of
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thrombotic thrombocytopenia may increase in vaccines based on
adenoviral vectors when accidentally administered intravenously
[101]. With respect to this, mucosal vaccines are safer as they are
locally administered with better tolerance on the site of antigen
deposition or expression and have a lower risk of administration error.
Inhaled or intranasal vaccines do not require sterile drug
reconstitution and administration, thus mass vaccination programmes
can be carried out in less stringent settings. Healthcare professionals
and resources, which could be in huge demand during a pandemic, can
be spared and allocated to patients who require greater medical
attention.
Intranasal and inhaled vaccines also eliminate the need for needles
for injection, which could be appealing to people with trypanophobia
(needle phobia) and potentially address the associated vaccine
hesitancy. The prevalence of trypanophobia was estimated to lie
between 20–50% in adolescents and 20–30% in young adults [102].
While needle fear is generally less prominent with increasing age, it
still constitutes to approximately 8–27% of avoidance of inluenza
vaccination among hospital workers and adult patients. Similar igures
have been reported by another survey in the UK [103]. As much as
26.2% of the adult population was screened positive for bloodinjection-injury phobia, which might account for about 10% of cases of
COVID-19 vaccine hesitancy. Non-invasive administration also
eliminates the risk of bloodborne disease transmission due to crosscontamination or needlestick injury, which could be more relevant in
less-developed regions where healthcare services are less accessible.
Recent meta-analyses reported that the annual global prevalence of
needle-stick injuries in healthcare workers was around 44%, with that
in the Southeast Asia region and Africa reaching above 50% [104, 105].
Inhaler devices or nasal sprays pose less risk of cross-contamination.
They can be disinfected more readily in a household setting with 70%
ethanol or diluted sodium hypochlorite if needed for reuse or before
disposal as domestic waste [106, 107]. The shear demand for inhaler
devices may also motivate and accelerate the development of inhaler
devices made of sustainable materials [108], as well as single-use
disposable inhalers [109, 110]. On the other hand, used needles must
be handled as clinical sharps, adding extra costs to waste management
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and putting additional risks to the environment [111]. This poses a
substantial burden particularly among countries with limited
resources that still heavily exercise suboptimal waste disposal
protocols such as opening and burning syringes and sharps without
burying them, disposing glass vials without disinfection, or direct
dumping, thus jeopardising both the human and environmental health
[112].
All vaccines currently on the market are administered as liquids,
including those formulated in solid dosage forms that require
reconstitution prior to administration. Regardless of the platform,
vaccines are primarily biopharmaceuticals with poor stability in liquid
formulations that often require cold-chain logistics. This increases the
cost of vaccine distribution and hampers vaccine coverage, which can
lead to considerable public health impacts in a race against time during
a pandemic. The short shelf-life combined with the requirement of
strict storage conditions implies that stockpiling vaccines in
preparation for a disease outbreak can be expensive to maintain.
These shortcomings have driven research of formulating
biopharmaceuticals including vaccines into solid dosage forms for
improved stability [113–116]. By manufacturing vaccines as dry
powder for reconstitution prior to administration, the cost associated
with vaccine production, transportation, storage, and wastage because
of the short shelf-life of liquid formulations can be reduced [117].
Nonetheless, only part of the problems can be addressed since
additional manpower and resources must be allocated to vaccine
reconstitution, which can be an error-prone procedure. Vaccine-related
errors such as inadequate mixing, inaccurate aspiration of
reconstitution vials, and spillage or leakage of vaccines during handling
are not uncommon [118], especially for multi-component formulations
in which vaccine components are physically stored in separate
containers [119]. Patients could inadvertently receive diluent only
[120] or undiluted vaccine concentrate [121]. These risks could be
avoided in intranasal and inhaled vaccines which permit direct
administration of vaccines.
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4 Challenges andLimitationsofIntranas aland
InhaledVaccines
Despite the unique merits offered by intranasal and inhaled vaccines,
their formulation development presents a distinctive set of challenges
that require further research, as elaborated below.
4.1 VaccineAdjuvantsandFormulationDesign
Immunisation at the mucosae is a double-edged sword. On the one
hand, mucosal immunity at the entry point of pathogens offers early
neutralisation and host immune responses against infection, even with
the potential of achieving sterilising immunity [122, 123]. Strong
mucosal immunity is effective in reducing infection and halting disease
transmission, thereby contributing to herd immunity. On the other
hand, as the mucosa is exposed to the environment, it is evolved to
tolerate external stimuli to prevent immune responses or
inlammation from being constitutively activated, which could
otherwise be overwhelming [124, 125]. Therefore, intranasal or
inhaled vaccines must be engineered to elicit adequate immune
response effectively. Traditional platforms like live-attenuated or
inactivated vaccines are usually preferred for their stronger
immunogenicity, including FluMist® Quadrivalent, the
irst intranasal
vaccine in the market. Conversely, emerging vaccine technologies,
namely, subunit- or nucleic acid-based vaccines, often suffer from their
reduced immunogenicity in exchange for improved safety, especially
when administered locally. The problem of insuf
icient immune
response is complicated by the limited availability of effective
adjuvants. Adjuvants are excipients often included in vaccine
formulations to enhance immunogenicity. Typical adjuvants such as
aluminium salts (e.g., hydrated potassium aluminium sulphate, or
alum) are used in injectable vaccines. Their mechanism as adjuvants
remains poorly understood and might be relevant to the route of
administration [126], with hypotheses including acting as a depot on
which the antigens adsorb for a sustained release resulting in a longlasting immune response, and the induction of strong innate immune
responses following mild inlammation at the injection site [127, 128].
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The role of aluminium-based adjuvants for intranasal vaccines has
been inconsistent [129]. Other adjuvants for mucosal vaccines are
being investigated, such as silica nanoparticles (SiO2), cyclic-dimeric
guanosine monophosphate (c-di-GMP) [43, 130] and immune
potentiators [131] like polyinosinic:polycytidylic acid (Poly(I:C)). The
immunogenicity of intranasal vaccines has been shown to be heavily
inluenced by the adjuvants used [132], yet the full mechanism of
immunopotentiation of these adjuvants remains to be elucidated.
In addition to the potentially complex and delicate molecular
structures of vaccines, especially the novel vaccine platforms, the task
of designing vaccine formulation is further challenged by the lack of
approved excipients for inhalation, especially for dry powder
formulations. Formulation excipients should exhibit desirable critical
attributes, such as a good safety proile, compatibility with the vaccine
components and adjuvants, and the capacity to confer formulation
stability during manufacture, storage, and aerosolisation [133]. pH
buffers, osmolarity regulators, and preservatives are general
excipients used in liquid formulations of biopharmaceuticals including
vaccines. Excipients commonly used in the development of dry powder
vaccine formulations include drying stabilisers such as mannitol,
trehalose, lactose, and dextran [133–135]. For inhaled particle
formulations, dispersion enhancers can be incorporated to improve
aerosol performance, with -leucine being the most investigated
excipient [136, 137]. On the other hand, intranasal formulations
contain functional excipients to increase drug retention time and
reduce the rate of mucociliary clearance, by using mucoadhesive
agents such as chitosan and cellulose derivatives [138, 139].
Microcrystalline cellulose or hypromellose also serves as a viscosity
agent to prolong the residence time of liquid formulations in the nasal
cavity [140]. Given that vaccines are biomacromolecules that are prone
to degradation during atomisation and drying, early incorporation of
suitable excipients in the formulation design is indispensable to the
success of an intranasal or inhalable vaccine.
4.2 DoseVariabilityandAdministrationDevice
Compared to injections, intranasal administration and inhalation could
be subject to larger dose variability. In intranasal administration, the
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vaccine is actively dispersed into the nostril as liquid or powder
aerosol using a nasal spray. While the emitted vaccine dose can be
controlled, the amount of antigen that deposits in the nasal cavity
depends on several factors [141], such as the surface tension and
viscosity of the liquid formulation, as well as the spray plume angles,
droplet sizes and spray velocities of the spray device. These factors can
be optimised during formulation development [142]. It may be
desirable for intranasal vaccines to be deposited at the nasalassociated lymphoid tissue (NALT) located at the nasopharynx where
it houses an abundant number of APCs and lymphocytes [143]. On the
contrary, patient factors are less controllable, such as individual
variations in anatomy and pathophysiology of the nasal cavity,
including the eficiency of mucociliary clearance [144, 145], as well as
the variations in the use of devices, including the insertion depth of the
device and the administration angle [146]. They also exert a profound
effect on deposited dose and constitute dose variability.
With respect to inhalation, dose variability can be even more
pronounced, and each type of inhaler device has its own strengths and
constraints in delivering vaccines (Table 4). Metered-dose inhalers
(MDIs) and Soft Mist™ Inhalers (SMI) [147] are less relevant for the
delivery of vaccines as they have limited drug payload and are better
suited for delivering potent small molecules. Nebulisers are frequently
used in clinical trials for the delivery of aerosolised vaccine candidates
[87, 148–150]. They offer distinct advantages. Firstly, investigational
vaccines can be formulated into simple aqueous solutions and be
aerosolised using existing nebulisers. It eliminates certain formulation
challenges associated with other inhaler devices, such as
biocompatibility with propellant in MDIs, or particle engineering in dry
powder inhalers (DPIs), thereby signiicantly reducing the barriers of
formulation at the early phase of new vaccine development. The drug
reservoir design also permits a high dose of vaccines to be delivered.
Since an external energy source is used to generate slow-moving
respirable droplets, vaccine aerosols can be inhaled during tidal
breathing without the need for hand-breath coordination. This makes
nebulisation more suitable for people with limited inspiration capacity.
However, nebulisation also comes with its downsides. The
administration time is long, which would become a bottleneck to the
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inoculation rate during a mass vaccination program. Nebulisers are
also associated with the risk of potential cross-contamination to the
environment by droplets aspirated from infected patients [151]. It can
be particularly concerning during an active outbreak of an epidemic or
pandemic. The risk of contamination can be reduced through adequate
ventilation and the use of outlet ilters, yet these measures inevitably
lead to additional costs to immunisation. A dry powder inhaler
presents as an attractive device for the delivery of inhaled vaccines. It
is the only kind of device that allows direct pulmonary administration
of vaccines in dry powder formulation, thus offering superior product
stability and reduced logistic cost. Most DPIs are passive devices that
rely solely on the inspiration force of the patients for powder
dispersion and aerosolisation. While there have been many clinical
trials on intranasal and inhaled vaccines of liquid formulations, there is
a very limited clinical trial of inhalable dry powder vaccine, with one
formulation targeting measles that was prepared by supercritical luid
drying [60, 152]. Even with optimised physicochemical and aerosol
properties of the formulation, difference in effective deposited dose
remains inevitable because of individual variations such as lung
functions and device manoeuvre technique [153–155]. DPIs also
possess a limit on the powder dose that can be delivered [156, 157],
and devices capable of delivering high powder doses are under active
research [158].
Table4 Strengths and limitations of different inhaler devices with respect to the
delivery of vaccines
Devices Strengths Limitations
Nebulisers Simple formulation design; ‘go-
to’ device in clinical trials for
vaccine candidates
Administration time can be long
(minutes)
Less compatibility issues Potential contamination of the
surrounding environment by
exhaled droplets [151]
Virtually unlimited payload.
Suit most patients
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Devices Strengths Limitations
Metered-dose
inhalers
Low cost Compatibility issues with organic
propellants
Disposable device [110] High shear stress during
aerosolisation
The payload can be limited
Soft mist
™
inhaler
Improved deep lung delivery
over MDI
The payload can be limited
Proprietary device [147]
Dry powder
inhalers
Higher drug payload (tens of
milligrams) [157]
Formulation design and particle
engineering can be challenging
Direct administration of solid
formulations
May not suit patients with
insuficient inspiratory force
Unit-dose design available
Longer shelf-life
Disposable device
Notwithstanding the various devices available for drug delivery
through intranasal route or inhalation, there are several common
considerations that deserve more attention before their adaptation for
vaccination. Notably, immune response and safety of intranasal and
inhaled vaccines must be meticulously evaluated in clinical trials to
ensure proper dosage, given their inherently larger dose variability.
Dose determination could be further complicated by the
aforementioned variations in mucosal tolerance between individuals.
Intranasal or inhaled vaccines can also result in a less consistent
particle deposition along the respiratory tract. For example, a fraction
of particles may deposit at the back of the throat and be swallowed
[159]. The evaluation of the effects of such off-target deposition on
immune response and vaccine safety becomes crucial. The less
predictable deposition pattern could result in different
pharmacokinetic and pharmacodynamic properties with more
pronounced variations that are distinct from their injectable
counterparts. It is prudent to evaluate not only the extent and the
duration of the triggered immune responses such as serum
immunoglobulin levels, but also the pharmacokinetics of the vaccine
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particles, especially with the newer vaccine platforms. Regarding
vaccine delivery, devices like MDI and nebuliser are designed to store
and deliver multiple doses of medications for managing chronic
respiratory disorders, whereas unit dose devices are more common for
nasal spray and DPI. Provided that vaccination is only given as a limited
number of doses separated by weeks or months, portable and
disposable single-use device that can be manufactured at large scale
and at low cost is suited for such purpose [109, 110].
4.3 PreclinicalandClin icalStudies,and
InadequatePublicRecognition
Preclinical studies of intranasal and inhaled vaccines can be dificult
because they require appropriate animal models. Ideally, they should
exhibit relevant immunogenicity to the vaccine and adjuvants with
comparable pathophysiology to the targeted pathogens, while
permitting vaccines to be given by the intended route of
administration. Studies involving multiple animal models are not
uncommon. The lack of in vitro-in vivo correlation for inhalable
formulations also implies that clinical trials of vaccines are often
needed [160]. Although healthy adults are often recruited in early
phases of clinical trials for their greater recovery capacity in case of
adverse reactions, thorough and careful evaluations must be
conducted when the use of investigational vaccines is extended to
susceptible populations such as the elderly, children and infants. Their
pulmonary functions and airway anatomy can differ from healthy
adults, which could affect the delivered dose and dose variability of
intranasal and inhaled vaccines. Additionally, as these cohorts are
usually more vulnerable to infections and thus beneit more from
vaccinations, they are prioritised to be immunised. Depending on the
targeted diseases, healthy adults could already be seropositive at the
baseline [78], confounding the interpretation of the outcomes.
Finally, recognising the signiicance of inhaled or intranasal
vaccines as a viable or even superior alternative to conventional
injectable vaccines by healthcare professionals and policymakers is of
paramount importance to the development of future intranasal and
inhaled vaccines. The utility of intranasal and inhaled vaccines has
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