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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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Vaccine
platform
Descriptions Pros Cons
Liveattenuated
Live virus particles
(capable of exhibiting
full virus replication
cycle) with
modiications to
reduce pathogenicity
Strong
immunogenicity as
the full virus is
exposed to the
immune system
Not suitable in
individuals with
compromised
immunity
Longer-lasting
immune response
Risk of microbe
reactivation
Inactivated ‘Killed’ virus particles
that have been
inactivated using
chemicals, heat, or
radiation
Strong
immunogenicity as
the full virus is
exposed to the
immune system
Adjuvants may be
required to enhance
the immune
response
Virus-like
particle
Consists of essential
structural proteins for
the formation of a virus
particle on which virus
antigens attach
Eficient cellular
entry
Adjuvants are often
needed to enhance
immunogenicity
Carries no genetic
materials, thus no
risk of infection
Subunit Comprises of viral
antigens which are
typically proteins [12,
13]
Carries no genetic
materials, thus no
risk of infection
Adjuvants are often
needed to enhance
immunogenicity
Viral vector Contains low
pathogenic viruses as
vectors whose viral
genomes have been
modiied to encode the
antigenic proteins [15]
Can be either
replicating or nonreplicating
Prior exposure to
the viral vector may
compromise
immunogenicity
Eficient cellular
entry
DNA Plasmid (circular) DNA
containing a genomic
sequence that
transcribes and
translates the antigenic
proteins
Sequence can be
adapted to express
different antigens
A delivery vector
must be used
No risk of infection Cellular and nuclear
entry can be
challenging
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Vaccine
platform
Descriptions Pros Cons
mRNA Messenger RNA
containing genomic
sequence that
translates to the
antigenic proteins [17]
Sequence can be
adapted to express
different antigens
A delivery vector
must be used
No risk of infection Cellular entry can be
challenging
All the above platforms deliver antigens directly to the recipient.
Another vaccination strategy is to deliver a viral genome that codes for
the antigens to the recipient, harnessing the host cellular machinery in
synthesising the antigens [14]. Viral vector vaccines adapt virus of low
virulent (e.g., adenovirus used in the COVID-19 vaccine
Vaxzevria™/Covishield™ co-developed by Oxford University and
AstraZeneca) as a vector to deliver genes that encode the target
antigens [15]. Viral vector vaccines can either retain their replication
ability or have the viral replication genes deleted for improved safety.
The antigen-encoding genes can also be delivered as plasmid DNA or
messenger RNA (mRNA) using non-viral vectors. Notably, two of the
injectable COVID-19 vaccines, tozinameran (Comirnaty® from P
izer
and BioNTech) and elasomeran (Spikevax™ from Moderna), belong to
mRNA vaccines. Both of them use lipid nanoparticles (LNP) as the
delivery vector [16, 17].
The existence of many vaccine platforms implies that vaccines do
not represent a single class of biomolecule but can take the form of full
microorganisms, proteins,
or nucleic acids. Each of the platforms thus
demands its own speciic requirements for intranasal and inhaled
formulations. Discussion on the delivery and formulation of respective
biologics is covered in other chapters of this book. Currently, most
vaccines are parenteral injections intended to induce strong systemic
immunity. There are only a handful of approved vaccines that are
administered through the mucosal route (Table 2) [18, 19]. While
approved intranasal and inhaled vaccines might be lacking in number,
they possess important immunological advantages over injectable
vaccines, as illustrated in this chapter. Other social and economic
beneits of these vaccines are also presented, followed by an overview
of their challenges and limitations.
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Table2 Examples of clinically available mucosal vaccines
Vaccine Targeted
pathogen
Vaccine
platform
Routeof
administration
(dosageform)
Biopolio®, mOPV, and
tOPV
Poliovirus Live
attenuated
Oral (liquid)
RotaTeq
®
Rotavirus Live
reassortant
Oral (liquid)
Rotarix™ Rotavirus Live
attenuated
Oral (liquid)
Typhi Vivotif
®
Salmonella
typhimurium
Live
attenuated
Oral (capsule)
Dukoral
®
Vi briocholerae Inactivated Oral (liquid)
Euvichol®/ShanChol
™
Vi briocholerae Inactivated Oral (liquid)
Vaxchora
®
Vi briocholerae Live
attenuated
Oral (liquid)
FluMist
®
Inluenza A & B Live
attenuated
Intranasal (liquid spray)
iNCOVACC
®
SARS-CoV-2 Viral vector Intranasal (liquid spray)
Convidecia® air
SARS-CoV-2 Viral vector Intratracheal (liquid for
nebulisation) [87]
Adapted from Refs. [18, 19]
mOPV monovalent oral polio vaccine, tOPV trivalent oral polio vaccine
2 Principl esofIntranas alandInhaledVaccines
Intranasal and inhaled vaccines are vaccines that are administered
through the intranasal route into the nose and pulmonary route into
the lung, respectively (Fig. 2). In addition to being non-invasive, the
rationale of intranasal and inhaled vaccines in protecting us from
respiratory infectious diseases arises from their capability to trigger
immune responses that closely resemble natural infection [18, 20].
Particularly, mucosal immunity are induced. It refers to the immune
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responses offered by the immune system localised at the mucosae that
comprise of mucosa-associated lymphoid tissue (MALT), lymphocytes,
as well as effector molecules including cytokines, chemokines and
antibodies (or immunoglobulins, Ig) that function independently of the
systemic immunity [20]. Mucosal immunity is inadequately induced by
injectable vaccines [21, 22]. Activation of the mucosal immune system
results in three critical immune responses, namely tissue-speciic
mucosal immune responses, common mucosal immune system, and
systemic immunogenicity (Table 3) [23]. These enhanced effector and
immune responses induced through direct exposure of antigens to the
mucosae allow intranasal and inhaled vaccines to provide better
protection than injectable vaccines [24], as elaborated below.
Fig.2 Intranasal administration (left) using an intranasal atomization device and
intratracheal administration (right) using a unit-dose dry powder inhaler
Table3 Summary of major responses of mucosal immunity
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Responses Features
Tissue-speciic mucosal
immune response [124]
Formation of iBALT
Humoral and cellular immune responses are mediated
through local production of sIgA and recruitment of
TRM CD8+ and CD4+ cells, respectively
Common mucosal
immune system
Mucosal immunity can be induced at sites other than
that initially exposed to the antigens [55]
Systemic immunogenicity
[65]
Serum-neutralising IgG has been detected upon mucosal
vaccination, resembling the course of a natural
infection
Seroconversion has been observed in different
respiratory infections such as inluenza, RSV infection,
and COVID-19
iBALT inducible bronchus-associated lymphoid tissue, Ig
immunoglobulin, RSV respiratory syncytial virus, sIgA secretory IgA,
TRM tissue-resident memory
2.1 Tissue-SpeciicMucosal ImmuneResponse
The bronchus-associated lymphoid tissue (BALT) is usually absent in
the lungs of healthy adults [25]. It can be induced by infection [26, 27]
or inlammation due to exogenous stimuli such as cigarette smoke [28]
and diesel exhaust [29]. The formation of inducible BALT (iBALT)
forms the basis of mucosal immune response. iBALT is a tertiary
lymphoid structure that neither demonstrates a well-deined structure,
nor situates at speciic anatomical locations. Rather, iBALT can be
found throughout the lung and it has a diverse composition, ranging
from isolated B cells clusters that lack obvious organisation [30] to
fully developed lymphoid tissues that consist of B cells, T cells, and
other antigen-presenting cells (APCs) including dendritic cells and
macrophages [31]. Hence, iBALT contributes to both humoral and
cellular immune responses. The development and organisation of
iBALT is regulated under homeostatic chemokines primarily through
the IL-17 pathway of inlammation, in which the expression of CXCL13
attracts B cells, and CCL19 and CCL21 attract T cells [32]. Upon the
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formation of iBALT, antigen acquisition and presentation can be
achieved by Microfold (M) cells which are often located at the nearby
epithelium [33], via the afferent lymphatics, or through the migration
of antigen-acquiring dendritic cells from the airways [34]. Detail on the
formation and physiology of iBALT has been recently reviewed [31].
B cells are the major lymphocytes involved in the humoral immune
response. After being presented with processed antigens through
major histocompatibility complexes (MHC) by the APCs, B cells begin
to differentiate into plasma cells that are responsible for the secretion
of Ig. Whilst IgG is the main class of Ig produced in systemic immune
response, stimulation of mucosal immunity initiates the local
production of a high level of secretory mucosal IgA (sIgA) in addition to
serum IgG [35]. sIgA is pivotal in facilitating passive immune
protection at mucosal surfaces since the mucosal secretion contains
only a low level of complement proteins and leucocytes which are
responsible for mediating strong immune effector functions [36]. sIgA
offers a wide array of protections. Foremost, it elicits an immediate
immune reaction by neutralisation, directly preventing pathogens
from interacting with receptors expressed on the host cells through
steric hindrance (immune exclusion) [37]. The protective effects of
sIgA are not conined to the mucosal surface. Antigens that have
crossed the epithelium and reached the lamina propria, and those that
are inside the infected cells can also be neutralised by sIgA
(intracellular neutralisation). These bound antigens are then expelled
to the airways via the polymeric immunoglobulin receptors (pIgR) on
the basolateral side of epithelial cells (antigen excretion) [38]. sIgA
also mediates cellular immune response, including phagocytosis and
cytokine release [39], through binding with the IgA Fc receptor FcαRI
(also known as CD89) expressed in myeloid lineage cells like
monocytes, macrophages, and neutrophils [40–42]. Eficient induction
and secretion of IgA into airway lumens through mucosal vaccination
is a characteristic distinction to injectable vaccines [43, 44], with the
former being more effective in alleviating disease progression during
the early phase of infection. Compared to sIgA, systemic antibodies are
less effective in preventing systemic invasion of pathogens or
abolishing disease transmission that occurs in the respiratory system
[45, 46].
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The induction of antigen-speciic tissue-resident memory T (TRM)
cells represents another signiicant immune response unique to
mucosal immunisation and constitutes the cellular component of an
adaptive immune response. Pulmonary TRM cells are critical in the
prevention of respiratory viral infection by eliciting specialised and
rapid effector responses in adaptive immunity, including the
expression of inlammatory cytokines and chemokines for the
enhancement of tissue antiviral resistance and recruitment of auxiliary
immune cells such as dendritic cells [47]. Speci
ically, the CD8+ T
RM
cells can react quickly upon reencountering the antigens or pathogens
[48] while the helper CD4+ TRM cells are engaged in the formation of
protective respiratory B cells and CD8+ T cells in the lung [49]. These
TRM cells were once considered lasting memory cells that confer
enduring mucosal immunity [50]. Recent studies have been suggesting
that CD8+ TRM cells in the lung are more short-lived than previously
thought, due to the lack of adhesion molecules CD69 and CD103, with a
half-life as short as 14
days and their population substantially declined
within 100–200 days. This contrasts with their counterparts in other
tissues such as the skin and the intestine [51, 52]. Nonetheless, CD4+ T
resident helper cells may still contribute to long-term immunity that
initiates a rapid response to subsequent infections [53]. A booster
dose in sustaining an effective memory cell population in the lungs has
been suggested [18], and additional research is warranted.
2.2
Common MucosalImmuneSystem
The common mucosal immune system is another major and
exploitable characteristic of mucosal immune response [54]. Although
the initial priming of mucosal immune response can be anatomically
conined to a speciic mucosal tissue, it has been shown that exposure
to antigens at one mucosa can trigger immunity at the distinct mucosal
regions, sometimes even in different physiological systems, for
example between respiratory and digestive systems [55]. This
property of cross-mucosal immunity opens the possibility of achieving
target mucosal immunity that is distant from the site of vaccination. In
the context of intranasal and inhaled vaccines, their immunogenicity
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could thus rely less on the site of vaccine deposition and antigen
uptake, due to common mucosal co-stimulation. In a deposition study
using a cotton rat model, the whole inactivated inluenza virus vaccine
was administered intratracheally either to the deep lung region as
liquid or to the trachea and central lung region as powders [56]. While
serum IgG levels were similar between the two groups and were
comparable to the positive control administered intramuscularly,
indicating priming of systemic immune response, vaccine-speciic IgA
was not only detected in the lung but also in nasal washes. The latter
was ascribed to antigen-speciic B cells migrating from the site of
induction to distant mucosal lymphoid tissue. In a follow-up study,
inhalable powder formulations containing both the inluenza subunit
vaccine and HBsAg were administered to mice intratracheally, using
two devices with different deposition proiles [57]. Both the lung
washes and serum displayed comparable titre levels of IgA and IgG,
respectively, against inluenza regardless of the administration device.
Intriguingly, only animals with antigens reaching the peripheral
regions expressed hepatitis B-speciic IgG in serum. It was proposed
that airborne pathogens exhibiting speciic molecular patterns can be
recognised along the respiratory tract, thus rendering the induction of
immune responses less dependent on the site of antigen deposition.
While there is no speciic receptor in the airway targeted by hepatitis
B, the deposition of antigens in the deep lung region could allow
suficient time to trigger immune responses. Besides, HBsAg could
form virus-like particles that passively diffuse from alveoli to draining
lymph nodes, inducing immune reactions [57]. In a separate study that
evaluated the effects of different sites of pulmonary deposition
through varying the route of delivery (intranasal or intratracheal
administration), the volume of delivered solution and the angle of tilt, a
monovalent inluenza vaccine was administered to BALB/c mice [58].
While similar IgA titres were detected in the nasal washes of all groups
regardless of the delivery methods, there was a 1-log reduction in IgA
titre in broncho-alveoli lavage for animals inoculated by the intranasal
route. No difference was observed otherwise between groups that
targeted deposition in different regions within the lungs. Nevertheless,
only the deep lung targeted groups could present similar serum IgG
titres to the control intramuscular group. Recently, a comparative
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study exploring the relationship between the biodistribution of
vaccine and their immunogenicity in the lung using murine models and
adenovirus-vectored vaccine was reported [59]. Mice vaccinated via
the intratracheal route exhibited more pronounced immune responses
and protective effects in the lungs than the intranasal route. These
studies clearly demonstrated some important distinctions between
intranasal and inhaled vaccines that call for further investigations,
especially clinical studies.
2.3 SystemicImmunogenicity
The capacity of intranasal and inhaled vaccines to trigger systemic
immunity in addition to mucosal immune responses conceivably
makes them more advantageous than their injectable counterparts.
Indeed, preclinical studies have reported that strong systemic
immunity comparable to intramuscular vaccination could be induced
by intranasal or inhaled vaccines [60–63], including the
aforementioned deposition studies [56–58]. For instance, intratracheal
administration of an inluenza vaccine containing haemagglutinin
antigen signiicantly induced robust serum antibodies as well as local
IgG and IgA in mice [43]. In another study that aimed to develop an
inhalable inluenza powder vaccine, both powder and reconstituted
vaccines administered by pulmonary route to rats induced similar
serum IgG levels and higher serum IgA levels as compared to that by
subcutaneous injection [64]. The inhaled vaccines could also trigger a
much higher mucosal IgA and to a lesser extent IgG without causing
acute histological toxicity to the lung.
Systemic immune responses triggered by intranasal and inhaled
mucosal vaccination are also observed clinically, including the
intranasal vaccine FluMist® among other vaccine candidates [65].
FluMist® was approved by the U.S. Food and Drug Administration
(FDA) and European Medicines Agency (EMA) in 2003 and 2012,
respectively [66]. It is currently indicated for the prevention of
in
luenza disease caused by inluenza type A and B in individuals of age
between 2 and 49 years old. As the vaccine effectiveness appeared to
decline over time, possibly due to the combined effects of antigenic
drift and inter-strain competition in multivalent preparations [11, 67,
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68], novel mucosal inluenza vaccine candidates with improved and
sustained protection are still in demand. For instance, intranasal
inoculation of live-attenuated H5N1 vaccine that lacked the highly
virulent non-structural protein 1 (delNS1-H5N1) was well-tolerated
and able to trigger profound vaccine-speciic serum Ig titres [69].
Seroconversion was observed in 75% of the subjects even after one
dose of vaccine, and sIgA responses were demonstrated in 42% of
participants upon completing the scheduled second vaccination. The
safety and immunogenicity of another haemagglutinin antigen-based
intranasal inluenza vaccine candidate adjuvanted with an E.coli-
derived heat-labile enterotoxin was evaluated in a phase II trial [70].
While the titres of induced serum anti-HA Ig were comparable among
the treatment groups (with or without adjuvants), only the adjuvanted
vaccines were shown to induce substantial levels of sIgA without
signiicant differences in adverse events proile after the second dose.
In another study, a single intranasal dose of M2SR (M2-deicient single
replication) H3N2 inluenza vaccine was shown to offer enhanced
mucosal and systemic immunity [68]. Compared to the 10% rate of
H3N2 seroconversion achieved by FluMist® in seronegative subjects,
the M2SR vaccine candidates led to a rise of serum antibody titre in
71% of the recipients, highlighting a possible improvement in disease
control.
Besides in
luenza, systemic and mucosal immunogenicity upon
intranasal and inhaled vaccination have also been observed for other
respiratory viral infections in clinical trials, notably respiratory
syncytial virus (RSV) infection and COVID-19. RSV infection remains
one of the leading causes of hospitalisation in infants [71], and there
are no approved intranasal or inhaled RSV vaccines at the time of
writing. Research on RSV vaccines has also been motivated by the
recent surge in RSV incidence in various parts of the world [72–74].
Social restrictions during the COVID-19 pandemic have not only
limited the spread of COVID-19 but also other respiratory infections,
including RSV, which resulted in a cohort of children with no natural
immunity against RSV [72]. The relaxation of these restrictions has led
to a spike in RSV infections in children during atypical season. Some
promising results on recent studies of RSV vaccines have been
reported. For instance, RSV could be attenuated through deletion of the
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