e21769

16

Brazilian Journal of

Article
Pharmaceutical Sciences
http://dx.doi.org/10.1590/s2175-97902023e21769

Oral and nasal vaccination: current

prospects, challenges, and impact of
nanotechnology-based delivery systems
Natália Floriano Paiva, Fabiana Testa Moura de Carvalho Vicentini

School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil

Currently, mucosal vaccine administration has stood out as an easier and non-invasive application
method. It can also be used to induce local and systemic immune responses. In the COVID-19
pandemic context, nasal and oral vaccines have been developed based on different technological
platforms. This review addressed relevant aspects of mucosal vaccine administration, with
emphasis on oral and nasal vaccinations, in addition to the importance of using nanotechnology-
based delivery systems to enable these strategies.

Keywords: Mucosal vaccination. Oral vaccine. Nasal vaccine. Nanocarriers. Nano-vaccinology.

INTRODUCTION three groups or generations. First-generation vaccines

are traditional or classic vaccines that use intact (entire)
Vaccines have contributed hugely to the maintenance pathogens but are subjected to treatments for their
of global health (Zhang, Billingsley, Mitchell, 2018a). Large- inactivation or attenuation. They include for example
scale immunization is crucial to reducing the risk of infection those vaccines against pertussis, smallpox, polio, rubella,
in individuals who are unvaccinated or cannot be vaccinated. measles, and adenovirus (Diniz, Ferreira, 2010).
It acts by interrupting disease transmission, whether direct Live-attenuated vaccines are those composed of
and restricted to the human population such as measles and pathogens unable to infect or replicate in humans, but
rubella, or indirectly such as yellow fever (Fernandes et al., still can evoke the immune response (Rockwell, 2017).
2021). Advances in vaccinology have provided significant Attenuated suspensions of pathogenic microorganisms
benefits to public health, eradicating diseases, preventing are obtained by serial passage method or chemical
epidemics, and reducing deaths from infectious diseases. mutagenesis, both techniques produce mutant strains
In this context, advances in biotechnology have enabled with reduced virulence and toxicity (Jiskoot, Kersten,
the development of increasingly safe and effective vaccines Mastrobattista, 2013). Among the advantages, these
(Braz et al., 2014). The main objective of a vaccine is to vaccines have high immunogenicity and can stimulate
present a specific antigen or set of antigens to the host’s Toll-Like Receptors (TLR) to the same extent as in live
immune system, as a way to fight against a pathogen viral pathogen infection. They can also offer longer-
(Negahdaripour et al., 2017) or a developed pathology, such lasting protection against viruses, for example (Han et
as cancer, for example. al., 2021). However, despite being an efficient strategy,
According to the literature, vaccines are classified the following disadvantages should be highlighted:
according to methods used in antigen preparation into integration of the pathogen’s nucleic acid sequence into
the host’s genome, somewhat unlikely reversal to a more
virulent strain or pathogen reactivation, and potentially
*Correspondence: F. T. M. de C. Vicentini. Faculdade de Ciências
Farmacêuticas de Ribeirão Preto. Universidade de São Paulo. Av. Café
serious complications in children and immunodeficient
S/N, Monte Alegre, Ribeirão Preto, São Paulo, Brasil. 14040-903, Ribeirão individuals. Thus, their use becomes restricted, not being
Preto, SP. Phone/Fax: 00 55 16 33154257 / 33154232. E-mail: fabtesta@
fcfrp.usp.br. ORCID: https://orcid.org/0000-0002-0842-9130 an efficient and safe method for the prevention and/or

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 Natália Floriano Paiva, Fabiana Testa Moura de Carvalho Vicentini

treatment of several diseases such as viral hepatitis, These purified antigens may be extracted from natural
acquired immunodeficiency syndrome (AIDS), and or synthetic sources, or even derived from recombinant
cancer (Jiskoot, Kersten, Mastrobattista, 2013). DNA technology (Braz et al., 2014).
Another important approach is vaccine production In this sense, subunit vaccines include only pathogen
from inactivated pathogens through heat, radiation, or fragments as antigens, e.g., proteins, polysaccharides,
chemical products (e.g., formalin and formaldehyde) or viral parts capable of producing virus-like particles
(Rockwell, 2017). These processes reduce the ability (VLPs). The former can be produced by purified antigenic
of microorganisms to multiply, consequently causing proteins from the entire pathogen, or by recombinant
disease, without losing their immunogenic potential. genetic engineering. This technique includes inserting a
The inactivation technique promotes changes in the gene that encodes an antigenic protein into an expression
envelope permeability and protein conformation of system capable of producing large amounts of the antigen
pathogens, besides damaging their genetic material of interest in cell cultures. First-generation polysaccharide
(Fernandes et al., 2021). Inactivated vaccines display vaccines are based on capsular polysaccharides purified
a complete repertoire of immunogenic components from whole pathogens; however, these vaccines have
of intact pathogens and, compared to live-attenuated poor immunogenicity, short-term protection, and
vaccines, they pose no risk of pathogen reactivation reduced immune response after some administrations.
(Li et al., 2020). As inactivated vaccines are non- Accordingly, conjugate vaccines have emerged, resulting
live vaccines, they cannot infect the host and cause from polysaccharides chemically bonding to carrier
disease for not containing any living or infectious proteins to induce a strong immune response (Vetter
particles; therefore, they have a good safety profile et al., 2018). Ultimately, virus-like particle vaccines
even in immunocompromised individuals (Vetter et are based on ordered viral self-assembly from protein
al., 2018). However, like the attenuated ones, they subunits that are noted in many different virus families.
also have disadvantages, such as little or no activation Such vaccines may present structures that are highly
of cell-mediated immunity; and more adverse effects antigenic to the immune system but are safer due to
compared to the attenuated and second- and third- the absence of the viral genome, which can revert to
generation vaccines, which will be discussed below virulence (Afrough, Dowall, Hewson, 2019).
(Jiskoot, Kersten, Mastrobattista, 2013). During As for its positive aspects, the subunit vaccine
the inactivation process, structural deformation of stands out for its absence of risks associated with
pathogen immunogenic epitopes may also occur, handling live pathogens in the laboratory (Han et al.,
leading to a decline in immune protection (Li et al., 2021). Besides being safer and easier to produce, other
2020). Therefore, these vaccines are considered less relevant advantages can be highlighted, such as the
immunogenic, not being able to provide long-term use of a greater variety of pathogenic microorganisms,
protection, thus requiring adjuvant addition and/ or increased stability, and fewer allergic and autoimmune
multiple doses (Han et al., 2021). responses (Negahdaripour et al., 2017). However, when
Second-generation vaccines are based on the fact it comes to disadvantages, these vaccines contain fewer
that, for some pathogens, protection can be given by antigens than those previously described, in addition
inducing antibodies directed at specific targets, such to their purification processes often eliminating innate
as the toxin responsible for disease symptoms or sugar immunity-triggering components, which may be less
present on the surface, allowing the host’s immune system immunogenic (Vetter et al., 2018). Therefore, this problem
to neutralize and eliminate pathogen (Diniz, Ferreira, can be minimized by the use of adjuvants and fusion
2010). Thus, this class includes subunit vaccines, which with immunostimulant molecules (Li et al., 2020).
use pathogen-specific fragments and components, such Vaccines against tetanus, diphtheria, and hepatitis B are
as proteins, carbohydrates, and capsids, to stimulate the examples of subunit vaccines, while vaccines designed
activation of a strong immune response (Han et al., 2021). to control meningococcal meningitis and pneumonia can

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Oral and nasal vaccination: current prospects, challenges, and impact of nanotechnology-based delivery systems

be mentioned as an example of polysaccharide subunit factor is potential mutagenesis or oncogenesis due to

vaccines (Diniz, Ferreira, 2010). their integration with the host chromosome, requiring
Finally, third-generation and newer vaccines are integration studies on DNA vaccine safety (Li et al.,
characterized by making use of the pathogen genome. 2020). Its relatively low immunogenicity is probably due
They are nucleic acid vaccines obtained by genetic to a low transfection rate, as a non-condensed plasmid
engineering methods, which encode relevant antigens has a highly distended and negatively charged structure,
to induce host immunity (Diniz, Ferreira, 2010). making it difficult to enter the cell. Even if cell entry
Immunization with nucleic acid vaccines involves the does occur, entry into the nucleus, which is required to
administration of genetic materials such as plasmid DNA achieve transcription, is extremely inefficient. Therefore,
or messenger RNA (mRNA), which encode antigens to increase DNA vaccine immunogenicity, plasmids
of interest (Jiskoot, Kersten, Mastrobattista, 2013). In may be produced to encode antigens, as well as encode
short, a specific nucleic acid is introduced into the host together immunostimulatory molecules to induce a strong
cells to initiate pathogen-protein synthesis; then, the immune response (Wallis, Shenton, Carlisle, 2019).
host immune system recognizes it as a foreign agent Among the third-generation vaccines, RNA
and triggers an immune response against it, as in a vaccines consist of linear RNA molecules transcribed
live pathogen infection (Han et al., 2021). In general, in vitro and then purified before administration. These
nucleic acids allow the encoding of a wide variety of vaccines have genetic information with appropriate
antigens and can induce long-term humoral and cellular translational elements, which provide efficient production
immunity (Jiskoot, Kersten, Mastrobattista, 2013). Thus, of the encoded antigen (Sasso et al., 2020). They are
different vaccines can be developed without the need for currently a promising alternative to conventional
new production, purification, and validation methods, vaccines, as they have high potency, rapid development,
leading to fast, flexible, and cost-effective development and low production costs. Besides that, they present a
and production since the characteristics of these vaccines greater safety profile, high efficacy, and fast production.
are independent of the encoded proteins (Fernandes et First, mRNA is not infectious and its platform is unable
al., 2021). to integrate into the human genome, with no risk of
Plasmid DNA is produced by replicating bacterial infection or insertional mutagenesis. Second, its high
cells, such as E. coli, which is further purified using efficiency is due to potential structural changes that make
established methods. Its administration route is mRNA more stable and highly translatable using delivery
intramuscular due to its low turnover rate, preventing systems, allowing a rapid uptake and expression within
DNA from being rapidly dispersed to cells in the the cytoplasm. Lastly, they display a high yield of in
division process. After intracellular DNA uptake, the vitro transcription reactions, resulting in fast, low-cost,
encoded protein is expressed on the surface of host and scalable production. There are two main types of
cells (Jiskoot, Kersten, Mastrobattista, 2013). Compared RNA used in vaccines: non-replicating (conventional)
to other vaccine technologies, DNA vaccines offer and virus-derived self-replicating. Conventional RNA
a platform for rapid and flexible development and vaccines encode the antigen of interest and contain
production, making it an attractive strategy for combating untranslated regions (UTRs), while self-amplifying
emerging epidemics, such as the COVID-19 pandemic. RNA ones encode not only the antigen of interest but
Furthermore, these vaccines produce antigens in target also the machinery needed for viral replication, allowing
cells, promoting the return of native conformation and intracellular RNA amplification and abundant protein
post-translational modification of pathogen antigens. expression (Pardi et al., 2018).
However, DNA vaccines pose some challenges that must In this context, viral vector vaccines are a versatile
be considered. One is the need for adjuvants and delivery platform for delivering the genetic code through
systems due to their limited immunogenicity, as they viruses to produce antigens in the cells of vaccinated
cannot be propagated and amplified in vivo. Another individuals. These vaccines can make use of attenuated

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 Natália Floriano Paiva, Fabiana Testa Moura de Carvalho Vicentini

and non-replicating viral vectors to deliver antigens vaccines. Finally, each viral vector employed requires
in the form of genetic information directly to cells, different cellular systems for production, which makes
improving its generation, targeting, and processing. the process complex and more expensive (Fernandes
This way, the antigen will undergo cellular synthesis et al., 2021).
and processing similar to those of a natural infection. Vaccines under development, or in use, in clinical
Furthermore, viral vector vaccines can be administered trials against COVID-19 may fall within the different
without additional adjuvants and accept variations as a technological platforms described above (Table I).
function of the vector used. They can induce a robust Additionally, according to World Health Organization
specific cellular and humoral immune response against (WHO) guidelines, most of the ongoing projects
the target antigen, with a better safety profile and high- for vaccination against COVID-19 have parenteral
yield production processes, which are essential in high- administration through intramuscular injection, intending
demand situations such as the covid-19 pandemic. to induce the production of high-titer neutralizing
However, some negative points should be highlighted, systemic antibodies that can control the infection.
such as the fact that viral vectors are genetically However, one of the most negative points of such a
modified organisms that may show potential health vaccination strategy is the induction of a mucosal immune
risks when exposed to the environment. Some safety response, whose efficacy and durability are low, allowing
issues are of concern such as a potential integration into the virus to enter the body through the oral-respiratory
the host genome or very high or persistent replication of tract (Ashraf et al., 2021).

TABLE I - Vaccines under development or in use against COVID-19 fall within the different technological platforms (adapted
from https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines - last update: 03/11/2022)

Number Route of
Vaccine platform Type of vaccine Phase Developers
of doses administration
MV-014-212
A live attenuated
Live attenuated vaccine that
1 Intranasal Phase 1 Meissa Vaccines, Inc.
virus expresses the
spike protein of
SARS-CoV-2
Live attenuated Codagenix and Serum
COVI-VAC 1-2 Intranasal Phase 3
virus Institute of India
CoronaVac
Sinovac Research and
Inactivated virus Inactivated SARS- 2 Intramuscular Phase 4
Development Co., Ltd
CoV-2 vaccine
Sinopharm, China
Inactivated SARS-
National Biotec Group
Inactivated virus CoV-2 vaccine 2 Intramuscular Phase 4
Co and Wuhan Institute
(Vero cell)
of Biological Products
CoV2-OGEN1,
Protein subunit 1-2 Oral Phase 1 USSF/Vaxform
protein based vaccine
Center for Genetic
Protein subunit RBD + AgnHB 3 Intranasal Phase 1/2 Engineering and
Biotechnology (CIGB)

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Oral and nasal vaccination: current prospects, challenges, and impact of nanotechnology-based delivery systems

TABLE I - Vaccines under development or in use against COVID-19 fall within the different technological platforms (adapted
from https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines - last update: 03/11/2022)

Number Route of
Vaccine platform Type of vaccine Phase Developers
of doses administration
Full length
recombinant SARS-
CoV-2 glycoprotein
Protein subunit 2 Intramuscular Phase 3 Novavax
nanoparticle
vaccine adjuvanted
with Matrix M
MVC-COV1901 Medigen Vaccine
(Spike-2P protein + Biologics, Dynavax and
Protein subunit adjuvant CpG 1018) 2 Intramuscular Phase 4 National Institute of
MVC-COV1901 Allergy and Infectious
(Beta) Diseases (NIAID)
Receptor Binding
Serum Institute of
Domain (RBD)
Virus like particle 2 Intramuscular Phase 1/2 India, Accelagen Pty
SARS-CoV-2 HBsAg
and SpyBiotech
VLP vaccine
Coronavirus-like
Virus like particle particle COVID-19 2 Intramuscular Phase 3 Medicago Inc.
(CoVLP)
Comirnaty
RNA based Pfizer/BioNTech and
BNT162b2 (3 2 Intramuscular Phase 4
vaccine Fosun Pharma
LNP – mRNAs)
Moderna and National
RNA based mRNA-1273 Institute of Allergy
2 Intramuscular Phase 4
vaccine Spikevax and Infectious
Diseases (NIAID)
DNA based BacTLR-Spike oral
1 Oral Phase 1 Symvivo Corporation
vaccine DNA vaccine
DNA based AnGes, Takara Bio
AG0301-COVID19 2 Intramuscular Phase 2/3
vaccine and Osaka University
Inovio Pharmaceuticals,
DNA based INO-4800 + International
2 Intradermal Phase 3
vaccine eletroporation Vaccine Institute and
Advaccine (Suzhou)
Viral vector rVSV-SARS-CoV- Israel Institute for
1 Intramuscular Phase 2/3
(replicating) 2-S vaccine Biological Research
University of Hong
Kong, Xiamen
Viral vector Intranasal flu-
2 Intranasal Phase 3 University and Beijing
(replicating) based-RBD
Wantai Biological
Pharmacy

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 Natália Floriano Paiva, Fabiana Testa Moura de Carvalho Vicentini

TABLE I - Vaccines under development or in use against COVID-19 fall within the different technological platforms (adapted
from https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines - last update: 03/11/2022)

Number Route of
Vaccine platform Type of vaccine Phase Developers
of doses administration
PIV5 vector that
Viral vector (non-
encodes the SARS- 1 Intranasal Phase 1 CyanVac LLC
replicating)
CoV-2 spike protein
VXA-CoV2-1 Ad5
Viral vector (non-
adjuvanted oral 2 Oral Phase 2 Vaxart
replicating)
vaccine platform
BBV154, Adenoviral
Viral vector (non- Bharat Biotech
vector COVID-19 1 Intranasal Phase 3
replicating) International Limited
vaccine
Covishield
Viral vector (non- AstraZeneca and
ChAdOx1-S 1-2 Intramuscular Phase 4
replicating) University of Oxford
(AZD1222)
Viral vector Janssen Pharmaceutical
Ad26.COV2.S 1-2 Intramuscular Phase 4
(non-replicating) Johnson & Johnson
Recombinant
CanSino Biological
Viral vector novel coronavirus
1 Intramuscular Phase 4 Inc./Beijing Institute
(non-replicating) vaccine (Adenovirus
of Biotechnology
type 5 vector)

In this way, mucosal vaccines stand out in the bioterrorism, studies have been dedicated to developing
production of local and systemic immune responses, having systems that allow vaccine administration in a non-
been shown to trigger a systemic response analogous to invasive way (without needles), as they are safer methods
that of parenteral administration. Therefore, it is extremely (Zheng et al., 2018).
important to evaluate mucosal vaccination strategies that Parenteral vaccination has been linked to several
can effectively trigger systemic and mucosal immunity successful cases of individual protection against major
(Shahiwala, Vyas, Amiji, 2007). Thus, this review will pathologies. However, in addition to its safety and low-
address aspects relevant to mucosa administration of acceptability issues, another limitation of this strategy,
vaccines, with emphasis on oral and nasal strategies, which is extremely relevant, might be its failure to induce
in addition to the importance of nanotechnology-based immunity when the pathogen enters the site, that is,
administration systems to make them feasible. mucosal surfaces (Corthésy, Bioley; 2018). Therefore,
mucosal delivery of vaccines stands out as a practical,
MUCOSAL VACCINATION non-invasive, and effective alternative to induce local
and systemic responses (De Magistris, 2006). When
Parenteral administration of vaccines by needle compared to parenteral vaccines, mucosal administration
and syringe has low acceptability by children and can promote more effective protective immune responses
infants, in addition to a high risk of infection due to due to the induction of secretory immunoglobulin A
the inappropriate reuse of these materials worldwide (IgA), cell-mediated immunity in mucosal tissues, and
(Kalam, Khan, Alshamsan, 2017). Within this framework, immunity at mucosal sites where pathogens enter the
in addition to the current occurrence of pandemics and body (Rhee, 2020).

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Oral and nasal vaccination: current prospects, challenges, and impact of nanotechnology-based delivery systems

Mucosal vaccines can stimulate all immune system specific T and B cells, and (c) control of antigen and
components, protecting against pathogens infecting the adjuvant delivery kinetics to promote a long-term
host through both mucosal surfaces and other routes. protective adaptive immune memory (Woodrow,
In more detail, mucosal vaccination stimulates the Bennett, Lo, 2012).
production of IgA antibodies against specific antigens Vaccine mucosal administration can be done via
at infection sites, as well as systemic IgG antibodies. oral, nasal, pulmonary, rectal, vaginal, ocular, sublingual,
Induction of secretory IgA production is essential or transcutaneous routes (Thakur, Foged, 2020). However,
because, in the intestinal region, for example, they current studies have focused in particular on oral and
have greater stability due to their secretory component, nasal vaccinations, which can induce stronger mucosal
in addition to helping to prevent the development immune responses (Kang, Cho, Yoo, 2009).
of pathogenic colonies in intestinal tissues through
pathogen agglutination, entrapment, and elimination Oral delivery
(Van der Weken, Cox, Devriendt, 2020). In addition,
mucosal vaccination can also induce immune responses Oral vaccines have several advantages over
at more distant sites due to the expression of specific conventional parenteral vaccines: large-scale low-cost
receptors by lymphocytes, besides activating cellular production, ease of administration, and induction of
responses mediated by CD4+ T helper lymphocytes immunity in the intestinal mucosa blocking disease
and CD8+ T cytotoxic lymphocytes, which are of great transmission and increasing herd immunity (Parker et
importance in combating intracellular pathogens (De al., 2018). Oral vaccination is associated with increased
Magistris, 2006). adherence, lower occurrence of adverse reactions, and
Thus, mucosal immunization stands out in its potential for self-administration, which make them
importance due to several reasons, including: (1) greater attractive for mass vaccination campaigns (Rhee, 2020).
adherence of individuals and greater capacity for mass Oral administration is the most used route since
immunization; (2) the potential of self-administration the intestinal epithelium has a high absorption capacity
as it does not need specialized professionals, decreasing due to its extensive surface area (around 300 to 400
vaccination costs significantly; (3) simpler methods of m 2). In addition, another important characteristic
production and storage as it does not need to follow strict is the presence of lymphoid tissue, also known as
sterilization protocols and have a high purity level; (4) gut-associated lymphoid tissue (GALT). The tissue
no interference with cultural or religious issues; (5) contains inductive sites where immune responses
induction of mucosal and systemic humoral immunity begin, in addition to effector sites where adaptive
by antigen-specific IgA and IgG antibody responses; immune responses are made (Davitt, Lavelle, 2015).
and (6) elimination of potential disease asymptomatic Studies have indicated that antibody-secreting cells
carriers, thus interrupting transmission of infections in the intestinal mucosa can persist for decades, then
among individuals (Skwarczynski, Toth, 2020). plasma cells provide long-lasting mucosal immunity.
However, despite its many advantages, the In some reports, oral immunization could more easily
strategy still has challenges concerning inefficient activate cytotoxic T lymphocytes and long-acting
immunogenicity, uptake, and presentation of antigens; mucosal memory immunoglobulins A when compared
and the occurrence of enzymatic degradation and to systemic immunization (New, 2019).
immune tolerance (Srivastava et al., 2015). Overall, The development of oral vaccine should include
effective strategies for mucosal immunization involve an understanding of the physical-chemical aspects
three important characteristics: (a) overcoming of the barriers that constitute the host’s first defense
physiological barriers of mucosa; (b) efficient specific against pathogens (Davitt, Lavelle, 2015). In general,
targeting of antigen-presenting cells (APCs) in the gastrointestinal mucosa has a protective mucous
mucosa for proper processing of antigens that activate membrane and a layer of epithelial cells, which

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 Natália Floriano Paiva, Fabiana Testa Moura de Carvalho Vicentini

provide the host’s protection against the unregulated pill form. This vaccine is composed of an enteric coating
entry of pathogens and harmful substances. A good with an adenoviral vector capable of coding genes for the
mucosal coating is a physical barrier that limits production of S and N nucleocapsid proteins of SARS-
molecular diffusion and penetration of microorganisms CoV-2. The enteric coating is essential for protecting
into the epithelium. Despite variable structures and vaccine formulation from the acidic environment of the
functions according to its location (oral, gastric, and stomach, as the tablet dissolves in the digestive tract, and
intestinal), the main function of the epithelial layer hence provides induction of protective mucosal immunity
is to prevent the absorption of undesirable pathogens against viral infection. The other proposal, called OraPro-
and macromolecules. In this context, additional COVID-19TM, includes the use of a non-replicating viral
forms of protection can be cited, such as secretion vector that expresses the S protein in an encapsulated
of antimicrobial compounds within the mucous form, providing thermal stability for the formulation.
membrane, low pH of the stomach region, presence Like the previous one, this proposal also has an enteric
of bile salts and digestive enzymes in the intestinal coating and, when orally administered, directly reaches
portion, and intestinal motility leading to gastric the intestinal lymphoid tissues. As a result, there is an
emptying (Coffey, Gaitha, Traverso; 2021). Thus, induction of cellular (CD4+ and CD8+ T-cell mediated)
vaccine oral delivery has faced several challenges and humoral (antibody-mediated) immune responses
since vaccines need formulations able to maintain their (Ashraf et al., 2021).
stability in the gastrointestinal environment and avoid
tolerance induction, resulting in the need for higher Intranasal delivery
doses of antigens to perform effective protection (Vela
Ramirez, Sharpe, Peppas, 2017). Although intestinal As mentioned for the oral route, intranasal
microbiota interferes with oral vaccination efficacy, administration for local and systemic delivery of
this aspect is not very well established (Van der Weken, therapeutic compounds is non-invasive and painless,
Cox, Devriendt, 2020). requires no sterilization, and can be self-administered.
The development of suitable oral vaccines must meet Besides these advantages, the nasal pathway has a large
important criteria such as sufficient protection against mucosal surface area due to the presence of numerous
antigens in the gastrointestinal environment, use of high microvilli, porous endothelial membranes, and highly
loads of antigens or other vehicles with encapsulation vascularized epithelium (Kang, Cho, Yoo, 2009).
capacity, prolonged exposure of antigens to antigen- In terms of anatomy, the nasal cavity has a surface
presenting cells, ability to reach intestinal cells, long- area of ​​150 cm2 and a volume of 15 to 20 mL, which
term systemic and mucosal memory, and high safety. is divided into five regions according to anatomical
To overcome these challenges, one important strategy and functional characteristics: nasal vestibule, atrium,
has been the study and application of delivery system breathing zone, olfactory region, and nasopharynx.
technologies for oral vaccination (Kang et al., 2018). In Drugs or vaccine antigens can be delivered in the
addition to protecting antigens against the gastrointestinal respiratory region due to their high permeability, large
environment, different delivery systems have also been surface area, and rich vascularization. The region is
developed for targeted delivery to immunological composed of a pseudostratified epithelium, in which
induction sites that allow their absorption by antigen- columnar and goblet-shaped cells are connected by tight
presenting cells, enhancing immune response robustness junctions, preventing paracellular passage of particulate
(Van der Weken, Cox, Devriendt, 2020). materials in inhaled air (Rhee, 2020). Thus, the
Currently, given the COVID-19 pandemic, two oral epithelial cell layer represents a barrier to penetration
vaccines are in progress to protect against the coronavirus. of pathogens, with the help of mucus production and
One of them is produced by the American company the presence of ciliary structures, as well as its ability
Vaxart and consists of a recombinant oral vaccine in a to detect and capture these organisms by endocytosis

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Oral and nasal vaccination: current prospects, challenges, and impact of nanotechnology-based delivery systems

or recognition of patterns such as Toll-Like Receptors should also be considered, as it is a simpler method of
(TLRs) (Yusuf, Kett, 2017). application (Pan et al., 2014; Köping-Höggård, Sánchez,
Another important characteristic of the nasal cavity Alonso, 2005).
is nasopharyngeal-associated lymphoid tissue (NALT) In the context of the COVID-19 pandemic, studies
(Rhee, 2020). The nasal mucosa immune system is conducted by Du Y and coworkers demonstrated that
composed of lymphoid tissue, B cells, T cells, and APCs, intranasal administration of a subunit vaccine containing
which are covered by an epithelial layer containing a recombinant SARS-CoV-2 receptor binding domain
memory (M) cells specialized in transporting antigens generated an excellent humoral immunity induction
through the epithelium. The action of epithelial cells, profile and immunity on the mucosal surfaces of the
together with lymphocytes and underlying antigen- nasal cavity, lung, genital tract, and intestine. They
presenting cells, induces an innate immune response also reported that mucosal B cells secrete IgA into the
to the invasion of foreign agents into the body (Yusuf, nasal cavity and lung, which provides the first line of
Kett, 2017). The associated lymphoid tissue, composed defense against viruses that enter the respiratory tract,
of immunocompetent cells and present in this nasal thus preventing these microorganisms from invading the
epithelium, is an ideal target for intranasal administration host’s cells (Du et al., 2021).
of vaccines capable of inducing an appropriate immune However, the development of nasal vaccines has
response (Islam et al., 2012). In addition to inducing some challenges related to inefficient absorption of
a local immune response, it also induces an immune soluble antigens by the region’s immune cells, rapid
response in mucous tissues distant from the nasal cavity, mucociliary clearance, short antigen residence time,
such as the vagina. This is because mucosal lymphocytes permeation of restricted molecular size through
are functionally connected, which can be advantageous epithelial barriers, absence of effectively safe
for developing vaccines against sexually transmitted adjuvants for human use, low stability of formulation
pathogens such as human immunodeficiency virus - HIV against nasal enzymes, low pH, and reduced delivery
(Li et al., 2016). volume due to low nasal cavity capacity (from 100
One of the advantages of intranasal vaccination is to 150 μL). Faced with these hindrances, the use of
the induction of protection against pathogens reaching the advanced delivery systems might help to increase the
respiratory tract, with responses generated in lymphoid residence time of administered vaccines in the nasal
tissue associated with the nasal cavity providing long- cavity, formulation stability, and absorption of vaccine
term protection. Several diseases, such as influenza, components (Marasini, Skwarczynski, Toth, 2017;
respiratory infections, measles, and meningitis, are Riese et al., 2014).
developed by the entry of microorganisms via the Figure 1 shows a schematic representation of immune
respiratory mucosa. In this context, a vaccination that response induction in nasal and stomach mucosa after
allows defense through this route is highly desirable, nasal or oral vaccine administration, respectively. Table
as it prevents infection of both the individual and the II displays a comparison between the main advantages
environment. In addition, reduced activity of degradation and disadvantages of oral and nasal administration routes
enzymes, better patient compliance, and cost reduction for vaccines.

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 Natália Floriano Paiva, Fabiana Testa Moura de Carvalho Vicentini

FIGURE 1 - Schematic representation of immune response induction in nasal and stomach mucosa after nasal or oral vaccine
administration, respectively. Vaccine antigens found in the nasal cavity or gastrointestinal environment, depending on the
administration route, are transported actively through microfold or epithelial cells to reach the lymphoid follicles. Then, on the
inductive site, with the main one being mucosal-associated lymphoid tissues (MALT), there are organized lymphoid tissues
where the antigen is taken up by dendritic cells (DCs) and other antigen-presenting cells (APCs). These antigens taken up by
dendritic cells are presented to T cells, which, with the help of follicular dendritic cells (FDCs) and T follicular helper (TFH),
contribute to the formation of germinal center in lymphoid follicles and activation of T and B cell responses in the inductive
sites. Activated B cells differentiate into IgA-secreting plasma cells, which are responsible for IgA antibody secretion. DCs
under maturation migrate to lymph nodes, but DCs already located in MALT can activate naïve CD4+ and CD8+ T cells, which
results in the differentiation of activated CD4+ T cells into T helper 1 (Th1), Th2, or Th17 cells, regulatory T cells (Tregs) or
follicular helper T cells (TFH). In the regional lymph nodes, DCs interact with T and B cells to produce IgG antibodies, which
protect distant systemic or mucosal sites after reaching the bloodstream. In this context, the effector sites are responsible for
protecting with the action of specific antibodies and CD4+ and CD8+ effectors, and where memory T cells reside.

TABLE II - Comparison between oral and nasal routes for vaccine administration

Route of administration Advantages Disadvantages

Possibility of self-administration
Induction of mucosal immune response Requires higher doses than those
Oral and Intranasal
Non-invasive and painless method used in the parenteral route
Applicable for mass vaccination
Mucosal coating is a barrier to
absorption of macromolecules
Ease of administration and Secretion of antimicrobial compounds
increased adherence occurs within the mucous membrane
Large-scale production with low costs Gastric degradation due to low stomach
Oral
High absorptive capacity of pH, presence
​​ of bile salts and enzymes
the intestinal epithelium First pass metabolism
Presence of constituent lymphoid tissue Intestinal motility and gastric emptying
Inaccurate dosage and
reduced bioavailability

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Oral and nasal vaccination: current prospects, challenges, and impact of nanotechnology-based delivery systems

TABLE II - Comparison between oral and nasal routes for vaccine administration

Route of administration Advantages Disadvantages

Large mucosal surface area, porous
endothelial membrane and high
vascularization of the epithelium
Presence of lymphoid tissue
Epithelial cell layer forms a
associated with the nasopharynx
barrier to absorption
Induction of the immune response
Fast mucociliary clearance
in mucous membranes further
Intranasal and short residence time
away from the nasal cavity
Reduced delivery volume due to
Protection against pathogens that
low nasal cavity capacity
enter the respiratory tract
Nasal Obstruction is an important obstacle
Prevents the spread of the
pathogen through the air
Reduced activity of degradation enzymes
and avoids 1st pass metabolism

NANOTECHNOLOGY APPLIED TO Thus, nanotechnology studies have been carried

VACCINOLOGY out to develop new vaccines and collaborate with
their worldwide implementation (Fries et al., 2021).
Notably, several vaccines have been successful in Applications of nanotechnology in pharmacology​​
preventing major infectious diseases in the past. However, (nanopharmacology) involve using small-scale particles
numerous vaccines still have not provided effective to improve therapeutic performance. This improvement
immunity to protect humans against some diseases, such stems from the pharmacokinetic profile modulation of
as malaria, tuberculosis, and acquired immunodeficiency formulations, increasing bioavailability and/or half-life,
syndrome - AIDS (Fries et al., 2021). In this sense, as well as from changes in pharmacodynamics that lead
nanotechnology studies have enabled the development to an increased efficacy (Apolinário et al., 2020).
of vaccine formulations with increased potency when The efficiency of a vaccine depends on its ability to
compared to traditional formulations (Zhou et al., 2019). promote immune responses different from those induced by
Nanotechnology emerged in the 1980s through the natural infection. Accordingly, nanomaterials, or nanoscale
development, synthesis, and manipulation of materials on materials, are advantageous due to their well-defined
a nanometric scale. It enabled visualizing biomolecular composition and length scale, and can safely engage major
interactions, as well as obtaining nanostructures to immune pathways (Fries et al., 2021). Nanoparticles may
eliminate disadvantages and obstacles related to the allow targeted delivery of antigens to immune system cells,
traditional pharmacological approaches (Contera, especially those whose surface is modified through the
Bernardino, Tetley, 2020). According to Roco (2003), addition of targeted ligands or antibodies. Such a delivery
nanotechnology is defined as the ability to work at atomic, improves vaccine efficacy by facilitating absorption with a
molecular, and supramolecular levels to understand, slow antigen release, inducing humoral and cellular immune
develop, and use materials, structures, devices, and responses (Rai et al., 2020). It is due to the ability of
systems with new properties and functions due to their nanocarriers to deliver, together with active pharmaceutical
small size. All biological systems have their first level ingredients, immunostimulating components and enable
of organization on a nanometric scale, within which a synergistic effect on the immune system (Zhu, Wang,
fundamental properties and functions are clearly defined. Nie, 2014). Furthermore, nanoparticles can activate APCs,

Braz. J. Pharm. Sci. 2023;59: e21769 Page 11/16

 Natália Floriano Paiva, Fabiana Testa Moura de Carvalho Vicentini

especially dendritic cells, thus increasing vaccine efficacy have contemplated the development of proper vaccine
(Rai et al., 2020). administration systems that contribute to improving
Therefore, the application of nanomaterials as aspects of the immunogenicity of antigens and induce a
vaccine delivery systems includes both antigen delivery more efficient immune response, in addition to enabling
and formulation adjuvant functions (Govindaraju reductions of applied dose and production costs (Jin et
et al., 2020) so that integration of delivery and al., 2019).
immunomodulatory effects of nanomaterials promote Nanotechnological applications have enabled the
highly relevant immunological outcomes for vaccination targeted delivery of vaccine antigens across mucosal
(Zhu, Wang, Nie, 2014). Finally, the unique size of surfaces, improving the solubility, stability, and surface
nanoparticles, which enhances the delivery of vaccine properties of antigens to achieve a better immune
components, is also highlighted as advantageous since response (Thakur, Foged, 2020). Nanomaterials are
there is more efficient drainage to lymphoid organs, advantageous carriers of vaccine formulations due
wherein antigen uptake and processing occur (Zhou et to their biocompatibility, mucosal absorptivity, and
al., 2019). biodegradability (mostly). They also have surface
Overall, nanoparticulate systems used for vaccine properties subject to modification and control, the ability
delivery have three different components or parts: (1) to allow entry of molecules into cells, and the protection
nanoparticle composition material (natural or synthetic of formulations against degradation (Jiao et al., 2018).
polymers, inorganic substances, among others); (2) Micro- and nanoparticulate delivery systems based
immunogen or immunomodulating agent conjugated by on synthetic or natural polymers have been widely used
covalent bond, adsorbed on the surface of nanoparticle for the development of vaccines delivered via mucosa.
or encapsulated within it; (3) targeting ligands and/or The use of nanoparticles, such as those mentioned above,
immunostimulators added to the surface of particles, helps to protect antigens from degradation, making
including immune system-specific ligands, tissue-specific formulations penetrate mucosal barriers and controlling
ligands, and pathogen-associated molecular patterns the release of antigens and immunomodulators in cells
(PAMPs) (Rai et al., 2020). and intracellular compartments of interest (Woodrow,
In general, nanomaterials allow the investigation Bennett, Lo, 2012). Thus, the application of nanoparticles
of structural characteristics and mechanisms of the in vaccine formulation helps increase antigen stability
immune system, which can be improved to increase and immunogenicity, and also allows for its targeted
immunogenicity, which is a result of the multivalence delivery. Mehrabi and collaborators reported that
of nano-vaccines. Currently, several nanocarriers have chitosan nanoparticles have immunological activity and
been studied as delivery platforms, which, combined with mucoadhesion properties, which are used as vaccine
advances in antigen design, allow us to obtain highly delivery systems for various antigens (Mehrabi et al.,
efficient vaccines that stimulate immune responses for still 2018). In addition, nanocarriers improve interaction
neglected diseases (Fries et al., 2021). The contribution with the epithelium, increasing absorption of antigens in
of nanoparticles to vaccinology comprises their ability mucosa-associated lymphoid tissues (MALT); therefore,
to load, protect, target, and deliver immunotherapeutic this process favors the interaction of antigens with
cargos to immune cells of interest, particularly to desired APCs, such as macrophages, and soon generates B and
APCs (Boushehri, Dietrich, Lamprecht, 2020). T lymphocytes, increasing the immune response at the
In the context of vaccination, free-form antigen site of interest (Caetano, Almeida, Goncalves; 2014).
delivery via the mucosa generally induces a weak
immune response, which is related to the diffusion of Nanoparticles in oral vaccines
antigens across mucosal barriers, mucociliary clearance,
and the presence of degrading enzymes (Caetano, Currently, there are numerous alternatives to protect
Almeida, Goncalves, 2014). Currently, several studies vaccines against the hostile gastrointestinal environment,

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Oral and nasal vaccination: current prospects, challenges, and impact of nanotechnology-based delivery systems

one of which includes transporting them inside or of antigen retention; (5) more sustained antigen release;
adsorbed to surfaces of nanoparticulate systems. Despite (6) antigen targeting ability; (7) delivery of immunogens
presenting less protection when antigens are adsorbed to a preferential antigen processing pathway; (8) presence
on the surface, they are more available for immune of adjuvant properties; and (9) foundation for binding
system recognition. Moreover, in both cases, additional immunomodulatory molecules (Riese et al., 2014). In
protection can be obtained through an enteric surface the nasal cavity, NALT is the most important region
coating on particles (Coffey, Gaitha, Traverso; 2021). for vaccine delivery to induce a favorable immune
Among the strategies to improve oral vaccine response; therefore, formulations that allow increasing
immune response, efforts to overcome formulation permanence time at this location may stand out (Tlaxca,
instability in the gastrointestinal environment have Ellis, Remmele, 2015).
excelled. In this context, acid-resistant biomaterials Therefore, nanoparticles are effective in improving
and coating techniques proved to be efficient for such nasal vaccine delivery by amplifying immune responses.
a function (e.g., enteric coating of nanoparticles and These particles are also preferentially absorbed by
packaging of antigen within the sturdy carrier). Enteric the NALT system. In a study, Illum suggested that
coating is based on polymers with different solubility at nanoparticles can be taken up by M cells in the NALT
different pH, which allows the delivery of antigens to the and transported to the lymphatic system, which then
GUT without being degraded in the acid environment reaches the bloodstream (Illum, 2007). Positively charged
(Zhang et al., 2021). particles can, for example, be cited as a nasal vaccine
Vehicles for oral vaccine delivery have been widely delivery system strategy, as they allow interaction
studied and employed, such as biodegradable and between particles and mucus, which is negatively charged.
biocompatible polymers, for example, poly-D, L-lactide- This mucoadhesion reduces the vaccine clearance rate
coglycolide (PLGA), and polylactide (PLA), micelles, in the nasal cavity, which facilitates antigen uptake (Jia,
liposomes, solid lipid nanoparticles, dendrimers, and Krishan, Omri, 2015).
metallic nanoparticles. These polymers encapsulate Currently, the use of nasal
​​ administration of drugs
antigens to protect them from metabolic degradation and vaccines has grown significantly due to increasing
and also release them gradually. Furthermore, these studies in nanotechnology, imaging, and administration
formulations provide better stability and activity (Kour devices. In this sense, to overcome nasal route limitations,
et al., 2018). nanoparticulate carriers with the potential for nasal
In general, adjuvants for oral vaccination should delivery of vaccines have been widely studied, which
be biocompatible, have a stable and controlled release, would allow for facilitating antigen absorption through
protect antigens from degradation in the gastrointestinal nasal barriers, presenting antigens more efficiently to the
tract, have targeted delivery, and be capable of delivering immune system (Mato, 2019).
antigens in a controlled manner to target immune cells to
improve the presentation of antigens (Zhang et al., 2018b). CONCLUSION

Nanoparticles in nasal vaccines Vaccination is known to broadly contribute to

the control of several diseases. However, new vaccine
Delivery systems have advantageous properties technologies must be developed to provide immune
that allow protecting and transporting vaccine antigens protection against various infectious diseases, including
to the desired location. Other important functions of those transmitted through mucosal pathways. In this
these systems to improve the formulation of intranasal context, mucosal vaccination has the potential for mass
vaccines are: (1) increased mucoadhesion; (2) ability immunization due to its several advantages. Two of them
to overcome mucociliary clearance; (3) increased are ease of administration and induction of mucosal
formulation permeation and penetration; (4) promotion immunity. However, there is still a limited number

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 Natália Floriano Paiva, Fabiana Testa Moura de Carvalho Vicentini

Apolinário AC, Salata GC, Bianco AFR, Fukumori C, Lopes

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