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The anatomy of the oral cavity. The sublingual and buccal regions for vaccine delivery are indicated.
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Because of their large surface area and immunological competence, mucosal tissues are attractive administration and target sites for vaccination. An important characteristic of mucosal vaccination is its ability to elicit local immune responses, which act against infection at the site of pathogen entry. However, mucosal surfaces are endowed with po...
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Context 1
... vaccine delivery in the mouth can be subdivided into sub- lingual and buccal delivery. Sublingual delivery occurs via the mucosa of the ventral surface of the tongue and the floor of the mouth under the tongue, whereas buccal delivery occurs via the buccal mucosa, which is located in the cheeks, the gums and the upper and lower inner lips (Fig. 1). The specific structure and cell composition of the sub- lingual and buccal regions in the mouth define whether they are more or less suitable for vaccine delivery (as described ...Context 2
... the oral cavity, some mucosal regions are lined by a keratinized stratified epithelium (gingival, hard palate, outer lips), whereas other regions are lined by a non-keratinized stratified epitheli- um (Fig. 1). The epithelium is supported by a basement membrane, which separates the two major layers of the oral mucosa: the epitheli- um and the underlying connective tissue or lamina propria. The ar- rangement of the hard palate and gingival, including the pluristratified keratinized mucosal epithelium and the lamina propria that is anchored ...Context 3
... of these membranes. The thickness of the human buccal mucosa has been estimated to be in the range of 500-800 μm, whereas the mucosal thickness of the sublingual region is about 100-200 μm [16]. In terms of permeability, the sublin- gual region is more permeable than the buccal region, which in turn is more permeable than the palatal region (Fig. 1). Sublingual administra- tion can provide a rapid uptake of macromolecules and thus appears to be an attractive route for dosage forms with a short delivery ...Similar publications
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Importance:
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Citations
... MDA is also a simpler method of administration in rodents. Moreover, a review comparing administration in humans suggested that oral/gastrointestinal administration induced a lower immune response in the respiratory tract than administration though the sublingual route, whereas the efficacy of buccal administration remains debatable [36]. ...
Bordetella bronchiseptica (Bb) is a Gram-negative bacterium responsible for canine infectious respiratory disease complex (CIRDC). Several vaccines targeting this pathogen are currently licensed for use in dogs, but their mechanism of action and the correlates of protection are not fully understood. To investigate this, we used a rat model to examine the immune responses induced and the protection conferred by a canine mucosal vaccine after challenge. Wistar rats were vaccinated orally or intranasally on D0 and D21 with a live attenuated Bb vaccine strain. At D35, the rats of all groups were inoculated with 103 CFU of a pathogenic strain of B. bronchiseptica. Animals vaccinated via either the intranasal or the oral route had Bb-specific IgG and IgM in their serum and Bb-specific IgA in nasal lavages. Bacterial load in the trachea, lung, and nasal lavages was lower in vaccinated animals than in non-vaccinated control animals. Interestingly, coughing improved in the group vaccinated intranasally, but not in the orally vaccinated or control group. These results suggest that mucosal vaccination can induce mucosal immune responses and provide protection against a Bb challenge. This study also highlights the advantages of a rat model as a tool for studying candidate vaccines and routes of administration for dogs.
... This was expected since both gut-associated lymphoid tissue (GALT) and nasopharyngeal-associated lymphoid tissue (NALT) are part of the mucosa-associated lymphoid tissue (MALT) network. While mucosal immunity is generated in the inductive sites, which would be NALT in this study given the nature of IN immunization, it is well established that antigen-specific mucosal IgA responses can be elicited at different effector sites [40,41]. This interconnected network of common mucosal immune system enabled the T. gondii-specific IgA responses to be observed from the intestinal tissues, despite the mice being immunized through IN route in our study. ...
Toxoplasma gondii host cellular invasion factors such as the rhoptry proteins, micronemal antigens, or other subcellular compartment proteins have shown limited vaccine efficacies. T. gondii cyst wall protein (CST1) as a cyst persistence factor is critical for cyst wall integrity and bradyzoite persistence. Here, we generated influenza virus-like particles (VLPs) expressing the T. gondii CST1 and evaluated the mucosal as well as systemic immunities induced by VLPs. Intranasal immunization with the VLPs induced parasite-specific IgG and IgA antibody responses in sera and intestines. VLP immunization showed higher levels of germinal center B cell response and antibody-secreting cell (ASC) response upon challenge infection, indicating memory B cell response was induced. VLP-immunized mice showed a significant reduction of cyst counts and lower levels of pro-inflammatory cytokines (IFN-γ, IL-6) production in the brain upon T. gondii ME49 challenge infection compared to unimmunized control. Thus, VLP immunization protected mice from the lethal dose challenge infection with T. gondii ME49 and did not incur bodyweight loss. These results indicated that T. gondii CST1 containing VLPs can induce mucosal and systemic immunity and also suggest its developmental potential as an effective vaccine candidate against T. gondii infection.
... Vaccine delivery through mucosal tissue is one of the most promising methods since oral mucosal is the site for microbial pathogens and particles to enter human body when in contact with mucosal tissue [3,4]. The oral mucosa, as the first surface to come into contact with various pathogens, is seen as a promising administration site for vaccines to generate the first line of defense against specific antigens on the mucosal surface [5,6]. Oral mucosal delivery of vaccines generated higher and more sustained mucosal immunity than those delivered parenterally. ...
... Despite their given potential, mucosal vaccines have not been used widely in clinical trials or real practices in clinical settings due to their elusive and complex mechanism of action have not yet being fully understood. The oral mucosal surface provides mechanical, chemical, and biological barriers that could interfere vaccine stability and penetration, leading to interrupted immune responses [6]. In this point, adjuvants are utilized to enhance a vaccine's immunomodulating properties as an antigen delivery system to promote immune stimulation and generate robust antigen processing activities in the innate immune system [12,13]. ...
... A previous study stated that sublingual and buccal mucosal regions are promising delivery sites owing to their lack of keratinized tissue, which makes them superior to intradermal administration sites. It was also demonstrated that gastrointestinal enzymatic activities could be avoided by delivering antigens through the vascularization-rich oral mucosa; however, intranasal routes might have a harmful effect on asthma and pulmonary disease patients [6,24,25]. ...
Vaccines manufacture and enhancement for preventing infection and promoting quality of life are of great concern worldwide. For vaccine enhancement, to date, only limited adjuvants have been approved globally. One of them is alum, which presents several side effects and limitations. Related to vaccine administration, mucosal vaccination is a promising method since it can induce both mucosal and systemic immunity since oral mucosa is the most exposed site of the body to various microbes, pathogens, and environmental particles. Consequently, an escalated specific local immunity is required in which stability and integrity of an encapsulated antigen is expected to result in a stable mucosal vaccine to protect the antigens from degradative chemical reactions occurring in the oral cavity and act as immunomodulator. Carbonate apatite (CHA) has been one of the most innovative materials as a newly developed vaccine adjuvant since it can adequately enhance drug and protein stability and delivery in various disease therapies. However, CHA fabrication that meets the parameters for adjuvants and immunomodulators remains challenging. In the form of nanoparticles, CHA is reported to enable targeted delivery of dendritic cells (DC), enhance uptakes, cross presentation, and biodistribution, as well as immune responses. Therefore, the development of nano-CHA-encapsulated vaccine antigens is required to enhance oral mucosal vaccinations and their effectiveness to prevent diseases. This study focuses on factors and strategies that affect the designing, fabrication, and testing of CHA nanoparticles for oral mucosal vaccines, especially in the aspect of physicochemical, immunological, cellular, surface chemistry, and biofunctionalization of the nanoparticle.
... 36 About one-third of these areas, including buccal mucosa are lined by nonkeratinized stratified epithelium, which is more elastic and permeable, hence more suitable for drug delivery. 37 The rich capillary network and large surface area of buccal mucosa enable the systemic absorption of drugs for buccal delivery. Also, ODFs can achieve systemic absorption via gastrointestinal tract after swallowing. ...
... It is estimated 17.9 million people die each year from cardiovascular diseases. 37 Extensive drugs were used for the treatment of cardiovascular diseases. There are also TIAN ET AL. many commercially available dosage forms for these drugs, such as oral tablets, capsules (Table 2). ...
Abstract Orodispersible films (ODFs) as a relatively novel delivery platform have increasingly attracted enormous attention owing to their various advantages compared to conventional oral dosage forms, including fast disintegration, ease of administration without consumption of water, and rapid absorption of incorporated drug, high patient compliance for pediatrics, geriatrics and patients with swallowing difficulties. This review aims to summarize the developments and possibilities that ODFs as the potential carrier for chemical drugs, vaccine, probiotics, and herbal extracts. Especially, with the outbreak of coronavirus disease 2019 (COVID‐19), the advantages of ODFs related to ease of transporation and distribution without cold‐chain as well as low‐cost manufacturing make ODFs a promising carrier for vaccines against COVID‐19. Subsequently, the current therapeutic applications of ODFs delivered either locally or systemically for potential patients suffering from various diseases are discussed, including oral inflammation, cardiovascular diseases, pain disorders, nausea and vomiting, mood or mental disorders, erectile dysfunction and pulmonary diseases. Finally, this review provides overview of the novel inkjet printing and three‐dimensional printing techniques, and the possibility of extemporaneous preparation for ODFs in hospital pharmacies via printing techniques are discussed as well.
... In fact, the respiratory tract as a potential vaccine delivery route is under active investigation for other infections. For the last two decades, several research groups have proposed the pulmonary site as an ideal target to deliver vaccines and induce immunity to combat respiratory infections (58)(59)(60)(61). To date, there are only six licensed intranasal vaccines for humans (Table 1), including vaccines against COVID- 19 (68). ...
Tuberculosis (TB) remains one of the most lethal infectious diseases globally. The only TB vaccine approved by the World Health Organization, Bacille Calmette-Guérin (BCG), protects children against severe and disseminated TB but provides limited protection against pulmonary TB in adults. Although several vaccine candidates have been developed to prevent TB and are undergoing preclinical and clinical testing, BCG remains the gold standard. Currently, BCG is administered as an intradermal injection, particularly in TB endemic countries. However, mounting evidence from experimental animal and human studies indicates that delivering BCG directly into the lungs provides enhanced immune responses and greater protection against TB. Inhalation therapy using handheld delivery devices is used for some diseases and allows the delivery of drugs or vaccines directly into the human respiratory tract. Whether this mode of delivery could also be applicable for live attenuated bacterial vaccines such as BCG or other TB vaccine candidates remains unknown. Here we discuss how two existing inhalation devices, the mucosal atomization device (MAD) syringe, used for influenza vaccines, and the Respimat ® Soft Mist ™ inhaler, used for chronic obstructive pulmonary disease (COPD) therapy, could be repurposed for mucosal delivery of live attenuated TB vaccines. We also outline the challenges and outstanding research questions that will require further investigations to ensure usefulness of respiratory delivery devices that are cost-effective and accessible to lower- and middle-income TB endemic countries.
... Oral vaccines are attractive because they can induce high intestinal immunity, are relatively non-invasive, and can be administered on a large scale (265). An alternative strategy of oral vaccination is to directly target the tissues within the oral mucosa for antigen delivery, targeting the buccal (inner cheek, B) and sublingual (below the tongue, SL) tissue (266,267). A recent study demonstrates the vaccine-mediated protection of MVA-HIV/cycP-gp120 immunization against a pathogenic, heterologous SHIV, as well as the viability and effectiveness of needle-free SL/B immunization as an alternative to conventional needle-based vaccination (268). ...
Human Immunodeficiency Virus (HIV) is still one of the major global health issues, and despite significant efforts that have been put into studying the pathogenesis of HIV infection, several aspects need to be clarified, including how innate immunity acts in different anatomical compartments. Given the nature of HIV as a sexually transmitted disease, one of the aspects that demands particular attention is the mucosal innate immune response. Given this scenario, we focused our attention on the interplay between HIV and mucosal innate response: the different mucosae act as a physical barrier, whose integrity can be compromised by the infection, and the virus-cell interaction induces the innate immune response. In addition, we explored the role of the mucosal microbiota in facilitating or preventing HIV infection and highlighted how its changes could influence the development of several opportunistic infections. Although recent progress, a proper characterization of mucosal innate immune response and microbiota is still missing, and further studies are needed to understand how they can be helpful for the formulation of an effective vaccine.
... The sublingual region on the floor of the oral cavity under the tongue provides an alternative route of medication administration. The direct absorption of medications into the systemic circulation via this route bypasses the first-pass hepatic metabolism effect and is suitable for medications with a high first- The sublingual region covers a surface area of about 26 cm 2 , making up about 11-30% of the surface area of the oral cavity [30,31]. The stratified squamous non-keratinized epithelium of this region is made up of eight to 12 layers of cells and covered by a thin layer of mucus derived from saliva ( Fig. 2) [30]. ...
... The direct absorption of medications into the systemic circulation via this route bypasses the first-pass hepatic metabolism effect and is suitable for medications with a high first- The sublingual region covers a surface area of about 26 cm 2 , making up about 11-30% of the surface area of the oral cavity [30,31]. The stratified squamous non-keratinized epithelium of this region is made up of eight to 12 layers of cells and covered by a thin layer of mucus derived from saliva ( Fig. 2) [30]. The underlying lamina propria and submucosa are rich in lymphatics and blood vessels derived from branches of the lingual artery and the accompanying veins [32]. ...
Vaso-occlusive crisis (VOC), characterized by periods of excruciating pain is the most common clinical manifestation of sickle cell disease (SCD), often resulting in emergency room presentation. These patients often experience long wait times in the emergency department before receiving their first dose of analgesia. This delay results from the complexities of the emergency care system. Using the intranasal or sublingual approach to administering analgesia to SCD patients with VOC offers a fast, safe, noninvasive, atraumatic, and easily accessible route of administration which could reduce the time to first dose of analgesia. With the evolving advances in the development and delivery of analgesic medications, providers should be conversant with the nuances of intranasal and sublingual analgesia in the management of acute vaso-occlusive pain crisis. This review explores the pharmacokinetic profiles, dosages, and administration of intranasal and sublingual analgesics with relevance to the SCD population.
... It must be emphasized that the sublingual delivery of drugs has a disadvantage of a salivary washout effect. To overcome this problem, it is essential to add mucoadhesive polymers in the sublingual formulation to limit the short mucosal retention time [82]. Singh and co-authors used chitosan, an excellent mucoadhesive polymer, together with HPMC (a film forming material) to extend the mucosal retention time. ...
Orodispersible Films (ODFs) are drug delivery systems manufactured with a wide range of methods on a big scale or for customized medicines and small-scale pharmacy. Both ODFs and their fabrication methods have certain limitations. Many pharmaceutical companies and academic research centers across the world cooperate in order to cope with these issues and also to find new formulations for a wide array of APIs what could make their work profitable for them and beneficial for patients as well. The number of pending patent applications and granted patents with their innovative approaches makes the progress in the manufacturing of ODFs unquestionable. The number of commercially available ODFs is still growing. However, some of them were discontinued and are no longer available on the markets. This review aims to summarize currently marketed ODFs and those withdrawn from sale and also provides an insight into recently published studies concerning orodispersible films, emphasizing of utilized APIs. The work also highlights the attempts of scientific communities to overcome ODF’s manufacturing methods limitations.
... Mucosal associated lymphoid tissue (MALT) in the oral cavity includes the Waldeyer's ring and palatine tonsils (Kraan et al., 2014). Buccal and sublingually administered antigens are captured by local antigen-presenting cells (APCs) such as Langerhan and dendritic cells and migrate to proximal draining lymph nodes where the antigens are presented (see Fig. 6), leading to the induction of strong cellular and humoral immune responses resulting in the production of secretory IgA, the predominating immunoglobulin along mucosal surfaces (Suárez et al., 2021, Kraan et al., 2014. ...
... Mucosal associated lymphoid tissue (MALT) in the oral cavity includes the Waldeyer's ring and palatine tonsils (Kraan et al., 2014). Buccal and sublingually administered antigens are captured by local antigen-presenting cells (APCs) such as Langerhan and dendritic cells and migrate to proximal draining lymph nodes where the antigens are presented (see Fig. 6), leading to the induction of strong cellular and humoral immune responses resulting in the production of secretory IgA, the predominating immunoglobulin along mucosal surfaces (Suárez et al., 2021, Kraan et al., 2014. ...
Therapeutic proteins and peptides (TPPs) are increasingly favoured above small drug molecules due to their high specificity to the site of action and reduced adverse effects resulting in increased use of these agents for medical treatments and therapies. Consequently, there is a need to formulate TPPs in dosage forms that are accessible and suitable for a wide range of patient groups as the use of TPPs becomes increasingly prevalent in healthcare settings worldwide. Orally disintegrating dosage forms (ODDF) are formulations that can ensure easy-to-administer medication to a wider patient population including paediatrics, geriatrics and people in low-resource countries. There are many challenges involved in developing suitable pharmaceutical strategies to protect TPPs during formulation and manufacturing, as well as storage, and maintenance of a cold-chain during transportation. This review will discuss advances being made in the research and development of pharmaceutical and manufacturing strategies used to incorporate various TPPs into ODDF systems.
... In addition, vaccines in the mucosal area are expected to be able to induce first-line immunity at the site of entry of pathogens to prevent infection/disease and to produce a systemic immune response [26]. The mucosa as the first line of defense against various infections contains many dendritic cells that act as APCs that will present antigens to the immune system and then induce both mucosal and systemic immune responses to eliminate pathogens [2][3][4]. ...
... The consideration for administering mucosal vaccines is that traditional vaccines via intramuscular injection induce only a small amount of mucosal immune response or no response at all, thereby reducing the effectiveness of preventing mucosal-borne infectious diseases [4,26]. Another reason for vaccination by the mucosal route is that most infections originate from mucosal surfaces, especially the nasal, oropharyngeal, respiratory, genitourinary, and gastrointestinal mucosa. ...
... First, the oral mucosa can be considered as a mucosal vaccination route because it has advantages compared to other mucosal routes, including the oral mucous membrane has a relatively low enzyme activity, prevents the risk of antigen damage due to exposure to very low pH acids in the stomach, and is a safe route. Oral mucosa is also more comfortable for the patient than other routes and has a lower risk of complications in the central nervous system than vaccination via intranasal [4]. Administration of mucosal vaccines through the oral cavity can be through the sublingual and buccal mucosa. ...
Currently, mucosal infectious diseases are still a very high global health burden, but there are few effective vaccines to prevent mucosal-borne diseases. The development of mucosal vaccines requires the selection of appropriate antigens, delivery system strategies, and adjuvants to increase vaccine efficacy but limited studies have been conducted. The aim of this review is to describe the mucosal immune system, as well as the potential for the development of vaccines and mucosal adjuvants, and their challenges. The study was conducted by applying inclusion criteria for the articles, and a review was conducted by two readers with the agreement. It was known that mucosal vaccination is a potential route to be applied in future preventive efforts through vaccination. However, limited studies have been conducted so far and limited mucosal vaccination has been approved. New technological approaches such as material development involving nano- and micro-patterning are important to intensively open and investigate the potential area of development to provide better vaccination methods.
