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<front>
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<journal-id journal-id-type="publisher-id">Front. Cell. Infect. Microbiol.</journal-id>
<journal-title>Frontiers in Cellular and Infection Microbiology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cell. Infect. Microbiol.</abbrev-journal-title>
<issn pub-type="epub">2235-2988</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcimb.2024.1388222</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cellular and Infection Microbiology</subject>
<subj-group>
<subject>Perspective</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Cutting-edge research frontiers in oral cavity vaccines for respiratory diseases: a roadmap for scientific advancement</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Sallard</surname>
<given-names>Erwan</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1439729"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/investigation/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Aydin</surname>
<given-names>Malik</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/627243"/>
<role content-type="https://credit.niso.org/contributor-roles/methodology/"/>
<role content-type="https://credit.niso.org/contributor-roles/formal-analysis/"/>
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<aff id="aff1">
<sup>1</sup>
<institution>Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), School of Medicine, Faculty of Health, Witten/Herdecke University</institution>, <addr-line>Witten</addr-line>, <country>Germany</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Laboratory of Experimental Pediatric Pneumology and Allergology, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Faculty of Health, Witten/Herdecke University</institution>, <addr-line>Witten</addr-line>, <country>Germany</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Institute for Medical Laboratory Diagnostics, Center for Clinical and Translational Research, Helios University Hospital Wuppertal, Witten/Herdecke University</institution>, <addr-line>Wuppertal</addr-line>, <country>Germany</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Daxiong Zeng, Soochow University, China</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Rino Rappuoli, Fondazione Biotecnopolo di Siena, Italy</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Malik Aydin, <email xlink:href="mailto:malik.aydin@uni-wh.de">malik.aydin@uni-wh.de</email>
</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>26</day>
<month>06</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>14</volume>
<elocation-id>1388222</elocation-id>
<history>
<date date-type="received">
<day>19</day>
<month>02</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>13</day>
<month>05</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Sallard and Aydin</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Sallard and Aydin</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>Intramuscular vaccines present limitations in eliciting robust mucosal immunity and preventing respiratory pathogens transmission. Sublingual vaccine administration offers promising advantages, including interconnected mucosal protection. Despite these advantages, only a few clinical trials have explored sublingual vaccines, underscoring the necessity of optimizing next-generation vaccine formulas. Critical research priorities include understanding vector behavior in the oral environment, understanding their interactions with mucosal immunity and developing formulations enabling sustained mucosal contact to facilitate efficient transduction. Consequently, tonsil organoids, as representative human mucosal models, could offer critical insights into sublingual immunization. Thus, a multi-disciplinary approach integrating pharmacological, immunological, and manufacturing considerations is pivotal for sublingual vaccines in targeting pathogen-aggravated prevalent respiratory diseases including asthma, COPD and lung cancer, as well as the antimicrobial resistance crisis.</p>
</abstract>
<kwd-group>
<kwd>vaccine</kwd>
<kwd>mucosal vaccine</kwd>
<kwd>respiratory disease</kwd>
<kwd>vaccinology</kwd>
<kwd>vector</kwd>
</kwd-group>
<counts>
<fig-count count="2"/>
<table-count count="0"/>
<equation-count count="0"/>
<ref-count count="59"/>
<page-count count="6"/>
<word-count count="2700"/>
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<custom-meta-wrap>
<custom-meta>
<meta-name>section-in-acceptance</meta-name>
<meta-value>Clinical Microbiology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="introduction">
<title>Main</title>
<p>Intramuscular administration remains the paradigm for vaccination due to well-understood systemic immune responses and highly standardized delivery procedures. However, intramuscular vaccines exhibit certain disadvantages including suboptimal induction of mucosal immunity, as stated in the literature. For example, the intramuscular polio vaccines induce lower antibody secretion in the gastrointestinal tract than their enteric counterpart (the Sabin vaccine) (<xref ref-type="bibr" rid="B40">Ogra, 1984</xref>). This is believed to be the main reason of their lower efficacy (<xref ref-type="bibr" rid="B41">Onorato et al., 1991</xref>; <xref ref-type="bibr" rid="B58">WHO Collaborative Study Group on Oral and Inactivated Poliovirus Vaccines, 1997</xref>), as supported by the negative correlation observed between intestinal antibody titers and poliovirus shedding (<xref ref-type="bibr" rid="B51">Swartz et&#xa0;al., 2008</xref>). Likewise, preclinical head-to-head comparisons of various immunization routes consistently found that mucosal administration induced superior protection against certain pathogens (<xref ref-type="bibr" rid="B3">Belyakov and Ahlers, 2009</xref>) including <italic>M. tuberculosis</italic> (<xref ref-type="bibr" rid="B56">Wang et&#xa0;al., 2004</xref>; <xref ref-type="bibr" rid="B13">Forbes et&#xa0;al., 2008</xref>), influenza (<xref ref-type="bibr" rid="B45">Perrone et&#xa0;al., 2009</xref>) and HIV (<xref ref-type="bibr" rid="B4">Belyakov et&#xa0;al., 2001</xref>) compared to intramuscular or intradermal administration. Suboptimal mucosal responses may contribute to the mediocre effectiveness of intramuscular coronavirus disease (COVID) vaccines in preventing pathogen transmission, despite them providing adequate disease prevention due to the systemic response. Starting in 2022, several mucosal COVID vaccines have been approved (<xref ref-type="bibr" rid="B47">Pilapitiya et&#xa0;al., 2023</xref>), among which the adenovirus-vectored Convidecia vaccine was shown to induce higher neutralizing antibody titers as an inhaled vaccine than after intramuscular delivery (<xref ref-type="bibr" rid="B30">Li et&#xa0;al., 2022</xref>).</p>
<p>Consequently, vaccines should ideally be delivered at the site of infection of the targeted pathogen, aiming at stimulating both systemic immunity and the resident lymphoid tissue of the vaccinated mucosa. Mucosal immunity relies on secretions such as saliva that provide the first barrier to microorganisms, while mucosa-associated lymphoid tissue (MALT) plays a robust defense role (<xref ref-type="bibr" rid="B25">Kiyono and Azegami, 2015</xref>). To establish effective protection, antigens need to cross the mucus and epithelial layers, be detected by sentinel cells including dendritic and Langerhans cells, and be reactogenic enough so that these antigen-presenting cells activate MALT cellular and humoral responses, the latter relying crucially on secreted dimeric Immunoglobulin (Ig)A antibodies (<xref ref-type="bibr" rid="B25">Kiyono and Azegami, 2015</xref>; <xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>).</p>
<p>Secreted IgGs are also known to play a crucial role at least in the lower respiratory and female reproductive tracts (<xref ref-type="bibr" rid="B43">Parr and Parr, 1998</xref>; <xref ref-type="bibr" rid="B49">Renegar et&#xa0;al., 2004</xref>). Activated CD4<sup>+</sup> T cells can differentiate into T helper (Th) 1 or Th2 subsets with mucosal and systemic activity, but also in the Th17 and Th22 subsets that are mostly mucocutaneous. Secretion of interleukin (IL)-6 and TGF&#x3b2; by dendritic cells induces both Th17 differentiation and IgA secretion, although the latter can also be induced by the more Th2-related IL-5 and IL-10 (<xref ref-type="bibr" rid="B48">Protti et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B25">Kiyono and Azegami, 2015</xref>). Finally, innate lymphoid cells play important roles in mucosal immunity and are found in high numbers in mucosal epithelia (<xref ref-type="bibr" rid="B59">Wu et&#xa0;al., 2014</xref>). These features of mucosal immunity have to be accounted for in the design of mucosal vaccines. While a dozen nasal (e.g., the Flumist<sup>&#xa9;</sup> anti-influenza spray) and enteric (rotavirus, poliovirus, cholera and salmonella) vaccines are already in clinical use (<xref ref-type="bibr" rid="B29">Lavelle and Ward, 2022</xref>; <xref ref-type="bibr" rid="B47">Pilapitiya et&#xa0;al., 2023</xref>), ongoing investigations explore buccal (defined here as targeting one or several subcompartments of the oral cavity), vaginal and rectal applications.</p>
<p>The sublingual route, in particular, offers critical advantages, including a reduced risk of anaphylactic shock and Bell&#x2019;s palsy (<xref ref-type="bibr" rid="B28">Kweon, 2011</xref>); in humans, a non-keratinized epithelium facilitating rapid absorption of the vaccine (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>); and a thin mucus layer that inactivates fewer antigens than in other mucosae (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>). In addition, the buccal lymphoid tissue displays a unique ability of inducing not only local, but also systemic immunity and responses in most other mucosae (upper and lower respiratory, gastrointestinal and genital tracts) leading to multi-organs protections (<xref ref-type="bibr" rid="B17">Hervouet et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B10">Czerkinsky et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B52">Tsai et&#xa0;al., 2023</xref>). This is achieved through the selective migration of IgA-secreting plasmablasts, as well as antigen-carrying dendritic cells to secondary lymphatic organs [reviewed in (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>)].</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>Advantages of buccal vaccination. Various vaccine types could be formulated as slowly dissolving pills or films and administered to the buccal mucosa. Crossing of mucus and epithelial barriers can facilitate antigen presentation to the immune system in different locations of the buccal cavity and lead to immune response in various organs if peripheral tolerance is avoided (APC, antigen presenting cell; URT, upper respiratory tract; LRT, lower respiratory tract; GIT, gastro-intestinal tract).</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-14-1388222-g001.tif"/>
</fig>
<p>It is important to highlight that the sublingual method of vaccine application not only enables rapid vaccine absorption within 20 minutes but also represents an important step in overcoming the first metabolic passage (first-pass effect) (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>). Within the first two hours post-application, a critical release of inflammatory cytokines and chemokines occurs, which play a crucial role in the maturation and activation of immune cells, including MHC-II<sup>+</sup>, CD11b<sup>+</sup>, and CD11c cells (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>). The intensity of the immune response is largely dependent on the quantity of dendritic cells and the effectiveness of antigen uptake (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>). The early immune response initiated by dendritic cells leads to the activation and proliferation of B and T lymphocytes (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>). This results in the spread of antigen-specific effector cells to various lymph nodes (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>). The humoral response typically manifests within three weeks following sublingual vaccination (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>) (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2</bold>
</xref>). However, enteric and inhaled vaccines deliveries can also stimulate the buccal mucosa along their paths, even it is not their intended target. Sublingual vaccines should also simplify manufacture and deployment since no delivery equipment is needed and non-invasive, pain-free and needle-free administration reduces the workload for healthcare professionals and enhances public approval (<xref ref-type="bibr" rid="B6">Braun et&#xa0;al., 2023</xref>).</p>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>Mucosal immunity induction in response to sublingual vaccine application. Several mediators of both innate and adaptive immunity are involved following vaccine application. Typically, humoral defense mechanisms and immune protection occur within 2 to 3 weeks. This figure aims to briefly present the relevant immunological pathways and does not include detailed information on chemokines, cytokines or immune cell subsets (<xref ref-type="bibr" rid="B44">Paulsen and Waschke, 2010</xref>; <xref ref-type="bibr" rid="B1">Aydin et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B2">Baehren et&#xa0;al., 2022</xref>) LHc, Langerhans cells; DCs, dendritic cells including plasmacytoid, conventional and monocyte-derived subsets; PCy, Plasmacytes; PB, Plasmablasts; TL, T lymphocytes/cells. This figure was created using <uri xlink:href="https://BioRender.com">BioRender.com</uri>.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-14-1388222-g002.tif"/>
</fig>
<p>Sublingual delivery has long been the gold standard for allergen-specific immunotherapy in allergology departments and outpatient paractices, with several commercially available products targeting house dust mites and pollen. Briefly, these immunotherapies aim at redirecting the allergic IgE-dominant response towards IgA and IgG dominant, Th1-biased protective immunity following the preferential activation of regulatory dendritic cells by high dose allergen and subsequent induction of TGF&#x3b2;- and IL10-expressing regulatory T cells (<xref ref-type="bibr" rid="B11">Durham and Shamji, 2023</xref>). Since these pathways partially match those required for efficient vaccination, despite their reliance on repeated administration and anti-inflammatory pathways that are not desired for vaccines, the knowledge on mucosal immunity and product formulation acquired with sublingual allergen immunotherapy may assist buccal vaccines development. In addition, the sublingual route is utilized to administer bacterial suspensions against wheezing (<xref ref-type="bibr" rid="B39">Nieto et&#xa0;al., 2021</xref>) or urinary tract bacterial infections (<xref ref-type="bibr" rid="B31">Lorenzo-Gomez et&#xa0;al., 2015</xref>), notably the approved Uromune<sup>&#xa9;</sup> treatment, that harness trained innate immunity to protect urinary or lower respiratory tract mucosae.</p>    <p>Despite these successes, only a limited number of clinical trials of buccal vaccines have been conducted to date. Two phase I trials (NCT02052934, NCT03548064) tested a subunit vaccine against <italic>E.coli</italic> but found the enteric route to be more immunogenic than sublingual delivery (<xref ref-type="bibr" rid="B5">Bernstein et&#xa0;al., 2019</xref>). However, in the NCT01488188 and NCT03017378 trials, sublingual and nasal deliveries of respectively the Flumist<sup>&#xa9;</sup> influenza live-attenuated vaccine and the TB/FLU-01L influenza-vectored tuberculosis vaccine proved comparably safe and immunogenic (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>). Moreover, in the NCT01443936 trial, administration of an HAdV-E4 adenovirus vector encoding H5 influenza hemagglutinin to tonsils proved superior to the oral route in terms of antibodies and memory induction and equal to the intranasal one, even at a low vector dose (<xref ref-type="bibr" rid="B33">Matsuda et&#xa0;al., 2019</xref>, <xref ref-type="bibr" rid="B34">Matsuda et&#xa0;al., 2021</xref>). In our opinion, buccal delivery thus represents a priority target for which a next generation of vaccines should be optimized.</p>
<p>Addressing this goal will require extensive investigations across several topics to overcome the obstacles that have until now burdened buccal vaccines, including poor mucosa penetration, limited immunogenicity or impractical vaccine production.</p>
<p>First, the behavior of various vector types (e.g., adenovirus vectors) in the buccal environment and their interactions with mucosal resident immunity remain insufficiently understood in comparison to systemic delivery. Most sublingual vectorized vaccines tested so far have been constructed from standard backbones (notably HAdV-C5 and <italic>B. subtilis</italic>) with little effort of optimization for the specificities of mucosal environments including the risks of neutralization by antimicrobial peptides, mucus trapping and insufficient epithelium penetration (<xref ref-type="bibr" rid="B26">Kraan et&#xa0;al., 2014</xref>). For example, the AstraZeneca adenovirus-vectored COVID vaccine, although highly immunogenic intramuscularly, proved insufficiently immunogenic as an intranasal vaccine (<xref ref-type="bibr" rid="B32">Madhavan et&#xa0;al., 2022</xref>), while the Bharat intranasal COVID vaccine, derived from another adenovirus type, reached market approval and, although head-to-head comparisons are missing, displayed a higher efficacy than certain intramuscular vaccines (<xref ref-type="bibr" rid="B50">Singh et&#xa0;al., 2023</xref>). Thus, vector engineering is a largely untapped but promising area of investigations. Research on buccal vaccines has predominantly focused so far on subunit vaccines paired with adjuvants, such as <italic>V. cholerae</italic> and <italic>E.coli</italic> toxin derivatives, whose safety remains nevertheless controversial (<xref ref-type="bibr" rid="B38">Mutsch et&#xa0;al., 2004</xref>). Other adjuvants including chitosan (<xref ref-type="bibr" rid="B35">Mohamed et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B15">Gong et&#xa0;al., 2022</xref>), which helps antigens to cross the mucus layer, and flagellin (<xref ref-type="bibr" rid="B24">Khim et&#xa0;al., 2023</xref>), a potent stimulant of mucosal innate immunity, are thus increasingly used. Optimized antigens and adjuvants may in the future be incorporated into more complex platforms like adenoviral vectors to synergistically enhance their advantages. Substantial advances have been made in the last decade in viral and bacterial vectors engineering (<xref ref-type="bibr" rid="B8">Capasso et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B16">Guiziou et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B55">Wang et&#xa0;al., 2019</xref>), antigen design (<xref ref-type="bibr" rid="B9">Cohen et&#xa0;al., 2022</xref>), and immunostimulatory peptide knowledge (<xref ref-type="bibr" rid="B57">Weiss et&#xa0;al., 2022</xref>), already showing success in synthetic biology, gene therapy or cancer treatment, and the application of these methods to mucosal vaccination may bring about a new wave of success.</p>
<p>Second, it is important to identify and avoid conditions in which antigen presentation leads to peripheral tolerance (<xref ref-type="bibr" rid="B52">Tsai et&#xa0;al., 2023</xref>). Interestingly, the sublingual mucosa appears to be less prone to peripheral tolerance than the intestine (<xref ref-type="bibr" rid="B52">Tsai et&#xa0;al., 2023</xref>). Furthermore, virus- to bacteria-sized particles appear less tolerogenic than isolated proteins (<xref ref-type="bibr" rid="B42">Paris et&#xa0;al., 2021</xref>), indicating that buccal vaccine research may benefit from focusing on vector vaccines. Ideally, these vectors would be derived from microorganisms adapted to the target mucosal environment, since their coevolution with the immune system can be expected to render them immunogenic and efficient at transducing the mucosa.</p>
<p>Third, sublingual vaccine components need to remain in contact with buccal mucosa for several minutes to efficiently transduce it. The failure of the buccal route in several vaccine trials may be attributed (alongside the use of vaccines originally designed for other routes) to the use of liquid formulation, leading to the quick dispersal of vaccine components (<xref ref-type="bibr" rid="B18">Huo et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B5">Bernstein et&#xa0;al., 2019</xref>). Furthermore, the buccal environment presents staggering individual differences due to the influence of nutrition, drinking, smoking etc. on saliva chemical composition as well as to the abundant microbiota and related possibilities of lesions and inflammation. All these factors may interfere with vaccine compounds release and absorption and thus lead to variable biodistribution with deleterious consequences on immunization success rate. Vaccine formulation should therefore include biodegradable mucoadhesive films, patches, microneedles or tablets that help buffer against the variability of mucosal environments and have already facilitated substantial improvements in exposure elongation (<xref ref-type="bibr" rid="B18">Huo et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B20">Jacob et&#xa0;al., 2021</xref>). The next high-impact goals in formulation are now production upscaling and adaptation to high-molecular weights vaccine types (vectors, mRNA, DNA) whose incorporation at high concentration in the delivery system and intact mucosal release are still challenging.</p>
<p>Fourth, representative models of the human mucosae are urgently needed. The oral cavity, which is covered by mucosal epithelium, extends from the lips to the tongue and circumvallate papillae on the tongue, oral flora, buccal mucosa, retromolar space, and includes the hard and soft palates, as well as mylohyoid muscle and buccomasseter (<xref ref-type="bibr" rid="B25">Kiyono and Azegami, 2015</xref>; <xref ref-type="bibr" rid="B36">Montero and Patel, 2015</xref>; <xref ref-type="bibr" rid="B12">Famuyide et&#xa0;al., 2022</xref>). This cavity also functions as a secondary airway and provides continuous defense against pathogens, supported by the mucosal immune system (<xref ref-type="bibr" rid="B25">Kiyono and Azegami, 2015</xref>; <xref ref-type="bibr" rid="B12">Famuyide et&#xa0;al., 2022</xref>). The pharynx is divided into nasopharynx, oropharynx, and laryngopharynx (<xref ref-type="bibr" rid="B37">Morris, 1988</xref>; <xref ref-type="bibr" rid="B2">Baehren et&#xa0;al., 2022</xref>). The tonsils, which are located on the isthmus faucium, at the lateral walls and at the back of the tongue and play an important role in immune defense (<xref ref-type="bibr" rid="B37">Morris, 1988</xref>; <xref ref-type="bibr" rid="B14">Fossum et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B1">Aydin et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B2">Baehren et&#xa0;al., 2022</xref>).</p>
<p>Mice models have been proven to poorly predict the consequences of sublingual and intranasal vaccination in humans (<xref ref-type="bibr" rid="B26">Kraan et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B21">Jameson and Masopust, 2018</xref>) due to substantial differences in immune response (<xref ref-type="bibr" rid="B7">Cai et&#xa0;al., 2022</xref>) and in respiratory and digestive tracts anatomy (<xref ref-type="bibr" rid="B53">Tuero and Robert-Guroff, 2014</xref>). Non-human primates (NHPs), although used for certain preclinical tests, present ethical challenges and were generally less predictive of mucosal vaccines results in human than they have been for systemic vaccination (<xref ref-type="bibr" rid="B23">Kayesh et&#xa0;al., 2021</xref>). The tree shrew <italic>Tupaia belangeri</italic>, already used to study numerous human pathogens (<xref ref-type="bibr" rid="B27">Kulkarni et&#xa0;al., 2009</xref>), may represent an acceptable compromise, being anatomically and phylogenetically closer to humans than rodents while easing the logistical and ethical burden of NHPs. Similarly, pigs are considered representative models of human buccal anatomy (<xref ref-type="bibr" rid="B54">Wagar et&#xa0;al., 2021</xref>). However, immunological studies in these models are impractical since dedicated reagents are rare.</p>
<p>The current lack of satisfactory animal models underscores the interest of human <italic>ex vivo</italic> models that can model native mucosal immune response and even inter-individual variability. In particular, cultures of primary lymphoid tissues from tonsillectomies have already been established and harnessed (<xref ref-type="bibr" rid="B46">Perry, 1994</xref>; <xref ref-type="bibr" rid="B22">Kastenschmidt et&#xa0;al., 2023</xref>). Tonsillar crypts, with their large contact surface at the crossroads between respiratory and digestive tracts and a reticulated epithelium intertwined with immune cells infiltrates (<xref ref-type="bibr" rid="B46">Perry, 1994</xref>), indeed represent a primary target for immunization. Efficient delivery methods such as mucoadhesive patches and microneedles are equally applicable to the sublingual compartment as to tonsils, making the latter a valid clinical target. Furthermore, the easily obtained and cultured tonsil lymphoid organoids may be associated with epithelia representative of native crypt architecture to obtain models that could facilitate the mechanistic understanding of mucosal immunization and the optimization of new vaccines. Owing to the extensive interconnexions between mucosal compartments, tonsil lymphoid organoids could alternatively be cultivated with sublingual or even non-buccal mucosal epithelium to better model the intended vaccine delivery site.</p>
<p>Fifth, the mucosal effector and memory response to vaccines needs to be deciphered in more detail. For instance, the involvement of dendritic and M cells in vaccine antigen uptake and presentation has been well-described in the intestine (<xref ref-type="bibr" rid="B19">Islam et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B29">Lavelle and Ward, 2022</xref>), but knowledge from other mucosae lags behind.</p>
<p>To conclude, there is a growing need for non-canonical delivery routes. Breakthroughs have occurred during the last years in nasal and oral vaccination, building on progress in immunology and the scientific and industrial experience acquired during the COVID pandemic, and similar advances may be achieved in a foreseeable future to harness the unique opportunities of the buccal route. In particular, targeted high-throughput vector engineering, adjuvant optimization and mucoadhesive formulations appear to be promising research fields that may contribute to make mucosal vaccination a potent tool in combatting current diseases, the antimicrobials resistance crisis, and future emerging diseases. Integrated approaches considering pharmacology, immunology and manufacture constraints already at early stages are warranted to unleash the full potential of next-generation vaccinology.</p>
</sec>
<sec id="s2" sec-type="author-contributions">
<title>Author contributions</title>
<p>MA: Writing &#x2013; review &amp; editing, Writing &#x2013; original draft, Validation, Supervision, Project administration, Conceptualization. ES: Writing &#x2013; review &amp; editing, Writing &#x2013; original draft, Visualization, Conceptualization.</p>
</sec>
</body>
<back>
<sec id="s3" sec-type="funding-information">
<title>Funding</title>
<p>The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by internal research funding (UW/H-IFF-2023-62) from the Witten/Herdecke University, Witten, Germany.</p>
</sec>
<sec id="s4" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s5" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
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