RESUMEN

Mucosal barrier tissues and their mucosal associated lymphoid tissues (MALT) are attractive targets for vaccines and immunotherapies due to their roles in both priming and regulating adaptive immune responses. The upper and lower respiratory mucosae, in particular, possess unique properties: a vast surface area responsible for frontline protection against inhaled pathogens but also simultaneous tight regulation of homeostasis against a continuous backdrop of non-pathogenic antigen exposure. Within the upper and lower respiratory tract, the nasal and bronchial associated lymphoid tissues (NALT and BALT, respectively) are key sites where antigen-specific immune responses are orchestrated against inhaled antigens, serving as critical training grounds for adaptive immunity. Many infectious diseases are transmitted via respiratory mucosal sites, highlighting the need for vaccines that can activate resident frontline immune protection in these tissues to block infection. While traditional parenteral vaccines that are injected tend to elicit weak immunity in mucosal tissues, mucosal vaccines (i.e., that are administered intranasally) are capable of eliciting both systemic and mucosal immunity in tandem by initiating immune responses in the MALT. In contrast, administering antigen to mucosal tissues in the absence of adjuvant or costimulatory signals can instead induce antigen-specific tolerance by exploiting regulatory mechanisms inherent to MALT, holding potential for mucosal immunotherapies to treat autoimmunity. Yet despite being well motivated by mucosal biology, development of both mucosal subunit vaccines and immunotherapies has historically been plagued by poor drug delivery across mucosal barriers, resulting in weak efficacy, short-lived responses, and to-date a lack of clinical translation. Development of engineering strategies that can overcome barriers to mucosal delivery are thus critical for translation of mucosal subunit vaccines and immunotherapies. This review covers engineering strategies to enhance mucosal uptake via active targeting and passive transport mechanisms, with a parallel focus on mechanisms of immune activation and regulation in the respiratory mucosa. By combining engineering strategies for enhanced mucosal delivery with a better understanding of immune mechanisms in the NALT and BALT, we hope to illustrate the potential of these mucosal sites as targets for immunomodulation.

Asunto(s)

Inmunidad Mucosa , Inmunomodulación , Humanos , Animales , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Tejido Linfoide/inmunología , Vacunas/inmunología , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Administración Intranasal

RESUMEN

BACKGROUND: Klebsiella pneumoniae (KP), responsible for acute lung injury (ALI) and inflammation of the gastrointestinal tract, is a zoonotic pathogen that poses a threat to livestock farming worldwide. Nevertheless, there is currently no validated vaccine to prevent KP infection. The development of mucosal vaccines against KP using Lactobacillus plantarum (L. plantarum) is an effective strategy. RESULTS: Firstly, the L. plantarum strains NC8-pSIP409-aCD11c' and NC8-pLc23-aCD11c were constructed via homologous recombination to express the aCD11c protein either inducibly or constitutively. Both NC8-pSIP409-aCD11c' and NC8-pLc23-aCD11c strains could enhance the adhesion and invasion of L. plantarum on bone marrow-derived dendritic cells (BMDCs), and stimulate the activation of BMDCs compared to the control strain NC8-pSIP409 in vitro. Following oral immunization of mice with NC8-pSIP409-aCD11c' and NC8-pLc23-aCD11c, the cellular, humoral, and mucosal immunity were significantly improved, as evidenced by the increased expression of CD4+ IL-4+ T cells in the spleen, IgG in serum, and secretory IgA (sIgA) in the intestinal lavage fluid (ILF). Furthermore, the protective effects of L. plantarum against inflammatory damage caused by KP infection were confirmed by assessing the bacterial loads in various tissues, lung wet/dry ratio (W/D), levels of inflammatory cytokines, and histological evaluation, which influenced T helper 17 (Th17) and regulatory T (Treg) cells in peripheral blood and lung. CONCLUSIONS: Both the inducible and constitutive L. plantarum strains NC8-pSIP409-aCD11c' and NC8-pLc23-aCD11c have been found to stimulate cellular and humoral immunity levels and alleviate the inflammatory response caused by KP infection. These findings have provided a basis for the development of a novel vaccine against KP.

Asunto(s)

Inmunidad Celular , Infecciones por Klebsiella , Klebsiella pneumoniae , Lactobacillus plantarum , Animales , Infecciones por Klebsiella/prevención & control , Infecciones por Klebsiella/veterinaria , Infecciones por Klebsiella/inmunología , Klebsiella pneumoniae/inmunología , Ratones , Administración Oral , Femenino , Ratones Endogámicos BALB C , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/administración & dosificación , Células Dendríticas/inmunología , Inflamación

RESUMEN

Despite concerted efforts to tackle the COVID-19 pandemic, the persistent transmission of SARS-CoV-2 demands continued research into novel vaccination strategies to combat the virus. In light of this, intranasally administered peptide vaccines, particularly those conjugated to an immune adjuvant to afford so-called "self-adjuvanted vaccines", remain underexplored. Here, we describe the synthesis and immunological evaluation of self-adjuvanting peptide vaccines derived from epitopes of the spike glycoprotein of SARS-CoV-2 covalently fused to the potent adjuvant, Pam2Cys, that targets toll-like receptor 2 (TLR2). When administered intranasally, these vaccines elicited a strong antigen-specific CD4+ and CD8+ T-cell response in the lungs as well as high titers of IgG and IgA specific to the native spike protein of SARS-CoV-2. Unfortunately, serum and lung fluid from mice immunized with these vaccines failed to inhibit viral entry in spike-expressing pseudovirus assays. Following this, we designed and synthesized fusion vaccines composed of the T-cell epitope discovered in this work, covalently fused to epitopes of the receptor-binding domain of the spike protein reported to be neutralizing. While antibodies elicited against these fusion vaccines were not neutralizing, the T-cell epitope retained its ability to stimulate strong antigen-specific CD4+ lymphocyte responses within the lungs. Given the Spike(883-909) region is still completely conserved in SARS-CoV-2 variants of concern and variants of interest, we envision the self-adjuvanting vaccine platform reported here may inform future vaccine efforts.

Asunto(s)

Adyuvantes Inmunológicos , Administración Intranasal , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Lipopéptidos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , SARS-CoV-2/inmunología , Ratones , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Glicoproteína de la Espiga del Coronavirus/inmunología , COVID-19/prevención & control , COVID-19/inmunología , Lipopéptidos/inmunología , Lipopéptidos/administración & dosificación , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Femenino , Humanos , Ratones Endogámicos BALB C , Adyuvantes de Vacunas/administración & dosificación , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/administración & dosificación , Inmunidad Celular , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología

RESUMEN

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains one of the top three causes of death. Currently, the only licensed vaccine against TB is the bacillus Calmette-Guerin (BCG), which lacks efficacy in preventing and controlling pulmonary TB in adults. We aimed to evaluate a nasal TB vaccine formulation composed of the Mtb-specific vaccine antigen ESAT-6, an Mtb-associated protein that can trigger protective immune responses, and S100A4, a recently characterized novel mucosal adjuvant. Mice were intranasally given recombinant ESAT-6 in the presence or absence of S100A4 as an adjuvant. We have provided experimental evidence demonstrating that S100A4 admixed to ESAT-6 could induce Mtb-specific adaptive immune responses after intranasal immunization. S100A4 remarkably augmented the levels of anti-ESAT-6 IgG in serum and IgA in mucosal sites, including lung exudates, bronchoalveolar lavage fluid (BALF) and nasal lavage. Furthermore, in both lung and spleen tissues, S100A4 strongly promoted ESAT-6-specific expansion of CD4 T cells. Both CD4 and CD8 T cells from these tissues expressed increased levels of IFN-γ, TNF-α, and IL-17, cytokines critical for antimicrobial activity. Antigen-reencounter-induced T cell proliferative responses, a key vaccine performance indicator, were augmented in the spleen of S100A4-adjuvanted mice. Furthermore, CD8 T cells from the spleen and lung tissues of these mice expressed higher levels of granzyme B upon antigen re-stimulation. S100A4-adjuvanted immunization may predict good mucosal protection against TB.

Asunto(s)

Adyuvantes Inmunológicos , Administración Intranasal , Antígenos Bacterianos , Proteínas Bacterianas , Mycobacterium tuberculosis , Proteína de Unión al Calcio S100A4 , Vacunas contra la Tuberculosis , Animales , Vacunas contra la Tuberculosis/inmunología , Vacunas contra la Tuberculosis/administración & dosificación , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Ratones , Mycobacterium tuberculosis/inmunología , Femenino , Proteína de Unión al Calcio S100A4/inmunología , Linfocitos T CD4-Positivos/inmunología , Tuberculosis/prevención & control , Tuberculosis/inmunología , Adyuvantes de Vacunas/administración & dosificación , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Pulmón/inmunología , Pulmón/microbiología , Linfocitos T CD8-positivos/inmunología , Inmunidad Mucosa , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Citocinas/metabolismo , Ratones Endogámicos C57BL , Bazo/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Ratones Endogámicos BALB C

RESUMEN

RSV infection remains a serious threat to the children all over the world, especially, in the low-middle income countries. Vaccine delivery via the mucosa holds great potential for inducing local immune responses in the respiratory tract. Previously, we reported the development of highly immunogenic RSV virus-like-particles (RSV-VLPs) based on the conformationally stable prefusogenic-F protein (preFg), glycoprotein and matrix protein. Here, to explore whether mucosal delivery of RSV-VLPs is an effective strategy to induce RSV-specific mucosal and systemic immunity, RSV-VLPs were administered via the nasal, sublingual and pulmonary routes to BALB/c mice. The results demonstrate that immunization with the VLPs via the mucosal routes induced minimal mucosal response and yet facilitated modest levels of serum IgG antibodies, enhanced T cell responses and the expression of the lung-homing marker CXCR3 on splenocytes. Immunization with VLPs via all three mucosal routes provided protection against RSV challenge with no signs of RSV induced pathology.

Asunto(s)

Anticuerpos Antivirales , Ratones Endogámicos BALB C , Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Vacunas de Partículas Similares a Virus , Proteínas Virales de Fusión , Proteínas de la Matriz Viral , Animales , Infecciones por Virus Sincitial Respiratorio/prevención & control , Infecciones por Virus Sincitial Respiratorio/inmunología , Vacunas contra Virus Sincitial Respiratorio/inmunología , Vacunas contra Virus Sincitial Respiratorio/administración & dosificación , Ratones , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Vacunas de Partículas Similares a Virus/inmunología , Vacunas de Partículas Similares a Virus/administración & dosificación , Proteínas Virales de Fusión/inmunología , Proteínas Virales de Fusión/genética , Proteínas Virales de Fusión/administración & dosificación , Femenino , Proteínas de la Matriz Viral/inmunología , Proteínas de la Matriz Viral/administración & dosificación , Proteínas de la Matriz Viral/genética , Inmunidad Mucosa , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Virus Sincitial Respiratorio Humano/inmunología , Pulmón/virología , Pulmón/inmunología , Glicoproteínas/inmunología , Glicoproteínas/administración & dosificación , Administración a través de la Mucosa , Virus Sincitiales Respiratorios/inmunología , Linfocitos T/inmunología

RESUMEN

Brucellosis is a chronic infectious disease that is zoonotic in nature. Brucella can infect humans through interactions with livestock, primarily via the digestive tract, respiratory tract, and oral cavity. This bacterium has the potential to be utilized as a biological weapon and is classified as a Category B pathogen by the Centers for Disease Control and Prevention. Currently, there is no approved vaccine for humans against Brucella, highlighting an urgent need for the development of a vaccine to mitigate the risks posed by this pathogen. Brucella primarily infects its host by adhering to and penetrating mucosal surfaces. Mucosal immunity plays a vital role in preventing local infections, clearing microorganisms from mucosal surfaces, and inhibiting the spread of pathogens. As mucosal vaccine strategies continue to evolve, the development of a safe and effective mucosal vaccine against Brucella appears promising.This paper reviews the immune mechanism of mucosal vaccines, the infection mechanism of Brucella, successful Brucella mucosal vaccines in animals, and mucosal adjuvants. Additionally, it elucidates targeting and optimization strategies for mucosal vaccines to facilitate the development of human vaccines against Brucella.

Asunto(s)

Vacuna contra la Brucelosis , Brucella , Brucelosis , Inmunidad Mucosa , Humanos , Animales , Brucella/inmunología , Inmunidad Mucosa/inmunología , Brucelosis/prevención & control , Brucelosis/inmunología , Brucelosis/microbiología , Vacuna contra la Brucelosis/inmunología , Adyuvantes Inmunológicos , Desarrollo de Vacunas

RESUMEN

Mucosal vaccines can prevent viruses from infecting the respiratory mucosa, rather than only curtailing infection and protecting against the development of disease symptoms. The SARS-CoV-2 spike receptor-binding domain (RBD) is a compelling vaccine target but is undermined by suboptimal mucosal immunogenicity. Here, we report a SARS-CoV-2-mimetic extracellular-vesicle vaccine developed using genetic engineering and dendritic cell membrane budding. After mucosal immunization, the vaccine recruits antigen-presenting cells rapidly initiating a strong innate immune response. Notably, it obviates the need for adjuvants and can induce germinal center formation through both intramuscular and intratracheal vaccination. It not only elicits high levels of RBD-specific antibodies but also stimulates extensive cellular immunity in the respiratory mucosa. A sequential immunization strategy, starting with an intramuscular injection followed by an intratracheal booster, significantly bolsters mucosal immunity with high levels of IgA and tissue-resident memory T cell responses, thereby establishing a formidable defense against pseudovirus infection.

RESUMEN

Periodontal disease (PD) is caused by microbial dysbiosis and accompanying adverse inflammatory responses. Due to its high incidence and association with various systemic diseases, disease-modifying treatments that modulate dysbiosis serve as promising therapeutic approaches. In this study, to simulate the pathophysiological situation, we established a "temporary ligature plus oral infection model" that incorporates a temporary silk ligature and oral infection with a cocktail of live Tannerella forsythia (Tf), Pophyromonas gingivalis (Pg), and Fusobacterium nucleatum (Fn) in mice and tested the efficacy of a new trivalent mucosal vaccine. It has been reported that Tf, a red complex pathogen, amplifies periodontitis severity by interacting with periodontopathic bacteria such as Pg and Fn. Here, we developed a recombinant mucosal vaccine targeting a surface-associated protein, BspA, of Tf by genetically combining truncated BspA with built-in adjuvant flagellin (FlaB). To simultaneously induce Tf-, Pg-, and Fn-specific immune responses, it was formulated as a trivalent mucosal vaccine containing Tf-FlaB-tBspA (BtB), Pg-Hgp44-FlaB (HB), and Fn-FlaB-tFomA (BtA). Intranasal immunization with the trivalent mucosal vaccine (BtB + HB + BtA) prevented alveolar bone loss and gingival proinflammatory cytokine production. Vaccinated mice exhibited significant induction of Tf-tBspA-, Pg-Hgp44-, and Fn-tFomA-specific IgG and IgA responses in the serum and saliva, respectively. The anti-sera and anti-saliva efficiently inhibited epithelial cell invasion by Tf and Pg and interfered with biofilm formation by Fn. The flagellin-adjuvanted trivalent mucosal vaccine offers a novel method for modulating dysbiotic bacteria associated with periodontitis. This approach leverages the adjuvant properties of flagellin to enhance the immune response, aiming to restore a balanced microbial environment and improve periodontal health.

RESUMEN

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.

Asunto(s)

Inmunidad Mucosa , Vacunas , Humanos , Vacunas/inmunología , Vacunas/administración & dosificación , Animales , Administración Sublingual , Enfermedades Respiratorias/inmunología , Enfermedades Respiratorias/prevención & control , Boca/microbiología

RESUMEN

The steady rise of drug-resistant tuberculosis (TB), which renders standard therapy regimens ineffective, necessitates the development of innovative treatment approaches. Immunotherapeutic vaccines have the potential to effectively regulate the anti-TB immune response and enhance the efficacy of anti-TB treatment. In the present study, we aimed to evaluate the potency of the mucosal vector vaccine TB/FLU-06E as part of a complex treatment regimen for drug-susceptible (DS) or drug-resistant (DR) tuberculosis in C57BL/6 mice. Incorporating TB/FLU-06E into the treatment protocol significantly increased the effectiveness of therapy for both forms of tuberculosis. It was evidenced by higher survival rates and reduced pulmonary bacterial load (1.83 lg CFU for DS tuberculosis and 0.93 lg CFU for DR tuberculosis). Furthermore, the treatment reduced pathomorphological lesions in the lungs and stimulated the local and systemic T-helper 1 (Th1) and cytotoxic T-lymphocyte (CTL) anti-TB immune responses. Thus, therapeutic immunization with the TB/FLU-06E vaccine significantly enhances the efficacy of tuberculosis treatment, which is particularly important in DR tuberculosis.

RESUMEN

BACKGROUND: The gastrointestinal tract contains a wide range of microorganisms that have evolved alongside the immune system of the host. The intestinal mucosa maintains balance within the intestines by utilizing the mucosal immune system, which is controlled by the complex gut mucosal immune network. OBJECTIVE: This review aims to comprehensively introduce current knowledge of the gut mucosal immune system, focusing on its interaction with commensal bacteria. RESULTS: The gut mucosal immune network includes gut-associated lymphoid tissue, mucosal immune cells, cytokines, and chemokines. The connection between microbiota and the immune system occurs through the engagement of bacterial components with pattern recognition receptors found in the intestinal epithelium and antigen-presenting cells. This interaction leads to the activation of both innate and adaptive immune responses. The interaction between the microbial community and the host is vital for maintaining the balance and health of the host's mucosal system. CONCLUSION: The gut mucosal immune network maintains a delicate equilibrium between active immunity, which defends against infections and damaging non-self antigens, and immunological tolerance, which allows for the presence of commensal microbiota and dietary antigens. This balance is crucial for the maintenance of intestinal health and homeostasis. Disturbance of gut homeostasis leads to enduring or severe gastrointestinal ailments, such as colorectal cancer and inflammatory bowel disease. Utilizing these factors can aid in the development of cutting-edge mucosal vaccines that have the ability to elicit strong protective immune responses at the primary sites of pathogen invasion.

Asunto(s)

Microbioma Gastrointestinal , Inmunidad Mucosa , Mucosa Intestinal , Humanos , Microbioma Gastrointestinal/inmunología , Inmunidad Mucosa/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Animales , Simbiosis/inmunología , Homeostasis/inmunología

RESUMEN

We generated a replication-competent OC43 human seasonal coronavirus (CoV) expressing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike in place of the native spike (rOC43-CoV2 S). This virus is highly attenuated relative to OC43 and SARS-CoV-2 in cultured cells and animals and is classified as a biosafety level 2 (BSL-2) agent by the NIH biosafety committee. Neutralization of rOC43-CoV2 S and SARS-CoV-2 by S-specific monoclonal antibodies and human sera is highly correlated, unlike recombinant vesicular stomatitis virus-CoV2 S. Single-dose immunization with rOC43-CoV2 S generates high levels of neutralizing antibodies against SARS-CoV-2 and fully protects human ACE2 transgenic mice from SARS-CoV-2 lethal challenge, despite nondetectable replication in respiratory and nonrespiratory organs. rOC43-CoV2 S induces S-specific serum and airway mucosal immunoglobulin A and IgG responses in rhesus macaques. rOC43-CoV2 S has enormous value as a BSL-2 agent to measure S-specific antibodies in the context of a bona fide CoV and is a candidate live attenuated SARS-CoV-2 mucosal vaccine that preferentially replicates in the upper airway.

Asunto(s)

Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Pruebas de Neutralización , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Humanos , Anticuerpos Neutralizantes/inmunología , Ratones , COVID-19/inmunología , COVID-19/virología , COVID-19/prevención & control , Anticuerpos Antivirales/inmunología , Pruebas de Neutralización/métodos , Ratones Transgénicos , Coronavirus Humano OC43/inmunología , Coronavirus Humano OC43/genética , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/inmunología , Chlorocebus aethiops , Células Vero , Macaca mulatta

RESUMEN

Introduction: Current vaccines against COVID-19 administered via parenteral route have limited ability to induce mucosal immunity. There is a need for an effective mucosal vaccine to combat SARS-CoV-2 virus replication in the respiratory mucosa. Moreover, sex differences are known to affect systemic antibody responses against vaccines. However, their role in mucosal cellular responses against a vaccine remains unclear and is underappreciated. Methods: We evaluated the mucosal immunogenicity of a booster vaccine regimen that is recombinant protein-based and administered intranasally in mice to explore sex differences in mucosal humoral and cellular responses. Results: Our results showed that vaccinated mice elicited strong systemic antibody (Ab), nasal, and bronchiole alveolar lavage (BAL) IgA responses, and local T cell immune responses in the lung in a sex-biased manner irrespective of mouse genetic background. Monocytes, alveolar macrophages, and CD103+ resident dendritic cells (DCs) in the lungs are correlated with robust mucosal Ab and T cell responses induced by the mucosal vaccine. Discussion: Our findings provide novel insights into optimizing next-generation booster vaccines against SARS-CoV-2 by inducing spike-specific lung T cell responses, as well as optimizing mucosal immunity for other respiratory infections, and a rationale for considering sex differences in future vaccine research and vaccination practice.

Asunto(s)

Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunidad Mucosa , Inmunogenicidad Vacunal , SARS-CoV-2 , Vacunas de Subunidad , Animales , Femenino , Ratones , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/virología , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/administración & dosificación , Masculino , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Pulmón/inmunología , Pulmón/virología , Linfocitos T/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Ratones Endogámicos C57BL , Administración Intranasal , Factores Sexuales , Inmunoglobulina A/inmunología , Células Dendríticas/inmunología , Inmunización Secundaria , Inmunidad Humoral

RESUMEN

The oral and nasal cavities serve as critical gateways for infectious pathogens, with microorganisms primarily gaining entry through these routes. Our first line of defense against these invaders is the mucosal membrane, a protective barrier that shields the body's internal systems from infection while also contributing to vital functions like air and nutrient intake. One of the key features of this mucosal barrier is its ability to protect the physiological system from pathogens. Additionally, mucosal tolerance plays a crucial role in maintaining homeostasis by regulating the pH and water balance within the body. Recognizing the importance of the mucosal barrier, researchers have developed various mucosal formulations to enhance the immune response. Mucosal vaccines, for example, deliver antigens directly to mucosal tissues, triggering local immune stimulation and ultimately inducing systemic immunity. Studies have shown that lipid-based formulations such as liposomes and virosomes can effectively elicit both local and systemic immune responses. Furthermore, mucoadhesive polymeric particles, with their prolonged delivery to target sites, have demonstrated an enhanced immune response. This Review delves into the critical role of material selection and delivery approaches in optimizing mucosal immunity.

Asunto(s)

Materiales Biocompatibles , Inmunidad Mucosa , Inmunidad Mucosa/efectos de los fármacos , Humanos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Vacunas/inmunología , Vacunas/administración & dosificación , Membrana Mucosa/inmunología , Animales

RESUMEN

The development of mucosal vaccines, which can generate antigen-specific immune responses in both the systemic and mucosal compartments, has been recognized as an effective strategy for combating infectious diseases caused by pathogenic microbes. Our recent research has focused on creating a nasal vaccine system in mice using enzymatically polymerized caffeic acid (pCA). However, we do not yet understand the molecular mechanisms by which pCA stimulates antigen-specific mucosal immune responses. In this study, we hypothesized that pCA might activate mucosal immunity at the site of administration based on our previous findings that pCA possesses immune-activating properties. However, contrary to our initial hypothesis, the intranasal administration of pCA did not enhance the expression of various genes involved in mucosal immune responses, including the enhancement of IgA responses. Therefore, we investigated whether pCA forms a complex with antigenic proteins and enhances antigen delivery to mucosal dendritic cells located in the lamina propria beneath the mucosal epithelial layer. Data from gel filtration chromatography indicated that pCA forms a complex with the antigenic protein ovalbumin (OVA). Furthermore, we examined the promotion of OVA delivery to nasal mucosal dendritic cells (mDCs) after the intranasal administration of pCA in combination with OVA and found that OVA uptake by mDCs was increased. Therefore, the data from gel filtration chromatography and flow cytometry imply that pCA enhances antigen-specific antibody production in both mucosal and systemic compartments by serving as an antigen-delivery vehicle.

RESUMEN

BACKGROUND & AIMS: The spread of foot-and-mouth disease virus (FMDV) through aerosol droplets among cloven-hoofed ungulates in close contact is a major obstacle for successful animal husbandry. Therefore, the development of suitable mucosal vaccines, especially nasal vaccines, to block the virus at the initial site of infection is crucial. PATIENTS AND METHODS: Here, we constructed eukaryotic expression plasmids containing the T and B-cell epitopes (pTB) of FMDV in tandem with the molecular mucosal adjuvant Fms-like tyrosine kinase receptor 3 ligand (Flt3 ligand, FL) (pTB-FL). Then, the constructed plasmid was electrostatically attached to mannose-modified chitosan-coated poly(lactic-co-glycolic) acid (PLGA) nanospheres (MCS-PLGA-NPs) to obtain an active nasal vaccine targeting the mannose-receptor on the surface of antigen-presenting cells (APCs). RESULTS: The MCS-PLGA-NPs loaded with pTB-FL not only induced a local mucosal immune response, but also induced a systemic immune response in mice. More importantly, the nasal vaccine afforded an 80% protection rate against a highly virulent FMDV strain (AF72) when it was subcutaneously injected into the soles of the feet of guinea pigs. CONCLUSIONS: The nasal vaccine prepared in this study can effectively induce a cross-protective immune response against the challenge with FMDV of same serotype in animals and is promising as a potential FMDV vaccine.

Asunto(s)

Administración Intranasal , Quitosano , Virus de la Fiebre Aftosa , Fiebre Aftosa , Nanosferas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Vacunas Virales , Animales , Quitosano/química , Quitosano/administración & dosificación , Virus de la Fiebre Aftosa/inmunología , Virus de la Fiebre Aftosa/genética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Fiebre Aftosa/prevención & control , Fiebre Aftosa/inmunología , Ratones , Nanosferas/química , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , Ratones Endogámicos BALB C , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Femenino , Ácidos Nucleicos/administración & dosificación , Inmunidad Mucosa , Sistemas de Liberación de Medicamentos

RESUMEN

BACKGROUND: Mannheimia haemolytica is a bovine respiratory pathogen commonly associated with bacterial bronchopneumonia. Current vaccine strategies have shown variable efficacy in feedlot cattle, and therefore novel vaccines are needed. Bacillus subtilis spores have been investigated as a mucosal vaccine platform, due to their ability to bind and present antigens to the mucosa and act as an adjuvant. The aim of this study was to develop two spore-based mucosal vaccines targeting M. haemolytica and evaluate their immunogenicity in mice. METHODS: Two antigen constructs composed of cholera toxin B subunit, M. haemolytica leukotoxin, and either the M. haemolytica outer membrane protein PlpE (MhCP1) or GS60 (MhCP2) were synthesized, purified and then bound to spores as vaccines. In two separate mice trials, the spore-bound vaccines (Spore-MhCP1 and Spore-MhCP2) were administered to mice through intranasal and intragastric routes, while free antigens were administered intranasally and intramuscularly. Unbound spores were also evaluated intranasally. Antigen-specific serum IgG and mucosal IgA from bronchoalveolar lavage, feces, and saliva were measured after vaccination. Mice sera from all treatment groups were assessed for their bactericidal activity against M. haemolytica. RESULTS: In both mice experiments, intramuscular immunization induced the strongest serum IgG antibody response. However, the intranasal administration of Spore-MhCP1 and Spore-MhCP2 elicited the greatest secretory IgA-specific response against leukotoxin, PlpE, and GS60 in bronchoalveolar lavage, saliva, and feces (p < 0.05). Compared to the intranasal administration of free antigen, spore-bound antigen groups showed greater bactericidal activity against M. haemolytica (p < 0.05). CONCLUSIONS: Since intranasally delivered Spore-MhCP1 and Spore-MhCP2 elicited both systemic and mucosal immune responses in mice, these vaccines may have potential to mitigate lung infection in cattle by restricting M. haemolytica colonization and proliferation in the respiratory tract. The efficacy of these mucosal spore-based vaccines merits further assessment against M. haemolytica in cattle.

RESUMEN

Chlamydia trachomatis is an obligate intracellular pathogen responsible for the most prevalent bacterial sexually transmitted disease globally. The high prevalence of chlamydial infections underscores the urgent need for licensed and effective vaccines to prevent transmission in populations. Bacterial outer membrane vesicles (OMVs) have emerged as promising mucosal vaccine carriers due to their inherent adjuvant properties and the ability to display heterologous antigens. In this proof-of-concept study, we evaluated the immunogenicity of Salmonella OMVs decorated with C. trachomatis MOMP-derived CTH522 or HtrA antigens in mice. Following a prime-boost intranasal vaccination approach, two OMV-based C. trachomatis vaccines elicited significant humoral responses specific to the antigens in both systemic and vaginal compartments. Furthermore, we demonstrated strong antigen-specific IFN-γ and IL17a responses in splenocytes and cervical lymph node cells of vaccinated mice, indicating CD4+ Th1 and Th17 biased immune responses. Notably, the OMV-CTH522 vaccine also induced the production of spleen-derived CD8+ T cells expressing IFN-γ. In conclusion, these results highlight the potential of OMV-based C. trachomatis vaccines for successful use in future challenge studies and demonstrate the suitability of our modular OMV platform for intranasal vaccine applications.

Asunto(s)

Infecciones por Chlamydia , Vacunas , Femenino , Animales , Ratones , Chlamydia trachomatis , Linfocitos T CD8-positivos , Antígenos Bacterianos , Salmonella , Inmunidad , Vacunas Bacterianas , Infecciones por Chlamydia/prevención & control , Anticuerpos Antibacterianos , Proteínas de la Membrana Bacteriana Externa

Asunto(s)

Antiinfecciosos , Vacunas , Inmunoglobulina A , Membrana Mucosa

RESUMEN

INTRODUCTION: Following the coronavirus disease pandemic, respiratory mucosal vaccines that elicit both mucosal and systemic immune responses have garnered increasing attention. However, human physiological characteristics pose significant challenges in the evaluation of mucosal immunity, which directly impedes the development and application of respiratory mucosal vaccines. AREAS COVERED: This study summarizes the characteristics of immune responses in the respiratory mucosa and reviews the current status and challenges in evaluating immune response to respiratory mucosal vaccines. EXPERT OPINION: Secretory Immunoglobulin A (S-IgA) is a major effector molecule at mucosal sites and a commonly used indicator for evaluating respiratory mucosal vaccines. However, the unique physiological structure of the respiratory tract pose significant challenges for the clinical collection and detection of S-IgA. Therefore, it is imperative to develop a sampling method with high collection efficiency and acceptance, a sensitive detection method, reference materials for mucosal antibodies, and to establish a threshold for S-IgA that correlates with clinical protection. Sample collection is even more challenging when evaluating mucosal cell immunity. Therefore, a mucosal cell sampling method with high operability and high tolerance should be established. Targets of the circulatory system capable of reflecting mucosal cellular immunity should also be explored.

Asunto(s)

Vacunas , Humanos , Inmunidad Mucosa , Inmunoglobulina A Secretora , Mucosa Respiratoria , Vacunación , Anticuerpos Antivirales