Mucosal immunization with a low-energy electron inactivated respiratory syncytial virus vaccine protects mice without Th2 immune bias.

The respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections associated with numerous hospitalizations. Recently, intramuscular (i.m.) vaccines against RSV have been approved for elderly and pregnant women. Noninvasive mucosal vaccination, e.g., by inhalation, offers an alternative against respiratory pathogens like RSV. Effective mucosal vaccines induce local immune responses, potentially resulting in the efficient and fast elimination of respiratory viruses after natural infection. To investigate this immune response to an RSV challenge, low-energy electron inactivated RSV (LEEI-RSV) was formulated with phosphatidylcholine-liposomes (PC-LEEI-RSV) or 1,2-dioleoyl-3-trimethylammonium-propane and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DD-LEEI-RSV) for vaccination of mice intranasally. As controls, LEEI-RSV and formalin-inactivated-RSV (FI-RSV) were used via i.m. vaccination. The RSV-specific immunogenicity of the different vaccines and their protective efficacy were analyzed. RSV-specific IgA antibodies and a statistically significant reduction in viral load upon challenge were detected in mucosal DD-LEEI-RSV-vaccinated animals. Alhydrogel-adjuvanted LEEI-RSV i.m. showed a Th2-bias with enhanced IgE, eosinophils, and lung histopathology comparable to FI-RSV. These effects were absent when applying the mucosal vaccines highlighting the potential of DD-LEEI-RSV as an RSV vaccine candidate and the improved performance of this mucosal vaccine candidate.

Immunogenicity and protective efficacy of a multivalent herpesvirus vectored vaccine against H9N2 low pathogenic avian influenza in chicken.

The application of recombinant herpesvirus of turkey, expressing the H9 hemagglutinin gene from low pathogenic avian influenza virus (LPAIV) H9N2 and the avian orthoavulavirus-1 (AOAV-1) (commonly known as Newcastle Disease virus (NDV)) fusion protein (F) as an rHVT-H9-F vaccine, is an alternative to currently used classical vaccines. This study investigated H9- and ND-specific humoral and mucosal responses, H9-specific cell-mediated immunity, and protection conferred by the rHVT-H9-F vaccine in specific pathogen-free (SPF) chickens. Vaccination elicited systemic NDV F- and AIV H9-specific antibody response but also local antibodies in eye wash fluid and oropharyngeal swabs. The ex vivo H9-specific stimulation of splenic and pulmonary T cells in the vaccinated group demonstrated the ability of vaccination to induce systemic and local cellular responses. The clinical protection against a challenge using a LPAIV H9N2 strain of the G1 lineage isolated in Morocco in 2016 was associated with a shorter duration of shedding along with reduced viral genome load in the upper respiratory tract and reduced cloacal shedding compared to unvaccinated controls.

Detection of SARS-CoV-2-specific mucosal antibodies in saliva following concomitant COVID-19 and influenza vaccination in the ComFluCOV trial.

The ComFluCOV trial randomized 679 participants to receive an age-appropriate influenza vaccine, or placebo, alongside their second COVID-19 vaccine. Concomitant administration was shown to be safe, and to preserve systemic immune responses to both vaccines. Here we report on a secondary outcome of the trial investigating SARS-CoV-2-specific mucosal antibody responses. Anti-spike IgG and IgA levels in saliva were measured with in-house ELISAs. Concomitant administration of an influenza vaccine did not affect salivary anti-spike IgG positivity rates to Pfizer/BioNTech BNT162b2 (99.1 cf. 95.6%), or AstraZeneca ChAdOx1 (67.8% cf. 64.9%), at 3-weeks post-vaccination relative to placebo. Furthermore, saliva IgG positively correlated with serum titres highlighting the potential utility of saliva for assessing differences in immunogenicity in future vaccine studies. Mucosal IgA was not detected in response to either COVID-19 vaccine, reinforcing the need for novel vaccines capable of inducing sterilising immunity or otherwise reducing transmission. The trial is registered as ISRCTN 14391248.

IL-22-dependent responses and their role during Citrobacter rodentium infection.

The mouse pathogen Citrobacter rodentium is utilized as a model organism for studying infections caused by the human pathogens enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and to elucidate mechanisms of mucosal immunity. In response to C. rodentium infection, innate lymphoid cells and T cells secrete interleukin (IL)-22, a cytokine that promotes mucosal barrier function. IL-22 plays a pivotal role in enabling mice to survive and recover from C. rodentium infection, although the exact mechanisms involved remain incompletely understood. Here, we investigated whether particular components of the host response downstream of IL-22 contribute to the cytokine's protective effects during C. rodentium infection. In line with previous research, mice lacking the IL-22 gene (Il22-/- mice) were highly susceptible to C. rodentium infection. To elucidate the role of specific antimicrobial proteins modulated by IL-22, we infected the following knockout mice: S100A9-/- (calprotectin), Lcn2-/- (lipocalin-2), Reg3b-/- (Reg3ß), Reg3g-/- (Reg3γ), and C3-/- (C3). All knockout mice tested displayed a considerable level of resistance to C. rodentium infection, and none phenocopied the lethality observed in Il22-/- mice. By investigating another arm of the IL-22 response, we observed that C. rodentium-infected Il22-/- mice exhibited an overall decrease in gene expression related to intestinal barrier integrity as well as significantly elevated colonic inflammation, gut permeability, and pathogen levels in the spleen. Taken together, these results indicate that host resistance to lethal C. rodentium infection may depend on multiple antimicrobial responses acting in concert, or that other IL-22-regulated processes, such as tissue repair and maintenance of epithelial integrity, play crucial roles in host defense to attaching and effacing pathogens.

Intranasal administration of unadjuvanted SARS-CoV-2 spike antigen boosts antigen-specific immune responses induced by parenteral protein subunit vaccine prime in mice and hamsters.

With the continued transmission of SARS-CoV-2 across widely vaccinated populations, it remains important to develop new vaccines and vaccination strategies capable of providing protective immunity and limiting the spread of disease. Heterologous prime-boost vaccination based on the selection of different vaccine formulations and administration routes for priming and booster doses presents a promising strategy for inducing broader immune responses in key systemic and respiratory mucosal compartments. Intranasal vaccination can induce mucosal immune responses at the site of SARS-CoV-2 infection; however, the lack of clinically approved mucosal adjuvants makes it difficult to induce robust immune responses with protein subunit vaccines. Herein, we evaluated the immunogenicity of heterologous prime-boost regimens in mice and hamsters based on a parenteral vaccination of the antigen in combination with sulfated lactosylarchaeol (SLA) archaeosomes, a liposome adjuvant comprised of a single semisynthetic archaeal lipid, followed by an intranasally administered unadjuvanted SARS-CoV-2 spike antigen. Intranasal administration of unadjuvanted spike to mice and hamsters increased serum spike-specific IgG titers and spike-neutralizing activity compared with nonboosted animals. Spike-specific IgA responses were also detected in the bronchoalveolar lavage fluid in the lungs of mice that received an intranasal boost. In hamsters, the intranasal boost showed high efficacy against SARS-CoV-2 infection by protecting from body weight loss and reducing viral titers in the lungs and nasal turbinate. Overall, our heterologous intramuscular prime-intranasal boost with SLA-adjuvanted and unadjuvanted spike, respectively, demonstrated the potential of protein subunit formulations to promote antigen-specific systemic and mucosal immune responses.

Possible transport routes of IgM to the gut of teleost fish.

Fish rely on mucosal surfaces as their first defence barrier against pathogens. Maintaining mucosal homeostasis is therefore crucial for their overall well-being, and it is likely that secreted immunoglobulins (sIg) play a pivotal role in sustaining this balance. In mammals, the poly-Ig receptor (pIgR) is an essential component responsible for transporting polymeric Igs across mucosal epithelia. In teleost fish, a counterpart of pIgR has been identified and characterized, exhibiting structural differences and broader mRNA expression patterns compared to mammals. Despite supporting evidence for the binding of Igs to recombinant pIgR proteins, the absence of a joining chain (J-chain) in teleosts challenges the conventional understanding of Ig transport mechanisms. The transport of IgM to the intestine via the hepatobiliary route is observed in vertebrates and has been proposed in a few teleosts. Investigations on the stomachless fish, ballan wrasse, revealed a significant role of the hepatobiliary route and interesting possibilities for alternative IgM transport routes that might include pancreatic tissue. These findings highlight the importance of gaining a thorough understanding of the mechanisms behind Ig transport to the gut in various teleosts. This review aims to gather existing information on pIgR-mediated transport across epithelial cells and immunoglobulin transport pathways to the gut lumen in teleost fish. It provides comparative insights into the hepatobiliary transport of Igs to the gut, emphasizing the current understanding in teleost fish while exploring potential alternative pathways for Ig transport to the gut lumen. Despite significant progress in understanding various aspects, there is still much to uncover, especially concerning the diversity of mechanisms across different teleost species.

Controlling Candida: immune regulation of commensal fungi in the gut.

The intestinal microbiome harbors fungi that pose a significant risk to human health as opportunistic pathogens and drivers of inflammation. Inflammatory and autoimmune diseases are associated with dysbiotic fungal communities and the expansion of potentially pathogenic fungi. The gut is also the main reservoir for disseminated fungal infections. Immune interactions are critical for preventing commensal fungi from becoming pathogenic. Significant strides have been made in defining innate and adaptive immune pathways that regulate intestinal fungi, and these discoveries have coincided with advancements in our understanding of the fungal molecular pathways and effectors involved in both commensal colonization and pathogenesis within the gut. In this review, we will discuss immune interactions important for regulating commensal fungi, with a focus on how specific cell types and effectors interact with fungi to limit their colonization or pathogenic potential. This will include how innate and adaptive immune pathways target fungi and orchestrate antifungal immune responses, in addition to how secreted immune effectors, such as mucus and antimicrobial peptides, regulate fungal colonization and inhibit pathogenic potential. These immune interactions will be framed around our current understanding of the fungal effectors and pathways regulating colonization and pathogenesis within this niche. Finally, we highlight important unexplored mechanisms by which the immune system regulates commensal fungi in the gut.

Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract.

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Microbiota and Immunity during Respiratory Infections: Lung and Gut Affair.

Bacterial and viral respiratory tract infections are the most common infectious diseases, leading to worldwide morbidity and mortality. In the past 10 years, the importance of lung microbiota emerged in the context of pulmonary diseases, although the mechanisms by which it impacts the intestinal environment have not yet been fully identified. On the contrary, gut microbial dysbiosis is associated with disease etiology or/and development in the lung. In this review, we present an overview of the lung microbiome modifications occurring during respiratory infections, namely, reduced community diversity and increased microbial burden, and of the downstream consequences on host-pathogen interaction, inflammatory signals, and cytokines production, in turn affecting the disease progression and outcome. Particularly, we focus on the role of the gut-lung bidirectional communication in shaping inflammation and immunity in this context, resuming both animal and human studies. Moreover, we discuss the challenges and possibilities related to novel microbial-based (probiotics and dietary supplementation) and microbial-targeted therapies (antibacterial monoclonal antibodies and bacteriophages), aimed to remodel the composition of resident microbial communities and restore health. Finally, we propose an outlook of some relevant questions in the field to be answered with future research, which may have translational relevance for the prevention and control of respiratory infections.

SARS-CoV-2-specific mucosal immune response in vaccinated versus infected children.

The anti-COVID-19 intramuscular vaccination induces a strong systemic but a weak mucosal immune response in adults. Little is known about the mucosal immune response in children infected or vaccinated against SARS-CoV-2. We found that 28% of children had detectable salivary IgA against SARS-CoV-2 even before vaccination, suggesting that, in children, SARS-CoV-2 infection may be undiagnosed. After vaccination, only receptor-binding domain (RBD)-specific IgA1 significantly increased in the saliva. Conversely, infected children had significantly higher salivary RBD-IgA2 compared to IgA1, indicating that infection more than vaccination induces a specific mucosal immune response in children. Future efforts should focus on development of vaccine technologies that also activate mucosal immunity.

Deciphering the developmental trajectory of tissue-resident Foxp3+ regulatory T cells.

Foxp3+ TREG cells have been at the focus of intense investigation for their recognized roles in preventing autoimmunity, facilitating tissue recuperation following injury, and orchestrating a tolerance to innocuous non-self-antigens. To perform these critical tasks, TREG cells undergo deep epigenetic, transcriptional, and post-transcriptional changes that allow them to adapt to conditions found in tissues both at steady-state and during inflammation. The path leading TREG cells to express these tissue-specialized phenotypes begins during thymic development, and is further driven by epigenetic and transcriptional modifications following TCR engagement and polarizing signals in the periphery. However, this process is highly regulated and requires TREG cells to adopt strategies to avoid losing their regulatory program altogether. Here, we review the origins of tissue-resident TREG cells, from their thymic and peripheral development to the transcriptional regulators involved in their tissue residency program. In addition, we discuss the distinct signalling pathways that engage the inflammatory adaptation of tissue-resident TREG cells, and how they relate to their ability to recognize tissue and pathogen-derived danger signals.

Colonization during a key developmental window reveals microbiota-dependent shifts in growth and immunity during undernutrition.

BACKGROUND: Childhood undernutrition is a major global health challenge with devastating lifelong consequences. Linear growth stunting due to undernutrition has been linked to poor health outcomes, and mothers who experience growth stunting in childhood are more likely to give birth to stunted children later in life. Based on these findings, we hypothesized that intergenerational colonization of mice with microbiota from human donors with undernutrition may recapitulate certain immune and growth changes observed in this disorder. RESULTS: To test this hypothesis, we developed a gnotobiotic murine model of undernutrition using microbiota from human infants with healthy or stunted growth trajectories. Intergenerational colonization with microbiota derived from children with growth stunting lead to less linear growth and the development of immune features of undernutrition and enteropathy, including intestinal villus blunting, lower liver IGF-1 and accumulation of intraepithelial lymphocytes and plasma cells in the small intestine. In contrast, colonization after weaning lead to fewer host phenotypic changes between these distinct microbial communities. CONCLUSIONS: These results are broadly consistent with previous findings demonstrating that exposure of the immune system to microbial products during the weaning phase is a critical determinant of later life immune function. Overall, our results suggest intergenerational colonization with human microbiota samples is a useful approach with which to investigate microbiota-dependent changes in growth and immunity in early life. Murine models that capture the intergenerational and multifactorial nature of undernutrition are critical to understanding the underlying biology of this disorder. Video Abstract.

Injectable Hydrogel Mucosal Vaccine Elicits Protective Immunity against Respiratory Viruses.

Intranasal vaccines, eliciting mucosal immune responses, can prevent early invasion, replication, and transmission of pathogens in the respiratory tract. However, the effective delivery of antigens through the nasal barrier and boosting of a robust systematic and mucosal immune remain challenges in intranasal vaccine development. Here, we describe an intranasally administered self-healing hydrogel vaccine with a reversible strain-dependent sol-gel transition by precisely modulating the self-assembly processes between the natural drug rhein and aluminum ions. The highly bioadhesive hydrogel vaccine enhances antigen stability and prolongs residence time in the nasal cavity and lungs by confining the antigen to the surface of the nasal mucosa, acting as a "mucosal mask". The hydrogel also stimulates superior immunoenhancing properties, including antigen internalization, cross-presentation, and dendritic cell maturation. Furthermore, the formulation recruits immunocytes to the nasal mucosa and nasal-associated lymphoid tissue (NALT) while enhancing antigen-specific humoral, cellular, and mucosal immune responses. Our findings present a promising strategy for preparing intranasal vaccines for infectious diseases or cancer.

Immune cell composition and inflammatory profile of human peri-implantitis and periodontitis lesions.

Peri-implantitis and periodontitis are common oral inflammatory diseases, which seem to exhibit critical differences in some of their molecular features. Thus, we assessed the immune cell composition of peri-implantitis and periodontitis lesions and the corresponding inflammatory profile in soft tissues and crevicular fluid. Peri-implantitis, periodontitis and control patients were recruited (n=62), and soft tissue biopsies were collected during surgery. Crevicular fluid around implant or tooth was collected. The proportions of major immune cell populations in tissues were analyzed by flow cytometry, and the inflammatory profile in tissue and crevicular fluid by a multiplex immunoassay. No significant difference was seen between peri-implantitis and periodontitis lesions in the proportions of immune cells. Peri-implantitis tissues showed an increased frequency of B cells in comparison with control tissues, along with higher levels of IL-1ß, TNF-α, IL-4, and BAFF in tissue and crevicular fluid. Moreover, TNF-α, IL-17A and BAFF were higher in peri-implantitis tissues, but not in periodontitis, than in control tissues. The immune cell composition did not differ significantly between peri-implantitis and periodontitis, but an enhanced inflammatory profile was seen in peri-implantitis tissue. Peri-implantitis lesions were enriched in B cells, and displayed increased levels of IL-1ß, TNF-α, IL-4, and BAFF in both tissue and crevicular fluid.

Comparison of SARS-CoV-2 spike-specific IgA and IgG in nasal secretions, saliva and serum.

Introduction: Several novel vaccine platforms aim at mucosal immunity in the respiratory tract to block SARS-CoV-2 transmission. Standardized methods for mucosal sample collection and quantification of mucosal antibodies are therefore urgently needed for harmonized comparisons and interpretations across mucosal vaccine trials and real-world data. Methods: Using commercial electrochemiluminescence antibody panels, we compared SARS-CoV-2 spike-specific IgA and IgG in paired saliva, nasal secretions, and serum from 1048 healthcare workers with and without prior infection. Results: Spike-specific IgA correlated well in nasal secretions and saliva (r>0.65, p<0.0001), but the levels were more than three-fold higher in nasal secretions as compared to in saliva (p<0.01). Correlations between the total population of spike-specific IgA and spike-specific secretory IgA (SIgA) were significantly stronger (p<0.0001) in nasal secretions (r=0.96, p<0.0001) as opposed to in saliva (r=0.77, p<0.0001), and spike-specific IgA correlated stronger (p<0.0001) between serum and saliva (r=0.73, p<0.001) as opposed to between serum and nasal secretions (r=0.54, p<0.001), suggesting transudation of monomeric spike specific IgA from the circulation to saliva. Notably, spike-specific SIgA had a markedly higher SARS-CoV-2 variant cross-binding capacity as compared to the total population of spike specific IgA and IgG in both nasal secretions, saliva and serum, (all p<0.0001), which emphasizes the importance of taking potential serum derived monomeric IgA into consideration when investigating mucosal immune responses. Discussion: Taken together, although spike-specific IgA can be reliably measured in both nasal secretions and saliva, our findings imply an advantage of higher levels and likely also a larger proportion of SIgA in nasal secretions as compared to in saliva. We further corroborate the superior variant cross-binding capacity of SIgA in mucosal secretions, highlighting the potential protective benefits of a vaccine targeting the upper respiratory tract.

Glycyrrhiza polysaccharides may have an antitumor effect in γδT cells through gut microbiota and TLRs/NF-κB pathway in mice.

Tumor immunotherapy can be a suitable cancer treatment option in certain instances. Here we investigated the potential immunomodulatory effect of oral glycyrrhiza polysaccharides (GCP) on the antitumor function of γδT cells in intestinal epithelial cells in mice. We found that GCP can inhibit tumor growth and was involved in the regulation of systemic immunosuppression. GCP administration also promoted the differentiation of gut epithelia γδT cells into IFN-γ-producing subtype through regulation of local cytokines in gut mucosa. GCP administration increased local cytokine levels through gut microbiota and the gut mucosa Toll-like receptors / nuclear factor kappa-B pathway. Taken together, our results suggest that GCP might be a suitable candidate for tumor immunotherapy, although further clinical research, including clinical trials, are required to validate these results.

Intestinal MAdCAM-1 imaging as biomarker for prognostic in murine models of multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Recent evidence suggests that lymphocyte trafficking in the intestines could play a key role in its etiology. Nevertheless, it is not clear how intestinal tissue is involved in the disease onset nor its evolution. In the present study, we aimed to evaluate intestinal inflammation dynamic throughout the disease course and its potential impact on disease progression. METHODS: We used tissue immunophenotyping (immunohistofluorescence and flow cytometry) and a recently described molecular magnetic resonance imaging (MRI) method targeting mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to assess intestinal inflammation in vivo in two distinct animal models of MS (Experimental Autoimmune Encephalomyelitis - EAE) at several time points of disease progression. RESULTS: We report a positive correlation between disease severity and MAdCAM-1 MRI signal in two EAE models. Moreover, high MAdCAM-1 MRI signal during the asymptomatic phase is associated with a delayed disease onset in progressive EAE and to a lower risk of conversion to a secondary-progressive form in relapsing-remitting EAE. During disease evolution, in line with a bi-directional immune communication between the gut and the central nervous system, we observed a decrease in T-CD4+ and B lymphocytes in the ileum concomitantly with their increase in the spinal cord. CONCLUSION: Altogether, these data unveil a crosstalk between intestinal and central inflammation in EAE and support the use of molecular MRI of intestinal MAdCAM-1 as a new biomarker for prognostic in MS patients.

Retinoic acid-loaded liposomes induce human mucosal CD103+ dendritic cells that inhibit Th17 cells and drive regulatory T-cell development in vitro.

The active vitamin A metabolite, all-trans-retinoic acid (RA), primes precursor dendritic cells (DCs) into a mucosal phenotype with tolerogenic properties characterized by the expression of integrin CD103. CD103+ DCs can counteract pathogenic Th1 and Th17 in inflammatory bowel disease (IBD) or celiac disease (CD). Tolerogenic manipulation of DCs using nanoparticles carrying tolerogenic adjuvants and disease-specific antigens is a valuable treatment strategy to induce antigen-specific mucosal tolerance in vivo. Here, we investigated the effects of RA-loaded liposomes on human DC phenotype and function, including DC-driven T-cell development, both during the generation of monocyte-derived DCs (moDCs) as well as by priming immature moDCs. RA liposomes drove CD103+ DC differentiation as well as ALDH1A2 expression in DCs. Neutrophil-dependent Th17 cell development was reduced by RA-liposome-differentiated and RA-liposome-primed DCs. Moreover, RA liposome treatment shifted T-cell development toward a Th2 cell profile. Importantly, RA liposomes induced the development of IL-10-producing and FoxP3+ regulatory T cells (Tregs) of various Treg subsets, including ICOS+ Tregs, that were potent inhibitors of bystander memory T-cell proliferation. Taken together, RA-loaded liposomes could be a novel treatment avenue for IBD or CD patients.

Chitosan-nanoparticle-based oral Salmonella enteritidis subunit vaccine elicits cross-protection against Salmonella typhimurium in broilers.

Non-typhoidal Salmonella infection is a significant health and economic burden in poultry industry. Developing an oral vaccine to induce robust mucosal immunity in the intestines of birds, especially cross protection against different Salmonella serotypes is challenging. Therefore, a potent oral vaccine platform that can mitigate different serotypes of Salmonella is warranted for the poultry industry. We reported earlier that the Salmonella enteritidis (SE) immunogenic outer membrane proteins (OMPs) and flagellin (FLA) entrapped in mannose chitosan nanoparticles (OMPs-FLA-mCS NPs) administered prime-boost (d-3 and 3-wk later) by oral inoculation elicits mucosal immunity and reduces challenge SE colonization by over 1 log10 CFU in birds. In this study, we sought to evaluate whether the SE antigens containing OMPs-FLA-mCS NPs vaccine induces cross-protection against Salmonella typhimurium (ST) in broilers. Our data indicated that the OMPs-FLA-mCS NPs vaccine induced higher cross-protective antibody responses compared to commercial Poulvac ST vaccine (contains a modified-live ST bacterium). Particularly, OMPs-FLA-mCS-NP vaccine elicited OMPs and FLA antigens specific increased production of secretory IgA and IgY antibodies in samples collected at both post-vaccination and post-challenge timepoints compared to commercial vaccine group. Notably, the vaccine reduced the challenge ST bacterial load by 0.8 log10 CFU in the cecal content, which was comparable to the outcome of Poulvac ST vaccination. In conclusion, our data suggested that orally administered OMPs-FLA-mCS-NP SE vaccine elicited cross protective mucosal immune responses against ST colonization in broilers. Thus, this candidate vaccine could be a viable option replacing the existing both live and killed Salmonella vaccines for birds.

Development of Orally Ingestible IgA Antibody Drugs to Maintain Symbiosis Between Humans and Microorganisms.

In recent years, dysbiosis, abnormalities in the gut microbiota, has been reported to be associated with the development of many diseases, and improving the gut microbiota is important for health maintenance. It has been shown that the host recognizes and regulates intestinal bacteria by means of IgA antibodies secreted into the gut, but the precise nature of the commensal gut bacteria recognized by each IgA antibody is unclear. We have cloned monoclonal IgA antibodies from mouse intestinal IgA-producing cells and are searching for bacterial molecules recognized by each IgA clone. Although the interaction of IgA antibodies with intestinal bacteria is still largely unknown and requires further basic research, we discuss the potential use of orally ingestible IgA antibodies as agents to improve intestinal microbiota.