Search Results (609)

Background/Objectives: Mucosal vaccines, delivered intranasally or via inhalation, are being studied for respiratory infectious diseases like COVID-19 and influenza. These vaccines aim to provide non-invasive administration and strong immune responses at infection sites, making them a promising area of research. This systematic review and meta-analysis assessed their immunogenicity, safety, and protective efficacy. Methods: The study design was a systematic review and meta-analysis, searching PubMed and Cochrane databases up to 30 May 2025. Inclusion criteria followed the PICOS framework, focusing on mucosal vaccines for COVID-19, influenza, RSV, pertussis, and tuberculosis. Results: A total of 65 studies with 229,614 participants were included in the final analysis. Mucosal COVID-19 vaccines elicited higher neutralizing antibodies compared to intramuscular vaccines (SMD = 2.48, 95% CI: 2.17–2.78 for wild-type; SMD = 1.95, 95% CI: 1.32–2.58 for Omicron), with varying efficacy by route (inhaled VE = 47%, 95% CI: 22–74%; intranasal vaccine VE = 17%, 95% CI: 0–31%). Mucosal influenza vaccines protected children well (VE = 62%, 95% CI: 30–46%, I² = 17.1%), but seroconversion rates were lower than those of intramuscular vaccines. RSV and pertussis vaccines had high seroconversion rates (73% and 52%, respectively). Tuberculosis vaccines were reviewed systemically, exhibiting robust cellular immunogenicity. Safety was comparable to intramuscular vaccines or placebo, with no publication bias detected. Conclusions: Current evidence suggests mucosal vaccines are immunogenic, safe, and protective, particularly for respiratory diseases. This review provides insights for future research and vaccination strategies, though limitations include varying efficacy by route and study heterogeneity. Full article

Recombinant vesicular stomatitis virus (rVSV) is a promising viral vaccine vector for addressing the COVID-19 pandemic. Inducing mucosal immunity via the intranasal route is an ideal strategy for rVSV-based vaccines, but it requires extremely stringent safety standards. In this study, we constructed two rVSV variants with amino acid mutations in their M protein: rVSV-M2 with M33A/M51R mutations and rVSV-M4 with M33A/M51R/V221F/S226R mutations, and developed COVID-19 vaccines based on these attenuated vectors. By comparing viral replication capacity, intranasal immunization, intracranial injection, and blood cell counts, we demonstrated that the M protein mutation variants exhibit significant attenuation effects both in vitro and in vivo. Moreover, preliminary investigations into the mechanisms of virus attenuation revealed that these attenuated viruses can induce a stronger type I interferon response while reducing inflammation compared to the wild-type rVSV. We developed three candidate vaccines against SARS-CoV-2 using the wildtype VSV backbone with either wild-type M (rVSV-JN.1) and two M mutant variants (rVSV-M2-JN.1 and rVSV-M4-JN.1). Our results confirmed that rVSV-M2-JN.1 and rVSV-M4-JN.1 retain strong immunogenicity while enhancing safety in hamsters. In summary, the rVSV variants with M protein mutations represent promising candidate vectors for mucosal vaccines and warrant further investigation. Full article

Background: Fowl typhoid (FT), a septicemic infection caused by Salmonella Gallinarum (SG), and H9N2 avian influenza are two economically important diseases that significantly affect the global poultry industry. Methods: We exploited the live attenuated Salmonella Gallinarum (SG) mutant JOL3062 (SG: ∆lon ∆pagL ∆asd) as a delivery system for H9N2 antigens to induce an immunoprotective response against both H9N2 and FT. To enhance immune protection against H9N2, a prokaryotic and eukaryotic dual expression plasmid, pJHL270, was employed. The hemagglutinin (HA) consensus sequence from South Korean avian influenza A virus (AIV) was cloned under the Ptrc promoter for prokaryotic expression, and the B cell epitope of neuraminidase (NA) linked with matrix protein 2 (M2e) was placed for eukaryotic expression. In vitro and in vivo expressions of the H9N2 antigens were validated by qRT-PCR and Western blot, respectively. Results: Oral immunization with JOL3121 induced a significant increase in SG and H9N2-specific serum IgY and cloacal swab IgA antibodies, confirming humoral and mucosal immune responses. Furthermore, FACS analysis showed increased CD4+ and CD8+ T cell populations. On day 28 post-immunization, there was a substantial rise in the hemagglutination inhibition titer in the immunized birds, demonstrating neutralization capabilities of immunization. Both IFN-γ and IL-4 demonstrated a significant increase, indicating a balance of Th1 and Th2 responses. Intranasal challenge with the H9N2 Y280 strain resulted in minimal to no clinical signs with significantly lower lung viral titer in the JOL3121 group. Upon SG wildtype challenge, the immunized birds in the JOL3121 group yielded 20% mortality, while 80% mortality was recorded in the PBS control group. Additionally, bacterial load in the spleen and liver was significantly lower in the immunized birds. Conclusions: The current vaccine model, designed with a host-specific pathogen, SG, delivers a robust immune boost that could enhance dual protection against FT and H9N2 infection, both being significant diseases in poultry, as well as ensure public health. Full article

Background: Vaccines that stimulate systemic and mucosal immunity to a level required to prevent SARS-CoV-2 infection and transmission are an unmet need. Highly protective hepatitis B and human papillomavirus nanoparticle vaccines highlight the potential of multivalent nanoparticle vaccine platforms to provide enhanced immunity. Here, we report the construction and characterization of self-assembling 60-subunit icosahedral nanoparticle SARS-CoV-2 vaccines using the bacterial enzyme lumazine synthase (LuS). Methods and Results: Nanoparticles displaying prefusion-stabilized SARS-CoV-2 spike ectodomains fused to the surface-exposed amino terminus of LuS were designed using structure-guided approaches. Negative stain-electron microscopy studies of purified nanoparticles were consistent with self assembly into 60-mer nanoparticles displaying 20 spike trimers. After two intramuscular doses, these purified spike-LuS nanoparticles elicited significantly higher SARS-CoV-2 neutralizing activity than spike trimers in vaccinated mice. Furthermore, intramuscular DNA priming and intranasal boosting with a SARS-CoV-2 LuS nanoparticle vaccine stimulated mucosal IgA responses. Conclusion: These data identify LuS nanoparticles as highly immunogenic SARS-CoV-2 vaccine candidates and support the further development of this platform against SARS-CoV-2 and its emerging variants. Full article

Background/Objectives: The ongoing evolution of SARS-CoV-2 has highlighted the limitations of parenteral vaccines in preventing viral transmission, largely due to their failure to elicit robust mucosal immunity. Methods: Here, we evaluated an intranasal (IN) vaccine formulation consisting of recombinant receptor-binding domain (RBD) adsorbed onto human probiotic Bacillus subtilis DG101 spores. Results: In BALB/c mice, IN spore-RBD immunization induced strong systemic and mucosal humoral responses, including elevated specific IgG, IgM, and IgA levels in serum, bronchoalveolar lavage fluid (BALF), nasal-associated lymphoid tissue (NALT), and saliva. It further promoted mucosal B cell and T cell memory, along with a Th1/Tc1-skewed T cell response, characterized by increased IFN-γ-expressing CD4⁺ and CD8⁺ T cells in the lungs. Conclusions: All in all, these findings highlight the potential of intranasal vaccines adjuvanted with probiotic B. subtilis spores in inducing sterilizing immunity and limiting SARS-CoV-2 transmission. Full article

Background: Mucosal immunity plays a pivotal role in preventing infections with SARS-CoV-2. While COVID-19 mRNA vaccines induce robust systemic immune responses in patients with inflammatory bowel disease (IBD), little is known about their efficacy in the mucosal immune compartment. In this sub-investigation of the ongoing STAR-SIGN study, we present the first analysis of mucosal immunity elicited by XBB.1.5 mRNA vaccines in immunocompromised patients with IBD. Methods: IgG and IgA antibodies targeting the receptor-binding domain of the SARS-CoV-2 JN.1 variant were quantified longitudinally in the saliva of IBD patients using the multiplex immunoassay MultiCoV-Ab. Antibody levels were quantified before and 2–4 weeks after vaccination with XBB.1.5 mRNA vaccines. All patients previously received three doses with original COVID-19 vaccines. Results: Mucosal IgG antibodies were readily induced by XBB.1.5 mRNA vaccines (p = 0.0013 comparing pre- and post-vaccination levels). However, mucosal IgA levels were comparable before and after vaccination (p = 0.8233). Consequently, mucosal IgG and IgA antibody levels correlated only moderately before and after immunization (pre-vaccination: r = 0.5294; p = 0.0239; post-vaccination: r = 0.4863; p = 0.0407). Contrary to a previous report in healthy individuals, vaccination did not induce serum IgA in patients with IBD (p = 0.5841 comparing pre- and post-vaccination levels). These data suggest that COVID-19 mRNA vaccines fail to elicit mucosal IgA in patients with IBD. Conclusions: Since mucosal IgA plays a pivotal role in infection control, the lack of IgA induction indicates that patients lack sufficient protection against SARS-CoV-2 infections which warrants the development of mucosal COVID-19 vaccines. Full article

A novel bivalent oral vaccine candidate against H5N1 and H9N2 avian influenza virus (AIV) was developed using Lactobacillus surface display technology without genetic modification. The hemagglutinin subunit 1 (HA1) antigens from both subtypes were fused to the surface layer-binding domain of Lactobacillus crispatus K313, expressed in Escherichia coli, and purified. Wild-type Lactobacillus johnsonii H31, isolated from chicken intestine, served as a delivery vehicle by adsorbing and stably displaying the HA1 proteins on its surface. This approach eliminates the need for bacterial engineering while utilizing lactobacilli’s natural capacity to protect surface-displayed antigens, as evidenced by HA1’s protease resistance. Mouse immunization studies demonstrated induction of strong systemic IgG and mucosal IgA responses against both H5N1 and H9N2 HA1. The system offers several advantages, including safety through non-GMO probiotics, potential for multivalent vaccine expansion, and intrinsic antigen protection by lactobacilli. These findings suggest this platform could enable development of cost-effective, multivalent AIV vaccines. Full article

Mucosal immunization represents a promising strategy for preventing enteric infections. Rotavirus (RV), a leading gastrointestinal pathogen distinguished by its remarkable stability and segmented double-stranded RNA genome, has been engineered into a versatile oral vaccine vector through advanced reverse genetics systems. The clinical efficacy of live-attenuated RV vaccines highlights their unique capacity to concurrently induce mucosal IgA responses and systemic neutralizing antibodies, positioning them as a multiple action vector for multiple immune protection. In this review, we summarize the RV colonization of the intestine and stimulation of intestinal immunity, as well as recent advancements in RV reverse genetics, and focus on their application in the rational design of a multivalent mucosal vaccine vector targeting enteric pathogens considering the advantages and challenges of RV as a vector. We further propose molecular strategies to overcome genetic instability in recombinant RV vectors, including the codon optimization of heterologous inserts. These insights provide a theoretical foundation for developing next-generation mucosal immunization platforms with enhanced safety, stability, and cross-protective efficacy. Full article

Respiratory syncytial virus (RSV) is a major etiological agent of lower respiratory tract infections, particularly among infants and the elderly. Activation of B cells in the mucosa and the production of specific neutralizing antibodies are essential for protective immunity against pulmonary infection. B-cell activating factor (BAFF) is a critical survival factor for B cells and has been associated with antiviral responses; however, its regulation during RSV infection remains poorly understood. This study examined BAFF regulation in BEAS-2B cells exposed to RSV or IFN-β. The treatments resulted in a progressive increase in gene expression over time, accompanied by higher protein levels. BAFF mRNA peaked at 12 h post-infection and declined by 48 h, coinciding with the release of soluble BAFF protein into the culture supernatant. Pre-treatment with anti-IFN-β antibodies prior to RSV infection reduced both BAFF mRNA and protein levels, indicating that IFN-β plays a regulatory role in BAFF production by airway epithelial cells. Western blot analysis revealed membrane-bound BAFF (~31 kDa) in non-infected cells, with elevated expression at 24 h post-infection. By 48 h, this form was cleaved into a soluble ~17 kDa form, which was detected in the supernatant. Immunostaining further demonstrated reduced surface expression of membrane-bound BAFF in RSV-infected cells compared to uninfected controls, suggesting that RSV infection promotes the cleavage and release of BAFF into the extracellular environment. Additionally, the release of BAFF was not affected by furin convertase inhibition or ER–Golgi transport blockade, indicating a potentially novel cleavage mechanism. Co-culturing BAFF produced by BEAS-2B cells with isolated B cells enhanced B cell viability. Overall, these results indicate that RSV infection stimulates BAFF production in airway epithelial cells through a pathway involving IFN-β, potentially contributing to B cell activation and promoting local antibody-mediated immunity. Understanding this mechanism may offer valuable insights for improving mucosal vaccine strategies and enhancing immunity against respiratory pathogens. Full article

Helicobacter pylori (H. pylori) is one of the most prevalent chronic bacterial infections globally, significantly contributing to gastritis, peptic ulcers, and gastric malignancies. Its pathogenesis involves a complex array of virulence factors—including cagA, vacA, and urease—which facilitate mucosal colonization, immune evasion, and persistent inflammation. A major challenge in vaccine development is the bacterium’s ability to manipulate both innate and adaptive immune responses, resulting in limited natural clearance and long-term persistence. This review synthesizes H. pylori pathogenesis and host immune dynamics, highlighting their implications for vaccine design. By elucidating the molecular and cellular mechanisms underlying host–pathogen interactions, we explore how these insights inform antigen selection, adjuvant optimization, and delivery strategies. By integrating basic science with translational objectives, this review aims to support the development of an effective H. pylori vaccine, addressing global health needs, particularly in regions with a high infection burden and limited access to treatment. Full article

Human cytomegalovirus (CMV) is the leading cause of congenital infections, often leading to mental retardation and neurological disorders. It is a major public health priority to develop a vaccine for preventing and controlling human CMV infection. In this report, we generated an oral Salmonella-based vaccine to express the M33 protein of murine cytomegalovirus (MCMV) and investigated the anti-MCMV immune responses induced in mice immunized with this vaccine. Compared to those administered with phosphate-buffered saline (PBS) or a control vaccine without M33 expression, mice immunized with the vaccine expressing the M33 protein exhibited a remarkable induction of antiviral serum IgG and mucosal IgA humoral responses and a significant elicitation of antiviral T cell responses. Successful inhibition of viral growth in lungs, spleens, livers, and salivary glands was also found in the vaccinated animals compared to the PBS-treated animals or those immunized with the control vaccine without M33 expression. Furthermore, substantial protection against MCMV challenge was observed in mice immunized with the vaccine. Thus, Salmonella-based vaccine expressing MCMV M33 can induce anti-MCMV effective immune responses and protection. Our study implies that attenuated Salmonella expressing human CMV antigens, including its homologue to M33, may represent promising oral anti-CMV vaccine candidates. Full article

Porcine epidemic diarrhea (PED), a highly contagious enteric disease caused by the porcine epidemic diarrhea virus (PEDV), is characterized by vomiting, diarrhea, and dehydration, leading to high mortality in newborn piglets and significant economic losses in the swine industry. The shortage of effective PED vaccines emphasizes the need to explore potent natural compounds for therapeutic intervention. It has been shown that glycerol monolaurate (GML) effectively inhibits PEDV replication in vivo and in vitro. Further investigation is needed to assess whether complex medium-chain triglycerides (CMCTs), composed of glyceryl tricaprylate/caprate (GTCC) and GML, offer an efficient anti-PEDV activity. In this study, piglets were orally infected with PEDV and exhibited typical clinical signs, including diarrhea and vomiting, accompanied by intestinal inflammation, oxidative stress, and tissue damage. CMCTs were administered orally twice daily for one week. In vivo findings indicate that CMCT treatment alleviated clinical signs and prevented weight loss. It significantly increased serum immunoglobulins (IgG, IgM, and IgA) and intestinal mucosal sIgA and MUC-2 levels, while reducing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-17) and increasing antiviral interferons (IFN-α and IFN-γ), anti-inflammatory cytokines (IL-4 and IL-10), and IL-22. Antioxidant enzyme activities (T-AOC, SOD, GSH-Px, and CAT) were elevated, whereas oxidative stress markers (iNOS, NO, and MDA) were decreased. Expression of intestinal tight junction proteins claudin-1 and ZO-1 was restored. Moreover, CD4⁺ and CD8⁺ T cell populations increased, and the functions of regulatory T cells (Tregs) were restored. Gut microbiota analysis showed increased beneficial genera (Streptococcus and Ligilactobacillus) and decreased pathogenic Escherichia-Shigella. These results demonstrate that CMCTs mitigate PEDV infection by enhancing anti-inflammation, antioxidation, and intestinal barrier function, as well as modulating gut microbiota composition. This study improves the understanding of the pathogenesis of PEDV and highlights CMCTs as a promising therapeutic candidate for PED. Full article

A killed, whole-cell vaccine was produced to induce immunity in dogs against leptospirosis. The vaccine, containing serovar Copenhageni, was produced and administered to 12 beagle dogs at both 8 and 12 weeks of age. Ten unvaccinated dogs of the same age group served as the control group. A live, virulent inoculum of Leptospira (1.52 × 10⁹–4.40 × 10⁹ leptospires per dog) was used to challenge the dogs at 2 weeks (Study 1) and 14 months (Study 2) post-booster vaccination. At regular intervals, pre- and post-challenge (PC), the microscopic agglutination test (MAT) was performed to measure antibody titers. Leptospiremia and leptospiruria were determined via culture, and the cytokine, biochemical, and pathological profiles of vaccinates and controls were also assessed. A high antibody response was measurable after booster administration. In Study 1 (onset of immunity), acute leptospirosis was observed in five (100%) out of five unvaccinated dogs. In contrast, no acute clinical leptospirosis developed in vaccinated dogs, except in one (20%) dog with mild clinical signs. In Study 2 (duration of immunity), mild clinical signs were observed in two (40%) of the control dogs, while all vaccinated dogs remained clinically normal. The incidence of leptospiruria and leptospiremia PC was lower in the vaccinated dogs compared to the unvaccinated group. Severe thrombocytopenia occurred in 100% (5/5) of the unvaccinated dogs in Study 1 that exhibited acute severe leptospirosis, whereas 80% (4/5) of the unvaccinated dogs in Study 2 showed mild to moderate thrombocytopenia 3 days after challenge. Four out of five unvaccinated dogs (80%) in Study 1 exhibited icteric tissues and hemorrhages in the lungs and mucosal surfaces of the stomach and intestines. A high IL-10 to TNF-α ratio, observed in the control group of both studies, and severe thrombocytopenia observed in the control group of Study 1, indicative of acute leptospiral disease, were detected. The vaccine prevented acute clinical leptospirosis and reduced the renal carrier state in beagle dogs, and further investigation is required using a larger sample size. Full article

Background:Salmonella Typhimurium is a major zoonotic pathogen, in which type 1 fimbriae play a crucial role in intestinal colonization and immune modulation. This study aimed to improve the protective immunity of a previously developed growth-deficient strain—a double auxotroph for D-glutamate and D-alanine—by engineering the inducible expression of type 1 fimbriae. Methods: P_tetA-driven expression of the fim operon was achieved by λ-Red mutagenesis. fimA expression was quantified by qRT-PCR, and fimbriation visualized by transmission electron microscopy. Adhesive properties were evaluated through FimH sequence analysis, yeast agglutination, mannose-binding/inhibition assays, and HT-29 cell adherence. BALB/c mice were immunized orogastrically with IRTA ΔΔΔ or IRTA ΔΔΔ P_tetA::fim. Safety and immunogenicity were assessed by clinical monitoring, bacterial load, fecal shedding, ELISA tests, and adhesion/blocking assays using fecal extracts. Protection was evaluated after challenging with wild-type and heterologous strains. Results: IRTA ΔΔΔ P_tetA::fim showed robust fimA expression, dense fimbrial coverage, a marked mannose-sensitive adhesive phenotype and enhanced HT-29 attachment. Fimbrial overexpression did not alter intestinal colonization or translocation to mesenteric lymph nodes (mLNs). Immunization elicited a mixed IgG1/IgG2a, significantly increased IgA and IgG against type 1 fimbriae-expressing Salmonella, and enhanced the ability of fecal extracts to inhibit the adherence of wild-type strains. Upon challenge (IRTA wild-type/20220258), IRTA ΔΔΔ P_tetA::fim reduced infection burden in the cecum (−1.46/1.47-log), large intestine (−1.35/2.17-log), mLNs (−1.32/0.98-log) and systemic organs more effectively than IRTA ΔΔΔ. Conclusions: Inducible expression of type 1 fimbriae enhances mucosal immunity and protection, supporting their inclusion in next-generation Salmonella vaccines. Future work should assess cross-protection and optimize FimH-mediated targeting for mucosal delivery. Full article

This review examines the potential and challenges of using hydrogel vaccine delivery systems in animal immunization. Traditional methods face issues like low immunogenicity, reliance on cold chains, and inefficient delivery, limiting their use in modern animal husbandry. Hydrogels offer a promising solution due to their biocompatibility, controlled drug release, and immune regulation. This paper highlights hydrogels’ benefits, such as mimicking natural infection through sustained antigen release, boosting antigen-presenting cell activity, activating immune responses, and forming barriers at mucosal sites to prevent pathogen invasion. Additionally, innovative delivery methods like microneedle patches and nasal sprays show promise in enhancing convenience and compliance in animal vaccination. By combining interdisciplinary efforts and technological advancements, the hydrogel vaccine delivery system is anticipated to be crucial in preventing animal diseases, supporting sustainable animal husbandry, and ensuring global animal health and food safety. Full article