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Salmonella enterica serovar Typhi produces significant morbidity and mortality worldwide despite the fact that there are licensed Salmonella Typhi vaccines available. This is primarily due to the fact that these vaccines are not used in the countries that most need them. There is growing recognition that an effective invasive Salmonella vaccine formulation must also prevent infection due to other Salmonella serovars. We anticipate that a multivalent vaccine that targets the following serovars will be needed to control invasive Salmonella infections worldwide: Salmonella Typhi, Salmonella Paratyphi A, Salmonella Paratyphi B (currently uncommon but may become dominant again), Salmonella Typhimurium, Salmonella Enteritidis and Salmonella Choleraesuis (as well as other Group C Salmonella). Live attenuated vaccines are an attractive vaccine formulation for use in developing as well as developed countries. Here, we describe the methods of attenuation that have been used to date to create live attenuated Salmonella vaccines and provide an update on the progress that has been made on these vaccines.

Invasive non-typhoidal Salmonella (iNTS) disease is an under-recognized high-burden disease causing major health and socioeconomic issues in sub-Saharan Africa (sSA), predominantly among immune-naïve infants and young children, including those with recognized comorbidities such as HIV infection. iNTS disease is primarily caused by Salmonella enterica serovar Typhimurium sequence type (ST) 313 and ‘African-restricted clades’ of Salmonella Enteritidis ST11 that have emerged across the African continent as a series of epidemics associated with acquisition of new antimicrobial resistance. Due to genotypes with a high prevalence of antimicrobial resistance and scarcity of therapeutic options, these NTS serovars are designated by the World Health Organization as a priority pathogen for research and development of interventions, including vaccines, to address and reduce NTS associated bacteremia and meningitis in sSA. Novel and traditional vaccine technologies are being applied to develop vaccines against iNTS disease, and the results of the first clinical trials in the infant target population should become available in the near future. The “Vaccine Value Profile” (VVP) addresses information related predominantly to invasive disease caused by Salmonella Enteritidis and Salmonella Typhimurium prevalent in sSA. Information is included on stand-alone iNTS disease candidate vaccines and candidate vaccines targeting iNTS disease combined with another invasive serotype, Salmonella Typhi, that is also common across sSA. Out of scope for the first version of this VVP is a wider discussion on either diarrheagenic NTS disease (dNTS) also associated with Salmonella Enteritidis and Salmonella Typhimurium or the development of a multivalent Salmonella vaccines targeting key serovars for use globally. This VVP for vaccines to prevent iNTS disease is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic, and societal value of pipeline vaccines and vaccine-like products. Future versions of this VVP will be updated to reflect ongoing activities such as vaccine development strategies and a “Full Vaccine Value Assessment” that will inform the value proposition of an iNTS disease vaccine. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the World Health Organization African Region. All contributors have extensive expertise on various elements of the iNTS disease VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Nontyphoidal Salmonellae cause a devastating burden of invasive disease in sub-Saharan Africa with high levels of antimicrobial resistance. Vaccination has potential for a major global health impact, but no licensed vaccine is available. The lack of commercial incentive makes simple, affordable technologies the preferred route for vaccine development. Here we compare equivalent Generalized Modules for Membrane Antigens (GMMA) outer membrane vesicles and O-antigen-CRM197 glycoconjugates to deliver lipopolysaccharide O-antigen in bivalent Salmonella Typhimurium and Enteritidis vaccines. Salmonella strains were chosen and tolR deleted to induce GMMA production. O-antigens were extracted from wild-type bacteria and conjugated to CRM197. Purified GMMA and glycoconjugates were characterized and tested in mice for immunogenicity and ability to reduce Salmonella infection. GMMA and glycoconjugate O-antigen had similar structural characteristics, O-acetylation, and glucosylation levels. Immunization with GMMA induced higher anti–O-antigen IgG than glycoconjugate administered without Alhydrogel adjuvant. With Alhydrogel, antibody levels were similar. GMMA induced a diverse antibody isotype profile with greater serum bactericidal activity than glycoconjugate, which induced almost exclusively IgG1. Immunization reduced bacterial colonization of mice subsequently infected with Salmonella. S. Typhimurium numbers were lower in tissues of mice vaccinated with GMMA compared with glycoconjugate. S. Enteritidis burden in the tissues was similar in mice immunized with either vaccine. With favorable immunogenicity, low cost, and ability to induce functional antibodies and reduce bacterial burden, GMMA offer a promising strategy for the development of a nontyphoidal Salmonella vaccine compared with established glycoconjugates. GMMA technology is potentially attractive for development of vaccines against other bacteria of global health significance.

Invasive nontyphoidal Salmonella (iNTS) infections, primarily caused by Salmonella enterica serovars Typhimurium (S. Typhimurium) and Enteritidis (S. Enteritidis), represent a significant public health concern, particularly in sub-Saharan Africa, where multidrug-resistant (MDR) strains are increasingly prevalent. Despite the substantial disease burden, no vaccines are currently licensed for iNTS. This study aimed to develop an iNTS conjugate vaccine by conjugating O-specific polysaccharide (OSP) antigens to carrier proteins using chemical conjugation, a proven method known for its efficiency and scalability in licensed glycoconjugate vaccines. Various carrier proteins and chemical conjugation processes were evaluated to optimize the iNTS OSP conjugate vaccine candidates. Through this optimization, diphtheria toxoid (DT) was identified as the carrier protein that significantly enhances the anti-OSP immunogenicity of the iNTS conjugates. Key properties, such as the molecular weight and OSP:DT ratio in the iNTS OSP conjugate were found to be controllable by adjusting the ratios of CDAP conjugate reagent and DT to iNTS OSP. Optimal conjugation process parameters were identified by evaluating the relationship between these property and immunogenicity through tests in mice. The optimized iNTS conjugates for S. Typhimurium and S. Enteritidis were further developed into a bivalent formulation. This formulation was selected based on a dose-dependent immunogenicity study and included alum as an adjuvant to enhance immune response. Ultimately, a trivalent drug product formulation was developed by combining the bivalent iNTS conjugate vaccine with a typhoid conjugate vaccine. Our findings demonstrated that the iNTS OSP-DT conjugates, at the optimal conjugation ratios, induced robust immune responses with high anti-OSP IgG titers for both iNTS serovars, comparable to or exceeding those of other formulations. The inclusion of alum further enhanced immunogenicity across all formulations. Notably, the trivalent vaccine formulation showed promising results, maintaining robust immunogenic responses against all iNTS OSP antigens and the Vi polysaccharide antigen of Salmonella Typhi, without compromising the immunogenicity of any individual antigens. This study suggests that a bivalent iNTS vaccine combined with a typhoid conjugate vaccine could provide broad protection against both iNTS infections and typhoid fever, addressing a critical unmet need in regions with limited resources.

Invasive nontyphoidal Salmonella disease (iNTS) is a leading cause of death and morbidity in Africa. The most common pathogens are Salmonella enterica serovars Typhimurium and Enteritidis. The O-antigen portion of their lipopolysaccharide is a target of protective immunity and vaccines targeting O-antigen are currently in development. Here we investigate the use of Generalized Modules for Membrane Antigens (GMMA) as delivery system for S. Typhimurium and S. Enteritidis O-antigen. Gram-negative bacteria naturally shed outer membrane in a blebbing process. By deletion of the tolR gene, the level of shedding was greatly enhanced. Further genetic modifications were introduced into the GMMA-producing strains in order to reduce reactogenicity, by detoxifying the lipid A moiety of lipopolysaccharide. We found that genetic mutations can impact on expression of O-antigen chains. All S. Enteritidis GMMA characterized had an O-antigen to protein w/w ratio higher than 0.6, while the ratio was 0.7 for S. Typhimurium ΔtolR GMMA, but decreased to less than 0.1 when further mutations for lipid A detoxification were introduced. Changes were also observed in O-antigen chain length and level and/or position of O-acetylation. When tested in mice, the GMMA induced high levels of anti-O-antigen-specific IgG functional antibodies, despite variation in density and O-antigen structural modifications. In conclusion, simplicity of manufacturing process and low costs of production, coupled with encouraging immunogenicity data, make GMMA an attractive strategy to further investigate for the development of a vaccine against iNTS.

Gamma-irradiated inactivated bacterial vaccines have emerged as a safer alternative, overcoming the safety and immunogenicity limitations of conventional live attenuated and inactivated vaccines. This study aimed to develop gamma-irradiated Salmonella Gallinarum (γ-SG) vaccine from a local field strain and evaluate its cell-mediated immune response in a chicken model, focusing on CD4+ and CD8+ T cell activation and IFN-γ production. Radiation doses ranging from 1.5 to 10 kGy were evaluated to determine the optimal level for inactivating bacterial replication while retaining metabolic activity. Dose of 7 kGy effectively inhibited replication while maintaining residual metabolic activity. In an immunization-challenge study, commercial broiler chickens (Ross 308) at 14 days of age were vaccinated twice at two-week intervals orally with γ-SG (γ-SG Oral), intramuscularly with oil-based γ-SG (γ-SG IM), oil-based formalin-inactivated SG (F-SG) and SG 9R vaccines with the concentration of each 2 × 108 CFU and SG 9R at the concentration of 2 × 107 CFU in 0.2 mL PBS. Our study showed that chickens vaccinated with γ-SG (Oral) exhibited significantly higher CD4+ T cell response (39.74 %) when compared with SG 9R (29.36 %), γ-SG (IM) (20.2 %) and F-SG (22.8 %) groups at three weeks post-vaccination (WPV). Similarly, CD8+ T cell response was highest in γ-SG (Oral) group (28.6 %) versus SG 9R (5.28 %), γ-SG (IM) (19.7 %), and F-SG (14.3 %) at 3WPV. IFN-γ concentrations were also significantly elevated in γ-SG (Oral) group (452.75 pg/mL) when compared with SG 9R (307.5 pg/mL), γ-SG (IM) (334 pg/mL), and F-SG (221.75 pg/mL) groups. In vivo efficacy study showed that γ-SG (Oral) provided 100 % protection with 0 % mortality, comparable to SG 9R while F-SG and γ-SG (IM) groups showed 40 % and 20 % mortality, respectively, compared to 70 % in unvaccinated chickens challenged with wild-type SG. These findings demonstrate that non-adjuvanted oral γ-SG vaccination is an effective strategy against fowl typhoid.

Salmonella enterica infections result in diverse clinical manifestations. Typhoid fever, caused by S. enterica serovar Typhi (S. Typhi) and S. Paratyphi A, is a bacteremic illness but whose clinical features differ from other Gram-negative bacteremias. Non-typhoidal Salmonella (NTS) serovars cause self-limiting diarrhea with occasional secondary bacteremia. Primary NTS bacteremia can occur in the immunocompromised host and infants in sub-Saharan Africa. Recent studies on host-pathogen interactions in Salmonellosis using genome sequencing, murine models, and patient studies have provided new insights. The full genome sequences of numerous S. enterica serovars have been determined. The S. Typhi genome, compared to that of S. Typhimurium, harbors many inactivated or disrupted genes. This can partly explain the different immune responses both serovars induce upon entering their host. Similar genome degradation is also observed in the ST313 S. Typhimurium strain implicated in invasive infection in sub-Saharan Africa. Virulence factors, most notably, type III secretion systems, Vi antigen, lipopolysaccharide and other surface polysaccharides, flagella, and various factors essential for the intracellular life cycle of S. enterica have been characterized. Genes for these factors are commonly carried on Salmonella Pathogenicity Islands (SPIs). Plasmids also carry putative virulence-associated genes as well as those responsible for antimicrobial resistance. The interaction of Salmonella pathogen-associated molecular patterns (PAMPs) with Toll-like receptors (TLRs) and NOD-like receptors (NLRs) leads to inflammasome formation, activation, and recruitment of neutrophils and macrophages and the production of pro-inflammatory cytokines, most notably interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and interferon-gamma (IFN)-γ. The gut microbiome may be an important modulator of this immune response. S. Typhimurium usually causes a local intestinal immune response, whereas S. Typhi, by preventing neutrophil attraction resulting from activation of TLRs, evades the local response and causes systemic infection. Potential new therapeutic strategies may lead from an increased understanding of infection pathogenesis.

Campylobacter and invasive non-typhoidal Salmonella (iNTS) are among the most common causative agents of gastroenteritis worldwide. As of now, no single combination licensed vaccine is available for public health use against both iNTS and Campylobacter species. Outer-membrane vesicles (OMVs) are nanoscale proteoliposomes released from the surface of gram-negative bacteria during log phase and harbor a variety of immunogenic proteins. Based on epidemiology of infections, we formulated a novel trivalent outer membrane vesicles (TOMVs)-based vaccine candidate against Campylobacter jejuni (CJ), Salmonella Typhimurium (ST) and Salmonella Enteritidis (SE). Isolated OMVs from CJ, ST and SE were combined in equal ratios for formulation of TOMVs and 5 µg of the developed vaccine candidate was used for intraperitoneal immunization of adult BALB/c mice. Immunization with TOMVs significantly activated both the humoral and cellular arm of adaptive immune response. Robust bactericidal effect was elicited by TOMVs immunized adult mice sera. TOMVs immunization induced long-term protective efficacy against CJ, ST and SE infections in mice. The study illustrates the ability of TOMVs-based combination immunogen in eliciting broad-spectrum protective immunity against prevalent Campylobacter and iNTS pathogens. According to the findings, TOMVs can work as a potent combination-based acellular vaccine candidate for amelioration of Campylobacter and iNTS-mediated gastroenteritis.

Controlled human infection model (CHIM) studies, which involve deliberate exposure of healthy human volunteers to an infectious agent, are recognised as important tools to advance vaccine development. These studies not only facilitate estimates of vaccine efficacy, but also offer an experimental approach to study disease pathogenesis and profile vaccine immunogenicity in a controlled environment, allowing correlation with clinical outcomes. Consequently, the data from CHIMs can be used to identify immunological correlates of protection (CoP), which can help accelerate vaccine development. In the case of invasive Salmonella infections, vaccination offers a potential instrument to prevent disease. Invasive Salmonella disease, caused by the enteric fever pathogens Salmonella enterica serovar Typhi ( S. Typhi) and S. Paratyphi A, B and C, and nontyphoidal Salmonella (iNTS), remains a significant cause of mortality and morbidity in low- and middle-income countries, resulting in over 200,000 deaths and the loss of 15 million DALYs annually. CHIM studies have contributed to the understanding of S . Typhi infection and provided invaluable insight into the development of vaccines and CoP following vaccination against S. Typhi. However, CoP are less well understood for S . Paratyphi A and iNTS. This brief review focuses on the contribution of vaccine-CHIM trials to our understanding of the immune mechanisms associated with protection following vaccines against invasive Salmonella pathogens, particularly in relation to CoP.

Salmonella infections pose a significant global public health concern due to the substantial expenses associated with monitoring, preventing, and treating the infection. In this study, we explored the core proteome of Salmonella to design a multi-epitope vaccine through Subtractive Proteomics and immunoinformatics approaches. A total of 2395 core proteins were curated from 30 different isolates of Salmonella (strain NZ CP014051 was taken as reference). Utilizing the subtractive proteomics approach on the Salmonella core proteome, Curlin major subunit A (CsgA) was selected as the vaccine candidate. csgA is a conserved gene that is related to biofilm formation. Immunodominant B and T cell epitopes from CsgA were predicted using numerous immunoinformatics tools. T lymphocyte epitopes had adequate population coverage and their corresponding MHC alleles showed significant binding scores after peptide-protein based molecular docking. Afterward, a multi-epitope vaccine was constructed with peptide linkers and Human Beta Defensin-2 (as an adjuvant). The vaccine could be highly antigenic, non-toxic, non-allergic, and have suitable physicochemical properties. Additionally, Molecular Dynamics Simulation and Immune Simulation demonstrated that the vaccine can bind with Toll Like Receptor 4 and elicit a robust immune response. Using in vitro , in vivo , and clinical trials, our findings could yield a Pan- Salmonella vaccine that might provide protection against various Salmonella species.