antibodies

2026-04-27 | Typhoid toxin: reframing enteric fever.

SUMMARYSalmonella enterica serovars Typhi and Paratyphi A cause enteric (typhoid/paratyphoid) fever, a systemic disease that remains a major source of morbidity and mortality worldwide. The most distinctive clinical manifestations, such as sustained fever with relative bradycardia, leukopenia, neuropsychiatric symptoms/encephalopathy, and ileal perforation, have long lacked a unifying mechanistic explanation. Over the past two decades, studies of typhoid toxin have reframed how we understand this disease. Typhoid toxin is a human-adapted, chimeric A2B5 exotoxin assembled exclusively inside infected cells. It couples an ADP-ribosyltransferase (PltA) and a DNase I-like nuclease (CdtB) on a pentameric delivery ring (PltB or the alternate, PltC), that recognizes N-acetylneuraminic acid (Neu5Ac)-terminated human sialoglycans. The toxin is produced by bacteria residing within the Salmonella-containing vacuole (SCV), secreted across the bacterial envelope into the SCV lumen by a phage-derived pathway now classified as type 10 secretion system, sorted for export by the host CI-M6PR/COPII trafficking machinery, and then re-enters distant target cells via retrograde transport to the endoplasmic reticulum (ER). Recent work has linked typhoid toxin to leukopenia, blood-brain barrier disruption causing encephalopathy, gut-vascular and immune dysfunction leading to intestinal perforation, and hepatobiliary injury. The discovery of an alternate B-subunit (PltC) established a paradigm of modular B-subunit exchange that diversifies receptor usage, tissue tropism, and biology. Collectively, these insights redefine typhoid fever as a toxin-driven immunovascular disease and identify actionable targets for neutralizing antibodies and barrier-protective therapies.

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2025-11-24 | Parallel Genome-Wide CRISPR Screens Reveal SORL1 and ZFYVE19 as Sequential Host Determinants of Salmonella Infection.

Salmonella enterica, a major cause of gastroenteritis and typhoid fever, hijacks host machinery to invade cells, and replicate within a specialized niche. While some host factors are known, a comprehensive, temporally-resolved understanding of the host-pathogen interface has been hindered by a lack of suitable genome-wide methodologies. To address this, a parallel CRISPR screening platform is developed to identify host determinants for distinct infection stages. An invasion screen captured factors for bacterial entry, while a fitness screen identified factors governing long-term survival. The screens reveal a temporal switch in host dependency, from endosomal trafficking in early infection to cell cycle and DNA damage response pathways governing host cell fitness in long-term infection. Notably, the approach uncovers two novel host factors with stage-specific roles, SORL1 as a mediator of bacterial invasion and ZFYVE19 as a factor supporting intracellular proliferation. Genetic disruption of SORL1 or ZFYVE19 validate these roles, leading to impaired invasion or replication, respectively. Importantly, antibody-mediated blockade of SORL1 effectively prevented Salmonella entry, highlighting it as a novel host-directed therapeutic target. Together, the screening strategy provides a powerful framework for the temporal dissection of host-pathogen interactions, revealing novel biology and promising therapeutic targets.

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2025-03-27 | Helminth driven gut inflammation and microbial translocation associate with altered vaccine responses in rural Uganda.

Vaccine responses are sometimes impaired in rural, low-income settings. Helminth-associated gut barrier dysfunction and microbial translocation (MT) may be implicated. We used samples from a trial of praziquantel treatment-effects on vaccine responses in Schistosoma mansoni (Sm)-endemic Ugandan islands, measuring intestinal fatty acid-binding protein 2 (I-FABP2), lipopolysaccharide-binding protein, anti-endotoxin core antibodies (EndoCab), soluble CD14 (sCD14) in plasma, and faecal lipocalin-2, occult blood (FOB), and calprotectin (fCAL), and evaluating their associations with baseline helminth infection, praziquantel treatment, and responses to BCG, yellow fever, typhoid, HPV, and tetanus-diphtheria vaccines. Sm associated positively with fCAL and FOB, hookworm with I-FABP2, and any helminth with EndoCab IgM, fCAL and FOB. Sm associated inversely with sCD14. Praziquantel treatment reduced all marker concentrations, significantly fCAL and FOB, implying that Sm-associated gut inflammation and MT is reversible. Associations of assessed markers with vaccine-specific responses were predominantly inverse. Interventions to improve gut barrier function may enhance vaccine responsiveness.

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2023-06-22 | Bacterial shedding and serologic responses following an outbreak of Salmonella Typhi in an endemic cohort.

Salmonella enterica serovar Typhi (Salmonella Typhi) is the cause of typhoid fever. Salmonella Typhi may be transmitted through shedding in the stool, which can continue after recovery from acute illness. Shedding is detected by culturing stool, which is challenging to co-ordinate at scale. We hypothesised that sero-surveillance would direct us to those shedding Salmonella Typhi in stool following a typhoid outbreak. In 2016 a typhoid outbreak affected one in four residents of a Nursing School in Malosa, Malawi. The Department of Health asked for assistance to identify nursing students that might spread the outbreak to other health facilities. We measured IgG antibody titres against Vi capsular polysaccharide (anti-Vi IgG) and IgM / IgG antibodies against H:d flagellin (anti-H:d) three and six months after the outbreak. We selected participants in the highest and lowest deciles for anti-Vi IgG titre (measured at visit one) and obtained stool for Salmonella culture and PCR. All participants reported whether they had experienced fever persisting for three days or more during the outbreak (in keeping with the WHO definitions of 'suspected typhoid'). We tested for salmonellae in the Nursing School environment. We obtained 320 paired serum samples from 407 residents. We cultured stool from 25 residents with high anti-Vi IgG titres and 24 residents with low titres. We did not recover Salmonella Typhi from stool; four stool samples yielded non-typhoidal salmonellae; one sample produced a positive PCR amplification for a Salmonella Typhi target. Median anti-Vi and anti-H:d IgG titres fell among participants who reported persistent fever. There was a smaller fall in anti-H:d IgG titres among participants who did not report persistent fever. Non-typhoidal salmonellae were identified in water sampled at source and from a kitchen tap. High titres of anti-Vi IgG did not identify culture-confirmed shedding of Salmonella Typhi. There was a clear serologic signal of recent typhoid exposure in the cohort, represented by waning IgG antibody titres over time. The presence of non-typhoidal salmonellae in drinking water indicates sub-optimal sanitation. Developing methods to detect and treat shedding remains an important priority to complement typhoid conjugate vaccination in efforts to achieve typhoid elimination.

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2022-12-21 | The Lack of Natural IgM Increases Susceptibility and Impairs Anti-Vi Polysaccharide IgG Responses in a Mouse Model of Typhoid.

Circulating IgM present in the body prior to any apparent Ag exposure is referred to as natural IgM. Natural IgM provides protective immunity against a variety of pathogens. Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Because mice are not permissive to S. Typhi infection, we employed a murine model of typhoid using S. enterica serovar Typhimurium expressing the Vi polysaccharide (ViPS) of S. Typhi (S. Typhimurium strain RC60) to evaluate the role of natural IgM in pathogenesis. We found that natural mouse IgM binds to S. Typhi and S. Typhimurium. The severity of S. Typhimurium infection in mice is dependent on presence of the natural resistance-associated macrophage protein 1 (Nramp1) allele; therefore, we infected mice deficient in secreted form of IgM (sIgM) on either a Nramp1-resistant (129S) or -susceptible (C57BL/6J) background. We found that the lack of natural IgM results in a significantly increased susceptibility and an exaggerated liver pathology regardless of the route of infection or the Nramp1 allele. Reconstitution of sIgM-/- mice with normal mouse serum or purified polyclonal IgM restored the resistance to that of sIgM+/+ mice. Furthermore, immunization of sIgM-/- mice with heat-killed S. Typhi induced a significantly reduced anti-ViPS IgG and complement-dependent bactericidal activity against S. Typhi in vitro, compared with that of sIgM+/+ mice. These findings indicate that natural IgM is an important factor in reducing the typhoid severity and inducing an optimal anti-ViPS IgG response to vaccination.

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small molecules

2026-08-17 | Direct Hospitalization Costs Associated with Resistant and Susceptible Salmonella and Shigella Infections in the United States, 2012-2019.

Antimicrobial-resistant enteric infections may be difficult to treat, associated with severe outcomes, and costly. To determine if resistant enteric infections are more costly, we described direct hospitalization costs for hospital admissions for typhoid fever, salmonellosis, and shigellosis infections by resistance status. We included all inpatient admissions with culture-confirmed infections from approximately 300 hospitals in the Premier Healthcare database during 2012-2019. We classified typhoid fever, salmonellosis, and shigellosis infections as clinically resistant if laboratory testing found resistance to ≥1 antibiotic class recommended for treatment. We examined patient demographic characteristics and underlying chronic conditions. We used the Wilcoxon rank sum test to assess the difference in median hospitalization cost for each patient admission by resistance status. We estimated adjusted cost and length of stay (LOS) using multivariable linear regression, adjusting for host and health care provider characteristics. Among 67 inpatient admissions for typhoid fever, 3421 for salmonellosis, and 619 for shigellosis, 33% of typhoid fever, 13% of salmonellosis, and 82% of shigellosis infections were clinically resistant. The unadjusted median costs for resistant salmonellosis were higher than susceptible infection-related costs ($7,753 vs. $6,909, p = 0.002). The unadjusted costs for resistant versus susceptible typhoid fever ($13,709 vs. $9,254, p = 0.111) and shigellosis were similar ($5,365 vs. $5,777, p = 0.167). For all three pathogens, the adjusted mean hospitalization costs were not statistically different for resistant and susceptible infections. Adjusted mean LOS was significantly longer for resistant typhoid fever compared with susceptible infections (6.50 days vs. 4.35 days, p = 0.001). Although adjusted cost differences for resistant infections were not significant, we observed differences by host factors including age and comorbidities, suggesting patient demographic characteristics for resistant infections are impactful on cost. These findings support the premise that public health interventions to limit the spread of resistant infections, particularly among individuals at higher risk for severe illness, could reduce hospitalization costs.

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2026-08-17 | OmpW-mediated sensing of MUC2 GalNAc contributes to the ileal tropism of Salmonella Typhi.

Salmonella Typhi (STy), the causative agent of typhoid fever, preferentially infects the ileum, but the basis for this preference has remained unknown. We show that STy exploits MUC2-derived monosaccharides, such as N-acetylgalactosamine (GalNAc), to upregulate invasion and target the ileum-opposite to the response of closely related S. Typhimurium (STm), whose invasion is inhibited by MUC2. Three STy-specific extracellular residues of the outer-membrane protein OmpW (K141/T142/Q193) engage GalNAc, and a periplasmic relay through the short FepE_STy, RS12510, and TonB transmits this signal to activate the master invasion regulator HilD. Mice lacking MUC2 or gut microbiota lose STy ileal tropism, which is restored by oral GalNAc-containing monosaccharides. An OmpW triple-mutant STy strain establishes a murine oral STy infection model, identifying STy-MUC2 glycan interactions as an early step of typhoid pathogenesis and a potential target for prevention.

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2026-08-10 | Mathematical Modelling of Typhoid Fever Transmission Dynamics Incorporating Antibiotic Resistance

Typhoid fever remains a significant public health challenge, particularly in developing countries with inadequate sanitation infrastructure. The emergence and spread of drug-resistant typhoid fever strains have complicated treatment, leading to prolonged illness, higher healthcare costs, and sustained transmission within communities. This growing resistance underscores the need for effective treatment approaches and disease control strategies. This study develops a mathematical model of typhoid fever transmission that incorporates antibiotic resistance. The model categorises infected individuals into drug-sensitive and drug-resistant typhoid fever strains. The impact of treatment modification through different therapeutic options is examined to assess its effect on the prevalence of both sensitive and resistant strains. The model is analysed qualitatively, and the basic reproduction number, R0 , is derived as the sum of two reproduction numbers, R0s and Rr0, representing the transmission contributions of the sensitive and resistant strains, respectively. Both local and global asymptotic stability conditions for disease-free and endemic equilibria are determined. Sensitivity analysis is conducted to identify the key parameters that influence typhoid fever transmission and persistence. Numerical simulations were performed to validate the analytical results, which demonstrated that typhoid vaccination, the use of appropriate treatment adjustment using first-line and second-line antibiotics, and improved hygiene and sanitation practices significantly reduce the prevalence of both drug-sensitive and drug-resistant strains, as well as the overall infection burden. These findings highlight the effectiveness of integrated prevention and treatment strategies in mitigating antibiotic resistance and enhancing typhoid fever control in the community

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2026-08-09 | Pregnancy-associated dense deposit disease with neurological complications caused by Salmonella Typhi: A case report.

Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of renal dysfunction and is increasingly being reclassified into immune complex-mediated and complement-mediated forms. Infections, particularly in endemic regions, may act as disease triggers. Pregnancy further complicates renal pathology through physiological and immunological changes. We describe a 22-year-old pregnant woman presenting with generalized edema, proteinuria, and cola-colored urine. Renal biopsy revealed diffuse endocapillary proliferation with mesangial and capillary wall C3 deposition, consistent with immune complex-mediated MPGN, with ultrastructural features suggestive of dense deposit disease (DDD). During hospitalization, she developed fever, papilledema, and neurological deficits. Blood cultures grew Salmonella Typhi, and urine cultures isolated vancomycin-resistant Enterococcus. Targeted antimicrobial therapy improved systemic symptoms, while cyclosporine was initiated for persistent proteinuria. This case report illustrates an atypical presentation of DDD during pregnancy, potentially triggered by typhoid fever and complicated by neurological involvement. It underscores the diagnostic challenges in resource-limited settings and the complex interplay among infection, complement dysregulation, and gestation. This case report illustrates an atypical presentation of MPGN during pregnancy, triggered by typhoid fever and complicated by multidrug-resistant infection and neurological involvement. The patient's renal and neurological symptoms improved with antibiotics and supportive care; however, the pregnancy resulted in intrauterine fetal demise at 28 weeks. Early recognition and multidisciplinary care were pivotal to maternal stabilization and fetal management.

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2026-07-31 | Schisandrins as novel efflux pumps inhibitors and non-antibiotic compounds against multi- and extensively-drug resistant clinical strains of Salmonella typhi: An in-vitro study.

Typhoid is a significant global health challenge due to its high pathogenicity and antimicrobial resistance. Salmonella typhi (S.typhi) can switch its lifestyles between biofilm and planktonic phase which allows it to evade host defenses and develop resistance to antibiotics. Salmonella sp. harbors multiple genes encoding efflux-pumps systems whose up-regulation contributes to multi-drug resistance (MDR) and extensive drug-resistance (XDR). To overcome the battle against resistant S. typhi strains, novel non-antibiotics inhibitors are required for inhibitory application. This study assesses the inhibitory effect of lignans against drug resistance of S. typhi. Clinical resistant and sensitive strains of S. typhi were obtained and characterized. The inhibitory effect of lignans, specifically Schisandrin A and B, purified from the plant Schisandra chinensis, are found to be effective non-antibiotic inhibitors were evaluated through standard microbiological techniques like growth curve and time-kill assays. Impact on bacterial morphology was analyzed using scanning electron microscopy (SEM). Our study explores two approaches, such as efflux pumps (EPs) inhibition and antibiofilm assays. Using colony-forming unit (CFU) assays, growth curve analysis, and SEM imaging, we observed significant bacteriostatic effects, with Schisandrin B causing notable membrane disruption. Schisandrin B also showed remarkable biofilm inhibition (90.33%) and strong efflux pumps inhibition. This study offers a strong basis for future research on addressing antibiotic resistance in clinically relevant pathogens.

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vaccines

2026-08-11 | 8-year vaccine protection following a single dose of Vi-tetanus toxoid conjugate vaccine in children in Nepal (TyVOID): a prospective cohort follow-up study of the TyVAC Nepal randomised controlled trial.

In low-income and middle-income countries, where typhoid fever remains a major public health problem, WHO recommends the use of typhoid conjugate vaccine (TCV). Here, we report vaccine effectiveness up to 8 years following a single dose of TCV in Nepal. TyVOID was a prospective cohort study that extended the follow-up of children enrolled in a phase 3, double-blind, randomised controlled trial in Lalitpur, Nepal (TyVAC; Nov 20, 2017, to Oct 20, 2021). Children aged 9 months to 15 years were randomly assigned (1:1) to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) or a capsular group A meningococcal conjugate (MenA) vaccine. After unmasking and crossover vaccination, our study followed the trial participants until Oct 31, 2025. TyVAC participants who received Vi-TT were eligible for this study and categorised into either the 2017-18 cohort or 2020-21 cohort, depending on when they received the Vi-TT vaccine. The primary outcome, which was assessed in children who received both Vi-TT and MenA vaccines and with known TCV vaccination status during the government catch-up campaign in 2022, was the incidence of blood culture-confirmed typhoid identified through facility-based passive surveillance and medical record review. Adjusted incidence rate ratios (IRRs) were estimated using Poisson regression adjusted for age and sex. Vaccine effectiveness at 1-5 years and 4-8 years post-vaccination was estimated using a test-negative design among febrile children presenting to surveillance clinics, comparing odds of Vi-TT vaccination between culture-confirmed typhoid cases with negative controls. 16 131 TyVAC participants were enrolled at TyVOID baseline, of whom 14 850 provided information on Vi-CRM197 vaccination during the government catch-up campaign. After crossover and unmasking, the primary analysis population included 4941 participants vaccinated with Vi-TT in 2017-18 and 4856 participants vaccinated with Vi-TT in 2020-21. In 4856 participants in the 2020-21 Vi-TT cohort, 2402 (49·5%) were female, 2454 (50·5%) were male, and the median age at Vi-TT vaccination was 10·4 years (IQR 7·3-13·7). In 4941 participants in the 2017-18 Vi-TT cohort, 2482 (50·2%) were female, 2459 (49·8%) were male, and the median age at Vi-TT vaccination was 7·7 years (IQR 4·5-11·0). During a median follow-up of 3·7 years (3·7-3·8), the typhoid incidence rate was 111 per 100 000 person-years (95% CI 64-177) in the 2017-18 cohort and 46 per 100 000 person-years (18-94) in the 2020-21 cohort (adjusted IRR 2·41 [95% CI 1·00-5·80]; one-sided p=0·025). Vaccine effectiveness was 77% (95% CI 46-90; p=0·0006) in the 2020-21 Vi-TT cohort (1-5 years after vaccination), and 53% (8-76; p=0·027) in the 2017-18 Vi-TT cohort (4-8 years after vaccination). A single Vi-TT dose confers strong protection in the first 4 years among Nepali children, with evidence of waning by 8 years. These findings support consideration of a booster dose to sustain protection in school-age children who remain at high risk of typhoid fever. Gates Foundation and Wellcome Trust.

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2026-08-09 | Cost-effectiveness and budget impact analyses of introducing typhoid conjugate vaccine into Indonesia's national immunisation program.

Typhoid fever remains a health threat in endemic countries. In Indonesia, it causes an estimated 470,000 cases and 6000 deaths annually. We assessed the cost-effectiveness and budget impact of introducing the typhoid conjugate vaccine (TCV) into Indonesia's routine National Immunisation Program (NIP) at 9 months of age, with or without a catch-up campaign up to 15 years of age. A validated dynamic model of typhoid transmission was used to project health outcomes over a 30-year analytical horison for each scenario. Cost-of-illness data were drawn from the Surveillance of Typhoid Fever in Indonesia study and published literature. Incremental cost-effectiveness ratios (ICERs) were estimated from healthcare sector and societal perspectives. Uncertainty was explored using one-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA). Budget impact analysis supported annual fiscal planning. Six-year budget impact costs were US$61 million (routine) and US$251 million (routine and catch-up), equivalent to 0.48%-2.95% and 2.97%-9.84% of the annual national immunisation budget, respectively. Compared to no vaccination, routine TCV yielded ICERs at US$240.6 and US$238.8 per DALY averted from the healthcare sector and societal perspectives, respectively, corresponding to 5% of GDP per capita. Compared with routine immunisation alone, adding a catch-up campaign yielded ICERs of US$521.3 and US$519.5 per DALY averted from the healthcare sector and societal perspective, respectively, corresponding to approximately 11% of GDP per capita. OWSA showed that both strategies remained very cost-effective at a willingness-to-pay threshold of 1xGDP. PSA estimated probabilities of cost-effectiveness of 99.7% (routine and catch-up vs. routine) and 99.2% (routine vs. no vaccination). The multi-strategy cost-effectiveness acceptability curve identified the combined routine and catch-up campaign as the optimal strategy. Introducing TCV into Indonesia's NIP is projected to be very cost-effective. A routine-only program requires a lower budget, but adding a catch-up campaign is an optimal strategy with greater public health impact while remaining very cost-effective. Gates Foundation grants to Murdoch Children's Research Institute in collaboration with Universitas Gadjah Mada [ref. no. INV-003867] and to TyVAC 2.0 [ref. no. INV-030857].

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2026-08-07 | Recent developments in typhoidal and non-typhoidal Salmonella vaccines.

Typhoidal and invasive non-typhoidal Salmonella (iNTS) serovars remain leading causes of bloodstream infection, mortality and morbidity, particularly in South Asia and sub-Saharan Africa. The rising burden of antimicrobial resistance has strengthened the case for vaccination as a control strategy. This review summarises recent advances in Salmonella vaccine development, highlighting progress, remaining challenges and future directions. The introduction of typhoid conjugate vaccine (TCV) programmes across some endemic countries represents a major public health milestone. Important questions remain, however. These include the durability of protection, optimal booster strategies and performance in diverse epidemiological settings. Vaccine development for S. Paratyphi A and iNTS has also accelerated, with candidates including conjugate, outer membrane vesicle/GMMA and live-attenuated, platforms advancing through preclinical and early clinical evaluation. Multivalent vaccine strategies have attracted growing interest. However, the divergent epidemiology of typhoidal and non-typhoidal disease, including differences in age-specific risk and geographic distribution, raises important questions about whether a single combination product is suitable for all settings. The Salmonella vaccine landscape is evolving rapidly from a focus on typhoid alone toward broader protection against multiple clinically important serovars. Although recent progress is encouraging, important scientific, regulatory, and implementation challenges remain. The practical case for integrated Salmonella vaccine strategies will depend on careful matching of vaccine composition to the differing epidemiology, age-specific risks, and delivery contexts of typhoidal and nontyphoidal disease.

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2026-08-06 | Impact of dosing interval on immunogenicity following a heterologous typhoid conjugate vaccine booster in Nepalese children: An observational study.

Typhoid conjugate vaccines (TCVs) are essential for controlling endemic typhoid fever in low- and middle-income countries. However, evidence suggests that TCV-induced protection wanes 3-5 years post-vaccination, particularly among children vaccinated before two years of age, raising the question of whether a booster dose is needed. This study leverages a unique context in Nepal, where the nationwide rollout of the Vi-CRM197 TCV occurred four years after a large-scale TCV efficacy trial using Vi-TT, allowing the study to assess the immunogenicity of a heterologous prime-boost schedule. We conducted a prospective observational study in Nepal, comparing antibody titres in participants who received: (1) a single dose of Vi-CRM197 (single-dose group); (2) a dose of Vi polysaccharide-tetanus toxoid (Vi-TT) vaccine followed by a Vi-CRM197 boost after a median interval of 4.2 years (4-year interval group); and (3) Vi-TT followed by Vi-CRM197 after a median interval of 2.1 years (2-year interval group). Anti-Vi IgG and IgA titres were measured 10-20 month after Vi-CRM197 vaccination. The primary objective was to show that the single-dose group was non-inferior to the 4-year interval group using a non-inferiority margin of 0.67 for the adjusted geometric mean ratio (aGMR). Pairwise GMRs were obtained by exponentiating differences in mean log10-transformed titres. We also compared anti-Vi antibody responses following a single dose of Vi-CRM197 with those among Vi-TT-primed participants who had received a single dose of Vi-TT in the original trial, with antibody measurement taken one to two years post-vaccination, including analyses stratified by Vi-TT vaccination time to account for differences in post-vaccination follow-up time. The single-dose Vi-CRM197 group exhibited significantly lower anti-Vi IgG and IgA geometric mean concentrations (GMCs) compared with the 4-year interval prime-boost group (reference), with aGMRs of 0.24 (95% CI: 0.18, 0.32) for IgG and 0.40 (0.30, 0.52) for IgA, leading to rejection of non-inferiority. Antibody responses in the 2-year interval prime-boost group were intermediate between those in the single-dose and 4-year interval groups, with aGMRs of 0.65 (95% CI: 0.41, 1.03) for anti-Vi IgG and 0.83 (0.54, 1.26) for anti-Vi IgA, all relative to the 4-year interval group. Compared with the immunogenicity among Vi-TT-primed participants, a single dose of Vi-CRM197 elicited lower anti-Vi IgG levels (aGMR: 0.56 [95% CI 0.47, 0.66]). When Vi-TT-primed participants were stratified by vaccination time (2017-2018 and 2020-2021), a single dose of Vi-CRM197 elicited lower anti-Vi IgG levels than those observed among participants primed with Vi-TT in both cohorts (aGMR: 0.52 [0.43, 0.61] and 0.68 [0.54, 0.85], respectively). A single dose of Vi-CRM197 is immunologically inferior to a heterologous prime-boost schedule, with the 2-year interval boost eliciting intermediate antibody responses and the 4-year interval boost inducing the highest immunogenicity. These findings provide critical real-world evidence supporting the implementation of a TCV booster dose with a longer interval, particularly in endemic settings, to maintain robust immunity against typhoid fever.

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2026-08-05 | Phage-Based Vaccine Platforms for Typhoid Fever: A Transformative Approach to Global Health and Antimicrobial Resistance

Typhoid fever, caused by Salmonella enterica serovars Typhi and Paratyphi, remains a major public health threat across Africa and Asia, causing substantial annual morbidity. Transmission persists in low- and middle-income countries (LMICs), where access to safe water and sanitation is limited. While improvements in water, sanitation, and hygiene (WASH) are essential, slow implementation makes vaccination the most practical preventive strategy. Current licensed vaccines have limitations, including suboptimal immune coverage in infants, limited duration of protection, and cold-chain requirements. This review examines bacteriophage-based vaccine platforms as emerging preclinical strategies for typhoid prevention. Phage technologies, including phage display, phage DNA, and hybrid models, offer potential advantages such as multivalent antigen display, projected thermostability, and cost-efficient production using bacterial manufacturing systems. Based on animal immunogenicity and proof-of-concept studies, these systems could theoretically induce durable immunity and broaden age-group protection, although their clinical feasibility and scalability remain unproven. We evaluate key technical hurdles, including endotoxin contamination, host strain engineering, and payload expression constraints. We also discuss how these potentially low-cost platforms may contribute to global antimicrobial resistance (AMR) mitigation efforts. Although phage-based vaccines remain in the preclinical stage, they represent promising research platforms for advancing vaccine equity and infectious disease resilience, provided regulatory and technical challenges are overcome. However, significant translational gaps must still be bridged before clinical application can be realized.

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proteins

2026-04-13 | Typhoid Toxin of Salmonella enterica Induces ISG15 Responses Mediating Host Cell Survival and Counteracting Intracellular Infection.

The typhoid toxin is a secreted virulence factor of typhoidal serovars of the bacterial pathogen Salmonella enterica implicated in typhoid fever and chronic infections. The toxin causes a DNA damage response in human cells, characterised by cell-cycle arrest and cellular distension, resulting in cellular senescence and increased bacterial burden. To better understand host responses to typhoid toxin, we performed a transcriptomic analysis of intoxicated host cells and found that the toxin induced expression of genes relating to the type-I interferon response, including the ubiquitin-like protein ISG15. ISG15 was upregulated in a STING-dependent manner, reduced bacterial burden, and was found to be critical to host cell survival in response to the typhoid toxin and interferon. This highlights ISG15 as an important component of the host cell defence to the typhoid toxin.

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2026-01-16 | A new mouse model of typhoid fever using Salmonella enterica serovar Paratyphi C as a surrogate pathogen.

Salmonella enterica serovar (S.) Typhi, the etiological agent of typhoid fever, is strictly human adapted, which presents a significant challenge for studying its pathogenesis in animal models. A common strategy to overcome this limitation is to infect mice with S. Typhimurium as a surrogate pathogen. Since S. Typhimurium is a non-typhoidal serovar that does not encode the virulence-associated capsular polysaccharide (Vi antigen) of S. Typhi, we explored whether the mouse virulent typhoidal Salmonella serovar Paratyphi C, which expresses the Vi antigen, would be better suited as a surrogate pathogen to study typhoid fever pathogenesis in the mouse. In contrast to the nontyphoidal serovar Typhimurium, which produced lethal morbidity in C57BL/6 mice within a few days after infection, S. Paratyphi C demonstrated prolonged colonization of systemic organs for up to 28 days after infection. Analysis of virulence factors revealed that the Vi antigen was important at very early stages after infection (up to 2 days), whereas the type III secretion system encoded by Salmonella pathogenicity island 2 became critical at later stages. Vaccination with purified Vi antigen suppressed S. Paratyphi C dissemination. Implantation of a biotelemetry device revealed that S. Paratyphi C triggered fever after an incubation period of 3 days, which was reminiscent of the prolonged incubation period of typhoid fever. In conclusion, our findings suggest that the use of S. Paratyphi C as a surrogate pathogen provides a mouse model for studying typhoid fever pathogenesis and vaccine development.IMPORTANCEThe emergence of extensively drug-resistant Salmonella enterica serovar (S.) Typhi poses a serious threat to public health, but its host restriction to humans poses a challenge for studying pathogenesis and vaccine development in animal models. Here, we used S. Paratyphi C, a mouse virulent typhoidal serovar that expresses the virulence-associated Vi capsular polysaccharide, as a surrogate pathogen for studying typhoid fever in a mouse model. Our model recapitulates key features of typhoid fever, including clinical symptoms such as a prolonged incubation period, fever, and splenomegaly. Notably, disseminated infection with S. Paratyphi C developed after inoculation by the natural oral route. We demonstrate the utility of this model for studying pathogenesis and vaccination. We conclude that our new mouse model for typhoid fever offers a promising platform for evaluating novel therapeutics and vaccine candidates to address the problem of drug resistance in S. Typhi and reduce the global burden of typhoid fever.

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2025-10-29 | Lacticaseibacillus rhamnosus D1 Fermented Milk Confers Protection Against Typhoid Fever Through Immunomodulation and Gut Microbiota Regulation in Mice.

This study investigated the protective effect of fermented milk by Lacticaseibacillus rhamnosus D1 in a murine model of Typhoid fever, focusing on cytokines, antimicrobial peptides and microbiota modulation. BALB/c mice were pre-treated with milk fermented by L. rhamnosus D1 prior to Salmonella Typhimurium challenge. Outcomes assessed included survival, weight change, bacterial translocation, mRNA expression of cytokines and antimicrobial peptides, in addition to gut microbiota modulation. Mice receiving fermented milk exhibited higher survival rates, reduced bacterial translocation and attenuated weight loss compared to controls. mRNA expression analyses revealed that L. rhamnosus D1 pre-treatment suppressed the expression of pro-inflammatory cytokines (IFN-γ, IL-6 and IL-12) and upregulated anti-inflammatory cytokines (IL-5, IL-10 and TGF-β), as well as antimicrobial peptides (Reg3β, Reg3γ and Lcn2). Furthermore, we observed that the consumption of fermented milk changed the gut microbiota of infected mice, not only by modulating the existing taxa, but also by facilitating the emergence of unique, potentially beneficial microbial lineages, such as Muribaculum, Roseburia, Intestinimonas, Bdellovibrio and Facklamia. These findings indicate that L. rhamnosus D1 protected mice against S. Typhimurium infection through immunomodulatory and microbiota-mediated mechanisms, changing mucosal immunity and strengthening the intestinal barrier by modulating gut microbiota and immune responses, in addition to promoting host antimicrobial defenses.

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2025-09-22 | FliC adjuvant augments protective efficacy of recombinant T2544 antigen against SalmonellaTyphiand Paratyphi A by increasing serum antibodies, intestinal secretory immunoglobulin A and T cell memory.

The need for safe, effective, and affordable vaccines against Salmonella Typhi and Paratyphi A remains urgent, particularly in endemic regions of Asia and Africa. Contrary to earlier beliefs, parenteral vaccines can induce mucosal immunity, especially when combined with mucosal trafficking signals. Recent findings show that systemic delivery of soluble flagellin (FliC) activates CD103+ dendritic cells via TLR5, promoting mucosal IgA and regulatory T cell responses. Building on this, we evaluated recombinant FliC (rFliC) from S. Typhimurium as an adjuvant to enhance both systemic and mucosal immunity of rT2544, a subunit vaccine candidate. Female BALB/c mice were immunized subcutaneously with varying doses of rT2544 and rFliC to identify an optimal formulation. The selected dose (5 μg rT2544 + 2.5 μg rFliC) was tested for humoral and cellular responses, including serum IgG/IgA titers, antibody-secreting cells, cytokines (IFN-γ, IL-4, IL-17), and CTL activity. Protective efficacy was evaluated in an iron-overload mouse model challenged with S. Typhiand S. Paratyphi A, by assessing survival and bacterial loads in the intestine, liver, and spleen. Co-administration of rFliC with rT2544 enhanced systemic IgG and intestinal IgA responses, with increased ASCs and strong bactericidal activity against S. Typhiand S. Paratyphi A. The vaccine induced robust Th1, Th2, and Th17 cytokines, and improved CTL activity. Immunized mice showed 83 % and 91 % survival against S. Typhiand S. Paratyphi A, respectively, with significantly reduced bacterial loads in the intestine, liver, and spleen. Importantly, subcutaneous rFliC delivery effectively induced intestinal sIgA, eliminating the need for mucosal administration. Subcutaneous co-administration of rFliC induced strong antigen-specific mucosal sIgA, overcoming limitations of conventional mucosal adjuvants. The rFliC-adjuvanted rT2544 elicited robust humoral, mucosal, and cellular responses, providing significant protection against S. Typhiand S. Paratyphi A. These findings support its potential as a promising injectable subunit vaccine for enteric fever.

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2025-07-23 | Salmonella Typhi gut invasion drives hypoxic immune subsets associated with disease outcomes.

Salmonella Typhi (S. Typhi), the causative agent of typhoid disease, remains a major public health concern. Owing to the human-restricted nature of S. Typhi, studies of typhoid pathogenesis in animal models are limited to a murine non-typhoidal pathogen. More recently, human challenge models have been conducted, providing insight into immune correlates of infection outcomes, which are still incompletely understood. Here, we performed an integrated single-cell analysis of immune responses from the human S. Typhi challenge model and mouse model of typhoid disease, to associate biological mechanism with human infection outcome. Most prominent, we revealed immune subsets with a hypoxia-related signature in the blood of individuals who developed disease in the human challenge model. This signature was also evident in the mouse model in activated macrophages infiltrating into the Peyer's patches, but not during infection with a mutant strain impaired for gut invasion. We further identified hypoxia-related signature as a general immune correlate of disease outcome in other infection-and inflammatory-related diseases. Collectively, we identified a hypoxia-associated immune signature that correlates with disease outcomes in humans. Using a mouse model, we demonstrated that this signature is driven by bacterial invasion to the Peyer's patches, implicating a causal role in the pathogenesis of typhoid fever.

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2026-05-04 | Advancing Needle-Free Jet Injectors for Global Vaccine Delivery.

Background: Global immunization programs continue to rely on needle-based injections despite persistent concerns regarding sharps disposal, accidental injuries, and the technical skill required for accurate intradermal administration. Needle-free jet injectors (NFJIs) are an alternative delivery method in which narrow, high-velocity liquid jets penetrate the skin without a needle. Contemporary designs, ranging from single-use disposable-syringe injectors to digitally controlled electromechanical devices, address historical safety issues and meet current WHO and FDA device expectations. Methods: Evidence from engineering analyses, preclinical modeling, and clinical trials was reviewed to characterize how jet velocity, nozzle structure, and formulation rheology influence skin penetration and drug dispersion. Published vaccine studies were examined for antibody responses, seroconversion, and reactogenicity compared with needle-syringe injection. Field vaccination campaign data from national campaigns and operational reports were evaluated to describe implementation steps, acceptability, and implementation constraints. Results: Published studies evaluating vaccines, including inactivated influenza, hepatitis B, typhoid, rabies, and measles, report antibody titers and seroconversion rates after NFJI administration that are comparable to those achieved with conventional intramuscular or intradermal needle injection. Needle-free delivery was associated with operational advantages in several immunization programs, including reduced sharps waste and improved vaccination rate during high-volume immunization campaigns. Local and systemic reactogenicity follows expected patterns, with slightly higher injection-site responses in some NFJI studies. Imaging and mechanical data confirm that jet performance depends on nozzle geometry and controlled pressure pulses. At the same time, formulation stability remains a critical determinant of successful jet-based vaccine administration, particularly for protein antigens, adjuvanted formulations, and emerging mRNA vaccines that may experience transient shear stress during high-velocity injection. Evidence from vaccination campaigns further indicates that needle-free jet injectors reduce sharps waste, simplify vaccine handling and administration procedures, and support rapid vaccine delivery in large-scale immunization programs. Conclusions: Needle-free jet injectors are a practical alternative to traditional needle-based injections for some vaccines. Their main benefits include enabling intradermal dose-sparing strategies, reducing reliance on sharps disposal methods, and enabling the efficient vaccination of large groups without compromising immunogenicity. Future research should define the physicochemical stability limits of biologic formulations subjected to jet injection and evaluate digitally controlled injectors capable of precise pressure modulation and adjustable delivery parameters. In addition, needle-free jet injection eliminates needle penetration and sharps handling, which may reduce needle-associated anxiety and improve vaccine acceptability among individuals with needle aversion.

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2024-09-07 | Oral Treatment with Saccharomyces cerevisiae CNCM I-3856 Mitigates the Inflammatory Response Experimentally Induced by Salmonella enterica subsp. enterica Serovar Typhimurium in Mice.

Salmonella spp. are intracellular, Gram-negative pathogens responsible for a range of diarrheal diseases, which can present either as self-limited (gastroenteritis) or as a systemic form (typhoid fever), characterizing a serious public health problem. In this study, we investigated the therapeutic effects of oral administration of Saccharomyces cerevisiae CNCM I-3856 in a murine model infected with Salmonella Typhimurium (ST). This yeast species has previously demonstrated the potential to support immune function and reduce inflammation and the ability to exert antimicrobial activity, which is important considering the increasing prevalence of antibiotic-resistant bacteria. Our findings revealed that mice infected with ST and only treated with sterile saline exhibited a higher mortality rate and body weight loss. In contrast, mice treated with I-3856 showed a notable reduction in these adverse outcomes. The yeast demonstrated a high capacity for co-aggregation with the pathogen. Furthermore, the significant amounts of yeast found in the feces of treated mice suggest that intestinal colonization was effective, which was associated with several beneficial effects, including reduced intestinal permeability, which likely limits bacterial translocation to extraintestinal organs. Additionally, the administration of I-3856 reduced levels of sIgA and resulted in a decrease in the recruitment of neutrophils and eosinophils to infection sites, indicating a modulation of the inflammatory response. Histological analyses showed attenuated liver and intestinal lesions in the yeast-treated mice, corroborating the protective effects of the yeast. In conclusion, the results suggest that S. cerevisiae CNCM I-3856 has the potential to control the inflammatory response experimentally induced by S. Typhimurium when administered to mice.

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2023-11-29 | Deletion of Salmonella enterica serovar Typhi tolC reduces bacterial adhesion and invasion toward host cells.

S. Typhi is a Gram-negative bacterium that causes typhoid fever in humans. Its virulence depends on the TolC outer membrane pump, which expels toxic compounds and antibiotics. However, the role of TolC in the host cell adhesion and invasion by S. Typhi is unclear. We aimed to investigate how deleting the tolC affects the adhesion and invasion of HT-29 epithelial and THP-1 macrophage cells by S. Typhi in vitro. We compared the adhesion and invasion rates of the wild-type and the tolC mutant strains of S. Typhi using in vitro adhesion and invasion assays. We also measured the expression levels of SPI-1 genes (invF, sipA, sipC, and sipD) using quantitative PCR. We found that the tolC mutant showed a significant reduction in adhesion and invasion compared to the wild-type strain in both cell types. We also observed that the expression of SPI-1 genes was downregulated in the tolC mutant. Our results suggest that TolC modulates the expression of SPI-1 genes and facilitates the adhesion and invasion of host cells by S. Typhi. Our study provides new insights into the molecular mechanisms of S. Typhi pathogenesis and antibiotic resistance. However, our study is limited by the use of in vitro models and does not reflect the complex interactions between S. Typhi and host cells in vivo.

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2023-01-11 | Identification of collaborative cross mouse strains permissive to Salmonella enterica serovar Typhi infection.

Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in humans is far greater and more complex than that in a single inbred strain of mice. The Collaborative Cross (CC) is a large panel of recombinant inbred strains which has a wider range of genetic diversity than laboratory inbred mouse strains. We found that the CC003/Unc and CC053/Unc strains are permissive to intraperitoneal but not oral route of S. Typhi infection and show histopathological changes characteristic of human typhoid. These CC strains are immunocompetent, and immunization induces antigen-specific responses that can kill S. Typhi in vitro and control S. Typhi in vivo. Our results indicate that CC003/Unc and CC053/Unc strains can help identify the genetic basis for typhoid susceptibility, S. Typhi virulence mechanism(s) in vivo, and serve as a preclinical mammalian model system to identify effective vaccines and therapeutics strategies.

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2022-02-09 | Systematic reconstruction of an effector-gene network reveals determinants of Salmonella cellular and tissue tropism.

The minimal genetic requirements for microbes to survive within multiorganism communities, including host-pathogen interactions, remain poorly understood. Here, we combined targeted gene mutagenesis with phenotype-guided genetic reassembly to identify a cooperative network of SPI-2 T3SS effector genes that are sufficient for Salmonella Typhimurium (STm) to cause disease in a natural host organism. Five SPI-2 effector genes support pathogen survival within the host cell cytoplasm by coordinating bacterial replication with Salmonella-containing vacuole (SCV) division. Unexpectedly, this minimal genetic repertoire does not support STm systemic infection of mice. In vivo screening revealed a second effector-gene network, encoded by the spv operon, that expands the life cycle of STm from growth in cells to deep-tissue colonization in a murine model of typhoid fever. Comparison between Salmonella infection models suggests how cooperation between effector genes drives tissue tropism in a pathogen group.

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