Typhoid Vaccine Research Articles

Characterization of Turbo, a TLR Ligand-based Adjuvant for Glycoconjugate Vaccines.

Many bacterial polysaccharide vaccines, including the typhoid Vi polysaccharide (ViPS) and tetravalent meningococcal polysaccharide conjugate (MCV4) vaccines, do not incorporate adjuvants and are not highly immunogenic, particularly in infants. I found that endotoxin, a TLR4 ligand in ViPS, contributes to the immunogenicity of typhoid vaccines. Because endotoxin is pyrogenic, and its levels are highly variable in vaccines, I developed monophosphoryl lipid A, a nontoxic TLR4 ligand-based adjuvant named Turbo. Admixing Turbo with ViPS and MCV4 vaccines improved their immunogenicity across all ages and eliminated booster requirement. To understand the characteristics of this adjuvanticity, I compared Turbo with alum. Unlike alum, which polarizes the response toward the IgG1 isotype, Turbo promoted Ab class switching to all IgG isotypes with affinity maturation; the magnitude of this IgG response is durable and accompanied by the presence of long-lived plasma cells in the mouse bone marrow. In striking contrast with the pathways employed by alum, Turbo adjuvanticity is independent of NLPR3, pyroptotic cell death effector Gasdermin D, and canonical and noncanonical inflammasome activation mediated by Caspase-1 and Caspase-11, respectively. Turbo adjuvanticity is primarily dependent on the MyD88 axis and is lost in mice deficient in costimulatory molecules CD86 and CD40, indicating that Turbo adjuvanticity includes activation of these pathways. Because Turbo formulations containing either monophosphoryl lipid A or TLR2 ligands, Pam2CysSerLys4, and Pam3CysSerLys4 help generate Ab response of all IgG isotypes, as an adjuvant Turbo can improve the immunogenicity of glycoconjugate vaccines against a wide range of bacterial pathogens whose elimination requires appropriate IgG isotypes.

An epidemiological study on morbidity profile among food handlers in Panaji city, Goa

ABSTRACT Context: Access to safe and nutritious food is key to promoting good health. An estimated 600 million fall ill after eating contaminated food, for which food handlers may constitute a common source of contamination. In addition to unhealthy food handlers, disease carriers handling the food play an equally important role in transmitting these diseases and pose a significant threat to public health. This study, therefore, aimed to know the morbidity profile among the food handlers employed in various food establishments in Panaji city. Methods and Material: Using stratified sampling techniques, we conducted a cross-sectional study among 227 participants selected from 12 food establishments. We did three visits to each food establishment. We excluded food handlers who were unavailable despite three visits at fortnightly intervals and those who did not consent to the study. We administered a pre-designed and pre-structured questionnaire to each participant. A general examination and laboratory investigations, including stool and urine routine, were performed on all participants. We performed descriptive and analytical statistics by using SPSS version 14 Results: Out of the 227 study participants, 79 (34.8%) had at least one morbidity at the time of examination. None of the food handlers had received a single dose of typhoid, hepatitis A, or cholera vaccines. Most (74.4%) study participants did not administer deworming tablets Conclusions: We found that the health status of the study participants was substandard. Food safety may be in peril among food handlers with lower education backgrounds with morbidities as they may have little understanding of the risk of microbial contamination of food. Therefore, it is essential to create awareness among them.

Need and Rationale of the Adult Immunisation in India: A Review

Abstract A comprehensive literature review of published articles (till October 2023) was done through PubMed, Embase and Google Scholar search engines to delineate the need for adult immunisation, recommended adult vaccines, barriers to adult immunisation, future research areas and way forward in the Indian context. A total of 29,894 articles were screened from PubMed, Embase and Google Scholar. Of these, a full-text review of 53 articles was done. The findings emphasised the need for adult immunisation in India because of the growing vulnerable elderly population with comorbidities, immunosenescence, waning immunity, rising incidence of VPDs leading to higher morbidity and mortality amongst them, rising cost of hospitalisation and the emergence of antimicrobial resistance. The recommended adult vaccines include human papilloma virus vaccine, pneumococcal vaccine, influenza and typhoid vaccine for healthy adults and special population groups, respectively. Challenges include less prioritisation in the National Vaccination Policy, insufficient awareness amongst healthcare providers and vaccine hesitancy.

The origins of haplotype 58 (H58) Salmonella enterica serovar Typhi

Antimicrobial resistance (AMR) poses a serious threat to the clinical management of typhoid fever. AMR in Salmonella Typhi (S. Typhi) is commonly associated with the H58 lineage, a lineage that arose comparatively recently before becoming globally disseminated. To better understand when and how H58 emerged and became dominant, we performed detailed phylogenetic analyses on contemporary genome sequences from S. Typhi isolated in the period spanning the emergence. Our dataset, which contains the earliest described H58 S. Typhi organism, indicates that ancestral H58 organisms were already multi-drug resistant (MDR). These organisms emerged spontaneously in India in 1987 and became radially distributed throughout South Asia and then globally in the ensuing years. These early organisms were associated with a single long branch, possessing mutations associated with increased bile tolerance, suggesting that the first H58 organism was generated during chronic carriage. The subsequent use of fluoroquinolones led to several independent mutations in gyrA. The ability of H58 to acquire and maintain AMR genes continues to pose a threat, as extensively drug-resistant (XDR; MDR plus resistance to ciprofloxacin and third generation cephalosporins) variants, have emerged recently in this lineage. Understanding where and how H58 S. Typhi originated and became successful is key to understand how AMR drives successful lineages of bacterial pathogens. Additionally, these data can inform optimal targeting of typhoid conjugate vaccines (TCVs) for reducing the potential for emergence and the impact of new drug-resistant variants. Emphasis should also be placed upon the prospective identification and treatment of chronic carriers to prevent the emergence of new drug resistant variants with the ability to spread efficiently.

The cost of typhoid illness in low- and middle-income countries, a scoping review of the literature.

Typhoid fever is responsible for a substantial health burden in low- and middle-income countries (LMICs). New means of prevention became available with the prequalification of typhoid conjugate vaccines (TCV) by the World Health Organization (WHO) in 2018. Policymakers require evidence to inform decisions about TCV. The economic burden related to typhoid fever can be considerable, both for healthcare providers and households, and should be accounted for in the decision-making process. We aimed to understand the breadth of the evidence on the cost of typhoid fever by undertaking a scoping review of the published literature. We searched scientific databases with terms referring to typhoid fever cost of illness to identify published studies for the period January 1st 2000 to May 24th 2024. We also conferred with stakeholders engaged in typhoid research to identify studies pending completion or publication. We identified 13 published studies reporting empirical data for 11 countries, most of them located in Asia. The total cost of a typhoid episode ranged from $23 in India to $884 in Indonesia (current 2022 United States Dollar [USD]). Household expenditures related to typhoid fever were characterized as catastrophic in 9 studies. We identified 5 studies pending completion or publication, which will provide evidence for 9 countries, most of them located in Africa. Alignment in study characteristics and methods would increase the usefulness of the evidence generated and facilitate cross-country and regional comparison. The gap in evidence across regions should be mitigated when studies undertaken in African countries are published. There remains a lack of evidence on the cost to treat typhoid in the context of increasing antimicrobial resistance. Decision-makers should consider the available evidence on the economic burden of typhoid, particularly as risk factors related to antimicrobial resistance and climate change increase typhoid risk. Additional studies should address typhoid illness costs, using standardized methods and accounting for the costs of antimicrobial resistance.

Global estimates on the reports of vaccine-associated myocarditis and pericarditis from 1969 to 2023: Findings with critical reanalysis from the WHO pharmacovigilance database.

Due to the limitation of previous studies examining adverse reports of myocarditis and pericarditis associated with vaccines other than the COVID-19 vaccine, there are challenges in establishing a comprehensive understanding of vaccine safety on a global scale. Hence, the objective of this study was to examine the worldwide burden of vaccine-associated pericarditis and myocarditis and the vaccines associated with these indications. This study utilized the World Health Organization international pharmacovigilance database, from which records of vaccine-associated pericarditis and myocarditis between 1969 and 2023 were extracted (over 130 million reports). We calculated global reporting counts, reported odds ratios (RORs), and information components (ICs) to discern the association between 19 vaccines and the occurrence of pericarditis and myocarditis across 156 countries and territories. We identified 49 096 reports (male, n = 30 013) of vaccine-associated pericarditis and myocarditis among 73 590 reports of all-cause pericarditis and myocarditis. There has been a significant increase in reports of vaccine-related cardiac adverse events over time, with a noteworthy surge observed after 2020, attributed to cases of pericarditis associated with COVID-19 mRNA vaccines. Smallpox vaccines were associated with most pericarditis and myocarditis reports (ROR: 73.68 [95% CI, 67.79-80.10]; IC [IC0.25]: 6.05 [5.91]), followed by COVID-19 mRNA vaccine (37.77 [37.00-38.56]; 3.07 [3.05]), anthrax vaccine (25.54 [22.37-29.16]; 4.58 [4.35]), typhoid vaccine (6.17 [5.16-7.38]; 2.59 [2.29]), encephalitis vaccine (2.00 [1.48-2.71]; 0.99 [0.47]), influenza vaccine (1.87 [1.71-2.04]; 0.90 [0.75]), and Ad5-vectored COVID-19 vaccine (1.40 [1.34-1.46]; 0.46 [0.39]). Concerning age and sex-specific risks, reports of vaccine-associated pericarditis and myocarditis were more prevalent among males and in older age groups. The age group between 12 and 17 years exhibited significant sex disproportion. Most of these adverse events had a short time to onset (median time: 1 day) and fatality rate was 0.44%. Our analysis of global data revealed an increase in pericarditis and myocarditis reports associated with vaccines, particularly live vaccines like smallpox and anthrax, notably in young males. While these adverse events are generally rare and mild, caution is warranted, especially for healthcare workers, due to potential myocardial injury-related in-hospital mortality. Further study with validated reporting is crucial to enhance accuracy in evaluating the correlation between vaccines and cardiac conditions for preventive measures.

A TLR4 ligand-based adjuvant for promoting the immunogenicity of typhoid subunit vaccines.

None of the typhoid Vi Polysaccharide (ViPS) subunit vaccines incorporate adjuvants, and the immunogenicity of ViPS vaccines (e.g. Typbar TCV® and Typhim Vi®) is in part due to associated TLR4 ligands such as endotoxin present in these vaccines. Since endotoxin content in vaccines is variable and kept very low due to inherent toxicity, it was hypothesized that incorporating a defined amount of a non-toxic TLR4-ligand such as monophosphoryl lipid A in ViPS vaccines would improve their immunogenicity. To test this hypothesis, a monophosphoryl lipid A-based adjuvant formulation named Turbo was developed. Admixing Turbo with Typbar TCV® (ViPS-conjugated to tetanus toxoid) increased the levels of anti-ViPS IgM, IgG1, IgG2b, IgG2a/c, and IgG3 in inbred and outbred mice. In infant mice, a single immunization with Turbo adjuvanted Typbar TCV® resulted in a significantly increased and durable IgG response and improved the control of bacterial burden compared to mice immunized without Turbo. Similarly, when adjuvanted with Turbo, the antibody response and control of bacteremia were also improved in mice immunized with Typhim Vi®, an unconjugated vaccine. The immunogenicity of unconjugated ViPS is inefficient in young mice and is lost in adult mice when immunostimulatory ligands in ViPS are removed. Nevertheless, when adjuvanted with Turbo, poorly immunogenic ViPS induced a robust IgG response in young and adult mice, and this was observed even under antigen-limiting conditions. These data suggest that incorporation of Turbo as an adjuvant will make typhoid vaccines more immunogenic regardless of their intrinsic immunogenicity or conjugation status and maximize the efficacy across all ages.

Adverse effects of Typbar-typhoid conjugated vaccine in children vaccinated in university of Lahore teaching hospital

Objective: To determine the frequency of adverse effects of Typbar TCV in children vaccinated in Hospital. Study design: Descriptive study Place & duration of study: Department of Pediatrics outpatient clinic, from 1 February to 2021 to 3rd March 2021. Methodology: Children aged 9 months to 15 years of age either gender coming for vaccination from 1st Feb-2021 to 17th Feb-2021 was included in study. Post vaccination Observation for 30 minutes was done for all children in hospital and were followed after 14 days on telephone for any local or systemic adverse effect after vaccination. Complications systemic and local were documented on proforma. All data was analyzed using SPSS 22. P-value calculation for change in percentage of adverse effects in the different age groups and gender Chi-square test was used. Results: In our study, total 835 children were enrolled out of which 666 responded. Contact with 169 children was not possible because their lack of response and unavailability. Mean age was 4.9±4.06 years. Regarding local adverse effects pain at site of injection was present in 30% children. Other local site reaction includes swelling in 17.7%, redness in 3% and limitation of movement in 2.4%. Systemic adverse effects included fever in 20.4%. Headache was present in 0.6% children. GI symptoms present in 0.9%. Conclusion: This study concluded that Typbar-TCV Typhoid Vi conjugate vaccine is safe among children aged 9 months to 15 years.

Typhoid fever in children in Goroka, Papua New Guinea.

Typhoid is endemic in many low-income countries, including in Papua New Guinea. This study aimed to describe the burden and clinical features of typhoid in children in a provincial hospital, to describe environmental conditions that lead to typhoid, and to document the antibiotic sensitivity of Salmonella spp. in the Eastern Highlands Province. A combined retrospective and prospective study of children admitted to with clinical features of typhoid to the Goroka Hospital throughout 2022. The study included 98 children, of which 54% were female. The median age was 8 (IQR 5-10.6) years. Over 60% of the patients were from Goroka District, the peri-urban area encompassing the town and surrounds. Ninety-four percent (92) of the patients used a pit latrine as a toilet and only 28% had access to treated water. Neuropsychiatric symptoms were common (60%), as was leukopenia (48%), thrombocytopenia (52%) and anaemia (42%). Thirty-seven patients had positive blood cultures for Salmonella typhi; all isolates were sensitive to third-generation cephalosporins, pefloxacin, ampicillin, trimethoprim and sulfamethoxazole, and only 54% sensitive to chloramphenicol. The median duration of hospitalisation was 6 days (IQR). There were no deaths. Prompt public health actions are needed to reduce the burden of typhoid infection in the Papua New Guinea. The conjugate typhoid vaccine should be considered in the highlands region, where typhoid is most endemic.

P155 Gene expression in hypermobility and the role of inflammation

Abstract Background/Aims Hypermobile conditions, including Ehlers-Danlos syndrome and joint hypermobility syndrome, encompass a broad spectrum of heterogenous clinical entities characterised by excessive range of joint movements and variable extra-articular features. The etiological basis of these conditions is thought to relate to abnormal collagen assembly, which impairs the structural integrity of connective tissue, although precise mechanisms remain both debated and incompletely understood. Despite the established strong heritability of hypermobility, a definitive genetic cause remains unidentifiable in most hypermobile patients, highlighting the need to further characterize the genetic landscape of hypermobile conditions. In this study, we therefore employ transcriptomic analysis as an alternate means of elucidating the genetic basis of hypermobility. Methods We tested for the effects of hypermobility on gene expression, at baseline and following an inflammatory challenge, by re-analysing existing transcriptomic data gathered from healthy subjects and patients with fibromyalgia and chronic fatigue using total RNA sequencing of blood samples (Illumina NextSeq 500). From each participant, two blood samples were taken on separate occasions: one after a saline injection and the other after an inflammatory challenge, the typhoid vaccination, in a cross-over design. Participants were assigned to hypermobile or non-hypermobile conditions in accordance with criterion 1: generalized joint hypermobility of the Diagnostic Criteria for Hypermobile Ehlers-Danlos Syndrome (hEDS) produced by the International Consortium on Ehlers-Danlos Syndromes & Related disorders. Differential gene expression analysis comparing hypermobile and non-hypermobile participants was performed using EdgeR software in R studio. Baseline differences were determined by comparing post-saline samples between groups. Differential responses to the inflammatory challenge were detected by comparison of post-typhoid samples between groups. Gene ontology on differentially expressed genes was performed using DAVID’s Functional Annotation Clustering tool. Results We found 288 differentially expressed genes post-saline (i.e at baseline) and 1113 post-typhoid at p < 0.05 although none passed false discovery rate. At baseline, differentially expressed genes were significantly enriched for nuclear, endoplasmic reticulum, and microtubular genes (enrichment score = 2.96, 2.02, 1.3 respectively); and post-typhoid, for 24 clusters, the three most significant being synaptic, ion transport, and plasma membrane genes (enrichment score = 11.34, 8.71, and 7.3 respectively). Conclusion These data demonstrate distinct patterns of gene expression, both at baseline and during inflammation, which implicate potential biological pathways in the pathophysiology of hypermobility. These results also contribute to a growing understanding of the genetic basis of hypermobility and may inform future higher-powered studies to validate our findings. Disclosure J. Porter: None. M. Amato: None. K. Themelis: None. H. Critchley: None. S. Newbury: None. K. Davies: None. N. Harrison: None. B. Towler: None. J. Eccles: Grants/research support; J.E. has received funding from Versus Arthritis, National Institute for Health Research and the Fibroduck Foundation.

Non-specific protection against severe COVID-19 associated to typhoid fever and DTP vaccination

Trained immunity (TRAIM) or the enhanced non-specific immune response after primary stimulation by infection or vaccination is a recent but well-recognized concept. To verify its predictions, our objective was to determine the effects of two bacterial vaccines, typhoid fever (TFV) and diphtheria-tetanus-pertussis (DTP) on the infection, hospitalization and death frequencies associated to COVID-19 in a retrospective study on subjects vaccinated or not with TFV and DTP in the 4 years prior to the start of COVID-19 pandemia in the Basque Country (Spain). The studied outcome records were split into two periods according to COVID-19 vaccination, the pre-vaccination (ACV) from March to December 2020 and the post-vaccination (PCV) from September 2021 to June 2022). In total, 13,673 subjects were vaccinated against TFV and 42,997 against DTP.A total of 2,005,084 individual records were studied in the ACV period and 1,436,693 in the PCV period. The proportion of infection, hospitalization and death associated to COVID-19 among controls in ACV was 4.97 %, 7.14 % and 3.54 %, respectively vs. 7.20 %, 2.24 % and 0.10 % among TFV subjects. Regarding DTP, the proportions were 4.97 %, 7.12 % and 3.58 % for controls and 5.79 %, 5.79 % and 0.80 % for vaccinees. In the PCV period, the proportion of infection, hospitalization and death among controls was 21.89 %, 2.62 % and 0.92 %, respectively vs. 31.19 %, 0.76 %, 0.00 % among TFV. For DTP, infection, hospitalization and death proportions were 21.89 %, 2.62 % and 0.92 %, respectively, among controls vs. 32.03 %, 1.85 % and 0.24 % among vaccinated subjects. The corresponding combined ACV and PCV odds ratios (OR) for SARS-CoV2 infection were 1.505 (95%CI 1.455–1.558; p < 0.0001; reduction −41.85 %) and 1.633 (95%CI 1.603–1.662; p < 0.0001; reduction −51.74 %), for TFV and DTP, respectively. Regarding COVID-19 associated hospitalization, the OR were 0.295 (95%CI 0.220–0.396; p = 0.0001; reduction 69.74 %) and 0.667 (95%CI 0.601–0.741; p = 0.0001; reduction 32.44 %), for TFV and DTP, respectively). COVID-19 associated death OR were 0.016 (95%CI 0.002–0.113, p < 0.0001; reduction 98.38 %) and 0.212 (95%CI 0.161–0.280; p = 0.0001; reduction 78.52 %), for TFV and DTP, respectively. We conclude that TRAIM effects by TFV and DTP vaccination in the four years prior to the pandemic SARS-CoV2 were supported by slightly increased infection rates, but strongly reduced COVID-19 associated hospitalization and death rates.

Monophosphoryl Lipid A-based Adjuvant to Promote the Immunogenicity of Multivalent Meningococcal Polysaccharide Conjugate Vaccines.

Activation of the adaptive immune system requires the engagement of costimulatory pathways in addition to B and T cell Ag receptor signaling, and adjuvants play a central role in this process. Many Gram-negative bacterial polysaccharide vaccines, including the tetravalent meningococcal conjugate vaccines (MCV4) and typhoid Vi polysaccharide vaccines, do not incorporate adjuvants. The immunogenicity of typhoid vaccines is due to the presence of associated TLR4 ligands in these vaccines. Because the immunogenicity of MCV4 is poor and requires boosters, I hypothesized that TLR4 ligands are absent in MCV4 and that incorporation of a TLR4 ligand-based adjuvant would improve their immunogenicity. Consistent with this hypothesis, two Food and Drug Administration-approved MCV4 vaccines, MENVEO and MenQuadfi, lack TLR4 ligands. Admixing monophosphoryl lipid A, a TLR4 ligand-based adjuvant formulation named "Turbo" with MCV4 induced significantly improved IgM and IgG responses to all four meningococcal serogroup polysaccharides in adult and aged mice after a single immunization. Furthermore, in infant mice, a single booster was sufficient to promote a robust IgG response and 100% seroconversion when MCV4 was adjuvanted with Turbo. Turbo upregulated the expression of the costimulatory molecules CD40 and CD86 on B cells, and Turbo-driven adjuvanticity is lost in mice deficient in CD40 and CD86. These data suggest that Turbo induces the required costimulatory molecules for its adjuvant activity and that incorporation of Turbo could make bacterial polysaccharide vaccines more immunogenic, minimize booster requirements, and be cost-effective, particularly for those individuals in low- and middle-income and disease-endemic countries.

Drug Resistant XDR Typhoid in Children Admitted in a Tertiary Care Hospital

Objective: To evaluate the prevalence and patterns of drug-resistant typhoid fever, including extensively drug-resistant (XDR) and multidrug-resistant (MDR) strains, among children admitted to a tertiary care Hospital. Methodology: This descriptive observational study was done at Paediatric department of LUMHS from May 2022-november 2022. Children aged 1-12 years, both gender and with confirmed diagnosis of typhoid fever based on positive blood cultures were included. Blood culture samples were collected from pediatric patients presenting with suspected typhoid fever are processed according to standard microbiological techniques. Isolation and identification of Salmonella Typhi are performed using appropriate culture media and biochemical tests. Antimicrobial susceptibility testing was conducted using standardized methods. Drug resistance patterns, including multidrug resistance (MDR) and extensively drug-resistant (XDR) phenotypes, are determined based on susceptibility testing results. MDR was defined as resistance to at least three classes of antibiotics commonly used for typhoid fever treatment, while XDR indicates additional resistance to fluoroquinolones and third-generation cephalosporins, which are frontline treatment options for typhoid fever. Data was entered and analyzed using SPSS version 26. Results: A total of 43 patients were studied, their mean age was 5.91 years. Boys were 72.15 and girls were 27.9%. Most of the cases 65.1% were consuming tap water. MDR resistance was observed in 9.4% of the cases, while XDR resistance was highly frequent among 83.7% of the patients. Very few cases 16.3% had history of typhoid vaccination. However, MDR and XDR resistance were statistically insignificant according to type of water consumption (p-&gt;0.05). Conclusion: In conclusion, the study revealed alarmingly high prevalence rates of extensively drug-resistant (XDR) typhoid with multidrug-resistant (MDR) strains observed in 9.4% of cases. These findings emphasize the urgent need for comprehensive strategies that address both antimicrobial resistance and vaccination efforts to combat the increasing burden of XDR typhoid in children.

Systems and Computational Screening identifies SRC and NKIRAS2 as Baseline Correlates of Risk (CoR) for Live Attenuated Oral Typhoid Vaccine (TY21a) associated Protection

AimWe investigated the molecular underpinnings of variation in immune responses to the live attenuated typhoid vaccine (Ty21a) by analyzing the baseline immunological profile. We utilized gene expression datasets obtained from the Gene Expression Omnibus (GEO) database (accession number: GSE100665) before and after immunization. We then employed two distinct computational approaches to identify potential baseline biomarkers associated with responsiveness to the Ty21a vaccine. Main methodsThe first pipeline (knowledge-based) involved the retrieval of differentially expressed genes (DEGs), functional enrichment analysis, protein-protein interaction network construction, and topological network analysis of post-immunization datasets before gauging their pre-vaccination expression levels. The second pipeline utilized an unsupervised machine learning algorithm for data-driven feature selection on pre-immunization datasets. Supervised machine-learning classifiers were employed to computationally validate the identified biomarkers. Key findingsBaseline activation of NKIRAS2 (a negative regulator of NF-kB signalling) and SRC (an adaptor for immune receptor activation) was negatively associated with Ty21a vaccine responsiveness, whereas LOC100134365 exhibited a positive association. The Stochastic Gradient Descent (SGD) algorithm accurately distinguished vaccine responders and non-responders, with 88.8%, 70.3%, and 85.1% accuracy for the three identified genes, respectively. SignificanceThis dual-pronged novel analytical approach provides a comprehensive comparison between knowledge-based and data-driven methods for the prediction of baseline biomarkers associated with Ty21a vaccine responsiveness. The identified genes shed light on the intricate molecular mechanisms that influence vaccine efficacy from the host perspective while pushing the needle further towards the need for development of precise enteric vaccines and on the importance of pre-immunization screening.

Mild exogenous inflammation blunts neural signatures of bounded evidence accumulation and reward prediction error processing in healthy male participants

BackgroundAltered neural haemodynamic activity during decision making and learning has been linked to the effects of inflammation on mood and motivated behaviours. So far, it has been reported that blunted mesolimbic dopamine reward signals are associated with inflammation-induced anhedonia and apathy. Nonetheless, it is still unclear whether inflammation impacts neural activity underpinning decision dynamics. The process of decision making involves integration of noisy evidence from the environment until a critical threshold of evidence is reached. There is growing empirical evidence that such process, which is usually referred to as bounded accumulation of decision evidence, is affected in the context of mental illness. MethodsIn a randomised, placebo-controlled, crossover study, 19 healthy male participants were allocated to placebo and typhoid vaccination. Three to four hours post-injection, participants performed a probabilistic reversal-learning task during functional magnetic resonance imaging. To capture the hidden neurocognitive operations underpinning decision-making, we devised a hybrid sequential sampling and reinforcement learning computational model. We conducted whole brain analyses informed by the modelling results to investigate the effects of inflammation on the efficiency of decision dynamics and reward learning. ResultsWe found that during the decision phase of the task, typhoid vaccination attenuated neural signatures of bounded evidence accumulation in the dorsomedial prefrontal cortex, only for decisions requiring short integration time. Consistent with prior work, we showed that, in the outcome phase, mild acute inflammation blunted the reward prediction error in the bilateral ventral striatum and amygdala. ConclusionsOur study extends current insights into the effects of inflammation on the neural mechanisms of decision making and shows that exogenous inflammation alters neural activity indexing efficiency of evidence integration, as a function of choice discriminability. Moreover, we replicate previous findings that inflammation blunts striatal reward prediction error signals.

Typhoid intestinal perforation in Francophone Africa, a scoping review.

Typhoid intestinal perforation (TIP) is a leading cause of peritonitis and indication for emergency surgery in Africa, with reported mortality rates up to 30% in pediatric patients. Currently, data on TIP in Western databases are primarily from countries that speak English, likely due to non-English publication and citation biases. Despite the high burden of infectious diseases in Francophone Africa, data from these countries regarding TIP remain limited. This study aims to highlight the incidence and morbidity of TIP in Francophone African countries using an extended search algorithm. We conducted a scoping review using the PubMed, EMBASE, and SCOPUS databases with the keywords "peritonitis", "non-traumatic ileal perforation", and "typhoid" in Francophone African countries. Additionally, we contacted surgeons in Africa and concurrently used citation chasing to obtain data not found in western databases. In total, 32 studies from 12 countries were identified and included in this review. A total of 22 publications were in French. Patient median age was 20 years and TIP caused a median of 35% of acute peritonitis cases. Mortality rates ranged from 6-37% (median: 16%). Rate of complications ranged from 15-92% (median: 46%). Ileostomy creation as a treatment for TIP varied between hospitals (0-79%), with the highest rates reported in Niger. In Francophone Africa, TIP is associated with high morbidity and mortality, most commonly in children and young adults. Interventions, including improved sanitation and the introduction of typhoid conjugate vaccines into routine vaccination programs, have the potential to significantly decrease typhoid fever and its complications.

The safety and immunogenicity of a bivalent conjugate vaccine against Salmonella enterica Typhi and Paratyphi A in healthy Indian adults: a phase 1, randomised, active-controlled, double-blind trial

Enteric fever caused by Salmonella enterica Typhi and Salmonella Paratyphi A is an important public health problem, especially in low-income and middle-income countries with limited access to safe water and sanitation. We present results from, to our knowledge, the first ever human study of a bivalent paratyphoid A-typhoid conjugate vaccine (Sii-PTCV). In this double-blind phase 1 study, 60 healthy Indian adults were randomly assigned (1:1) to receive a single intramuscular dose of either Sii-PTCV or typhoid conjugate vaccine (Typbar-TCV). Safety was assessed by observing solicited adverse events for 1 week, unsolicited events for 1 month, and serious adverse events (SAEs) over 6 months. Immunogenicity at 1 month and 6 months was assessed by measuring anti-capsular polysaccharide antigen Vi (anti-Vi) IgG and IgA against Salmonella Typhi and anti-lipopolysaccharide (LPS) IgG against Salmonella Paratyphi A by ELISA, and functional antibodies using serum bactericidal assay (SBA) against Salmonella Paratyphi A. This study is registered with Clinical Trial Registry-India (CTRI/2022/06/043608) and is completed. 60 participants were enrolled. Of these 60 participants, 57 (95%) participants were male and three (5%) participants were female. Solicited adverse events were observed in 27 (90%) of 30 participants who received Sii-PTCV and 26 (87%) of 30 participants who received Typbar-TCV. The most common local solicited event was pain in 27 (90%) participants who received Sii-PTCV and in 23 (77%) participants who received Typbar-TCV. The most common solicited systemic event was myalgia in five (17%) participants who received Sii-PTCV, whereas four (13%) participants who received Typbar-TCV had myalgia and four (13%) had headache. No vaccine-related unsolicited adverse events or SAEs were reported. The seroconversion rates on day 29 were 96·7% (95% CI 82·8-99·9) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgG; 93·3% (77·9-99·2) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgA; 100·0% (88·4-100·0) with Sii-PTCV and 3·3% (0·1-17·2) with Typbar-TCV for anti-LPS (paratyphoid); and 93·3% (77·9-99·2) with Sii-PTCV and 0% (0·0-11·6) with Typbar-TCV for SBA titres (paratyphoid). Paratyphoid anti-LPS immune responses were sustained at day 181. Sii-PTCV was safe and immunogenic for both typhoid and paratyphoid antigens indicating its potential for providing comprehensive protection against enteric fever. Serum Institute of India.

Cost-effectiveness and public health impact of typhoid conjugate vaccine introduction strategies in Bangladesh

PurposeTyphoid fever causes substantial morbidity and mortality in Bangladesh. The government of Bangladesh plans to introduce typhoid conjugate vaccines (TCV) in its expanded program on immunization (EPI) schedule. However, the optimal introduction strategy in addition to the costs and benefits of such a program are unclear. MethodsWe extended an existing mathematical model of typhoid transmission to integrate cost data, clinical incidence data, and recently conducted serosurveys in urban, semi-urban, and rural areas. In our primary analysis, we evaluated the status quo (i.e., no vaccination) and eight vaccine introduction strategies including routine and 1-time campaign strategies, which differed by age groups targeted and geographic focus. Model outcomes included clinical incidence, seroincidence, deaths, costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for each strategy. We adopted a societal perspective, 10-year model time horizon, and 3 % annual discount rate. We performed probabilistic, one-way, and scenario sensitivity analyses including adopting a healthcare perspective and alternate model time horizons. ResultsWe projected that all TCV strategies would be cost saving compared to the status quo. The preferred strategy was a nationwide introduction of TCV at 9–12 months of age with a single catch-up campaign for children ages 1–15, which was cost saving compared to all other strategies and the status quo. In the 10 years following implementation, we projected this strategy would avert 3.77 million cases (95 % CrI: 2.60 – 5.18), 11.31 thousand deaths (95 % CrI: 3.77 – 23.60), and save $172.35 million (95 % CrI: −14.29 – 460.59) compared to the status quo. Our findings were broadly robust to changes in parameter values and willingness-to-pay thresholds. ConclusionsWe projected that nationwide TCV introduction with a catch-up campaign would substantially reduce typhoid incidence and very likely be cost saving in Bangladesh.

AN OVERVIEW OF CURRENT VACCCINES FOR THE PROPHYLAXIS OF BACTERICAL INFECTIONS

Antibacterial vaccines play a central role in modern medicine by providing an effective approach to combating infectious diseases caused by bacteria. The importance of these vaccines lies in their ability to stimulate the immune system to recognise and neutralise bacterial pathogens, or exotoxins produced by them, thereby preventing, or mitigating the severity of bacterial infections. The development and widespread use of antibacterial vaccines have contributed significantly to reducing the global burden of diseases such as pneumonia, meningitis, and sepsis. Today, the global increase in vaccine-preventable diseases is a worrying trend that is closely linked to the emergence and advocacy of anti-vaccination policies. According to the latest World Health Organisation report, vaccination coverage in Serbia has declined over the past decade, jeopardising the collective immunity and led to recent outbreaks of vaccine-preventable diseases such as whooping cough and measles. Understanding the significance of antibacterial vaccines underscores their importance in promoting individual and community immunity, which ultimately leads to a healthier population and the prevention of antibiotic resistance. This paper summarises the main characteristics of the different types of antibacterial vaccines, such as whole cell vaccines, subunit vaccines and toxoid vaccines, and provides an overview of the types of bacterial antigens contained in vaccines available for mandatory immunisation (vaccines against tuberculosis, diphtheria, tetanus, pertussis, Haemophilus influenzae and pneumoccus) or for non-mandatory immunisation (meningococcal vaccine, typhoid vaccine, cholera vaccine).

Typhoid Conjugate Vaccine: A Boon for Endemic Regions.

Typhoid fever has the highest disease burden in countries in low- and middle-income countries, primarily located in Asia and Sub-Saharan Africa. Previous typhoid vaccines such as the live attenuated typhoid (Ty21a) vaccine and Vi (virulence) capsular polysaccharide vaccine had the limitation that they could not be administered with other standard childhood immunizations and were ineffective in children under two years of age. To address these shortcomings of the previous vaccines, typhoid conjugate vaccines (TCVs) were developed and prequalified by the World Health Organization. Cross-reacting material and tetanus toxoid are widely used as carrier proteins in TCVs. According to various studies, TCV has higher efficacy, has a more extended protection period, and is safe and immunogenic in infants as young as six months. This review article aims to comprehensively appraise the data available on TCVs' efficacy, duration of protection, safety, and immunogenicity in endemic regions.