RESUMEN
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.
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Infecciones por Salmonella , Vacunas contra la Salmonella , Humanos , Vacunas contra la Salmonella/inmunología , Infecciones por Salmonella/inmunología , Infecciones por Salmonella/prevención & control , Salmonella typhi/inmunología , Vacunación , Eficacia de las Vacunas , Fiebre Tifoidea/prevención & control , Fiebre Tifoidea/inmunología , Salmonella/inmunologíaRESUMEN
Vaccine safety and immunogenicity data in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children are important for decision-making in HIV and typhoid co-endemic countries. In an open-label study, we recruited Malawian HEU and HIV unexposed uninfected (HUU) infants aged 9 - 11 months. HEU participants were randomized to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) at 9 months, Vi-TT at 15 months, or Vi-TT at 9 and 15 months. HUU participants received Vi-TT at 9 and 15 months. Safety outcomes included solicited and unsolicited adverse events (AE) and serious AEs (SAEs) within 7 days, 28 days, and 6 months of vaccination, respectively. Serum was collected before and at day 28 after each vaccination to measure anti-Vi IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Cohort 1 (66 participants) enrollment began 02 December 2019, and follow-up was terminated before completion due to the COVID-19 pandemic. Cohort 2 (100 participants) enrollment began 25 March 2020. Solicited AEs were mostly mild, with no significant differences between HEU and HUU participants or one- and two-dose groups. All six SAEs were unrelated to vaccination. Anti-Vi geometric mean titers (GMT) increased significantly from 4.1 to 4.6 ELISA units (EU)/mL at baseline to 2572.0 - 4117.6 EU/mL on day 28 post-vaccination, and similarly between HEU and HUU participants for both one- and two-dose schedules. All participants seroconverted (>4-fold increase in GMT) by the final study visit. Our findings of comparable safety and immunogenicity of Vi-TT in HUU and HEU children support country introductions with single-dose Vi-TT in HIV-endemic countries.
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Anticuerpos Antibacterianos , Infecciones por VIH , Inmunogenicidad Vacunal , Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Vacunas Conjugadas , Humanos , Masculino , Femenino , Malaui , Lactante , Infecciones por VIH/inmunología , Vacunas Tifoides-Paratifoides/inmunología , Vacunas Tifoides-Paratifoides/efectos adversos , Vacunas Tifoides-Paratifoides/administración & dosificación , Vacunas Conjugadas/inmunología , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/administración & dosificación , Anticuerpos Antibacterianos/sangre , Fiebre Tifoidea/inmunología , Fiebre Tifoidea/prevención & control , Inmunoglobulina G/sangre , Toxoide Tetánico/inmunología , Toxoide Tetánico/efectos adversos , Toxoide Tetánico/administración & dosificación , Esquemas de Inmunización , VacunaciónAsunto(s)
Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Vacunas Conjugadas , Humanos , Malaui , Vacunas Tifoides-Paratifoides/administración & dosificación , Fiebre Tifoidea/prevención & control , Fiebre Tifoidea/epidemiología , Vacunas Conjugadas/administración & dosificación , Niño , PreescolarRESUMEN
This study presents a reliable mathematical model to explain the spread of typhoid fever, covering stages of susceptibility, infection, carrying, and recovery, specifically in the Sheno town community. A detailed analysis is done to ensure the solutions are positive, stay within certain limits, and are stable for both situations where the disease is absent and where it is consistently present. The Routh-Hurwitz stability criterion has been used and applied for the purpose of stability analysis. Using the next-generation matrix, we determined the intrinsic potential for disease transmission. It showing that typhoid fever is spreading actively in Sheno town, with cases above a critical level. Our findings reveal the instability of the disease-free equilibrium point alongside the stability of the endemic equilibrium point. We identified two pivotal factors for transmission of the disease: the infectious rate, representing the speed of disease transmission, and the recruitment rate, indicating the rate at which new individuals enter the susceptible population. These parameters are indispensable for devising effective control measures. It is imperative to keep these parameters below specific thresholds to maintain a basic reproduction number favorable for disease control. Additionally, the study carefully examines how different factors affect the spread of typhoid fever, giving a detailed understanding of its dynamics. At the end, this study provides valuable insights and specific strategies for managing the disease in the Sheno town community.
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Fiebre Tifoidea , Fiebre Tifoidea/transmisión , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Humanos , Etiopía/epidemiología , Dinámicas no Lineales , Modelos Teóricos , Número Básico de ReproducciónRESUMEN
BACKGROUND: In 2019, following a large outbreak of typhoid fever, the Zimbabwe Ministry of Health and Child Care conducted a typhoid conjugate vaccine (TCV) vaccination campaign in nine high-risk suburbs of Harare. We aimed to evaluate TCV vaccination coverage, vaccine perceptions, and adverse events reported after vaccination. METHODS: We conducted a two-stage cluster survey to estimate vaccination coverage in the campaign target areas among children aged 6 months-15 years and to classify coverage as either adequate (≥75 % coverage) or inadequate (<75 % coverage) among adults aged 16-45 years in one suburb. Questionnaires assessed socio-demographic factors, TCV vaccination history, reasons for receiving or not receiving TCV, adverse events following immunization, and knowledge and attitudes regarding typhoid and TCV. RESULTS: A total of 1,917 children from 951 households and 298 adults from 135 households enrolled in the survey. Weighted TCV coverage among all children aged 6 months-15 years was 85.3 % (95 % CI: 82.1 %-88.0 %); coverage was 74.8 % (95 % CI: 69.4 %-79.5 %) among children aged 6 months-4 years and 89.3 % (95 % CI: 86.2 %-91.7 %) among children aged 5-15 years. Among adults, TCV coverage was classified as inadequate with a 95 % confidence interval of 55.0 %-73.1 %. Among vaccinated persons, the most reported reason for receiving TCV (96 % across all age groups) was protection from typhoid fever; the most common reasons for non-vaccination were not being in Harare during the vaccination campaign and not being aware of the campaign. Adverse events were infrequently reported in all age groups (10 %) and no serious events were reported. CONCLUSIONS: The 2019 TCV campaign achieved high coverage among school-aged children (5-15 years). Strategies to increase vaccination coverage should be explored for younger children as part of Zimbabwe's integration of TCV into the routine immunization program, and for adults during future post-outbreak campaigns.
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Conocimientos, Actitudes y Práctica en Salud , Programas de Inmunización , Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Cobertura de Vacunación , Vacunas Conjugadas , Humanos , Zimbabwe , Adolescente , Vacunas Tifoides-Paratifoides/administración & dosificación , Vacunas Tifoides-Paratifoides/inmunología , Vacunas Tifoides-Paratifoides/efectos adversos , Niño , Adulto , Fiebre Tifoidea/prevención & control , Femenino , Masculino , Preescolar , Lactante , Cobertura de Vacunación/estadística & datos numéricos , Adulto Joven , Persona de Mediana Edad , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/inmunología , Encuestas y Cuestionarios , Programas de Inmunización/estadística & datos numéricos , Vacunación/estadística & datos numéricosRESUMEN
BACKGROUND: Salmonella enterica serotype Typhi (Salmonella Typhi) causes severe and occasionally life-threatening disease, transmitted through contaminated food and water. Humans are the only reservoir, inadequate water, sanitation, and hygiene infrastructure increases risk of typhoid. High-quality data to assess spatial and temporal relationships in disease dynamics are scarce. METHODS: We analyzed data from a prospective cohort conducted in an urban slum area of Dhaka City, Bangladesh. Passive surveillance at study centers identified typhoid cases by microbiological culture. Each incident case (index case) was matched to two randomly selected index controls, and we measured typhoid incidence in the population residing in a geographically defined region surrounding each case and control. Spatial clustering was evaluated by comparing the typhoid incidence in residents of geometric rings of increasing radii surrounding the index cases and controls over 28 days. Temporal clustering was evaluated by separately measuring incidence in the first and second 14-day periods following selection. Incidence rate ratios (IRRs) were calculated using Poisson regression models. RESULTS: We evaluated 141 typhoid index cases. The overall typhoid incidence was 0.44 per 100,000 person-days (PDs) (95% CI: 0.40, 0.49). In the 28 days following selection, the highest typhoid incidence (1.2 per 100,000 PDs [95% CI: 0.8, 1.6]) was in the innermost cluster surrounding index cases. The IRR in this innermost cluster was 4.9 (95% CI: 2.4, 10.3) relative to the innermost control clusters. Neither typhoid incidence rates nor relative IRR between index case and control populations showed substantive differences in the first and second 14-day periods after selection. CONCLUSION: In the absence of routine immunization programs, geographic clustering of typhoid cases suggests a higher intensity of typhoid risk in the population immediately surrounding identified cases. Further studies are needed to understand spatial and temporal trends and to evaluate the effectiveness of targeted vaccination in disrupting typhoid transmission.
Asunto(s)
Áreas de Pobreza , Salmonella typhi , Fiebre Tifoidea , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Humanos , Bangladesh/epidemiología , Masculino , Femenino , Incidencia , Adolescente , Niño , Adulto , Preescolar , Adulto Joven , Estudios Prospectivos , Vacunas Tifoides-Paratifoides/administración & dosificación , Análisis Espacio-Temporal , Lactante , Análisis por Conglomerados , Vacunación , Persona de Mediana Edad , Población Urbana , Estudios de Casos y ControlesRESUMEN
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.
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Costo de Enfermedad , Países en Desarrollo , Fiebre Tifoidea , Humanos , Fiebre Tifoidea/economía , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Países en Desarrollo/economía , Vacunas Tifoides-Paratifoides/economíaRESUMEN
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.
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Adyuvantes Inmunológicos , Anticuerpos Antibacterianos , Lípido A , Receptor Toll-Like 4 , Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Vacunas de Subunidad , Animales , Vacunas Tifoides-Paratifoides/inmunología , Vacunas Tifoides-Paratifoides/administración & dosificación , Ratones , Receptor Toll-Like 4/inmunología , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/administración & dosificación , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Lípido A/análogos & derivados , Lípido A/inmunología , Fiebre Tifoidea/prevención & control , Fiebre Tifoidea/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Femenino , Ligandos , Polisacáridos Bacterianos/inmunología , Inmunogenicidad Vacunal , Adyuvantes de Vacunas , Salmonella typhi/inmunología , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: This study aimed to assess the longevity of serologic response and seroconversion rates at several time points following TCV vaccination among children living with HIV aged 6 months to 15 years in Pakistan. METHODS: From November 20, 2020, to January 2, 2021; 336 children were enrolled and followed up prospectively for 12 months. Blood samples were collected before the administration of TCV and at 4-6 weeks, 6 months, and 1 year after administration of a single dose (0.5 ml) of intramuscular Typbar TCV®. Samples were analyzed for anti-Vi-IgG antibodies using ELISA. Geometric mean titers (GMTs), seroconversion rates (fourfold rise in anti-Vi-IgG from baseline) were assessed, and factors associated with sustained seroconversion at 1 year were evaluated using generalized linear mixed models. FINDINGS: The seroconversion rates were significantly lower in children aged 6 months to 5 years compared to children > 5 years; (127/216 (58·8%)) versus (81/111 (73·0%)) at 6 months and (110/217 (50·7%)) versus (78/109 (71·6%)) at 1 year, only two-third; 188/326 (57·7%) remained seroconverted at 1 year. The GMTs (95 % CI) were significantly lower in children aged 6 months to 5 years compared to children > 5 years, 9·6 (7·6, 12·0) versus 28·9 (20·2, 41·4) at 6 months, and 6·6 (5·4, 8·0) versus 23·1 (16·4, 32·5) at 1 year time point. The odds of sustained seroconversion significantly decreased with time (adjusted odds ratio (aOR): 0.23; 95 % CI: 0.14, 0.40). The odds of sustained seroconversion following 1 year of TCV vaccination were significantly higher among children with non-severe HIV clinical disease (aOR: 10·61; 95% CI: 1·52, 73·98) and children in elder age group (aOR: 7·45; 95% CI: 1·18, 47·03). CONCLUSIONS: A significant decrease in seroconversion rates was observed among children living with HIV following one year of TCV administration. The decline was significantly higher in children with severe or advanced HIV clinical disease and children younger than five years of age.
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Anticuerpos Antibacterianos , Infecciones por VIH , Seroconversión , Vacunas Tifoides-Paratifoides , Humanos , Estudios Prospectivos , Infecciones por VIH/inmunología , Masculino , Preescolar , Femenino , Pakistán/epidemiología , Niño , Lactante , Anticuerpos Antibacterianos/sangre , Adolescente , Vacunas Tifoides-Paratifoides/inmunología , Vacunas Tifoides-Paratifoides/administración & dosificación , Fiebre Tifoidea/prevención & control , Fiebre Tifoidea/inmunología , Vacunas Conjugadas/inmunología , Vacunas Conjugadas/administración & dosificación , Inmunoglobulina G/sangre , Vacunación/métodosRESUMEN
Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of Typhoid fever. Blood culture is the gold standard for clinical diagnosis, but this is often difficult to employ in resource limited settings. Environmental surveillance of waste-impacted waters is a promising supplement to clinical surveillance, however validating methods is challenging in regions where S. Typhi concentrations are low. To evaluate existing S. Typhi environmental surveillance methods, a novel process control organism (PCO) was created as a biosafe surrogate. Using a previous described qPCR assay, a modified PCR amplicon for the staG gene was cloned into E. coli. We developed a target region that was recognized by the Typhoid primers in addition to a non-coding internal probe sequence. A multiplex qPCR reaction was developed that differentiates between the typhoid and control targets, with no cross-reactivity or inhibition of the two probes. The PCO was shown to mimic S. Typhi in lab-based experiments with concentration methods using primary wastewater: filter cartridge, recirculating Moore swabs, membrane filtration, and differential centrifugation. Across all methods, the PCO seeded at 10 CFU/mL and 100 CFU/mL was detected in 100% of replicates. The PCO is detected at similar quantification cycle (Cq) values across all methods at 10 CFU/mL (Average = 32.4, STDEV = 1.62). The PCO was also seeded into wastewater at collection sites in Vellore (India) and Blantyre (Malawi) where S. Typhi is endemic. All methods tested in both countries were positive for the seeded PCO. The PCO is an effective way to validate performance of environmental surveillance methods targeting S. Typhi in surface water.
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Monitoreo del Ambiente , Escherichia coli , Salmonella typhi , Salmonella typhi/genética , Salmonella typhi/aislamiento & purificación , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Monitoreo del Ambiente/métodos , Aguas Residuales/microbiología , Fiebre Tifoidea/microbiología , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/diagnóstico , Fiebre Tifoidea/prevención & control , Humanos , Microbiología del AguaRESUMEN
PURPOSE: Typhoid 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: We projected that nationwide TCV introduction with a catch-up campaign would substantially reduce typhoid incidence and very likely be cost saving in Bangladesh.
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Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Niño , Humanos , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Análisis Costo-Beneficio , Vacunas Conjugadas , Salud Pública , Bangladesh/epidemiologíaRESUMEN
Tropical infectious diseases inflict an unacceptable burden of disease on humans living in developing countries. Although anti-pathogenic drugs have been widely used, they carry a constant threat of selecting for resistance. Vaccines offer a promising means by which to enhance the global control of tropical infectious diseases; however, these have been difficult to develop, mostly because of the complex nature of the pathogen lifecycles. Here, we present recently developed vaccine candidates for five tropical infectious diseases in the form of a catalog that have either entered clinical trials or have been licensed for use. We deliberate on recently licensed dengue vaccines, provide evidence why combination vaccination could have a synergistic impact on schistosomiasis, critically appraise the value of typhoid conjugate vaccines, and discuss the potential of vaccines in the efforts to eliminate vivax malaria and hookworms.
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Dengue , Humanos , Dengue/prevención & control , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/administración & dosificación , Esquistosomiasis/prevención & control , Enfermedades Transmisibles , Medicina Tropical , Vacunas/inmunología , Fiebre Tifoidea/prevención & control , Malaria Vivax/prevención & control , Desarrollo de VacunasRESUMEN
BACKGROUND: 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). METHODS: 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. FINDINGS: 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. INTERPRETATION: Sii-PTCV was safe and immunogenic for both typhoid and paratyphoid antigens indicating its potential for providing comprehensive protection against enteric fever. FUNDING: Serum Institute of India.
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Salmonella enterica , Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Adulto , Femenino , Humanos , Masculino , Antibacterianos , Inmunoglobulina A , Inmunoglobulina G , Mialgia , Salmonella typhi , Fiebre Tifoidea/prevención & control , Vacunas Combinadas , Vacunas Conjugadas , Método Doble CiegoRESUMEN
BACKGROUND: Typhoid is a serious public health threat in many low-income and middle-income countries. Several vaccines for typhoid have been recommended by WHO for typhoid prevention in endemic countries. This study aimed to review the efficacy of typhoid vaccines against culture-confirmed Salmonella enterica serovar Typhi. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase for studies published in English between Jan 1, 1986 and Nov 2, 2023. We included randomised controlled trials (RCTs) comparing typhoid vaccines with a placebo or another vaccine. This meta-analysis evaluated the efficacy and safety of several typhoid vaccines, including live attenuated oral Ty21a vaccine, Vi capsular polysaccharide (Vi-PS), Vi polysaccharide conjugated to recombinant Pseudomonas aeruginosa exotoxin A vaccine (Vi-rEPA), and Vi-tetanus toxoid conjugate vaccine (TCV). The certainty of evidence for key outcomes was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations methodology. The outcome of interest was typhoid fever confirmed by the isolation of Salmonella enterica serovar Typhi in blood and adverse events following immunisation. This study is registered with PROSPERO (CRD42021241043). FINDINGS: We included 14 RCTs assessing four different vaccines (Ty21a: four trials; Vi-PS: five trials; Vi-rEPA: one trial; TCV: four trials) involving 585â253 participants. All trials were conducted in typhoid endemic countries and the age of participants ranged from 6 months to 50 years. The pooled efficacy against typhoid fever was 45% (95% CI 33-55%; four trials; 247â649 participants; I2 59%; moderate certainty) for Ty21a and 58% (44-69%; five trials; 214â456 participants; I2 34%; moderate certainty) for polysaccharide Vi-PS. The cumulative efficacy of two doses of Vi-rEPA vaccine at 2 years was 91% (88-96%; one trial; 12â008 participants; moderate certainty). The pooled efficacy of a single shot of TCV at 2 years post-immunisation was 83% (77-87%; four trials; 111â130 participants; I2 0%; moderate certainty). All vaccines were safe, with no serious adverse effects reported in the trials. INTERPRETATION: The existing data from included trials provide promising results regarding the efficacy and safety of the four recommended typhoid vaccines. TCV and Vi-rEPA were found to have the highest efficacy at 2 years post-immunisation. However, follow-up data for Vi-rEPA are scarce and only TCV is pre-qualified by WHO. Therefore, roll-out of TCV into routine immunisation programmes in typhoid endemic settings is highly recommended. FUNDING: There was no funding source for this study.
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Salmonella typhi , Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Humanos , Vacunas Tifoides-Paratifoides/administración & dosificación , Vacunas Tifoides-Paratifoides/inmunología , Salmonella typhi/inmunología , Fiebre Tifoidea/prevención & control , Fiebre Tifoidea/epidemiología , Enfermedades Endémicas/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Eficacia de las VacunasRESUMEN
Typhoid is endemic in India and has high global incidence. There were large outbreaks of typhoid in India between 1990 and 2018. Available typhoid vaccines induce variable levels of protective antibodies among recipients; thus, there is variability in response to the vaccine. Interindividual genomic differences is hypothesized to be a determinant of the variability in response. We studied the antibody response of ~1000 recipients of the Vi-polysaccharide typhoid vaccine from Kolkata, India, who showed considerable variability of antibody response, i.e., anti-Vi-polysaccharide antibody level 28 days postvaccination relative to prevaccination. For each vaccinee, wholegenome genotyping was performed using the Infinium Global Screening Array (Illumina). We identified 39 SNPs that mapped to 13 chromosomal regions to be associated with antibody response to the vaccine; these included SNPs on genes LRRC28 (15q26.3), RGS7 (1q43), PTPRD (9p23), CERKL (2q31.3), DGKB (7p21.2), and TCF4 (18q21.2). Many of these loci are known to be associated with various blood cell traits, autoimmune traits and responses to other vaccines; these genes are involved in immune related functions, including TLR response, JAK-STAT signalling, phagocytosis and immune homeostasis.
Asunto(s)
Proteínas RGS , Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Humanos , Vacunas Tifoides-Paratifoides/genética , Formación de Anticuerpos , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Genómica , PolisacáridosRESUMEN
Multiple TonB dependent transporters (TBDTs) contribute to bacterial virulence due to the importance roles that their substrates play in bacterial growth, and possess vaccine potential. A putative TBDT, YncD, had been identified as one of in vivo induced antigens during human infection of typhoid fever, and is required for the pathogenicity of Salmonella enterica Serovar Typhi. The present study was aimed to determine the function and immunogenicity of YncD. Homologous recombination method was used to construct an yncD-deletion mutant and cirA-iroN-fepA-deletion mutant from the wild-type S. Typhi Ty2. The growth of mutants and the wild-type strain were assessed in iron-deficient medium, as well as in human macrophage cells. Recombinant YncD protein was expressed and purified using Ni-NTA affinity chromatography and anion exchange. A mouse model was then used to evaluate the immunogenicity and protection efficacy of the recombinant YncD. Antibody levels, serum bactericidal efficiency, passive immune protection, opsonophagocysis were assayed to analyse the immunoprotection mechanism of the recombinant YncD. Our results showed that YncD is associated with the iron-uptake of S. Typhi. The yncD-deletion mutant displayed impaired growth in iron-deficient medium, comparable to that the cirA-iroN-fepA-deletion mutant did. The mutation of yncD markedly decreased bacterial growth within human macrophage cells. Moreover, subcutaneous immunization of mice with recombinant YncD elicited high levels of specific anti-YncD IgG, IgG1 and IgG2a, which protected the immunized mice against the intraperitoneal challenge of S. Typhi, and decreased bacterial burdens in the livers and spleens of the infected mice. Passive immunization using the immunized sera also efficiently protected the mice from the challenge of S. Typhi. Moreover, the immunized sera enhanced in vitro bactericidal activity of complement, and opsonophagocytosis. Our results showed that YncD displays a role in the iron-uptake of S. Typhi and possesses immunogenicity.
Asunto(s)
Fiebre Tifoidea , Vacunas , Animales , Ratones , Humanos , Salmonella typhi , Fiebre Tifoidea/prevención & control , Proteínas de Transporte de Membrana , Proteínas Recombinantes , Hierro , Ratones Endogámicos BALB CAsunto(s)
Fiebre Paratifoidea , Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Humanos , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Fiebre Paratifoidea/epidemiología , Fiebre Paratifoidea/prevención & control , Vacunas Conjugadas , Vacunas Combinadas , Salmonella typhiRESUMEN
BACKGROUND: Typhoid Fever remains a major cause of morbidity and mortality in low-income settings. The Severe Typhoid in Africa programme was designed to address regional gaps in typhoid burden data and identify populations eligible for interventions using novel typhoid conjugate vaccines. METHODS: A hybrid design, hospital-based prospective surveillance with population-based health-care utilisation surveys, was implemented in six countries in sub-Saharan Africa. Patients presenting with fever (≥37·5°C axillary or ≥38·0°C tympanic) or reporting fever for three consecutive days within the previous 7 days were invited to participate. Typhoid fever was ascertained by culture of blood collected upon enrolment. Disease incidence at the population level was estimated using a Bayesian mixture model. FINDINGS: 27â866 (33·8%) of 82â491 participants who met inclusion criteria were recruited. Blood cultures were performed for 27â544 (98·8%) of enrolled participants. Clinically significant organisms were detected in 2136 (7·7%) of these cultures, and 346 (16·2%) Salmonella enterica serovar Typhi were isolated. The overall adjusted incidence per 100â000 person-years of observation was highest in Kavuaya and Nkandu 1, Democratic Republic of the Congo (315, 95% credible interval 254-390). Overall, 46 (16·4%) of 280 tested isolates showed ciprofloxacin non-susceptibility. INTERPRETATION: High disease incidence (ie, >100 per 100â000 person-years of observation) recorded in four countries, the prevalence of typhoid hospitalisations and complicated disease, and the threat of resistant typhoid strains strengthen the need for rapid dispatch and implementation of effective typhoid conjugate vaccines along with measures designed to improve clean water, sanitation, and hygiene practices. FUNDING: The Bill & Melinda Gates Foundation.