Spatial heterogeneity of socio-economic determinants of typhoid/paratyphoid fever in one province in central China from 2015 to 2019.

BACKGROUND: Typhoid fever and paratyphoid fever are one of the most criticial public health issues worldwide, especially in developing countries. The incidence of this disease may be closely related to socio-economic factors, but there is a lack of research on the spatial level of relevant determinants of typhoid fever and paratyphoid fever. METHODS: In this study, we took Hunan Province in central China as an example and collected the data on typhoid and paratyphoid incidence and socio-economic factors in 2015-2019. Firstly spatial mapping was made on the disease prevalence, and again using geographical probe model to explore the critical influencing factors of typhoid and paratyphoid, finally employing MGWR model to analysis the spatial heterogeneity of these factors. RESULTS: The results showed that the incidence of typhoid and paratyphoid fever was seasonal and periodic and frequently occurred in summer. In the case of total typhoid and paratyphoid fever, Yongzhou was the most popular, followed by Xiangxi Tujia and Miao Autonomous Prefecture, Huaihua and Chenzhou generally focused on the south and west. And Yueyang, Changde and Loudi had a slight increase trend year by year from 2015 to 2019. Moreover, the significant effects on the incidence of typhoid and paratyphoid fever from strong to weak were as follows: gender ratio(q = 0.4589), students in ordinary institutions of higher learning(q = 0.2040), per capita disposable income of all residents(q = 0.1777), number of foreign tourists received(q = 0.1697), per capita GDP(q = 0.1589), and the P values for these factors were less than 0.001. According to the MGWR model, gender ratio, per capita disposable income of all residents and Number of foreign tourists received had a positive effect on the incidence of typhoid and paratyphoid fever. In contrast, students in ordinary institutions of higher learning had a negative impact, and per capita GDP shows a bipolar change. CONCLUSIONS: The incidence of typhoid and paratyphoid fever in Hunan Province from 2015 to 2019 was a marked seasonality, concentrated in the south and west of Hunan Province. Attention should be paid to the prevention and control of critical periods and concentrated areas. Different socio-economic factors may show other directions and degrees of action in other prefecture-level cities. To summarize, health education, entry-exit epidemic prevention and control can be strengthened. This study may be beneficial to carry out targeted, hierarchical and focused prevention and control of typhoid fever and paratyphoid fever, and provide scientific reference for related theoretical research.

Paediatric enteric fever in Brussels: a case series over 16 years.

Enteric fever (EF) is a major public health problem and a witness of the global health disparities. It is caused by Salmonella enterica serovar Typhi (Salmonella ser. Typhi) and Salmonella enterica serovar Paratyphi A, B, C (Salmonella ser. Paratyphi) and is estimated to infect 12-26 million persons yearly. Paediatric data on enteric fever in Europe are scarce. A case series of EF was analysed to describe the clinical presentation, laboratory characteristics and diagnostic challenges identified in a paediatric population in Brussels. We performed a retrospective study of all lab-confirmed cases of enteric fever in children aged 0-15 years at two Brussels teaching hospitals, between January 2005 and December 2020. We reviewed age, gender, travel history, consultations before diagnosis, hospitalisation duration, clinical symptoms and laboratory findings. There were 34 positive isolates of S. typhi and S. paratyphi: 31 patients had positive blood culture, 1 patient had positive bone aspirate and 2 patients had positive stool culture (one was excluded for missing data). There were 20 girls (60%). Median age was 3.5 years (range 5 months to 14 years). Travel to EF endemic areas was present in 55% of patients. Diagnosis was delayed in 80% of children. Eosinopenia was present in 93% of the cohort. The patients had not received any preventive travel education or vaccination.  Conlusion: Enteric fever poses diagnostic challenges to clinicians. Eosinopenia in a febrile patient coming from the tropics should raise suspicion of EF. Travellers to endemic areas should be better educated about EF risks, and typhoid fever vaccination must be promoted. What is Known: • Enteric fever is a global public health problem and includes typhoid and paratyphoid fever. • Typhoid fever is vaccine preventable disease. Paratyphoid fever is not vaccine preventable. What is New: • Enteric fever diagnosis is very challenging in non-endemic settings, and a large proportion of patients may develop serious complications if they receive delayed management. Occurrence of small family clusters is possible and mandates education and monitoring of the families of enteric fever affected children. • We report that the widest majority of our enteric fever affected patients (69%) had aneosinophilia (zero eosinophil count), and almost all patients (93%) had eosinopaenia (less than 50 eosinophil count) during their bacteriaemic phase.

Prospects of Future Typhoid and Paratyphoid Vaccines in Endemic Countries.

Low- and middle-income countries face a high burden of typhoid and paratyphoid fever due to poor water quality and inadequate sanitation. The World Health Organization (WHO) recommends the use of typhoid conjugate vaccines (TCV) in endemic settings and Gavi, the Vaccine Alliance, supports TCV introduction. There are currently 2 WHO-prequalified TCVs with Typbar TCV introduced in Pakistan, Liberia, and Zimbabwe. Countries should assess disease burden and consider introduction of TCV for programmatic use. Several paratyphoid vaccine candidates are in early stages of development. An effective bivalent vaccine would be the most efficient way to control typhoid and paratyphoid fever.

Salmonella Paratyphi A Outer Membrane Vesicles Displaying Vi Polysaccharide as a Multivalent Vaccine against Enteric Fever.

Typhoid and paratyphoid fevers have a high incidence worldwide and coexist in many geographical areas, especially in low-middle-income countries (LMIC) in South and Southeast Asia. There is extensive consensus on the urgent need for better and affordable vaccines against systemic Salmonella infections. Generalized modules for membrane antigens (GMMA), outer membrane exosomes shed by Salmonella bacteria genetically manipulated to increase blebbing, resemble the bacterial surface where protective antigens are displayed in their native environment. Here, we engineered S Paratyphi A using the pDC5-viaB plasmid to generate GMMA displaying the heterologous S Typhi Vi antigen together with the homologous O:2 O antigen. The presence of both Vi and O:2 was confirmed by flow cytometry on bacterial cells, and their amount was quantified on the resulting vesicles through a panel of analytical methods. When tested in mice, such GMMA induced a strong antibody response against both Vi and O:2, and these antibodies were functional in a serum bactericidal assay. Our approach yielded a bivalent vaccine candidate able to induce immune responses against different Salmonella serovars, which could benefit LMIC residents and travelers.

Multi-epitope DnaK peptide vaccine accords protection against lethal S. typhimurium challenge: Elicits both cell mediated immunity and long-lasting serum-neutralizing antibody titers.

Typhoid vaccine development has been impeded by inability of currently available vaccines to induce cellular immunity along with neutralizing antibodies against all serovars of S. Typhi and S. Paratyphi. Unfortunately, antibiotic treatment has shown to be an ineffective therapy due to development of resistance against multiple antibiotics. In the present study, we have explored the immunogenicity and protective efficacy of in-silico designed multi-epitope DnaK peptides as candidate vaccine molecules against Salmonella. Immunization studies in mouse typhoid model revealed three of these peptides (DP1, DP5 and DP7) are highly efficacious, stimulating both humoral and cell mediated immunity along with long lasting antibody memory response. There was significant increase in antibody titers (IgG, IgG1, IgG2a, IgA and IgM), lymphocyte proliferative responses and cytokine levels. Immunized groups showed marked reduction in organ bacterial load, fecal shedding and pronounced protection (upto 80%) as compared to unimmunized controls after challenge with S. typhimurium. Our results demonstrate the huge potential of DnaK peptide vaccine candidates (DP1, DP5 and DP7) to accord protective immunity with significant increase in survivability against Salmonella infection in mice, thus commending these molecules as promising agents to tackle typhoid.

Syntheses of Salmonella Paratyphi†A Associated Oligosaccharide Antigens and Development towards Anti-Paratyphoid Fever Vaccines.

With the emergence of multidrug resistant Salmonella strains, the development of anti-Salmonella vaccines is an important task. Currently there are no approved vaccines against Salmonella Paratyphi A, the leading cause of paratyphoid fever. To fill this gap, oligosaccharides corresponding to the O-polysaccharide repeating units from the surface of Salmonella Paratyphi A have been synthesized through convergent stereoselective glycosylations. The synthetic glycan antigen was conjugated with a powerful immunogenic carrier system, the bacteriophage Qß. The resulting construct was able to elicit strong and long-lasting anti-glycan IgG antibody responses, which were highly selective toward Salmonella Paratyphi A associated glycans. The availability of well-defined glycan antigen enabled the determination that one repeating unit of the polysaccharide is sufficient to induce protective antibodies, and the paratose residue and/or the O-acetyl modifications on the backbone are important for recognition by antibodies elicited by a Qß-tetrasaccharide conjugate. Immune sera provided excellent protection to mice from lethal challenge with Salmonella Paratyphi A, highlighting the potential of the synthetic glycan-based vaccine.

[Typhoid and paratyphoid fever]. / Typhus abdominalis und Paratyphus.

Typhoid fever and paratyphoid fever are systemic infectious diseases of global significance caused by Salmonella enterica subspecies enterica Serovar Typhi (short name: Salmonella Typhi) or Serovar Paratyphi (short name: Salmonella Paratyphi). The course of these fecal-orally transmitted diseases is mainly characterized by a high fever. Left untreated, the course of typhoid fever can be severe and lethal. The infection is almost always acquired outside of Europe (mainly in India) and is notifiable in Germany, Austria and Switzerland. Paratyphoid is an attenuated disease of typhoid fever caused by Salmonella Paratyphi. Available vaccines only protect against Salmonella Typhi. Antibiotic resistance reflects the situation in endemic countries and shows a worrying increase of multi-drug resistant isolates. Currently, third-generation cephalosporins such as ceftriaxone are recommended as first-line therapy; if sensitive to quinolones, fluoroquinolones such as ciprofloxacin may continue to be administered. Crucial preventive measures for travelers to endemic regions include consistent water and food hygiene as well as vaccination, whereby only protection rates of 50-70 % are achieved by currently available vaccines. In the light of increasing multi-drug resistance, a more effective conjugate vaccine against Salmonella Typhi with cross-reactivity against Salmonella Paratyphi is needed more than ever.

The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies.

BACKGROUND: Shedding of Salmonella Typhi or Paratyphi in the stool or urine leads to contamination of food or water, which is a prerequisite for transmission of enteric fever. Currently, there are limited data on the effect of vaccination or prior exposure on stool shedding. METHODS: Six Salmonella Typhi or Paratyphi human challenge studies were conducted between 2011 and 2017. Participants were either unvaccinated or vaccinated with 1 of 4 vaccines: Vi-polysaccharide (Vi-PS), Vi-tetanus-toxoid conjugate vaccine (Vi-TT), live oral Ty21a vaccine, or an experimental vaccine (M01ZH09). Daily stool cultures were collected for 14 days after challenge. RESULTS: There were 4934 stool samples collected from 430 volunteers. Participants who received Vi-PS or Vi-TT shed less than unvaccinated participants (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.15-0.77; P = .010 and OR, 0.41; 95% CI, 0.19-0.91, P = .029 for Vi-PS and Vi-TT, respectively). Higher anti-Vi immunoglobulin G titers were associated with less shedding of S. Typhi (P < .0001). A nonsignificant reduction in shedding was associated with Ty21a vaccine (OR, 0.57; 95% CI, 0.27-1.20; P = .140). Individuals previously exposed to S. Typhi shed less than previously unexposed individuals (OR, 0.30; 95% CI, 0.1-0.8; P = .016). Shedding of S. Typhi was more common than S. Paratyphi. CONCLUSIONS: Prior vaccination with Vi vaccines, or natural infection, reduces onward transmission of S. Typhi. Field trials of Vi-TT should be designed to detect indirect protection, reflecting the consequence of reduced stool shedding observed in the human challenge model.

Epidemiology of Typhoid and Paratyphoid: Implications for Vaccine Policy.

BACKGROUND: Typhoid and paratyphoid remain the most common bloodstream infections in many resource-poor settings. The World Health Organization recommends typhoid conjugate vaccines for country-specific introduction, but questions regarding typhoid and paratyphoid epidemiology persist, especially regarding their severity in young children. METHODS: We conducted enteric fever surveillance in Bangladesh from 2004 through 2016 in the inpatient departments of 2 pediatric hospitals and the outpatient departments of 1 pediatric hospital and 1 private consultation clinic. Blood cultures were conducted at the discretion of the treating physicians; cases of culture-confirmed typhoid/paratyphoid were included. Hospitalizations and durations of hospitalizations were used as proxies for severity in children <12 years old. RESULTS: We identified 7072 typhoid and 1810 paratyphoid culture-confirmed cases. There was no increasing trend in the proportion of paratyphoid over the 13 years. The median age in the typhoid cases was 60 months, and 15% of the cases occurred in children <24 months old. The median age of the paratyphoid cases was significantly higher, at 90 months (P < .001); 9.4% were in children <24 months old. The proportion of children (<12 years old) hospitalized with typhoid and paratyphoid (32% and 21%, respectively) decreased with age; there was no significant difference in durations of hospitalizations between age groups. However, children with typhoid were hospitalized for longer than those with paratyphoid. CONCLUSIONS: Typhoid and paratyphoid fever are common in Dhaka, including among children under 2 years old, who have equivalent disease severity as older children. Early immunization with typhoid conjugate vaccines could avert substantial morbidity, but broader efforts are required to reduce the paratyphoid burden.

Typhoid and the Military in the Early 20th Century.

BACKGROUND: In the decades following the discovery of the bacillus causing typhoid, in 1880, understanding of the disease formerly known as enteric fever was transformed, offering new possibilities for prevention. Gradually, measures that aimed to prevent infection from human carriers were developed, as were inoculations designed to confer immunity against typhoid and paratyphoid fevers. These were initially introduced in European armies that were regularly ravaged by typhoid, especially garrisons stationed in the colonies. This article reviews the research undertaken in the armed forces and the measures that they implemented in the years up to and during the First World War. METHODS: The article is based on an analytical review of scientific literature from the early 19th century, focusing on the United Kingdom, Germany, and France. RESULTS: The armies of the United Kingdom, Germany, and France undertook important work on the transmission of typhoid in the years between 1890 and 1918. Many preventive measures were introduced to deal with the spread of typhoid but these varied between the 3 countries, depending largely on their political traditions. Inoculation was particularly successful in preventing typhoid and greatly reduced the number of casualties from this disease during the First World War. Despite this, it proved difficult to prevent paratyphoid infection, and debates continued over which vaccines to use and whether or not immunization should be voluntary. CONCLUSIONS: By the end of the First World War, the value of inoculation in preventing the spread of typhoid had been proven. Its successful implementation demonstrates the importance of vaccination as a public health intervention during times of conflict and social upheaval.

Cell mediated immune responses elicited in volunteers following immunization with candidate live oral Salmonella enterica serovar Paratyphi A attenuated vaccine strain CVD 1902.

The incidence of Salmonella enterica serovar Paratyphi A (PA) infection is on the rise and no licensed vaccines are available. We evaluated cell mediated immune (CMI) responses elicited in volunteers following immunization with a single dose (109 or 1010 cfu) of a novel attenuated live oral PA-vaccine strain (CVD 1902). Results showed increases in PA-lipopolysaccharide-specific IgG- and/or IgA B-memory cells and production of IFN-γ, TNF-α, IL-10, IL-23 and RANTES following stimulation with PA-antigens by peripheral blood mononuclear cells obtained 28 days post immunization. Flow cytometry assays revealed that vaccine elicited PA-specific CD8+ and/or CD4+ T effector/memory cells were predominantly multifunctional concomitantly expressing CD107a and/or producing IFN-γ, TNF-α and/or IL-2. Similar proportions of these MF cells expressed, or not, the gut homing marker integrin α4ß7. The results suggest that immunization with CVD 1902 elicits CMI responses against PA supporting its further evaluation as a potential vaccine candidate against paratyphoid A fever.

Characterization and protective efficacy of a Salmonella pathogenicity island 2 (SPI2) mutant of Salmonella Paratyphi A.

Paratyphoid fever caused by Salmonella Paratyphi A is a serious public health problem in many countries. In order to and develop a live attenuated candidate vaccine of Salmonella Paratyphi A, a Salmonella pathogenicity island 2 (SPI2, approximate 40 kb) deletion mutant of Salmonella Paratyphi A was constructed by lambda Red recombination, then the biological characteristics and protective ability of the Salmonella Paratyphi A SPI2 mutant were evaluated. Our results showed that the growth and biochemical properties of the SPI2 mutant were consistent with that of its parent strain, and the mutant was stable with the loss of SPI2. The mice lethal test showed that the virulence of the SPI2 mutant was significantly decreased, it can colonize and persistent more than 14 days in the liver and spleen of mice. Vaccination with the SPI2 mutant in mice revealed no significant effect on body weight and clinical symptoms compared to control animals, and specific humoral and cellular immune responses were also significantly induced. Immunization of mice offered efficient protection against Salmonella Paratyphi A strain challenge at 14 days post vaccination based on mortality and clinical symptoms relative to control group. Overall, these findings suggested that SPI2 plays an important role in pathogenicity of Salmonella Paratyphi A, and the SPI2 mutant showed its potential to develop a live attenuated vaccine candidate.

Typhoid and paratyphoid fever: a call to action.

PURPOSE OF REVIEW: Enteric fever remains a major global-health concern, estimated to be responsible for between 11.9 and 26.9 million cases annually. Long-term prevention of enteric fever will require improved access to safe drinking water combined with investment in sanitation and hygiene interventions. In the short-to-medium term, new control strategies for typhoid fever have arrived in the form of typhoid Vi-conjugate vaccines (TCVs), offering hope that disease control can be achieved in the near future. RECENT FINDINGS: The diagnosis of enteric fever is complicated by its nonspecific clinical presentation, coupled with the low sensitivity of commonly used diagnostics. Investment in diagnostics has the potential to improve management, to refine estimates of disease burden and to facilitate vaccine impact studies. A new generation of reliable, diagnostic tests is needed that are simultaneously accessible, cost-effective, sensitive, and specific. The emergence and global dissemination of multidrug-resistant, fluoroquinolone-resistant, and extensively drug-resistant (XDR) strains of Salmonella Typhi emphasizes the importance of continued surveillance and appropriate antibiotic stewardship, integrated into a global strategy to address antimicrobial resistance (AMR). Current empirical treatment guidelines are out of date and should be updated to respond to local trends in AMR, so as to guide treatment choices in the absence of robust diagnostics and laboratory facilities. In September 2017, the WHO Strategic Advisory Group of Experts (SAGE) immunization recommended the programmatic use of TCVs in high burden countries. Ongoing and future studies should aim to study the impact of these vaccines in a diverse range of setting and to support the deployment of TCVs in high-burden countries. SUMMARY: The advent of new generation TCVs offers us a practical and affordable public-health tool that - for the first time - can be integrated into routine childhood immunization programmes. In this review, we advocate for the deployment of TCVs in line with WHO recommendations, to improve child health and limit the spread of antibiotic-resistant S. Typhi.

Overview of the impact of Typhoid and Paratyphoid fever. Utility of Ty21a vaccine (Vivotif®).

Cases of diarrhoeal disease number from 1.7 to 5 billion per year worldwide. One of the main causes of diarrhoeal disease is typhoid fever, which is a potentially life-threatening multi-systemic illness. According to the most recent estimates, a total of 26.9 million typhoid fever episodes occurred in 2010. The geographical distribution of the disease differs widely; in developed countries, the incidence rate per 100,000 per year varies from < 0.1 to 0.3, and the disease mainly affects people who travel to endemic areas located in low- and middle-income countries. Low- and middle-income countries are mainly affected owing to the lack of clean water and proper sanitation. In the fight against this plague, prevention is fundamental, and vaccination against typhoid is an effective measure. Vivotif® is an oral live attenuated vaccine which contains a mutated strain of Salmonella (Ty21a) and reproduces the natural infection. The vaccine was first licensed in Europe in 1983 and in the US in 1989, and over the years it has proved efficacious and safe. It is indicated for adults and children from 5 years of age upwards. Specifically, in the most developed countries, vaccination is suggested for highrisk population groups and particularly for international travellers to destinations where the risk of contracting typhoid fever is high. It must also be borne in mind that international travel is increasing. Indeed, international tourist arrivals totalled 1,184 million in 2015 and, on the basis of current trends, international travel is expected to grow by 3-4% in 2017. Vivotif® appears to be a powerful means of disease prevention, the importance of which is highlighted by the spread of antibiotic-resistant strains of Salmonella typhy (S. typhi).

Typhoid fever.

Control of typhoid fever relies on clinical information, diagnosis, and an understanding for the epidemiology of the disease. Despite the breadth of work done so far, much is not known about the biology of this human-adapted bacterial pathogen and the complexity of the disease in endemic areas, especially those in Africa. The main barriers to control are vaccines that are not immunogenic in very young children and the development of multidrug resistance, which threatens efficacy of antimicrobial chemotherapy. Clinicians, microbiologists, and epidemiologists worldwide need to be familiar with shifting trends in enteric fever. This knowledge is crucial, both to control the disease and to manage cases. Additionally, salmonella serovars that cause human infection can change over time and location. In areas of Asia, multidrug-resistant Salmonella enterica serovar Typhi (S Typhi) has been the main cause of enteric fever, but now S Typhi is being displaced by infections with drug-resistant S enterica serovar Paratyphi A. New conjugate vaccines are imminent and new treatments have been promised, but the engagement of local medical and public health institutions in endemic areas is needed to allow surveillance and to implement control measures.

Construction of an attenuated Salmonella enterica serovar Paratyphi A vaccine strain harboring defined mutations in htrA and yncD.

The global epidemic features of enteric fever have changed greatly in recent years. The incidence of enteric fever caused by Salmonella enterica serovar Paratyphi A has progressively increased. In some areas of Asia, infections with S. Paratyphi A have exceeded those with S. Typhi, resulting in S. Paratyphi A becoming the main causative agent of enteric fever. However, two currently licensed typhoid vaccines do not confer adequate cross-protection against S. Paratyphi A infection. Therefore, development of specific vaccines against enteric fever caused by S. Paratyphi A is urgently needed. In the present study, an attenuated strain was constructed by double deletion of the htrA and yncD genes in a wild-type strain of S. Paratyphi A and its safety and immunogenicity assessed. In a mouse model, the 50% lethal dose of the double deletion mutant and the wild-type strain were 3.0 × 10(8) CFU and 1.9 × 10(3) CFU, respectively, suggesting that the double deletion resulted in remarkably decreased bacterial virulence. Bacterial colonization of the double deletion mutant in the livers and spleens of infected mice was strikingly less than that of the wild-type strain. A single nasal administration of the attenuated vaccine candidate elicited high concentrations of anti-LPS and anti-flagellin IgG in a mouse model and protected immunized mice against lethal challenge with the wild-type strain. Thus, our findings suggest that the attenuated vaccine strain is a promising candidate worthy of further evaluation both as a human enteric fever vaccine and as a vaccine delivery vector for heterologous antigens.

Cross-reactive immune response induced by the Vi capsular polysaccharide typhoid vaccine against Salmonella Paratyphi strains.

There are no vaccines in clinical use against paratyphoid fever, caused by Salmonella Paratyphi A and B or, rarely, C. Oral Salmonella Typhi Ty21a typhoid vaccine elicits a significant cross-reactive immune response against S. Paratyphi A and B, and some reports suggest cross-protective efficacy against the disease. These findings are ascribed to the O-12 antigen shared between the strains. The Vi capsular polysaccharide vaccine has been shown to elicit antibodies reactive with O-9,12. Twenty-five volunteers immunized with the parenteral Vi vaccine (Typherix(®) ) were explored for plasmablasts cross-reactive with paratyphoid strains; the responses were compared to those in 25 age- and gender-matched volunteers immunized with Ty21a (Vivotif(®) ). Before vaccination, 48/50 vaccinees had no plasmablasts reactive with the antigens. Seven days after vaccination, 15/25 and 22/25 Vi- and Ty21a-vaccinated volunteers had circulating plasmablasts producing antibodies cross-reactive with S. Paratyphi A, 18/25 and 23/25 with S. Paratyphi B and 16/25 and 9/25 with Paratyphi C, respectively. Compared to the Ty21a group, the Vi group showed significantly lower responses to S. Paratyphi A and B and higher to S. Paratyphi C. To conclude, the Vi vaccine elicited a cross-reactive plasmablast response to S. Paratyphi C (Vi antigen in common) and less marked responses to S. Paratyphi A and B than the Ty21a preparation. S. Paratyphi A and B both being Vi-negative, the result can be explained by trace amounts of bacterial cell wall O-12 antigen in the Vi preparation, despite purification. The clinical significance of this finding remains to be determined.

Typhoid epidemiology, diagnostics and the human challenge model.

PURPOSE OF REVIEW: Infection caused by ingestion of human-restricted Salmonella enterica serovars Typhi and Paratyphi predominantly affects the most impoverished sections of society. In this review, we describe recent advances made in estimating the burden of illness and the important role improved diagnostic tests may have in controlling infection and report the development of a new human challenge model of typhoid infection. RECENT FINDINGS: Typhoid continues to be a major cause of morbidity, particularly in children and young adults in south east Asia, although accurate assessments are still hindered by the lack of reliable surveillance data. Recent reports of high rates of infection in Africa and the dominance of paratyphoid in several geographic areas are of particular concern. Diagnosis of enteric fever remains frustrated by the nonspecific clinical presentation of cases and the lack of test sensitivity. Methods to improve diagnostic accuracy are hindered by the incomplete understanding of immunobiological mechanisms of infection and lack of a suitable animal infection model. SUMMARY: Enteric fever is a major global problem, the burden of which has only partially been recognized. Control strategies utilizing cheap accurate diagnostics and effective vaccines are urgently required, and their development should be accelerated by the use of a human challenge model.