The International Conference on Typhoid Fever and Other Salmonelloses is organized every two to three years and has usually taken place in Asia. The first meeting was held in Malaysia 15 years ago. The 6th international meeting, held in Guilin, China, in November 2005, was organized by the Guangxi Centre for Disease Prevention and Control, in collaboration with the World Health Organization (WHO), the International Vaccine Institute (IVI), and the American Society for Microbiology (ASM). Two hundred fifty participants from 27 countries, including Africa, participated. Nine sessions covering the major topics of interest provided the latest updated information on typhoid fever. These include: Epidemiology and disease burden; Molecular pathogenesis and genomics; Contemporary issues in vaccine development; Diagnostics in typhoid fever; Antimicrobial resistance in typhoid fever; Clinical and therapeutic aspects; Socio-behavioural research; Other salmonelloses-related contemporary issues; and a Roundtable on Expanding Vaccine Implementation in Developing Countries. Travel grants for participants from developing countries were supported by the WHO, IVI, and the ASM, and by the Conference Organizing Committee. Epidemiology and disease burden During the epidemiology session, general consensus was raised that typhoid fever remains an important, but under-estimated, disease which has high mortality in developing countries, particularly in Asia. However, there are extremely limited data from Africa, and the burden of disease is probably under-estimated in this region. Endemic disease in South-East Asia is observed to be high, although it varies greatly in different settings. In addition, disease in the paediatric population was higher than previously recognized. The latest published figure for the estimated number of cases is approximately 22 million per year, with an estimated 210,000 deaths (1). This number of deaths was calculated from a conservative figure using a case-fatality rate (CFR) of 1%. However, the reported CFR from presentations during the meeting was generally much higher than this in different studies, with the general agreement that this 1% estimate was under-estimated and that additional robust studies are required. It was suggested that WHO should convene a consultative meeting to resolve this during 2006. Second, the increasing number of Salmonella Paratyphi A isolates recovered in Asia, particularly in China and Pakistan, was noted with concern. In Guingxi province of China, 94% of Salmonella isolates are currently S. Paratyphi A. This situation raised the point of accelerating the development of S. Paratyphi A vaccine candidates. Molecular pathogenesis and genomics Developments in molecular pathogenesis and genomics highlighted the difficulties that surround the serotyping of Salmonella species and the classification of Salmonella strains. The full genome sequence of Salmonella strains indicates that the S. Typhi and S. Paratyphi A have a recent evolutionary history. Using this sequence data, a novel system based on multi-locus sequences typing (MLST) has been devised which should help type Salmonella strains in a more precise approach and could replace classical serotyping in future. New data from Viet Nam showed that a haplotype of the TNF region was associated with fever-clearance time in patients. Individuals who have the protective haplotype (*12*22**1) cleared their fever significantly faster than individuals who did not have this haplotype. Better understanding of the organization of Salmonella pathogenicity islands and diversity of Typhi flagellar antigen expression were presented. Finally, it was recommended that further research was required on (a) S. Typhimurium in Africa, (b) paediatric versus adult strains of S. Typhi, and (c) molecular epidemiology of outbreaks versus endemic strains. Contemporary issues in vaccine development Besides the currently-licensed and available vaccines (Vi polyssacharide and Ty21a), other candidate vaccines, consisting of either subunit vaccine or live-attenuated vaccines, were described. …

Objectives: To report results on coverage, safety and logistics of a large-scale, school-based Vi polysaccharide immunization campaign in North Jakarta.Methods: Of 443 primary schools in North Jakarta, Indonesia, 18 public schools were randomly selected for this study. Exclusion criteria were fever 37.5 degrees C or higher at the time of vaccination or a known history of hypersensitivity to any vaccine. Adverse events were monitored and recorded for 1 month after immunization. Because this was a pilot programme, resource use was tracked in detail.Results: During the February 2004 vaccination campaign, 4828 students were immunized (91% of the target population); another 394 students (7%) were vaccinated during mop-up programmes. Informed consent was obtained for 98% of the target population. In all, 34 adverse events were reported, corresponding to seven events per 1000 doses injected; none was serious. The manufacturer recommended cold chain was maintained throughout the programme.Conclusions: This demonstration project in two sub-districts of North Jakarta shows that a large-scale, school-based typhoid fever Vi polysaccharide vaccination campaign is logistically feasible, safe and minimally disruptive to regular school activities, when used in the context of an existing successful immunization platform. The project had high parental acceptance. Nonetheless, policy-relevant questions still need to be answered before implementing a widespread Vi polysaccharide vaccine programme in Indonesia. (c) 2006 The Royal Institute of Public Health. Published by Elsevier Ltd. All rights reserved.

Phase-III vaccine efficacy trials typically employ individually randomized designs intended to ensure that measurements of vaccine protective efficacy reflect only direct vaccine effects. As a result, decisions about introducing newly licensed vaccines into public health programmes often fail to consider the substantially greater protection that may occur when a vaccine is deployed in public health programmes, due to the combination of direct plus indirect vaccine protective effects. Vaccine total protection can be better evaluated with cluster randomized trials. Such a design was considered to generate policy relevant data to accelerate the rationale introduction of the licensed typhoid fever Vi polysaccharide (PS) vaccine in Asia by the Diseases of the Most Impoverished (DOMI) typhoid fever programme. The DOMI's programme multi-country study is one of the largest cluster randomized vaccine trials ever mounted in Asia, which includes approximately 200,000 individuals. Its main objective is to determine the effectiveness of a licensed Vi PS vaccine. The rationale and design of this study are discussed. Preliminary results are presented that determined the final planning of the trial before immunization. Important methodological and practical issues regarding vaccine cluster randomized designs are illustrated.

For 5 years, we have conducted sentinel surveillance for rotavirus at 6 hospitals in 4 cities in Vietnam. Stool samples obtained from >10,000 children <5 years old who were admitted to the hospital with diarrhea have been screened for rotavirus. Overall, 55% of samples were positive, and there was little variability in rates of detection of rotavirus between sites (44%-62%). In Vietnam, the characteristics of rotavirus infection more closely resemble those seen in developed countries, rather than those seen in developing countries: children become infected at an older age, the percentage of stool samples in which rotavirus is detected is extremely high, and the rotavirus strains appear to be the common types, with fewer mixed infections occurring. It is estimated that 5300-6800 children <5 years old die of rotavirus infection each year in Vietnam, representing 8%-11% of all deaths in this age group (cumulative risk per child by age 5 years, 1 in 200 to 1 in 285). Additional studies are ongoing to document the economic cost of the disease and to assess the burden of both fatal cases and milder cases of disease. Study outcomes will provide information for future testing and potential use of a rotavirus vaccine.

OBJECTIVE:To study the epidemiological status on rotavirus diarrhea in Kunming to improve the rotavirus vaccine immunization program. METHODS:A hospital-based sentinel surveillance program for rotavirus was set up among children less than 5 years old with acute diarrhea in Kunming Children's Hospital. Clinical information and fecal specimens were collected and rotavirus were detected by polyacrylamide gel electrophoresis (PAGE) and/or enzyme linked immunosorbent assay (ELISA). Positive specimens were further serotyped or genotyped by ELISA and/or RT-PCR. RESULTS:During the three years of surveillance, 466 specimens were collected. Rotavirus were detected on 246 (52.8%) specimens. 97% of the rotavirus diarrhea cases occurred among children less than 2 years old. There was a peak of admissions for rotavirus diarrhea cases between October and December which accounted for 48% of all the rotavirus hospitalizations each year. Among 204 specimens with G serotyping, the predominant strain was serotype G1 (47.5%) followed by G2 (17.6%), G3 (15.7%), G9 (4.9%) and G4 (1.0%). Mixed infection (2.5%) were rare and 22 specimens (10.8%) remained non-typeable. P genotyping showed P[4], P[8] and P[6] were the most common strains, accounting for 29.3%, 27.6% and 13.8% respectively. P[4]G2 was the most common strain which accounted for 34.1% (14/41) followed by P[8]G1 (29.3%) and P[6]G9 (12.2%). Another 7 uncommon P-G combinations were also identified. CONCLUSION:Rotavirus was the major cause of acute diarrhea in Kunming. An effective rotavirus vaccine for prevention and control of rotavirus diarrhea should be developed.

Despite the availability of at least two licensed typhoid fever vaccines--injectable sub-unit Vi polysaccharide vaccine and live, oral Ty21a vaccine--for the last decade, these vaccines have not been widely introduced in public-health programmes in countries endemic for typhoid fever. The goal of the multidisciplinary DOMI (Diseases of the Most Impoverished) typhoid fever programme is to generate policy-relevant data to support public decision-making regarding the introduction of Vi polysaccharide typhoid fever immunization programmes in China, Viet Nam, Pakistan, India, Bangladesh, and Indonesia. Through epidemiological studies, the DOMI Programme is generating these data and is offering a model for the accelerated, rational introduction of new vaccines into health programmes in low-income countries. Practical and specific examples of the role of epidemiology are described in this paper. These examples cover: (a) selection of available typhoid fever vaccines to be introduced in the programme, (b) generation of policy-relevant data, (c) providing the 'backbone' for the implementation of other multidisciplinary projects, and (d) generation of unexpected but useful information relevant for the introduction of vaccines. Epidemiological studies contribute to all stages of development of vaccine evaluation and introduction.

OBJECTIVETo establish baseline patterns of rotavirus diarrhea and to describe its epidemiologic features in Changchun city, prior to rotavirus vaccine immunization.METHODSHospital-based surveillance was conducted among children under 5 years old with acute diarrhea in Changchun Children's Hospital. Fecal samples were determined to identify rotavirus by PAGE and/or ELISA. G serotypes of rotavirus were identified by ELISA and/or nested RT-PCR. P genotyping were carried out by RT-PCR. All data were computerized and analysed by "Generic Manual on Rotavirus Surveillance" set by CDC in the USA.RESULTSIn total, 2 343 diarrhea cases were screened and 1 211 fecal samples were collected. Rotavirus was detected in 31.0% among outpatients and 52.9% in inpatients. During the peak of the season (November through March), 58.6% of diarrhea was caused by rotavirus among inpatients. 95.0% of rotavirus diarrhea cases occurred among children aged < 2 years. The predominant strain was serotype G1 (82.4%), followed by G2 (5.0%), G3 (3.3%), G4 (0.9%). P genotyping showed that P[8] and P[4] were the most common ones. Nine different P-G combinations were identified, four strains (P[8]G1, P[4]G2, P[8]G3, and P[8]G4) commonly seen worldwide accounted for 75.6% of the total. Taken together with uncommon strains, including the novel types P[4]G4 and P[8]G2, it highlights the extraordinary diversity of rotaviruses circulating in China.CONCLUSIONRotavirus is the major cause of severe child diarrhea in Changchun. Developing a rotavirus vaccine for prevention of severe disease and reduction of treatment costs seemed to be necessary.

OBJECTIVE:To provide information on epidemiology of rotavirus infection in Beijing, China.METHODS:An ongoing hospital-based surveillance was conducted among children < 5yr old with acute diarrhea according to WHO generic protocol (CID-98). During a 3-year study (Apr. 1998 to Mar. 2001), a total of 484 stool samples were collected from 1 457 patients, including 275 samples from 1 048 outpatients and 209 samples from 409 inpatients.RESULTS:The overall detection rate of rotavirus infection was 25.4%. Rotavirus was responsible for 27.3% of diarrhea inpatients on a yearly base, and 46.2% during rotavirus season. Two peaks of diarrhea were observed each year, one in the summer (June-Sep.) due to bacterial dysentery (16.7%) and another in fall winter (Oct.-Dec.) due to rotavirus infection (23.0%). The detection rate on rotavirus was the highest in age group of 6 - 11 months (38.2%), followed by 1 - 2 years old (28.5%). Ninety six point eight percentage of children were infected under 3 years of age. The number of deaths, possibly caused by rotavirus diarrhea were accounted for 40% of all diarrhea deaths and 11.1% of the total deaths. Serotyping of 123 rotavirus isolates showed that serotype G1 (55.3%) was predominant, followed by G2 (26.8%), G3 (9.8%), G4 (0.8%), and 10 isolates (8.1%) remained non-typeable. Mixed infections (0.8%) seemed to be rare.CONCLUSION:Rotavirus diarrhea was an important infectious disease among children in Beijing. Safe and effective rotavirus vaccines for the prevention of severe diarrheas and the reduction of treatment costs are of significant importance to China.

ABSTRACT As part of a national rotavirus surveillance activity, we collected fecal specimens from 3,177 children with acute diarrhea in 10 regions of China between April 1998 and April 2000 and screened them for rotavirus. Rotavirus was detected in 41% ( n = 1,305) of specimens, and in these, G1 was the predominant serotype (72.6%), followed by G3 (14.2%), G2 (12.1%), G4 (2.5%), G9 (0.9%), and G untypeable (0.7%). Among 327 G-typed strains tested for P genotype, 14 different P-G combinations were identified, with the globally common strains P[8]G1, P[4]G2, P[8]G3, and P[8]G4 representing 75.6% of all typed rotavirus strains. Among the uncommon strains, 11 were P[6]G9, and others included P[6]G1, P[6]G3, and five novel P-G combinations (P[9]G1, P[4]G1, P[4]G3, P[4]G4, and P[8]G2). Our results indicate that while the common rotavirus strains remain predominant, the diversity of strains is much greater than was previously recognized.

Objective To evaluate a killed oral cholera vaccine produced in Viet Nam, and to compare the Vietnamese vaccine with one that is licensed internationally.Method Two-dose regimens of a locally produced, bivalent, anti-O1, anti-O139 killed oral whole-cell cholera vaccine (biv-WC) and of a commercially available, monovalent (anti-O1) oral recombinant B subunit-killed whole-cell cholera vaccine (rBS-WC) were compared in two trials in Viet Nam. In the first trial, 144 adults were randomized to biv-WC with or without buffer, rBS-WC with buffer, or placebo without buffer, In the second, 103 children aged 1-12 years were randomized to biv-WC without buffer, rBS-WC with buffer, or placebo without buffer.Findings No regimen was associated with significant side-effects. In adults, ca 60% of recipients of either vaccine exhibited at least fourfold serum anti-O1 vibriocidal antibody responses and ca 40% of recipients of biv-WC demonstrated anti-O139 vibriocidal responses, Both anti-O1 (ca 90% in each vaccine group and anti-O139 (68% in the biv-WC group) vibriocidal responses occurred more frequently in children, The responses to biv-WC were unaffected by the receipt of buffer.Conclusion It was concluded that biv-WC was safe and immunogenic, that it could be administered without buffer, and that it could elicit robust immune responses even in children, for whom the risk of endemic cholera is highest.

The disease burden of rotavirus diarrhea in Vietnam was assessed by surveillance of children <5 years old who were hospitalized for diarrhea at 3 centers in the north and 3 centers in the south. Rotavirus was identified in 56% (range, 47%-60%) of the 5768 patients surveyed between July 1998 and June 2000. G-typing of the first 224 strains indicated that only 2% were non-typeable, 9% were in mixed infections, and the remainder were of the common serotypes G1, G2, G3, G4, and G9. In Vietnam, diarrhea accounts for 9880 deaths per year, which is approximately 15% of all deaths among children <5 years old, or 6.5 deaths per 1000 children. If even 50% of these diarrhea-related deaths in Vietnam were due to rotavirus, the number would represent 4%-8% of all deaths among children <5 years old, 2700-5400 rotavirus-related deaths per year, and 1 death per 280-560 children during the first 5 years of life. Thus, the disease burden of rotavirus in Vietnam is substantial, and programs to encourage the use of oral rehydration should be encouraged while efforts to develop vaccines continue.

Policy decisions regarding whether to incorporate new vaccines into routine public health practice in developing countries will depend in part on the costs of vaccine purchase and of vaccine delivery. In March, 1997, a large-scale effectiveness trial of a locally produced, orally administered bivalent vaccine against Vibrio cholerae 01 and 0139 began in Viet Nam. Empirical data obtained from the trial was used to determine the costs of the immunization campaign from the government perspective. The study population, including the children less than one year of age and pregnant women who were ineligible for immunization, was 353926. A total of 289041 persons received two doses of vaccine, and 13340 persons received one dose of vaccine. Two-dose vaccine coverage was 83.4%. The total cost of vaccine delivery during the immunization campaign was $66527. The cost of each dose of vaccine was $0.31. Therefore, the total cost of the immunization campaign was $0.44 per dose administered, and $0.91 per fully immunized person. Attempts to reduce the cost per dose of vaccine (e.g. the use of a monovalent vaccine against serogroup 01) are likely to have a large impact on the cost of future similar immunization campaigns.

The WHO Vaccine Trial Registry prospectively registers clinical vaccine studies supported by WHO. Through December 1999, the registry includes 103 studies from 43 countries, with nearly 80% in developing countries. The registry documents an expanding research capacity, with an average of 3.9 new studies per year during 1987–1993, rising to 10.7 per year during 1994–2000. The studies concern a broad spectrum of infectious organisms, including: Clostridium tetani (tetanus), dengue virus, enterotoxigenic Escherichia coli (ETEC), Haemophilus influenzae type b (Hib), hepatitis B virus, measles virus, Mycobacterium tuberculosis, Neisseria meningitidis (meningococcus), poliovirus, respiratory syncytial virus (RSV), rotavirus, Salmonella typhi, Shigella, Streptococcus pneumoniae (pneumococcus), and Vibrio cholerae.

A total of 35 volunteers were recruited for an IRB-approved inpatient dose-escalation challenge. The goal was to identify a dose that produced an observed cholera attack rate ≥80% and an illness of sufficient severity during the defined study period such that the model would be useful for determining vaccine protection. Volunteers were challenged in groups of 5 with V. cholerae O139 that had been reconstituted immediately before use. Only 2 out of 5 volunteers who received the lowest dose (4.3×104 cfu) had diarrhea. As the inoculum size increased, the attack rate of diarrhea increased to 3–4 of 5 volunteers. At the highest dose tested, approximately 5×107 cfu, the attack rate was 73%. We recommend the use of frozen V. Cholera O139 in a human experimental challenge model to assess cholera vaccine efficacy (VE) in a cholera endemic area but with 4 days observation period before initiation of tetracycline to allow assessment of severity.

Le but de l'étude est de comparer l'épidémiologie et la sémiologie entre sujets infectés par un seul virus et sujets présentant plus d'un virus dans un même site de prélèvement. Des indicateurs de l'atteinte respiratoire basse ont été recueillis de façon prospective chez 202 nourrissons hospitalisés pour bronchiolite. L'étude des aspirations nasales a comporté une immunofluorescence, une culture virale (CV) et une étude en biologie moléculaire par amplification génique. La recherche de Rotavirus a été effectuée dès l'admission. Une co-infection virale respiratoire est présente chez 55 nourrissons (27 %); 121 (60 %) ont une infection à virus unique; 26 (13 %) n'ont aucun virus respiratoire identifié. Le Rotavirus est présent chez 40 nourrissons (20 %) sans relation statistique avec le portage d'un virus respiratoire. Le virus respiratoire syncytial est le plus souvent retrouvé lors des co-infections virales (46/55); l'association avec l'adénovirus (21/55) est la plus fréquente. II n'existe aucune différence entre les infections monovirales d'une part et multivirales d'autre part en fonction de l'âge, du poids, des pathologies néonatales, de la présence ou non d'une atopie familiale ou personnelle, de la température centrale, du score de Silverman, de l'oxygénodépendance, de la durée d'hospitalisation, des données bactériologiques. En conclusion, une co-infection virale ne paraît pas constituer un facteur de sévérité de la bronchiolite chez les nourrissons immunocompétents.The nature of viral infection was prospectively investigated in 202 immunocompetent infants with bronchiolitis. Nasal aspirates were evaluated by immunofluorescence assay, viral isolation technique and polymerase-chain-reaction-hybridization assay. In 55 infants (27 %) more than one respiratory virus were detected. A Rotavirus was found in 40 infants (20 %), without any relationship with the respiratory viral status, respiratory syncytial virus being the main virus (46/55), and the association of respiratory syncytial virus and adenovirus being the most frequent (21/55). No difference was found between monoviral infections on the one hand and simultaneous viral infections on the other hand according to age, weight, neonatal disease, past history of personal or familial atopy, central temperature, Silverman's index, oxygen dependency, length of hospitalization, microbiology data. There was no indication that simultaneous virus infections were associated with an increased severity of the bronchiolitis in immunocompetent infants.