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Typhoid Fever

Diarrhoeal Diseases Introduction Caliciviruses Campylobacter Cholera Enterotoxigenic Escherichia coli (ETEC) Rotavirus Shigellosis Typhoid Fever

Disease Burden

Typhoid fever is caused by Salmonella typhi, the typhoid bacillus. It is characterized by the sudden onset of sustained fever, severe headache, nausea, loss of appetite, constipation or sometimes diarrhoea. Severe forms have been described with mental dullness and meningitis. Case-fatality rates of 10% can be reduced to less than 1% with appropriate antibiotic therapy. However, strains resistant to chloramphenicol and other recommended antibiotics (ampicillin, cotrimoxazole and even ciprofloxacin) have become prevalent in several areas of the world. Paratyphoid fever can be caused by any of three serotypes of S. paratyphi A, B and C. It is similar in its symptoms to typhoid fever, but tends to be milder, with a lower fatality rate.

Typhoid fever remains a serious public health problem throughout the world, with an estimated 16–33 million cases and 500 000 to 600 000 deaths annually. In the last outbreak in the Democratic Republic of Congo, between 27 September 2004 and early January 2005, no less than 42 564 cases of typhoid fever were reported, including 214 deaths and 696 cases of peritonitis and intestinal perforations. In virtually all endemic areas, the incidence of typhoid fever is highest in children from 5–19 years old. The disease is almost exclusively transmitted by food and water contaminated by the faeces and urine of patients and carriers. Polluted water is the most common source of typhoid transmission. In addition, shellfish taken from sewage-contaminated beds, vegetables fertilized with night-soil and eaten raw, contaminated milk and milk products have been shown to be a source of infection. Typhoid fever has been virtually eliminated in most areas of the industrialized world with the advent of proper sanitary facilities. Most cases in developed countries are imported from endemic countries. People can transmit the disease as long as the bacteria remain in their body; most people are infectious prior to and during the first week of convalescence, but 10% of untreated patients will discharge bacteria for up to 3 months. In addition, 2–5% of untreated patients will become permanent, lifelong carriers of the bacteria in their gall-bladder.

S. paratyphi is becoming predominant in some provinces in China and increasing numbers of cases are being reported from Pakistan.

Bacteriology

Taxonomy within the genus Salmonella has been the source of great confusion. The most recent classification, based on DNA sequences, has left only two species, S. enteritica and S. bongori, further subdivided into subspecies and serovars. To avoid confusion, S. enteritica serovar Typhi continues to be referred to as S. typhi. The bacteria is characterized by its flagellar antigen, H, its lipopolysaccharidic O antigen, and, in addition, its PS capsular Vi (for virulence) antigen, found at the surface of freshly isolated strains. The complete sequence of the 4,809 037-bp genome has been determined. In addition to the plasmid encoding antibiotic resistance, a virulence plasmid was found that shows homology with the virulence plasmid of Yersinia pestis.

Upon ingestion, typhoid bacilli rapidly penetrate the small intestinal mucosa by transcytosis through M cells and enterocytes, and are taken up by macrophages or diffuse into mesenteric lymph nodes. A primary bacteraemia follows and the pathogen rapidly attains intracellular haven throughout the reticuloendothelial system. This is followed by a sustained secondary bacteraemia asssociated with clinical illness. S. typhi also shows remarkable predilection for the gall-bladder, where infection tends to become chronic especially in individuals with a pathologic gall-bladder condition.

Vaccine

Heat-killed, phenol preserved whole-cell S. typhi were utilized as parenteral vaccines as far back as 1896 in England and Germany, and still are licensed today in many countries in spite of their high reactogenicity.

The attenuated S. typhi strain Ty21a was generated in Switzerland by chemical mutagenesis of wild-type strain Ty2 and developed as the first live oral typhoid fever vaccine. The strain is characterized as lacking both a functional galactose-epimerase (galE) gene and the Vi antigen, although other mutations in the genome probably are responsible for the attenuated phenotype. The Ty21a vaccine is presented in the form of phtallate-coated gelatin capsules containing 2 to 6 x 10E9 cfu of Ty21a to be swallowed every other day for one week. It can be taken simultaneously with the attenuated CVD103-HgR V. cholerae vaccine. Ty21a is licensed in 56 countries in Africa, the Americas Asia and Europe.

A subunit S. typhi polysaccharide (PS) vaccine was developed in the 1980s in the laboratory of John Robbins at the NIH and licensed to Sanofi-Pasteur. The vaccine is based on purified Vi antigen, a linear homopolymer of galacturonic acid that is purified from the bacteria by treatment with Cetavlon, the detergent used for the preparation of the meningococcal PS vaccine. The vaccine elicits serum anti-Vi antibodies in approximately 85–95% of adults and children above two years of age after a single parenteral injection of a 25 µg dose of purified PS. The lack of immunogenicity in younger children has prompted the development of a conjugate Vi vaccine using Pseudomonas aeruginosa exotoxin A as a carrier. The Vi vaccine has shown 72–77% efficacy in trials in Nepal and South Africa, and is now licensed in more than 92 countries in the five continents. The Vi conjugate vaccine has shown a 91.5% protection rate in a large-scale randomized, 2-dose controlled trial in 2–5 year-old children in Viet Nam and Cambodia, and a 88% protection rate at 16 months.

A head-to-head comparison of the Ty21a and Vi vaccines has been proposed by WHO in order to make future recommendations for countries severely affected by typhoid.

Among several other new attenuated S. typhi strains that could be used as live oral vaccines, three are currently at an advanced clinical stage of development.

• The Ty800 live attenuated oral vaccine, a phoP/ phoQ deletion mutant of Ty2, has been shown to stimulate vigorous IgA and serum O antibody responses in Phase I trials (Avant Immunotherapeutics).
• The CVD908-htrA live attenuated oral vaccine, an aroC/ aroD/ htrA deletion mutant, has successfully been tested in Phase II trials. Its Vi+ derivative, CVD909, which constitutively expresses the Vi antigen, has now completed Phase I testing (Acambis/Berna).
• An attenuated S. typhi strain has been developed by Microscience (USA) as a live vector (spi-VEC) for oral vaccines.

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