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Typhoid Fever

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

Introduction

Salmonella infections in humans are divided into typhoid fever caused by S typhi and S paratyphi (see below) and a range of diarrhoeal diseases caused by a large number of non-typhoidal Salmonella serovars (NTS). These NTS, which usually have a broad vertebrate host range, show dramatically more severe and invasive presentation in immunocompromized individuals especially HIV carriers, including severe and progressive diseases such as chronic granulomatosis disease, blockade of IL-12/ IL-23 /IL-17 and TNF, suppurative foci and bacteremia which may be recurrent. Invasive recurrent NTS bacteremia associated with HIV disease is becoming a huge problem worldwide [208].

Typhoid fever (TF) is a more classical systemic infection caused by the typhoid bacillus, Salmonella enteritica serovar Typhi (commonly referred to as S typhi), the most common cause of enteric fever, which also includes paratyphoid fever caused by S paratyphi A, B and C. These pathogens only infect humans. The disease is transmitted by ingestion of food, including dairy products, or water contaminated by excreta from patients or chronic carriers or handled by infected persons [209] [210] . Highest incidence usually occurs where water supplies serving large populations are contaminated by faecal matter, as existed at the end of the 19th century in many large cities in the USA and Western Europe.

Disease Burden

TF is spread by the faecal-oral route and closely associated with poor hygiene, lack of clean drinking water and inadequate sanitation. 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.

Although TF has practically disappeared from industrialized countries, it remains a serious public health problem in several Asian regions of the former USSR and in parts of South and South-East Asia, Africa and South America. 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. Also, multiresistant strains of S typhi are becoming increasingly common worldwide, further compounding the risk to people living in regions with high endemic disease and to travellers [211] [212] . Strains resistant to chloramphenicol and other recommended antibiotics (ampicillin, cotrimoxazole and even ciprofloxacin) have become prevalent in several areas of the world [213].

TF is characterized by the sudden onset of sustained fever, severe headache, nausea, abdominal pains, loss of appetite, constipation or sometimes diarrhoea. The illness can last for several weeks and even months. The most frequent complications, which arise with a frequency of 1% to 4%, include gastro-intestinal bleeding and intestinal perforation. Severe neurological forms also have been described with mental dullness, stupor, delirium and shock. Hospitalization of TF cases varies from 10% to 40% of cases and usually lasts for 10-15 days or more. Case-fatality rates, which varied from 10% to 30% before the advent of antibiotics, has now been reduced to about 1%-4% with appropriate antibiotic therapy [214] . Paratyphoid fever, which is caused by any of three serotypes of S. paratyphi A, B and C, is similar in its symptoms to typhoid fever, but tends to be milder, with a lower fatality rate.

People can transmit TF 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.

The true burden of TF in developing countries is difficult to estimate. According to recent estimates, 22 million (range 16 million - 33 million) cases occur each year causing 216,000 deaths, predominantly in school-age children and young adults [214]. Asia, with 274 cases per 100,000 persons has the highest incidence of TF cases worldwide, especially in Southeast Asian countries and on the Indian subcontinent, followed by sub-Saharan Africa and Latin America with 50 cases per 100,000 persons. In an urban slum in Dhaka, incidence of bacteremic TF was found to be 390/100,000 population, with a 9-fold higher risk for pre-school children than for older persons [215].

Recent prospective population-based disease-surveillance studies supported by the Bill and Melinda Gates Foundation and conducted by the Diseases of the Most Impoverished (DOMI) Program at five sites in China, India, Indonesia, Pakistan and Vietnam revealed high rates of TF among children in urban slums, including children below 5 years of age. In three urban slums in Karachi, Kolkata and North Jakarta, incidence of blood-confirmed TF cases among children 5 to 15 years of age ranged from 180 cases to 494 cases per 100,000 [216].

The introduction of TF vaccines in routine vaccination programs in Asia would be highly beneficial in view of the burden of disease and cost of illness to governments and individuals [217] . But, so far, only two countries, China and Vietnam, have incorporated typhoid vaccination into their routine immunization programs, and only in a limited fashion. The Dehli State, India, also introduced vaccination in 2004 in 2-5 years old children through community-based campaigns. The reason why these efforts have not be more generalized lies in part in the fact that most developing countries are uncertain of their true TF disease burden, due to lack of rapid diagnostic tools, infrequency of laboratory testing and poor reporting system [218].

Most cases of TF in industrialized countries are imported cases from endemic countries [219].

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 (LPS) O antigen, and, in addition, its polysaccharide (PS) capsular virulence (Vi) 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 associated 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

The heat-killed, phenol-preserved, injectable whole-cell S. typhi vaccine that was utilized as far back as 1896 in England and Germany, is still licensed today in several countries in spite of its high reactogenicity. Two new vaccines are currently licensed and widely used worldwide, a subunit (Vi PS) vaccine administered by the intramuscular route and a live attenuated S typhi strain (Ty21a) for oral immunization [220] [221] . Several typhoid vaccination programs that involve annual children vaccination campaigns using the injectable Vi vaccine have been carried out in Asia, resulting in a marked reduction or near disappearance of the disease, including in age groups not targeted for vaccination, thus suggesting a possible herd protective effect of vaccination [222].

The Vi polysaccharide vaccine

The A subunit of S. typhi PS was developed as a vaccine 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. First licensed in 1994, the vaccine (Typhim TM, Sanofi-Pasteur; TypbarTM, Bharar) is administered as one dose of 25 ?g by the IM or SC route. It now is in the public domain and is produced by several manufacturers including developing country manufacturers. The vaccine is progressively introduced into school attending children vaccination programs in Asian countries [223] [224] [225].

Its efficacy was demonstrated in multiple randomized trials. One of the first trials in Nepal involved persons aged 5-44 years and showed a 75% protection against TF during 20 months of active surveillance. Another study in South Africa demonstrated a 64% protective efficacy after 21 months in children aged 5-16 years, declining to 55% at 3 years after vaccination [226] [227] . A locally produced Vi vaccine prepared by the Shanghaï Institute of Biological Products, which was evaluated in a randomized placebo-controlled, double-blind trial on about 60 000 5-19 years old children in China showed a 69% efficacy against blood culture-confirmed TF over 19 months [228] . The Vi vaccine is considered to be protective for at least three years; it also has demonstrated a remarkable safety profile. Several high-quality producers from developing countries have acquired the technology to produce it at low cost, including two producers in China.

As is the case with other PS vaccines, Vi PS is poorly immunogenic in infants and cannot be used to vaccinate children less than 2 years of age. This has prompted the development of a Vi conjugate vaccine at the National Institutes of Health, USA, using recombinant Pseudomonas aeruginosa exotoxin A as the protein carrier (Vi-rEPA). In a Phase IIb 2-dose trial among 5525 2-5 year old children in the Mekong Delta of Vietnam, where TF is highly endemic, the Vi-rEPA vaccine demonstrated 91% efficacy over 27 months and 89% over 46 months of follow-up [229] . Similar results were obtained in Cambodia [230] . The NIH prototype vaccine is not being commercially developed, partly due to the complexity introduced by the exotoxin A carrier, but a diphtheria toxoid-based conjugate Vi vaccine has been developed at the International Vaccine Institute (IVI) in Seoul and transferred to Shantha, Indonesia. A Phase I clinical trial is planned to begin soon. Another Vi conjugate vaccine is in development at the All India Institute of Medical Sciences in New Delhi using the OmpC protein from S typhi as carrier.

The live attenuated Ty21a vaccine

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 vaccine (Vivotif TM) is currently manufactured by Crucell (formerly Berna Biotech) as enteric-coated capsules to be swallowed every other day for one week. A liquid formulation of the vaccine is no longer manufactured. The vaccine 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.

The vaccine was extensively tested in Alexandria, Egypt, where the liquid formulation showed 96% protection for 3 years, and in Santiago, Chile, where it was found to elicit a 67% protection against blood culture-confirmed TF over 3 years and 62% over 7 years [231] . The liquid formulation was shown to be 78% protective at 5 years. Ty21a is therefore considered to provide protection for at least 5-7 years. The vaccine was less efficacious when tested in Indonesia, where protective efficacy was found to be only 33%-53%, suggesting that in-the-field effectiveness in TF hyper-endemic areas, such as Indonesia, were quite lower than in areas with lower incidence of the disease, such as Egypt or Chile. In Chile, Ty21a also showed 42%-56% cross-protection against paratyphoid fever caused by serovar Paratyphi B [232].

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.

Other live attenuated S typhi vaccines

Several live attenuated S typhi strains are being developed to be used as oral TF vaccines. In preliminary clinical trials, these strains seem to be even more immunogenic than Ty21a [233].

Perhaps the most advanced of these live attenuated candidate vaccines is Ty800, a phoP/phoQ deletion mutant of Ty2, which is developed by AVANT Immunotherapeutics [234] and has passed Phase II trials. The vaccine has been shown to stimulate vigorous IgA and serum O antibody responses in volunteers.

Another attenuated strain is CVD909, an aroC/aroD/htrA deletion mutant which was engineered to constitutively express the S typhi Vi antigen. The strain, which induces anti-Vi antibodies in orally vaccinated subjects [235] , is developed as a live attenuated TF vaccine by Acambis and Crucell.

The third live attenuated vaccine candidate is ZH09, a Salmonella typhimurium strain deleted of the Salmonella pathogenicity island, which is developed by Emergent Biosolutions and is in Phase II trial [236] . A killed but metabolically active S typhimurium strain, CKS362, is also being developed as a candidate Salmonella vaccine [237].

In addition, an attenuated S. typhi Ty2 strain with deletions in ssaV and aroC genes has been developed by Microscience (UK) as a live vector (spi-VEC) for oral vaccines against TF and ETEC diarrhoea [125] (see ETEC vaccines above)

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