Vaccines against invasive Salmonella disease

Serovars of the Gram-negative bacterium Salmonella enterica are usually associated with food-borne diarrheal illness in high-income countries. Such gastrointestinal disease is normally self-limiting and rarely life-threatening. Perhaps surprisingly, Salmonella has not been identified as a principal etiological agent of diarrhea in developing countries. 1 Nevertheless, Salmonellae are responsible for a huge global disease burden through two forms of invasive illness: enteric fever and invasive nontyphoi-dal Salmonella (iNTS) disease. Enteric fever is principally caused by Salmonella enterica serovar Typhi (S. Typhi), for which the disease is also called typhoid fever, and S. Paratyphi A. Disease due to both serovars is a major problem in South and SouthEast Asia (Fig. 1A). S. Typhi is the leading pathogen isolated from blood cultures in South Asia, 2 though in some areas enteric fever caused by S. Paratyphi A is more common. 5 The annual global burden of disease due to typhoid fever was estimated at 21.7 million cases in 2000 with a case-fatality rate of 1% resulting in 217 000 deaths. 3 Preschool and school-aged children are the most affected age groups. 6-8 The global burden of disease attributable to S. Paratyphi A in 2000 was 5.4 million cases. 3 In contrast, iNTS disease is a neglected disease and is mainly a problem in sub-Saharan Africa (Fig. 1B). Published global burden of disease estimates are not currently available, though case fatality rates, at 20–25%, 9 are much higher than for enteric fever, with an overall annual mortality likely to be well in excess of 100,000 and not dissimilar from that of enteric fever. In sub-Saharan African countries, nontyphoidal Salmonellae (NTS) are either the leading or next most common pathogenic blood culture isolate after pneumococcus, 4 for which vaccines are available and are being implemented in the region. The two main serovars responsible for iNTS disease are Typhimurium and Enteritidis and the two groups most affected by iNTS disease are children under two years and HIV-infected individuals. Fever surveillance across 12 sites in sub-Saharan Africa during the RTS,S/AS01 malaria vaccine phase 3 trials gave an incidence of Salmonella bacteremia in children under two years of around 500/100 000 children/year. 10 It is not clear why invasive Salmonella disease is a problem in the developing world and not in high-income countries, particularly with respect to iNTS disease. This could be due to differences in transmission, host immunity or the bacteria themselves. 11 Multi-locus sequencing typing (MLST) …