Rethinking typhoid fever vaccines: implications for travelers and people living in highly endemic areas.

© 2009 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine, Volume 16, Issue 1, 2009, 46–52 E (typhoid or paratyphoid) fever is a systemic infection caused by Salmonella enterica , including S enterica serotype Typhi ( S typhi ) and serotypes Paratyphi A, B, and C ( S paratyphi ). Humans are the only host for these pathogens, which are transmitted by fecal contamination of food and water. Salmonella typhi caused an estimated 22 million illnesses and 200,000 deaths, and S paratyphi caused 5.4 million illnesses worldwide during the year 2000. 1 The actual global burden of enteric fever is diffi cult to determine because many cases are unrecognized, particularly in young children who may have a nonspecifi c illness, 2 – 4 and it is not a notifi able disease in endemic countries. In addition, there are no specifi c clinical diagnostic criteria, and the laboratory techniques for diagnosis lack sensitivity and specifi city. 5 According to the recently estimated global incidence, the highest concentration of typhoid fever is in Asia, especially in the Indian subcontinent ( Table 1 ). 1 Southern Africa and Latin America also have a high disease burden ( Table 1 ). Previously, S paratyphi was thought to have caused 10% of cases of enteric fever and a milder form of disease than S typhi. 6,7 However, recent reports suggest that these two pathogens cause similar diseases 8 – 10 and that there has been a disproportionate increase in the incidence of enteric fever caused by S paratyphi , with up to 50% of enteric fever cases caused by S paratyphi in some highly endemic areas of the world. 9,11 – 15 Enteric fever also affects short-term and long-term travelers bound to highly endemic areas. 16 Among the travel-related cases, most occur in foreign-born residents who visited friends or family in their country of origin. 17 Travel to the Indian subcontinent is associated with the highest risk of contracting enteric fever. 18 – 20 In addition, enteric fever in travelers from the UK due to S paratyphi A surpassed disease due to S typhi . 21 Given the signifi cant burden of enteric fever and the threat of increasing antimicrobial resistance, 22 – 29 the role of preventive vaccines is critical. Currently, there are two available vaccines against S typhi ( Table 2 ): the live attenuated oral vaccine containing the S typhi strain Ty21a (Ty21a vaccine) and the parenteral capsular polysaccharide vaccine based on the S typhi Vi antigen (Vi vaccine). The live attenuated vaccine is formulated in enteric capsules. It is licensed for children ≥ 6 years of age in the United States and, in other parts of the world, for children ≥ 2 to 5 years of age depending on the country. The parenteral capsular polysaccharide vaccine based on the S typhi Vi antigen (Vi vaccine) is licensed for children ≥ 2 years of age. There are currently no licensed vaccines against S paratyphi . 30 The live attenuated Ty21a vaccine was developed by Germanier and Füer 31 by treatment of the wild-type strain of Ty2 with the mutagenic agent nitrosoguanidine. A mutant was selected that lacked the Vi antigen and the enzyme uridine diphosphate-galactose-4-epimerase. 32 There have been no documented cases of the Ty21a vaccine reverting to virulence in any of the multiple large fi eld trials conducted, which is likely due to the fact that this strain contains multiple mutations as a result of chemical mutagenesis. Ty21a induces protection against S typhi by inducing mucosal [immunoglobulin (Ig) A] and serum (IgG) antibodies against the lipopolysaccharide O antigen, H antigen, and others. The Ty21a vaccine has also been shown to induce some cell-mediated immunity. 33 Serum IgG antibodies and gut-derived O antigen – specifi c IgA antibody – secreting cells are the best surrogate markers of protection. 34