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Volume 357:1069-1071 September 13, 2007 Number 11 Next

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Although typhoid fever, caused by infection with Salmonella enterica serovar Typhi (often called S. typhi), long ago ceased to be a public health problem in industrialized countries, it is still a substantial cause of illness and death in many developing countries. According to the World Health Organization (WHO), there are 16 million to 33 million cases and 500,000 to 600,000 deaths from typhoid fever annually,¹ though one study conservatively estimated that 22 million cases and 216,000 related deaths occurred in 2000.² This death rate is not much lower than the estimated 270,000 annual deaths from cervical cancer, caused largely by the human papillomavirus (HPV), and is considerably greater than mortality from meningococcal meningitis and Japanese encephalitis.³ But whereas there has been considerable international momentum behind introducing vaccines against HPV and meningococcus, vaccination against typhoid fever has largely fallen off the international radar screen.

View larger version (37K): [in this window] [in a new window]   Salmonella typhi bacteria. From Dr. Dennis Kunkel/Getty Images.

 
Among the major reasons for this apparent neglect is a sense of complacency inspired by the introduction, beginning several decades ago, of relatively inexpensive antibiotics that initially reduced the rate of typhoid-related deaths substantially; unfortunately, these drugs have progressively become ineffective, since the bacterium has developed resistance to them. Another key factor is that the burden of typhoid fever is unknown and is probably underestimated in most developing countries, owing to the difficulty of differentiating the disease from other febrile illnesses, the infrequency of appropriate confirmatory laboratory testing, the reliance in many countries on private health care providers or on self-treatment with antibiotics, and the generally poor disease-reporting systems in developing countries. And unlike dengue fever and meningococcal meningitis, which occur in epidemics that command the attention of the media and political leaders, typhoid fever is largely an endemic illness. Finally, whereas policymakers have prioritized vaccines that reduce the rates of illness and death among children under 5 years of age, typhoid fever has long been considered a disease of school-aged children.

In industrialized countries, typhoid fever, which is spread by the fecal–oral route by means of contaminated water or food, was largely controlled through the improvement of water and sanitation systems. However, the development of such infrastructure requires huge investments and is unlikely to reach slums and other high-risk areas in developing countries for many years to come.

View larger version (71K): [in this window] [in a new window]   Slum in Dhaka, Bangladesh. Courtesy of Lorenzo von Seidlein, IVI.

 
Vaccination can provide a near-term solution, as demonstrated in Thailand, where mass vaccination of schoolchildren with injectable, inactivated, whole-cell vaccines in the 1970s and 1980s led to sharp decreases in the incidence of typhoid fever and is credited with largely controlling the disease. However, because of their high rates of side effects, these older-generation vaccines have generally been abandoned as public health tools.

Fortunately, two newer-generation typhoid vaccines, which have been available for approximately two decades, have proved extremely safe. Vi polysaccharide is a subunit vaccine administered parenterally in a single dose; it was found in studies to confer about 70% protection, lasting at least 3 years, and is licensed for use in persons 2 years of age or older. The orally administered, live attenuated Ty21a vaccine, licensed for use in persons 2 years of age or older, is given in three or four doses and confers 53 to 96% protection, depending on the vaccine formulation and the context of the evaluation.⁴ Protection for 7 years after administration has been shown. The continued high incidence of typhoid fever in many regions, along with the rise and spread of drug-resistant strains, led the WHO in 2000 to recommend immunizing school-aged children with these newer vaccines in areas where typhoid fever is a substantial public health problem and particularly where antibiotic-resistant S. typhi strains are prevalent. But so far, only two countries — China and Vietnam — have incorporated typhoid vaccination into their routine immunization programs, and only in a limited fashion.

However, a number of recent developments and new data have strengthened the case for refocusing attention on typhoid vaccination. Standardized, 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 large Asian countries (Hechi, China; Kolkata [formerly Calcutta], India; North Jakarta, Indonesia; Karachi, Pakistan; and Hue, Vietnam) revealed high typhoid rates among children in the three urban slums (Karachi, Kolkata, and North Jakarta). At these sites, annual rates of blood-culture–confirmed typhoid fever among children 5 to 15 years of age ranged from 180 cases per 100,000 to 494 cases per 100,000, and the true incidence may be twice as high, since the sensitivity of blood cultures is only around 50%.

The DOMI studies, in which we participated, highlight the complexity of epidemiologic patterns of typhoid and other causes of enteric fever. Although typhoid fever is generally considered a disease of school-aged children, high rates were also seen among children younger than 5 years at the Karachi, Kolkata, and North Jakarta sites. Moreover, the incidence can vary considerably even within a single country. In Vietnam, a countrywide analysis showed that 90% of typhoid cases are confined to one third of provinces — rural areas with poor water and sanitation systems (see map inset). In many other countries, the disease predominantly affects urban slums. The DOMI studies also showed that enteric fever due to another serovar of S. enterica, S. Paratyphi A, traditionally considered to be of minor importance epidemiologically, is occurring at increasing rates in several Asian countries and is becoming resistant to multiple antibiotics. S. Paratyphi A was responsible for 64% of culture-proven cases of enteric fever in Hechi, 24% of those in Kolkata, and 15% of those in Karachi.⁵

View larger version (30K): [in this window] [in a new window]   Mean Annual Incidence of Typhoid Fever per 100,000 Persons. Country-specific incidence rates, some of which are estimates, are for 2000. Province-specific incidence rates for Vietnam are for children 5 to 14 years of age, between 1999 and 2003 (inset). Country data are from Crump et al.2 Provincial data for Vietnam are from a meta-analysis conducted by the DOMI Program.

 
These findings have important implications for typhoid and enteric-fever immunization strategies. First, since the currently available typhoid vaccines cannot be given to infants, school-based vaccination is a sensible option in countries where preschoolers are at relatively low risk, whereas in many areas of South and Southeast Asia where typhoid fever is highly endemic, a dual strategy of school- and community-based vaccination for 2-to-5-year-olds may be required. In those areas, a typhoid vaccine that can be given to infants through the WHO Expanded Program on Immunization would be ideal, once vaccines effective in this age group become available. Vi-protein–conjugate vaccines seem promising in this regard, although they are still years away from commercial availability. Second, in most countries, vaccination in geographically targeted, high-risk populations, rather than universal immunization, will most cost-effectively control the disease. And finally, future vaccine strategies for Asia will need to focus on S. paratyphi as well as S. typhi.

The DOMI studies also documented the continued rise and spread of antibiotic-resistant strains of S. typhi. Strains resistant to all three first-line antibiotics (ampicillin, chloramphenicol, and trimethoprim–sulfamethoxazole) accounted for 65% of isolates tested in Karachi. Resistance to nalidixic acid — a marker of reduced sensitivity to fluoroquinolones — was found in 44 to 57% of isolates tested in Hue, Kolkata, and Karachi. Clearly, as resistance grows, so will the difficulty and cost of treating the disease, and the occurrence of serious sequelae.

Vi vaccine has become increasingly available and inexpensive, as more high-quality producers from developing countries have acquired the technology to produce it. Indian producers have recently offered the vaccine to public-sector programs for $0.50 or less per dose. Moreover, demonstration projects conducted by DOMI in nearly 200,000 persons at the five sites have found community- and school-based immunization with Vi to be feasible and acceptable.

Given this evidence, policymakers in Pakistan and Indonesia plan to introduce targeted typhoid vaccination with Vi vaccine, beginning with school-based pilot projects. However, if typhoid fever is to be controlled globally, the international health community will need to increase the priority and sense of urgency accorded to the control of this disease.

Drs. Jodar and Clemens report receiving grants from GlaxoSmithKline, Merck, Wyeth, and Emergent Europe (formerly MicroScience). Dr. Clemens reports receiving consulting fees from Merck and Iomai. No other potential conflict of interest relevant to this article was reported.

Source Information

Ms. DeRoeck is the coordinator of social-science research and institutional development, Dr. Jodar the deputy director-general, and Dr. Clemens the director-general of the International Vaccine Institute, based in Seoul, Korea.

References

1. Initiative for Vaccine Research. Typhoid fever. (Accessed August 23, 2007, at http://www.who.int/vaccine_research/diseases/diarrhoeal/en/index7.html.) 
2. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ 2004;82:346-353. [ISI][Medline]
3. GAVI Alliance home page. (Accessed August 23, 2007, at http://www.gavialliance.org.)
4. Acosta CJ, Galindo CM, Deen JL, et al. Vaccines against cholera, typhoid fever and shigellosis for developing countries. Expert Opin Biol Ther 2004;4:1939-1951. [CrossRef][ISI][Medline]
5. Ochiai RL, Wang X, von Seidlein L, et al. Salmonella paratyphi A rates, Asia. Emerg Infect Dis 2005;11:1764-1766. [ISI][Medline]

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