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New data on the epidemiologic, clinical and microbiologic aspects of typhoid fever in sub-Saharan Africa call for new strategies and new resources to bring the regional epidemic under control. Areas with endemic disease at rates approaching those in south Asia have been identified; large, prolonged and severe outbreaks are occurring more frequently; and resistance to antimicrobial agents, including fluoroquinolones is increasing. Surveillance for typhoid fever is hampered by the lack of laboratory resources for rapid diagnosis, culture confirmation and antimicrobial susceptibility testing. Nonetheless, in 2010, typhoid fever was estimated to cause 725 incident cases and 7 deaths per 100,000 person years in sub-Saharan Africa. Efforts for prevention and outbreak control are challenged by limited access to safe drinking water and sanitation and by a lack of resources to initiate typhoid immunization. A comprehensive approach to typhoid fever prevention including laboratory and epidemiologic capacity building, investments in water, sanitation and hygiene and reconsideration of the role of currently available vaccines could significantly reduce the disease burden. Targeted vaccination using currently available typhoid vaccines should be considered as a short- to intermediate-term risk reduction strategy for high-risk groups across sub-Saharan Africa.
In 2000, Salmonella enterica servovar Typhi (S. Typhi) was estimated to cause 22 million cases of typhoid fever and 216,000 deaths worldwide annually, with the bulk of cases and deaths occurring in the south Asia region.1 The authors noted the paucity of reliable data from sub-Saharan Africa, and based on only 3 population-based studies, classified the region as “medium incidence,” with an adjusted* annual incidence of 100 cases per 100,000 person-years.2 A more recent publication, including additional studies published in the past decade, estimated adjusted typhoid fever associated morbidity and mortality in sub-Saharan Africa to be 725 cases and 7 deaths per 100,000 person-years.3 This increase, which may result in part from better surveillance, is compatible with an increase in prolonged, severe and widespread outbreaks of typhoid fever that have been documented in both rural and urban populations in sub-Saharan Africa during the past decade; it is likely that many smaller, less severe outbreaks still go unrecognized. Antimicrobial resistance, notably to fluoroquinolones, is observed more frequently in isolates from persons with sporadic and outbreak-associated cases, leaving limited treatment options that are expensive and difficult to procure.4,5 These new data on the epidemiologic, clinical and microbiologic aspects of typhoid fever in Africa highlight the need for new strategies and new resources to bring the regional epidemic under control, before resistance to fluoroquinolones increases further, more lives are lost and more chronic carriers are seeded within the population. Despite our understanding of disease transmission, detection, prevention and treatment, we appear to be losing the battle against typhoid fever in most countries in sub-Saharan Africa. The promise of conjugate typhoid fever vaccines that are safe, efficacious and easily integrated into routine immunization programs is at best several years away.6 It is time to reinvigorate non-vaccine prevention efforts to improve water, sanitation and hygiene, and to reconsider the role of currently available typhoid fever vaccines in typhoid fever prevention and control programs.
Two new generation typhoid fever vaccines are currently available: an oral live-attenuated Ty21a vaccine and an injectable Vi capsular polysaccharide vaccine7,8; both vaccines have been shown to be safe and effective in several clinical trials and field settings. Protective efficacy and field effectiveness of the Ty21a vaccine is reported to range from 51% to 67%9 (up to 77% for the liquid formulation). Enteric capsule efficacy in a prospective trial in Chile was 67% at 3 y and 62% at 7 y10; and was 43% in a prospective trial in Indonesia.11 Protection lasts for 5–7 y, and immunity is engendered 1 week after the last dose. A potential benefit of Ty21a vaccine, though, is that it has also demonstrated cross-protection against S. Paratyphi B.12 The Vi polysaccharide polysaccharide vaccine is a single dose vaccine approved for use in persons ≥ 2 y old, with revaccination recommended every 2–3 y. Reported efficacy and field effectiveness ranges from 55% to 72%9; a recently conducted large phase 3 cluster-randomized trial in India demonstrated Vi effectiveness of 57% among all residents in vaccine clusters.13 Additionally, herd protection has been demonstrated with both vaccines. The vaccines must be maintained in cold chain (2–8°C) during storage and distribution until the vaccine is administered. Efficacy of both vaccines also varies by age. Although neither vaccine is an ideal candidate for integration in routine immunization systems or for outbreak mitigation, Vi polysaccharide vaccines offer advantages because only a single dose is required, they can be administered at a younger age than Ty21a capsule formulation.
Across sub-Saharan Africa in the last decade, outbreaks in Zambia,14 Zimbabwe,15,16 Uganda,17,18 Malawi and Mozambique,4 South Africa,19,20 the Democratic Republic of Congo,21 and the Ivory Coast,22 have resulted in more than 8,000 suspected cases of typhoid fever, a considerable increase in both the number of outbreaks and cases of typhoid fever from the previous decade. The outbreaks in Zambia, Zimbabwe and DRC occurred primarily in low income neighborhoods of the capital city, although other areas of the country were also affected. The remaining outbreaks occurred primarily in rural areas. Recent data from a 2012 Kenyan report indicate that endemic incidence of typhoid bacteremia in an urban slum was 247 cases per 100,000 person-years of observation (pyo),23 similar to endemic incidence (ranging from 21.3–451.7 cases per 100,000 pyo) in Kolkata, India, North Jakarta, Indonesia24 and Dong Thap province, Vietnam.25 Among children 5–9 y old in Kenya, the rate of S. Typhi bacteremia was 596 per 100,000 pyo.23
The outbreaks in the DRC21 and Uganda17,18 were characterized by high rates of intestinal perforation associated with high case-fatality rates. Typhoid fever is also recognized as the leading cause of intestinal perforation in children in Ghana and other countries in west Africa.26 The outbreak in Malawi and Mozambique was characterized by many cases of severe neurologic disease in reports by Lutterloh et al. and Sejvar et al..4, 27
Alarmingly, nearly 75% of isolates from population- based surveillance in Kenya were multidrug resistant; 3.2% of isolates were fully resistant and 7% showed reduced susceptibility to nalidixic acid.23 Typhoid fever cases reported from Ghana have also been caused by strains of S. Typhi resistant to multiple agents including amoxicillin/clavulanic acid (24%), gentamicin (46%), tetracycline (64%), ampicillin/amoxicillin (70%), trimethoprim/sulfamethoxazole (71%) and chloramphenicol (73%).26 Nearly 10% of isolates from a 2011–2012 outbreak of typhoid fever in Lusaka, Zambia were determined locally to be resistant to ciprofloxacin, 33% of isolates were resistant to nalidixic acid, and 61% were resistant to chloramphenicol.14
Typhoid fever vaccines have been recommended for wider use in endemic countries and for outbreak control by the World Health Organization (WHO).23,25 While improvements in drinking water and sanitation infrastructure and in food safety are the definitive longer-term solution to preventing transmission of typhoid fever and other enteric infections, these approaches will take decades to fully fund and implement. The targeted use of currently available typhoid fever vaccines could help mitigate the risk of typhoid fever in the intermediate term and reduce typhoid fever-associated morbidity and mortality in endemic areas. Although both available typhoid fever vaccines have limitations, notably in the duration of protection after immunization, they may be able to interrupt community transmission in the short- to medium-term by decreasing the force of infection. The Vi polysaccharide vaccine is not licensed for administration to children aged < 2 y; however, immunizing other high risk populations, such as school-aged children, could decrease the risk among younger children by conferring herd protection.23,28 Additionally, recent surveillance data from Kenya found the highest rate of S. Typhi bacteremia among children 5–9 y old, an age group suitable for immunization with the polysaccharide vaccine.23,28 Mathematical modeling of immunization strategies has quantified the potential impact of vaccinating high-risk groups against other vaccine-preventable diseases29, 30 and recent epidemiologic data described above could provide important insights for target groups for typhoid fever vaccination.
The long and variable incubation period of typhoid fever (ranging from 6–30 d from exposure to symptom onset)7 and the challenges in confirming the diagnosis, can create a long period during which disease transmission may occur before an outbreak is recognized. Detection of outbreaks is difficult because patients in sub-Saharan Africa often have limited access to healthcare, those who present at a healthcare facility with typhoid fever may initially be misdiagnosed as malaria, and blood culture–the best method of diagnosing typhoid fever–is not widely available. Delays in diagnosis make it likely that many persons will have already been exposed before outbreaks are recognized. This delay may blunt the effectiveness of a reactive vaccine campaign for outbreak control; however, prolonged outbreaks, such as the 2009–2011 typhoid fever outbreak in rural western Uganda, would be potential high-impact targets for reactive vaccination.17,18 Immunization of persons who have already been exposed to S. Typhi is not well-studied and warrants further investigation. If the decision to organize an outbreak response campaign is made and vaccine is not available in country, procurement may take weeks to months. However, some outbreaks of typhoid fever are long lasting, and may be associated with high mortality because of limited access to medical and surgical care.17 In these instances, vaccines may still be useful interventions if administered early on to populations at high-risk. Mathematical modeling of typhoid fever outbreaks could help further delineate the potential impact in terms of expected reductions of morbidity and mortality.
Routine vaccination of 3–5 y olds with a locally-produced Vi polysaccharide vaccine through the World Health Organization Expanded Program on Immunization (EPI) was associated with a decline in typhoid fever incidence in Vietnam, although improvements in water and sanitation coverage also contributed to this reduction.31,32 The success in Vietnam raises important questions about the use of typhoid fever vaccine in sub-Saharan Africa. If age-specific incidence is as high in urban slums in Africa as in Asia, can cases of typhoid fever be prevented with targeted use of the polysaccharide vaccine before conjugate vaccines become available? Would use of vaccine among high-risk groups (whether defined by age or access to treated water) be a cost-effective or cost-saving strategy? With a single WHO prequalified typhoid vaccine manufacturer, are a sufficient number of doses available in a timely manner, especially for outbreak response?
In September 2011, the Global Alliance for Vaccines and Immunisation (GAVI) made a decision to not provide financial support to countries for introduction of the current Vi polysaccharide vaccine. This decision was made given the absence of reliable data on relative and absolute disease burden, and the promise of Vi conjugate vaccines under development that could be added to EPI programs, would provide longer duration of immunity and overcome the problem of immune hyporesponsiveness associated with polysaccharide vaccines.23 However, GAVI did recognize that polysaccharide vaccine could be a cost-effective solution especially in urban slums, and supported the need to revisit this decision in the near future when more data are available, and if uncertainty about the development of conjugate vaccines persists.29 Deferring vaccination against typhoid fever until the conjugate vaccine is available will leave large populations at risk of typhoid fever for several years and possibly much longer. Necessary improvements to water and sanitation infrastructure are also likely to take decades to achieve. With growing antimicrobial resistance, treatment options may become extremely limited and costly, raising concerns about increased mortality among untreated or inappropriately treated patients. While not a perfect solution, targeted use of Vi polysaccharide vaccine could potentially reduce morbidity and mortality at reasonably low cost and help pave the way for introduction of newer-generation conjugate vaccines when these become available. Targeted vaccination using the currently available typhoid vaccines should be considered for high-risk groups across sub-Saharan Africa, while efforts to make conjugate vaccines available are accelerated.
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
No potential conflicts of interest were disclosed.
*Typhoid fever incidence was adjusted by a factor of 2 in all studies to account for the low sensitivity of culture for typhoid fever diagnosis.
Previously published online: www.landesbioscience.com/journals/vaccines/article/23007