Typhoid in Africa and vaccine deployment
Authors: Gordon Dougan
Journal: The Lancet Global Health (2017)

Typhoid, one of the classic infectious diseases afflicting humanity, is still a relatively common illness in many lower-income and middle-income countries (LMIC).1Dougan G Baker S Salmonella enterica serovar Typhi and the pathogenesis of typhoid fever.Annu Rev Microbiol. 2014; 68: 317-336Crossref PubMed Scopus (163) Google Scholar The disease is associated with chronic fever that, if not treated, can lead to complications such as intestinal perforation or neurological problems.2Azmatullah A Qamar FN Thaver D Zaidi AK Bhutta ZA Systematic review of the global epidemiology, clinical and laboratory profile of enteric fever.J Glob Health. 2015; 5: 020407Crossref PubMed Scopus (79) Google Scholar The diagnosis of typhoid is complicated because clinical presentation can be non-specific and can resemble a number of other diseases, such as malaria, typhus, and various viral infections. The current typhoid diagnostic kits are relatively unreliable, and microbial culture from blood or other bodily secretions of the main bacterial aetiological agents Salmonella enterica serotype Typhi and S enterica serotype Paratyphi A remains the gold standard.3Wain J Hosoglu S The laboratory diagnosis of enteric fever.J Infect Dev Ctries. 2008; 2: 421-425Crossref PubMed Scopus (36) Google Scholar Microbial culture requires the availability of adequate laboratory facilities, including blood and microbial culture equipment, and appropriate bacteriological expertise. Unfortunately, these are not always present in LMIC settings and the incidence of typhoid in many regions, particularly Africa, remains relatively undefined. Nevertheless, more than 20 million cases of typhoid have been estimated globally, most of which are caused by S Typhi, with between 200 000 and 600 000 deaths.1Dougan G Baker S Salmonella enterica serovar Typhi and the pathogenesis of typhoid fever.Annu Rev Microbiol. 2014; 68: 317-336Crossref PubMed Scopus (163) Google Scholar However, the estimates are compromised by limited epidemiological information and restricted geographical coverage, as well as the problems with diagnosis. Interest in typhoid has increased in recent years, driven by a number of factors. Multidrug resistance has been increasingly reported as a characteristic of S Typhi isolated in the past decade and from different parts of the globe.4Kaurthe J Increasing antimicrobial resistance and narrowing therapeutics in typhoidal Salmonellae.J Clin Diagn Res. 2013; 7: 576-579PubMed Google Scholar Although there is historical evidence that typhoid has been established in south and southeast Asia for decades, there have been increasing reports of typhoid in different African countries, potentially associated with multidrug resistance.5Al-Emran HM Eibach D Krumkamp R et al.A multicountry molecular analysis of Salmonella enterica serovar Typhi with reduced susceptibility to ciprofloxacin in sub-Saharan Africa.Clin Infect Dis. 2016; 62: S42-S46Crossref PubMed Scopus (24) Google Scholar Furthermore, a particular haplotype of S Typhi, known as H58 or 4.3.1, has been linked to the spread of multidrug resistance, and this strain might be driving typhoid into new geographical areas where typhoid was previously absent or under reported.6Wong VK Baker S Pickard DJ et al.Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.Nat Genet. 2015; 47: 632-639Crossref PubMed Scopus (286) Google Scholar Multidrug resistant S Typhi respond more slowly to antibiotic treatment,7Bhutta ZA Khan IA Shadmani M Failure of short-course ceftriaxone chemotherapy for multidrug-resistant typhoid fever in children: a randomized controlled trial in Pakistan.Antimicrob Agents Chemother. 2000; 44: 450-452Crossref PubMed Scopus (44) Google Scholar and such strains might be stimulating an increased use of antibiotics (and indirectly promoting multidrug resistance) in the community, where antibiotics are freely available without prescription. Additionally, a new generation of typhoid vaccines, based on conjugate technology and the Vi capsular antigen of S Typhi, are being developed and have been licenced in some countries.8Verma R Bairwa M Chawla S Prinja S Rajput M New generation typhoid vaccines: an effective preventive strategy to control typhoid fever in developing countries.Hum Vaccin. 2011; 7: 883-885Crossref PubMed Scopus (14) Google Scholar In response to the lack of epidemiological information on typhoid in Africa, the Typhoid Fever Surveillance in Africa Programme (TSAP), funded by the Bill & Melinda Gates Foundation and covering ten countries and 13 sites across Africa, was established between 2010 and 2014. In this issue of The Lancet Global Health, Florian Marks and colleagues9Marks F von Kalckreuth V Aaby P et al.Incidence of invasive salmonella disease in sub-Saharan Africa: a multicentre population-based surveillance study.Lancet Global Health. 2017; 5: e310-e323Summary Full Text Full Text PDF PubMed Scopus (162) Google Scholar present the results of a multicentre population-based surveillance study implemented by TSAP that uses standardised approaches based around blood culture, to provide an estimate of typhoid disease burden. S Typhi, together with isolates of other non-typhoidal Salmonella serovars (eg, Typhimurium, Enteritidis, Dublin) were the most common bacteria found in the blood at many of the sites, outstripping Streptococcus pneumoniae and Escherichia coli. A large variation existed in the adjusted incidence rates (AIR) of S Typhi between the different sites, with no isolates at all in Sudan and Ethiopia but with estimated levels of 383 per 100 000 at one site in Burkina Faso. Typhoid was found in both young infants and in school age children, with higher AIR in children younger than 15 years old. Thus, the incidence of typhoid varied significantly between the sites, suggesting that the epidemiology is complex and potentially a highly variable patchwork exists across the region. Worryingly, significant levels of multidrug resistance were found in S Typhi and in non-typhoidal Salmonella at some of the sites. The establishment of these linked sites across Africa has the added bonus of providing an infrastructure for further studies on typhoid, but this system can also be potentially exploited for other studies on infectious diseases, antimicrobial resistance, or even non-communicable diseases. For example, the epidemiology of many of the non-Salmonella bacteria isolated in the study (eg, Klebsiella) is poorly understood in the region. These data indicate that typhoid is a substantial disease burden in many parts of Africa, with the incidence levels likely to be an underestimate because of the difficulty of estimating true levels on the basis of microbial culture. The report has encouraged the funding of TSAP to be continued for a further 2 years to gather more information, and these data, together with information from other sites, have prompted further funding into typhoid vaccine development and deployment. A key challenge is to determine how useful an efficacious vaccine might be in LMICs, where the levels of disease vary so greatly between different regions. Such studies might be pivotal to facilitate the deployment of such vaccines. In this regard, a need exists to develop economic models that provide governments and agencies with information that will inform decision making. The changing epidemiological pattern, the emergence of a potentially more aggressive multidrug resistant clade, and the likelihood of increased antibiotic usage in communities affected by the disease are creating a sense of urgency. Indeed, typhoid might prove to be a useful model of how to measure any benefit of vaccination on controlling the indiscriminate use of antibiotics. Other areas of interest will be the development of better diagnostics for the disease and the provision of proof that typhoid conjugate vaccines are as efficacious in different settings as the single efficacy study performed to date suggested.10Lin FY Ho VA Khiem HB et al.The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children.N Engl J Med. 2001; 344: 1263-1269Crossref PubMed Scopus (366) Google Scholar I declare no competing interests. Incidence of invasive salmonella disease in sub-Saharan Africa: a multicentre population-based surveillance studyTyphoid fever and iNTS disease are major causes of invasive bacterial febrile illness in the sampled locations, most commonly affecting children in both low and high population density settings. The development of iNTS vaccines and the introduction of S Typhi conjugate vaccines should be considered for high-incidence settings, such as those identified in this study. Full-Text PDF Open Access