The challenge of enteric fever

doi:10.1016/j.jinf.2013.09.013

Journal of Infection

Volume 68, Supplement 1, January 2014, Pages S38-S50

https://doi.org/10.1016/j.jinf.2013.09.013 Get rights and content

Summary

Enteric fever, a non-specific, systemic infection caused by S. Typhi or Paratyphi A, B or C, is common in resource-limited regions of the world, where poor sanitation infrastructure facilitates faeco-oral transmission. Prompt treatment with appropriate antibiotics minimises illness severity, but presentation to health care facilities is often delayed because of the non-specific nature of the symptoms and the lack of reliable diagnostic tests. Disease prevention requires significant investment in provision of clean water and sanitation in the long term; vaccination offers a more realistic strategy for medium term control. However, implementation of existing vaccines and development of more efficacious vaccines has been hindered by the lack of an established correlate of protection and under appreciation of the true disease burden. Human microbial infection studies could provide a vehicle for the rapid evaluation of novel vaccines and investigation of the immunobiology of enteric infection.

Introduction

Enteric fever is a systemic infection caused by Salmonella enterica subspecies enterica serovars Typhi (S. Typhi, causing typhoid fever) or Paratyphi A, B or C (S. Paratyphi A, B or C, causing paratyphoid fever). Enteric fever is common in resource-poor regions of the world, where poor sanitation and inadequate clean water provision facilitate the spread of infection via faeco-oral transmission.

Enteric fever produces a wide range of non-specific symptoms and is clinically indistinguishable from many other diseases, both infectious and non-infectious. Prompt treatment minimises illness severity, but late presentation to health care facilities often delays initiation of appropriate antibiotic therapy. Treatment delay is compounded by a lack of reliable diagnostic tests.

Although typhoid could be controlled by improvements in public infrastructure (for example, clean water and separate sewage systems), the significant funding investments required in many regions are unlikely to be forthcoming in the near future. Fortunately, disease control in the interim may be possible through effective vaccination. Indeed, prevention of typhoid fever has been attempted through vaccination for over 100 years.¹ Three licensed vaccines for typhoid fever exist, but are only moderately efficacious and unsuitable for infant immunisation. There are currently no licensed vaccines to prevent paratyphoid infection. The implementation of existing vaccines and development of new efficacious vaccines has been hindered by a lack of understanding of typhoid immunobiology. S. Typhi and Paratyphi are human restricted pathogens and require a relatively high dose to cause infection. Consequently the development of a suitable vaccine could lead to the eradication of enteric fever. To reach this goal, an improved understanding of the immunobiology of typhoid fever is needed.

Section snippets

Epidemiology

Typhoid fever is estimated to affect at least 26.9 million people per year, of whom 1% will die.² Paratyphoid fever has been estimated to affect 5.4 million people per year,³ and appears to be increasingly prevalent, with recent reports attributing up to half of all enteric fever cases to paratyphoid infection in some Asian countries.4, 5 The incidence of paratyphoid fever in returning travellers is also increasing.6, 7 The majority of the global disease burden is borne by children and

Acute typhoid fever

Enteric fever is a highly variable, non-specific illness. Typhoid fever and paratyphoid fever cannot be distinguished on clinical grounds.⁶ Fever is the most frequent and universal symptom with other frequent symptoms being malaise, chills, anorexia, diarrhoea, headache, weight loss, abdominal pain and rash.23, 24 Nausea, constipation, myalgia, arthralgia and cough are also reported.25, 26, 27 Severity of symptoms is highly variable, with some patients able to continue normal activity and some

Chronic carriage

In 1902, Robert Koch postulated that healthy people could carry disease causing organisms and serve as reservoirs of infection.²⁹ Applying this idea to typhoid fever, Koch noted that humans were the only source of S. Typhi, and hypothesised that a carrier state could bridge the gap between one typhoid outbreak and the next. Prospective studies of patients with typhoid fever in Germany confirmed this, with identification of ongoing excretion of S. Typhi in the stool of symptomatic individuals.²⁹

Diagnosis

Prompt diagnosis and treatment of typhoid fever decreases disease complications and limits opportunity for disease spread.¹² Achieving a prompt and reliable diagnosis is difficult however. Enteric fever leads to a diverse range of clinical symptoms and signs, and cannot be reliably distinguished on clinical grounds from other diseases that are common in endemic regions, including malaria, tuberculosis, dengue fever and brucellosis.¹² Diagnostic tests that are both sensitive and specific are

Sanitation and clean water

Endemic enteric fever results from a lack of basic hygiene and sanitation infrastructure which facilitates disease spread. The importance of sanitation and clean water in the prevention of endemic typhoid fever has long been recognised.⁶⁷ During the early part of the 20th century, resource-rich countries saw a marked decline in the incidence of typhoid fever following the routine provision of sanitation and clean water, along with the advent of antibiotics that limited infectivity.68, 69

Novel vaccine strategies

The development of novel vaccines has been facilitated by scientific advances allowing precise manipulation of bacteria to introduce attenuating mutations.¹²³ Approaches to strain attenuation, including mutations in biochemical pathways, heat shock proteins, regulatory genes and putative virulence genes have all been tried. The availability of the complete genome of strain CT 18¹²⁴ and subsequently of Ty2¹²⁵ has facilitated this approach. Despite these advances, the lack of an animal model in

Controlled human infection studies with Salmonella Typhi

Animal models of typhoid fever are limited in their applicability to human infection as S. Typhi is a human restricted pathogen. In order to assess typhoid fever vaccines quantitatively,¹⁵⁸ controlled human infection experiments with S. Typhi were conducted at the University of Maryland from the 1950s to the 1970s.¹¹⁹ As well as permitting the investigation of typhoid vaccines, these investigations allowed insights into the disease and its pathogenesis to be gained.159, 160 Since that time,

Establishing a 21st century challenge model

Novel, affordable typhoid vaccines with improved efficacy over existing vaccines that can be used in infants are desperately needed. Vaccine development is a long, costly and challenging process with many potential vaccines failing to progress on the path to licensure.¹⁶⁴ The poor understanding of typhoid immunobiology, and, in particular, the absence of a correlate of protection for typhoid fever that could be used in efficacy trials was highlighted as a rate-limiting factor in the slow

Conclusion

Infections caused by S. Typhi and S. Paratyphi cause a considerable world-wide burden of disease. Clinical diagnosis is difficult and reliable diagnostic tests are not available. Moderately efficacious vaccines against typhoid fever are available today but have not been widely deployed and none are suitable for young children. Novel vaccines are needed, and there are several promising strategies on the horizon. However, as a human restricted pathogen, clinically relevant models for appraising

Conflict of interest

The authors have no conflict of interest to report.

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Typhoid fever is one of the major public health problems worldwide (Crump and Mintz, 2010). It enormously contributes to morbidity and mortality in the developing world because of overcrowding, with inadequate clean water and unhygienic conditions (Crump et al., 2004; Waddington et al., 2014). The reported global burden of typhoid in 2010 was 26.9 million cases per annum (Buckle et al., 2012), however the true burden of this disease is likely to be higher (Crump and Mintz, 2010; Buckle et al., 2012).
Efficacious typhoid vaccines for young children will significantly reduce the disease burden in developing world. The Vi polysaccharide based conjugate vaccines (Vi-rEPA) against Salmonella Typhi Vi positive strains has shown high efficacy but may be ineffective against Vi negative S. Typhi. In this study, for the first time, we report the synthesis and evaluation of polysaccharide-protein conjugates of Vi negative S. Typhi as potential vaccine candidates. Four different conjugates were synthesized using recombinant exoprotein A of Pseudomonas aeruginosa (rEPA) and human serum albumin (HSA) as the carrier proteins, using either direct reductive amination or an intermediate linker molecule, adipic acid dihydrazide (ADH). Upon injection into mice, a significantly higher antibody titer was observed in mice administrated with conjugate-1 (OSP-HSA) (P = 0.0001) and conjugate 2 (OSP-rEPA) (P ≤ 0.0001) as compared to OSP alone. In contrast, the antibody titer elicited by conjugate 3 (OSP_ADH-HSA) and conjugate 4 (OSP_ADH-rEPA) were insignificant (P = 0.1684 and P = 0.3794, respectively). We conclude that reductive amination is the superior method to prepare the S. Typhi OSP glycoconjugate. Moreover, rEPA was a better carrier protein than HSA. Thus OSP-rEPA conjugate seems to be efficacious typhoid vaccines candidate, it may be evaluated further and recommended for the clinical trials.
Salmonella infection: Interplay between the bacteria and host immune system
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Most cases occur in developing countries, or among travelers to these countries, and a recent analysis of global mortality data revealed that in endemic regions (such as sub-Saharan Africa and Asia), the relative years of life lost to enteric fever ranks similarly to those lost to breast cancer, prostate cancer, and leukemia in North America [19,20]. One particular difference between S. Typhi and NTS strains is the presence of the polysaccharide capsular antigen, Vi [21], which is thought to be a virulence factor of S. Typhi, allowing it to survive the acidic environment of the stomach early after infection, as acapsular S. Typhi is less virulent [22]. Unlike NTS broad host specificity, S. Typhi is restricted to humans only [23].
Salmonella infection causes morbidity and mortality throughout the world with the host immune response varying depending on whether the infection is acute and limited, or systemic and chronic. Additionally, Salmonella bacteria have evolved multiple mechanisms to avoid or subvert immunity to its own benefit and often the anatomical location of infection plays a role in both the immune response and bacterial fate. Here, we provide an overview of the interplay between the immune system and Salmonella, while discussing how different host and bacterial factors influence the outcome of infection.
Vaccination of active component US military personnel against Salmonella Typhi
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Infection with Salmonella enterica, serovar Typhi (hereafter referred to as S. Typhi) and the resulting illness known as typhoid fever has been a major cause of morbidity and mortality globally throughout history [1].
Vaccination against Salmonella Typhi is one of the leading public health interventions reducing the risk of typhoid fever. There are two available licensed vaccines, Vivotif, oral live-attenuated, and Typhim Vi, intramuscular Vi capsular polysaccharide. The US military is a high risk travel population commonly vaccinated for S. Typhi. We describe the use of S. Typhi vaccination in this population and the acute reactogenicity profile of these vaccines.
Data were obtained from the Defense Medical Surveillance System and vaccination identified between 1998 and 2011 from vaccination codes. Clinical outcomes were assessed for four weeks post vaccination. Adverse event rates and odds ratios were estimated across the two vaccine types.
A total of 1.9 million predominately male military personnel received 3.6 million S. Typhi vaccinations with 94.3% of vaccinees receiving the Vi capsule vaccine though variability in the vaccine administered was observed. Receipt of other vaccinations in the 6 months surrounding the S. Typhi vaccine was common. Rates of nausea (195 per 100,000 vaccinations), headache (13 per 100,000 vaccinations) and fever (40 per 100,000 vaccinations) were significantly higher following Vi capsule vaccination compared to receipt of Vivotif (130, 2, 10 per 100,000 vaccinations, respectively). In contrast the rates of rash and non-infectious diarrhea (186 and 426 per 100,000 vaccinations, respectively) were increased in those receiving Vivotif compared to the Vi capsule vaccine.
The US military is a major consumer of S. Typhi vaccines. The parenterally administered vaccine appears to be more amenable, though we were limited in our ability to assess the reasons for its higher usage. While we observed a higher rate of several adverse events in subjects receiving the intramuscular vaccination, the overall rate of these events was low. Future studies assessing more long-term health outcomes are warranted.
A review of typhoid fever transmission dynamic models and economic evaluations of vaccination
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While labour-intensive, such investigations could be integrated into wider control efforts [45]. Chronic Salmonella Typhi carriage can be treated with antibiotics and/or cholecystectomy for gallstone-associated infection, but there is no demonstrated role for vaccination in clearance of carriage [46,47]. Premised on this, Cvjetanović’s and Pitzer's models demonstrate that where carriage contributes substantially to transmission in endemic settings, vaccination is unlikely to result in elimination in the short-to-medium term [18,24].
Despite a recommendation by the World Health Organization (WHO) that typhoid vaccines be considered for the control of endemic disease and outbreaks, programmatic use remains limited. Transmission models and economic evaluation may be informative in decision making about vaccine programme introductions and their role alongside other control measures. A literature search found few typhoid transmission models or economic evaluations relative to analyses of other infectious diseases of similar or lower health burden.
Modelling suggests vaccines alone are unlikely to eliminate endemic disease in the short to medium term without measures to reduce transmission from asymptomatic carriage. The single identified data-fitted transmission model of typhoid vaccination suggests vaccines can reduce disease burden substantially when introduced programmatically but that indirect protection depends on the relative contribution of carriage to transmission in a given setting. This is an important source of epidemiological uncertainty, alongside the extent and nature of natural immunity.
Economic evaluations suggest that typhoid vaccination can be cost-saving to health services if incidence is extremely high and cost-effective in other high-incidence situations, when compared to WHO norms. Targeting vaccination to the highest incidence age-groups is likely to improve cost-effectiveness substantially. Economic perspective and vaccine costs substantially affect estimates, with disease incidence, case-fatality rates, and vaccine efficacy over time also important determinants of cost-effectiveness and sources of uncertainty. Static economic models may under-estimate benefits of typhoid vaccination by omitting indirect protection.
Typhoid fever transmission models currently require per-setting epidemiological parameterisation to inform their use in economic evaluation, which may limit their generalisability. We found no economic evaluation based on transmission dynamic modelling, and no economic evaluation of typhoid vaccination against interventions such as improvements in sanitation or hygiene.
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In contrast to commensal bacteria, which establish a well-balanced equilibrium with their host, Salmonella is an aggressive enteric pathogen that infects a broad range of mammals including humans [58]. Salmonella typhi infection, for example, is an important human pathogen that infects millions of people in countries with lower socio-economic status with high morbidity and mortality rates [59]. After ingestion, this pathogen is taken up by macrophages and cDCs at Peyer's patches which represent the major port of entry.
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The challenge of enteric fever

Summary

Introduction

Section snippets

Epidemiology

Acute typhoid fever

Chronic carriage

Diagnosis

Sanitation and clean water

Novel vaccine strategies

Controlled human infection studies with Salmonella Typhi

Establishing a 21st century challenge model

Conclusion

Conflict of interest

Trans R Soc Trop Med Hyg

Lancet Infect Dis

Trans R Soc Trop Med Hyg

Lancet

Lancet

Lancet

Lancet

Lancet

Am J Med

Lancet

Acta Trop

Lancet

Comp Immunol Microbiol Infect Dis

Public Health

Int J Infect Dis

Lancet

Who introduced typhoid vaccination: Almroth Write or Richard Pfeiffer?

Rev Infect Dis

Typhoid fever and paratyphoid fever: systematic review to estimate global morbidity and mortality for 2010

J Glob Health

Global trends in typhoid and paratyphoid fever

Clin Infect Dis

Salmonella paratyphi A rates, Asia

Emerg Infect Dis

Imported enteric fever: case series from the hospital for tropical diseases, London, United Kingdom

Am J Trop Med Hyg

Salmonella typhi and Salmonella paratyphi laboratory reports (cases only)

The global burden of typhoid fever

Bull World Health Organ

Part I. Analysis of data gaps pertaining to Salmonella enterica serotype typhi infections in low and medium human development index countries, 1984–2005

Epidemiol Infect

Typhoid fever in children in Africa

Trop Med Int Health

Typhoid fever

N Engl J Med

Current concepts in the diagnosis and treatment of typhoid fever

BMJ

A study of typhoid fever in five Asian countries: disease burden and implications for controls

Bull World Health Organ

Typhoid vaccines come of age

Pediatr Infect Dis J

Diagnostic value of the Widal test in areas endemic for typhoid fever

Am J Trop Med Hyg

Specimens and culture media for the laboratory diagnosis of typhoid fever

J Infect Dev Ctries

Laboratory-based surveillance of Salmonella serotype typhi infections in the United States: antimicrobial resistance on the rise

J Am Med Assoc

Typhoid fever among children, Ghana

Emerg Infect Dis

Community acquired bacteremia in young children from central Nigeria–a pilot study

BMC Infect Dis

The burden of invasive bacterial infections in Pemba, Zanzibar

PLoS One

Clinical and laboratory manifestations of typhoid fever at Persahabatan Hospital, Jakarta

Acta Med Indones

Clinical and microbiological investigations of typhoid fever in an infectious disease hospital in Kuwait

J Med Microbiol

Typhoid fever; clinical analysis of three hundred and sixty cases

Arch Intern Med

Typhoid fever and other Salmonella infections

Typhoid fever. An epidemic with remarkably few clinical signs and symptoms

Arch Intern Med

Immunity to salmonellosis

Immunol Rev

Discussion on recently acquired knowledge concerning the bionomics of pathogenic organisms and its bearing on the spread of disease

Br Med J