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Meiring, J.E. orcid.org/0000-0001-9183-5174, Khanam, F., Basnyat, B. et al. (12 more
authors) (2023) Typhoid fever. Nature Reviews Disease Primers, 9 (1). 71. ISSN 2056-
676X

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 1 Typhoid fever
2 James E. Meiring1,2, Farhana Khanam3, Buddha Basnyat4, Richelle C. Charles5, John A.
3 Crump6, Frederic Debellut7, Kathryn E. Holt8,9, Samuel Kariuki10, Emmanuel Mugisha11,
4 Kathleen M. Neuzil12, Christopher M. Parry13, 14, Virginia E. Pitzer15, Andrew J. Pollard16,
5 Firdausi Qadri3, Melita A. Gordon2, 17,†
6
1
7 Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, United
8 Kingdom.
2
9 Malawi-Liverpool-Wellcome Trust Programme, Blantyre, Malawi.
3
10 International Centre for Diarrhoel Disease Research, Bangladesh
4
11 Oxford University Clinical Research Unit, Nepal
5
12 Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston,
13 MA, USA.
6
14 Centre for International Health, University of Otago, Dunedin, New Zealand
7
15 Center for Vaccine Innovation and Access, PATH, Geneva, Switzerland
8
16 Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene &
17 Tropical Medicine, London, UK
9
18 Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Victoria 3004,
19 Australia
10
20 Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya
11
21 Center for Vaccine Innovation and Access, PATH, Seattle, WA, USA
12
22 Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore,
23 Maryland, USA
13
24 Liverpool School of Tropical Medicine, Department of Clinical Sciences and Education, Pembroke Place,
25 Liverpool, UK
14
26 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford,
27 Oxford, UK
15
28 Department of Epidemiology of Microbial Diseases and Public Health Modeling Unit, Yale School of Public
29 Health, Yale University, New Haven, CT, USA
16
30 Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical
31 Research Centre, Oxford, UK
17
32 Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
33
†
34 Email: [email protected]
35
36 Abstract
37 Typhoid fever is an invasive bacterial disease associated with bloodstream infection that
38 causes a high burden of disease in Africa and Asia.Typhoid primarily affects individuals
39 ranging from infancy through to young adulthood. The causative organism, Salmonella
40 enterica serovar Typhi is transmitted via the faecal-oral route, crossing the intestinal
41 epithelium and disseminating to systemic and intracellular sites, causing an undifferentiated
42 febrile illness. Blood culture remains the practical reference standard for diagnosis of
43 typhoid fever, where culture testing is available, but novel diagnostic modalities are an
44 important priority under investigation. Since 2017, remarkable progress has been made in
45 defining the global burden of both typhoid fever and antimicrobial resistance; in
46 understanding disease pathogenesis and immunological protection through the use of
47 controlled human infection; and in advancing effective vaccination programmes through
48 strategic multi-partner collaboration and targeted clinical trials in multiple high-incidence
49 priority settings. This primer article thus offers a timely update of progress and perspective
50 on future priorities for the global scientific community.
51 [H1] Introduction
52 Typhoid fever, also known as typhoid, is a serious invasive infection involving the blood-
53 stream and deep reticulo-endothelial tissues. The organism responsible for the clinical
54 syndrome of typhoid fever, Salmonella enterica subsp. enterica serovar Typhi (S. Typhi), is
55 found within the Enterobacterales family. S. Typhi is a rod-shaped, Gram-negative,
56 facultative anaerobic bacteria within the Salmonella genus, and is host-restricted to
57 humans1.
58 The WHO defines a confirmed case of typhoid fever as an individual with laboratory
59 confirmation of S. Typhi by culture, or molecular methods such as detection of S. Typhi DNA,
60 from a normally sterile site2. A suspected case of typhoid fever is defined as an individual
61 with fever for at least three out of seven consecutive days in an endemic area, or following
62 travel from an endemic area, or after a household contact with a confirmed case2. In
63 endemic areas where appropriate diagnostics are lacking, clinical symptoms are relied upon
64 for establishing a diagnosis. However, with numerous other infectious conditions presenting
65 with a similar undifferentiated fever, clinical symptoms lack both sensitivity and specificity3.
66 Typhoid fever was the first human disease in which asymptomatic carriage was
67 demonstrated, in 1904, to be a source of disease transmission,4 including in the famous case
68 of Mary Mallon5. Generally, ~2–5% of acute typhoid illnesses are thought to develop
69 asymptomatic chronic carriage6. Chronic carriage is defined as apparently healthy
70 individuals with evidence of S. Typhi shedding in stool at least 12 months after finishing an
71 appropriate course of antimicrobial treatment and the resolution of symptoms, following a
72 laboratory confirmed episode of acute disease, or alternatively, two positive stool samples
73 for S. Typhi 12 months apart.2
74 S. Typhi is transmitted via the faecal-oral route crossing the intestinal epithelium and
75 disseminating to systemic sites. Blood culture, where available, remains the practical
76 reference standard for diagnosis of typhoid fever7. Timely administration of appropriate
77 antimicrobials is the mainstay of treatment for typhoid fever; however, with escalating
78 antimicrobial resistance, treatment has become challenging in some parts of the world8.
79 With improvements in sanitation infrastructure, drinking water quality, and enhanced food
80 safety procedures the incidence of typhoid fever can be reduced.9,10 However, in some low-
81 resource settings, the comprehensive changes required in setting up such infrastructure
 82 may take decades or even generations, and hence, the burden of disease from infancy
83 through to young adulthood, remains unacceptably high.
84 The term ‘enteric fever’ encompasses both typhoid fever and the clinically similar syndrome
85 caused by Salmonella enterica serovars Paratyphi A, B, or C (S. Paratyphi A, B, C). A full
86 description of paratyphoid fever is beyond the scope of this primer, but it is mentioned in
87 brief where there are relevancies, similarities, or contrasts — in particular for S. Paratyphi A,
88 which accounts for ~25% of enteric fever cases in South Asia11. Salmonella serovars other
89 than S. Typhi and S. Paratyphi A, B, or C are known as non-typhoidal Salmonella (NTS).
90 Although NTS can cause a severe invasive syndrome (iNTS disease), which is particularly
91 prevalent among African children, a description of NTS disease is also beyond the scope of
92 this Primer.
93 In this Primer, we discuss the epidemiology of typhoid fever, detailing the burden and
94 pattern of disease, modes of transmission, and risk factors for infection. Furthermore, we
95 explore the literature on S. Typhi bacterial genomics as well as pathogenesis and the host
96 response to infection. Finally, we outline the current patterns of antimicrobial resistance
97 globally and the antimicrobial treatment options available. As typhoid has a variable and
98 often non-specific clinical presentation, we emphasize the need for improved diagnostics for
99 clinical use and epidemiological use.

100 [H1] Epidemiology

101 [H2] Reservoir, source, and mode of transmission
102 S. Typhi is a human-restricted pathogen with no non-human animal reservoir12. S. Typhi is
103 shed in human faeces from sites of infection in the gallbladder and small bowel. In high-
104 incidence areas with poor sanitation infrastructure, the major source of new infections is
105 indirect transmission via water and via food contaminated with the faeces13 of an infected
106 person, who might shed the bacteria during acute infection, convalescence, or chronic
107 carriage. As typhoid fever incidence declines within a specific population, the treatment of
108 chronic carriers with antimicrobials and in some cases, cholecystectomy, might become
109 necessary to prevent new infections. Studies have reported direct transmission of S. Typhi
110 associated with oral-anal sex14. In addition, S. Typhi may also survive outside the human
111 host for extended periods without evidence of multiplication 15 in a viable, non-culturable
112 state, contributing to persistence and transmission over large distances and extended time
113 scales16. Changes in expression of S. Typhi genes involved in metabolism and the respiratory
114 chain may provide insights into the mechanisms for survival of S. Typhi in aqueous and other
115 environments17. Improvements in the sensitivity of detection of S. Typhi in environmental
116 samples by nucleic acid amplification have enhanced our understanding of the role of
117 environmental contamination in community-level risk of typhoid fever18.

118 [H2] Measuring disease burden

119 Studies have established S. Typhi as the leading cause of community-onset bloodstream
120 infection in south and southeast Asia19 and an important albeit less prominent cause in
121 Africa20,21. Since 2020s, the number and geographic representativeness of studies of enteric
122 fever and typhoid fever incidence and outcome has improved greatly22-26, as have
123 approaches to extrapolating incidence,27-30 and modelling burden of disease31.
124 In 2017, typhoid fever was estimated to cause 10.9 (95% uncertainty interval, UI 9.3–12.6)
125 million illnesses globally and 116,800 (95% UI 65,400–187,700) deaths globally31. The global
126 case fatality ratio is estimated at 0.95%.
127 Based on population-based cohorts and national surveillance data in medium-incidence and
128 high-incidence regions combined with registration sources in low incidence regions, global
129 incidence of enteric fever was estimated to be 197.8 (95% UI 172.0–226.2) per 100 000
130 person-years11. Typhoid-specific global incidence is estimated to be 130.96 (95% UI 83.94-
131 199.55) per 100 000 person years (Figure 1).32
132 Considering variation by super-regions, defined as areas of the world grouped by
133 epidemiological similarlity and geographical proximity, south Asia had the highest age-
134 standardised incidence rate of enteric fever (549, 95% UI 481–625, cases per 100 000
135 person-years) and the largest number of illnesses (10.3 million, 95% UI 9.0–11.7),
136 accounting for 71·8% of global illnesses in 201711. Southeast Asia, east Asia, and Oceania
137 combined accounted for 14·1% of enteric fever illnesses (2.02 million, 95% UI 1.82–2.23)
138 with an incidence ranging from 51.0 (east Asia) to 219.8 (southeast Asia) per 100,000
139 person-years. Sub-Saharan Africa accounted for 12·1% of enteric fever illnesses (1.73
140 million, 95% UI 1.45–2.06), and had an incidence ranging from 151–161 per 100,000 person-
141 years in West and East Africa respectively, to 2.3 per 100,000 person-years in southern
142 Africa11.
143 To estimate burden of disease, a natural history approach is undertaken, which includes
144 collation of studies of typhoid incidence using active population-based surveillance, or
145 hybrid surveillance methods, and extrapolating to areas without data33,34,35. In addition, the
146 prevalence of major complications such as intestinal perforation, and the case fatality
147 ratio36,37 are applied to estimate disability and death owing to typhoid fever31. Overall, in
148 2017, enteric fever was responsible for 8.4 (95% UI 4.7 – 13.6) million disability-adjusted life
149 years, comprising 8.3 (95% UI 4.6 - 13.4) million years of life lost and 105,000 years lived
150 with disability)11.

151 [H2] Risk factors

152 [H3] Age
153 In high-incidence and medium-incidence endemic settings, typhoid fever is observed from
154 infancy onwards. Globally the disease peaks at 5–9 years of age, however, this average
155 conceals considerable heterogeneity in incidence by age between regions and countries11.
156 The peaks and decline in the incidence of typhoid fever with age in endemic settings are
157 believed to be related to the rate at which susceptible individuals acquire infection and,
158 therefore, the acquisition of immunity cumulatively from natural infection and repeated
159 subclinical or asymptomatic exposure to the pathogen38. This means that across these age-
160 bands there is considerable variation in age-distribution by location. For example, incidence
161 may be high or even reach peak levels among infants in very high incidence areas, but peak
162 incidence might be observed in older children or even young adults, in areas of medium
163 incidence. Incidence subsequently declines gradually with age through adulthood and
164 incidence is typically low in all elderly populations31. Re-infection, as opposed to relapse, has
165 been documented, suggesting only moderate levels of protection conferred by an episode
166 of clinical infection39.
167 [H3] Environmental exposures.
168 A systematic review and meta-analysis of case-control studies evaluated associations
169 between typhoid fever and water, sanitation and hygiene (WASH) and food exposures. 40
170 The authors identified 19 manuscripts describing 22 case-control studies, with 20 studies
171 (90.9%) having medium or high risk of bias. In the meta-analysis, good hygiene and water
172 treatment were most strongly associated with protection from typhoid fever (OR = 0.52 and
173 0.59, respectively), whereas poor hygiene and untreated water were most strongly
174 associated with the risk of typhoid fever (OR = 2.2 and 2.4, respectively). Of the sanitation
175 factors household latrine availability and use, safe waste management, unsafe waste
176 management, and open defecation, unsafe waste management was significantly associated
177 with typhoid fever (OR = 1.6, 95% CI = 1.3–2.0). Hygenic food practices were significantly
178 associated with decreased odds of typhoid fever (OR = 0.74), and risky food practices and
179 consuming food or drink outside the home were associated with significantly higher odds of
180 typhoid fever (OR = 1.6–1.7) than consuming home-based meals. Dairy, ice cream and fruits,
181 and juices were significantly associated with typhoid fever (OR = 1.4–1.5)40. In a cluster
182 randomized controlled trial of typhoid conjugate vaccine (TCV), living in a household with
183 better WASH practices at baseline was associated with a significant reduction in the
184 incidence of typhoid fever independent of vaccine intervention41. By contrast, in typhoid
185 non-endemic countries, cases of typhoid fever were almost exclusively related to recent
186 travel, contact with a traveller from an endemic country, or exposure to food prepared by a
187 chronic carrier42.
188 [H3] Human genetic factors.
189 A genome-wide association study performed among individuals with and without blood
190 culture-confirmed enteric fever in Vietnam showed a strong association of rs7765379, a
191 marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1, with an
192 increased risk of infection43. This finding was replicated in a large cohort in Nepal and in a
193 second independent study from Vietnam.43 HLA-DRB1 was implicated as a major contributor
194 to resistance against enteric fever, likely mediated by antigen presentation.
195 [H3] Seasonal and environmental factors.
196 Improvements in WASH and food exposures and increased use of TCV in typhoid-endemic
197 countries, are likely to strengthen typhoid fever prevention and control. An analysis of
198 seasonal patterns of typhoid and paratyphoid fevers observed a distinct seasonal pattern by
199 latitude, with seasonal variability in incidence, more pronounced further from the
200 equator44. The investigators found evidence of a positive association between preceding
201 rainfall and enteric fever among regions 35°–11°N and a positive association between
202 higher temperature and enteric fever incidence across most regions of the world. The
203 underlying mechanisms that drive the seasonality of typhoid fever are poorly understood.
204 The impact of climate change that contribute to faecal contamination of water and food,
205 such as flooding or water shortages that increase dependence on unsafe water and
206 deterioration in food safety might likely be associated with an increased risk of typhoid
207 fever45-47.
208 [H2] Pathogenic variants
209 Since the 1900s, phage typing has identified distinct variants of S. Typhi and S. Paratyphi
210
48,49. Global diversity studies have shown that both pathogens harbour multiple distinct
211 phylogenetic lineages, which are linked to specific geographic regions50,51. However, no
212 evidence exists showing association of different S. Typhi or S. Paratyphi A variants with
213 demographic factors such as age or sex52,53. Futhermore, the variants also do not exhibit
214 differences in disease presentation or severity. Currently, pathogen genome sequencing
215 have replaced phage typing and S. Typhi variants have been defined and identified using the
216 GenoTyphi genotyping scheme, which was first developed in 2016 using ~2,000 pathogen
217 genome sequences from 65 countries54. This scheme is regularly updated to reflect newly-
218 identified variants or genotypes; for instance, the latest updates to the scheme (December
219 2022) were based on analyses of 13,000 genomes from 111 countries by the Global Typhoid
220 Genomics Consortium55,56. These data provide a comprehensive view of the distribution of
221 S. Typhi variants across different parts of the world, although some regions, especially
222 Central and Northern Africa, Western Asia and Latin America, still lack sequence data. The
223 distribution of variants is quite distinct by region (Figure 2)57. For example, genotype 4.3.1
224 (previously known as H58) dominates the pathogen population in South Asia (where it is
225 thought to have emerged in the early 1990s)58 and Eastern Africa (where it is thought to
226 have been introduced multiple times in the last 10–20 years)52, but is rare elsewhere. In
227 Western Africa, the dominant genotypes are 3.1.1 and 2.3.1(ref59), whereas the dominant
228 variants are 2,2.5 and 3.5 in Central America and South America60,61. In addition, island
229 nations have their distinct genotypes — 3.5 in Samoa, 3.5 and 4.2 in Fiji, 4.2 and 2.1.7 in
230 Papua New Guinea)55,62,63. The reason for geographic separation of variants is not fully
231 understood, although human migration patterns might be the driving factor as S. Typhi is a
232 human-restricted pathogen64. For example, the transfer of 4.3.1 to Eastern Africa could be
233 linked to frequent migration of South Asians to Kenya and neighbouring countries in East
234 Africa, whereas the distinct S. Typhi populations in Western Africa could reflect greater
235 stability of communities within that setting.

236 [H1] Mechanisms/Pathophysiology

237 Non-typhoidal Salmonella enterica (S. enterica) serovars cause foodborne gut luminal
238 inflammation and enterocolitis in healthy humans. However, S. Typhi once ingested can
239 rapidly cross the intestinal epithelium and disseminate to systemic sites, including the liver,
240 spleen, bone marrow, and gallbladder1 (Figure 3). S. Typhi is unusual among S. enterica
241 serovars in that it harbours an exopolysaccharide capsule known as Vi — the target of
242 modern conjugate vaccines65. The Vi capsule is hypothesized to be crucial in S. Typhi
243 pathogenesis; however, S. Paratyphi A causes a clinically indistinguishable infection despite
244 lacking a Vi capsule, and these two human-restrictive invasive serovars do not share any
245 additional or unique virulence factors66. Unlike non-typhoidal serovars that have a broad
246 host-range among vertebrates, the genomes of serovars Typhi and Paratyphi A show
247 evidence of functional gene loss, characteristic of host-restricted adaptation. Approximately
248 4% of S. Typhi and S. Paratyphi A genes carry these inactivating mutations, known as
249 pseudogenes, compared with ≤1% in other non-typhoidal S. enterica serovars67-70.

250 [H2] Insights from disease models

251 [H3] Infection of intestinal epithelium and dissemination to tissues.
252 Owing to the human-restricted nature of S. Typhi and S. Paratyphi A, much of the
253 foundational understanding of typhoid pathogenesis has come from the study of mice
254 infected with the ‘generalist’ serovar S. enterica serovar Typhimurium (S. Typhimurium)
255 causing an invasive illness. This has elucidated a range of pathogenic mechanisms, and been
256 considered a helpful model of typhoid. Furthermore, a range of related in vivo and ex vivo
257 models have yielded important mechanistic insights into the complex interplay between the
258 pathogen, the microbiota and the host response70 . Following oral ingestion by mice,
259 generalist non-typhoidal serovars survive gastric acidity and evade colonisation resistance
260 by inducing inflammatory competition with the resident microflora, thereby altering the
261 metabolic landscape in the lumen to optimise access to luminal host-derived resources such
262 as oxygen, nitrate, tetrathionate and lactate71. S. Typhi , by contrast, is a stealth pathogen
263 that employs several adaptation techniques to rapidly cross the gut epithelium, inducing
264 minimal inflammation66,72. S. Typhi possesses the regulatory locus, TviA, encoding a protein
265 with a complex counter-balanced regulatory function, which downregulates flagellin-
266 associated inflammation and upregulates expression of the Vi capsule polysaccharide that
267 mediates immune evasion73. The genes encoding the Vi capsule comprise the viaB locus
268 within the salmonella pathogenicity island 7 (SPI-7), which also encodes the type III
269 secretion system (T3SS) effector, SopE and a type IVB pilus74.
270 Invasive salmonella serovars, in a susceptible host, can potentially cross the intestinal
271 barrier by a multiplicity of routes, which include direct invasion of enterocytes, invasion by a
272 transcellular route, direct uptake by dendritic cells across the epithelium or invasion of
273 specialised antigen-sampling epithelial microfold cells (M cells). The M-cells overlie the
274 organised lymphoid tissue of Peyer's patches, found particularly in the terminal ileum75.
275 Salmonellae are transported via M cells to be presented to B cells and dendritic cells that
276 reside within the microfolds in Peyer’s patches76. Chronic infection of the lymphoid tissue in
277 human intestinal Peyer’s patches is a key element of pathogenesis, which acts as a source of
278 ongoing enteric shedding in the stool and transmission. Chronic infection may also lead to
279 necrosis of the Peyer’s patch tissue and consequently, intestinal perforation — a serious
280 complication of typhoid fever.
281 Once salmonellae have gained access to the host circulation causing a transient
282 asymptomatic primary blood stream infection, they can disseminate to different organs by
283 several mechanisms77. During extracellular vascular dissemination in the circulation, the Vi
284 capsule inhibits phagocytosis and confers serum resistance, likely by shielding the surface
285 lipopolysaccharide O-antigen from antibodies78. In addition, the ability to survive and
286 disseminate intracellularly is a key pathogenic strategy and bacteria are also translocated
287 from the gut within CD18+ cells. This cellular population encompasses the reticulo-
288 endothelial system including monocyte or macrophages, dendritic cells and
289 polymorphonuclear leukocytes, and phagocytes in the liver, spleen and bone marrow67.
290 Within minutes of contact with phagocytic cells, invasive salmonella are internalized into
291 the salmonella-containing vacuole67, a highly specialised modified phagosome that prevents
292 endosomal fusion with the phagocyte oxidase complex, thus establishing a chronic, deep-
293 seated intracellular reticuloendothelial infection66. This established infection results in a
294 persistent secondary blood stream infection associated with high fever. Salmonellae to
295 thence enter and colonise the gall bladder, particularly if there are gallstones or other
296 structural abnormalities, providing an important niche from where they may be shed back
297 into the gastrointestinal tract in bile. This is the hallmark mechanism of chronic carriage of
298 typhoid in human disease, enabling ongoing community transmission of the pathogen to
299 new hosts. This re-infection of the upper gastrointestinal tract may also result in re-infection
300 of Peyers patches, leading to necrosis of tissue and consequently, intestinal perforation — a
301 serious complication of typhoid fever requiring surgery, which may be accompanied by a
302 tertiary blood stream infection with a range of enteric micro-organisms.

303 [H2] Controlled human infection model

304 A controlled human infection model (CHIM) for study of typhoid infection, was established
305 at Oxford University in 2011 to further our understanding of disease pathogenesis and
306 accelerate the development of candidate vaccines79. The CHIM model involved deliberate
307 infection of healthy adult volunteers with an antibiotic-sensitive strain of S. Typhi,
308 manufactured under Good Manufacturing Practice , originally derived from the gallbladder
309 of a woman with chronic typhoid infection in Maryland in the 1950s 79,80. After screening and
310 informed consent procedures, participants ingested 10,000 colony-forming units (CFU) of S.
311 Typhi in a bicarbonate solution. Approximately two thirds of individuals developed a fever
312 for >12 hours and/or bacteraemia over the next 2 weeks (median time to onset was 8 days),
313 thus meeting the study definition of typhoid fever and triggering cessation of infection with
314 oral antibiotics79. A similar model was established to study paratyphoid infection, although
315 1,000 CFU of S. Paratyphi A were sufficient to cause consistent infection (60%)81. In the
316 paratyphoid infection model, the proportion of individuals with bacteraemia and the
317 cytokine responses of participants were similar to those in the typhoid infection model.
318 However, bacteraemia was more prolonged (median 53 hours) and blood-culture positive
319 asymptomatic infection was more common (55%) in individuals with paratyphoid fever than
320 in individuals with typhoid81.
321 [H3] Inflammatory response.
322 After ingestion of the bacteria, the typhoid model showed evidence of transient but
323 asymptomatic bacteraemia in the first 24 hours documented by detection of DNA in
324 peripheral blood82, This bacteraemia might represent the initial transit of bacteria from the
325 gut mucosa to the lymphoid tissues prior to the incubation period. The initial DNAaemia is
326 associated with a systemic cytokine response, notably consisting of sCD40L, fractalkine
327 (CX3CL1), GROα, IL1RA, EGF and VEGF, regardless of whether the individual later goes on to
328 develop overt typhoid disease. This cytokine response may represent inflammatory
329 perturbation at the gut mucosa, perhaps implying that the infection is limited to the
330 mucosa, but could also be consistent with invasive infection even among those who do not
331 go on to show evidence of overt infection83. Onset of clinical invasive disease was heralded
332 by a gradual fall in eosinophil count over the 5 days preceding onset of symptoms, followed
333 by a fall in total white cell count, lymphocytes, neutrophils and platelets after the onset of
334 clinical disease79. Whether these changes represent successful deployment of an
335 appropriate immune and inflammatory response to the infection or a failure of an
336 appropriate protective response are not clear. Almost all individuals had positive blood
337 cultures associated with diagnosis of infection in the model, with a median of 1 CFU per ml
338 of blood detected.79
339 After the onset of febrile symptoms, the profile of transcriptomic responses reflected the
340 presence of strong type I and II interferon signals that were associated with bacteraemia in
341 the study83. Evidence shows that this interferon signalling interfered with tryptophan
342 metabolism, which might indicate that part of the host response exists to limit bacterial
343 growth. As a component of the acute innate immune response to infection, studies have
344 shown an increase in hepcidin levels increased and decrease in blood iron levels.Limiting the
345 iron availability for extracellular bacteria in the blood and concomitantly increasing iron
346 availability in macrophages supporting survival of internalised bacteria is a characteristic
347 feature of S.Typhi infection84 .

348 [H3] Antibody response.

349 Among those challenged with S. Typhi who progressed to develop clinical disease, IgG, IgM
350 and IgA responses against H (flagellar) antigen and lipopolysaccharide were detected in the
351 peripheral blood, but no measurable anti-Vi antibody response were detected in these
352 previously unexposed individuals79. Responses in the CHIM were further probed using a
353 250-antigen array, and serodiagnostic signatures containing flagellin, OmpA, HlyE, sipC, and
354 IgG, IgM and IgA antibody responses against lipopolysaccharide could distinguish typhoid
355 from other febrile illnesses in an endemic setting85 . IgA against lipopolysaccharide antigen
356 performed particularly well as a diagnostic marker in the model. In addition, a set of five
357 gene expression profiles that could distinguish individuals with typhoid infection from other
358 febrile illnesses were identified using the CHIM86.
359 [H3] Role of typhoid toxin.
360 Studies have shows that typhoid toxin induced some of the hall mark clinical features of the
361 disease in murine models, suggesting that the toxin may be an important virulence factor
362 for S. Typhi87,88. However, the toxin also found in other typhoidal and non-typhoidal
363 salmonellae including serovars that do not cause the clinical syndrome of enteric
364 fever68,89,90. To assess the virulency of the toxin, volunteers were challenged either with a
365 toxin-negative or wild-type strain and no difference was found in the proportion of
366 individuals developing typhoid between the two groups. Unexpectedly, bacteraemia was
367 more prolonged in the toxin-negative group than in the wild-type group. These observations
368 indicate no role for typhoid toxin in imparting susceptibility to typhoid infection91.
369 [H3] Infection-derived immunity.
370 Immunity acquired from S. Typhi infection is likely an important factor to be considered
371 when understanding the impact of vaccination on transmission of the pathogen. Whilst
372 modelling studies include acquisition of natural immunity as an important variable, few data
373 are available on the level and duration of protection afforded by clinical disease
374 episodes92,93. After prior CHIM infection (median 19 months previously, range 12–67
375 months), volunteers who underwent rechallenge with the same serovar as their initial
376 challenge (homologous challenge with S. Typhi or S. Paratyphi A) had a moderately reduced
377 risk of developing typhoid (36%) or paratyphoid (57%), but no protection was conferred by
378 challenge of the alternative organism(heterologous cross-challenge)38. In those who did
379 develop enteric fever, no difference in symptoms was found between naïve individuals
380 (those not previously challenged) and those who had previously been challenged.
381 Interestingly, baseline anti-lipopolysaccharide, anti-H and anti-Vi antibody levels were
382 similar between the naïve and rechallenged groups, and no obvious boost in antibody was
383 observed in those with prior exposure38.
384 [H3] Stool shedding.
385 Six typhoid and paratyphoid CHIM studies with 4,934 stool samples were analyzed to
386 identify factors that might reduce stool shedding and potentially reduce transmission in
387 field settings94. Prior infection in those who were rechallenged in the CHIM was associated
388 with reduced shedding (OR 0.30; 95% CI: 0.1–0.8) as was prior vaccination with a Vi-
389 containing vaccine (OR 0.34, 95% CI: 0.15–0.77 for Vi polysaccharide vaccine; and OR 0.41,
390 95% CI: 0.19–0.91 for TCV)94. A non-significant reduction in stool shedding was associated
391 with the live oral Ty21a vaccine94. The Oxford CHIM has been used in assessing vaccine
392 efficacy of a number of typhoid vaccines (Box 1).

393 [H2] Antimicrobial resistance

394 Antimicrobial resistance is common in both S. Typhi and S. Paratyphi A, and is typically
395 driven by local overprescription of antibiotics95,96. Multidrug resistant (MDR) S. Typhi is
396 defined as resistance to the combination of three first-line treatments — chloramphenicol,
397 ampicillin and trimethoprim-sulfamethoxazole. MDR S. Typhi, a clinical problem since the
398 1980s, emerges through the simultaneous acquisition of multiple resistance genes encoded
399 on a single transmissible plasmid, which can be transferred between bacterial species and
400 strains97. By the 1990s, in parts of south and southeast Asia the majority of S. Typhi
401 infections were MDR98, prompting a switch to fluoroquinolones and azithromycin as the
402 mainstays of treatment. However, fluoroquinolone resistance is now highly prevalent in
403 these regions, mostly owing to gyrA and parC mutations in 58,99. Extensively-drug resistant
404 (XDR) S. Typhi, defined as the combination of MDR plus resistance to fluoroquinolones and
405 third-generation cephalosporins, has now emerged. A large outbreak of XDR S. Typhi was
406 reported in Pakistan in 2016 and the corresponding variant (4.3.1.1.P1), which has spread
407 throughout the country, caused the majority of typhoid cases reported there in 2018–2019
408 (Ref100,101). Although this XDR variant has been detected in other countries, its incidence is
409 usually linked to travel to Pakistan102,103. The prevalence of MDR S. Typhi has declined <10%
410 in India and Nepal. However, as MDR plasmids still circulate amongst other salmonellae in
411 these regions, return to previous drugs is not favoured as it might prompt a re-emergence
412 of MDR and subsequently, XDR S. Typhi. Azithromycin resistance has been reported, mainly
413 in south Asia, but remains rare (<1%)57. By contrast, in sub-Saharan Africa, MDR S. Typhi is
414 common in most countries and fluoroquinolone resistance is increasing in countries where
415 this drug class is overprescribed104; azithromycin and XDR strains are, however, extremely
416 rare52,59,95,96. S. Paratyphi A infections are rarely MDR, but are almost always
417 fluoroquinolone resistant49,51,95. Azithromycin resistance is reported in S. Paratyphi A in
418 south Asia but, similar to S. Typhi, remains rare .

419 [H1] Diagnosis, screening, and prevention

420 [H2] Diagnosis
421 One major obstacle to controlling typhoid fever is the absence of reliable and easily
422 deployable diagnostics. In most resource-constrained settings, diagnosis is based on clinical
423 symptoms and in most cases, the Widal test, which is non-specific, is used105. Most patients
424 with typhoid fever present with nonspecific clinical features, with fever predominating,
425 alongside symptoms such as malaise and headache106. Hence, differentiating typhoid fever
426 from other febrile illnesses, such as malaria, dengue or scrub typhus, can be challenging.12
427 Multiple studies in typhoid-endemic areas in Asia have demonstrated that relying on clinical
428 features to diagnose typhoid fever is unreliable with low specificity (< 15%) and positive
429 predictive values (≤ 10%)107,108.
430 Efforts are in progress to create a benchmark specification for an improved diagnostic test
431 for typhoid fever. Ideally, this test would fulfill several key criteria — it would be
432 inexpensive (for instance, costing <1 dollar), highly accurate (with a high sensitivity and
433 specificity), quick (results available in <15 minutes) and user-friendly, requiring no data-
434 interpretation, minimal training or sample processing, and not dependent on a stable water
435 or power supply. A test that meets these standards would markedly improve the clinical
436 diagnosis and management of typhoid fever, thereby reducing its morbidity and mortality.
437 Improved diagnostics will also contribute to combat antimicrobial resistance. The available
438 tests for typhoid do not currently meet these specificationsand promising assays are in
439 development.
440 [H3] Culture testing.
441 A positive culture test from a normally sterile site (blood or bone marrow) is considered the
442 reference standard for typhoid fever. However, the results might take several days and
443 culture testing requires substantial laboratory capacity, which is not widely available in
444 resource-constrained areas. The sensitivity of culture depends on the specimen type, prior
445 antimicrobial use, timing of collection and sample volume owing to differences in bacterial
446 burden at systemic sites7. For example, the organism burden in bone marrow is orders of
447 magnitude higher than in the peripheral blood (median of 10 vs. 0.5 colony forming
448 units/mL, respectively)109 and bacterial load in the blood peaks during the first week of
449 infection7. Bone marrow culture has the highest sensitivity (>90%)110 and bacterial load
450 remains high in bone marrow for several weeks, but this method has limited clinical utility
451 due to its invasiveness. Blood culture has a sensitivity of only 50–70%7,111, and stool culture
452 has a sensitivity of 30–40%112. In addition to having low sensitivity, a positive stool culture
453 may indicate either acute disease, convalescent disease or chronic carriage and is,
454 therefore, not considered diagnostic of current invasive disease.
455 [H3] Molecular testing.
456 Molecular diagnostics offer great promise to improve sensitivity and decrease time-to-
457 result. Multiple nucleic acid detection methods have been developed including
458 conventional, nested, multiplex, and real-time PCR and loop-mediated isothermal
459 amplication; however, these methods share the same limitations as blood culture113.
460 Moreover, current PCR-based methods require laboratory capacity, and the stochasticity of
461 genomes in small blood samples can lead to false negatives82,114. Owing to the low
462 magnitude of bacteremia in typhoid fever, a pre-culture may be required to improve
463 sensitivity.
464 [H3] Novel serodiagnostics.
465 Commercially available serum-based diagnostics, including the Widal agglutination test and
466 latest generation rapid diagnostic tests are widely available and detect antibodies against S.
467 Typhi in serum or plasma. Although simple and fast, these tests have moderate sensitivity
468 and specificity due to pre-existing antibodies from prior exposure and cross-reactivity105. In
469 a Cochrane review of 37 typhoid rapid diagnostic tests, the best-performing assay, Tubex,
470 had a sensitivity of 78% and specificity of 87%105 and a prospective and hybrid retrospective
471 study of 9 commercially available rapid diagnostic tests showed the best-performing test
472 was Enterocheck with 73.8% sensitivity and 94.5% specificity115. These results underscore
473 the need for improved tests that accurately detect the S. Typhi.
474 Advances in antigen discovery have revealed several novel antigen targets to improve
475 serodiagnostic assays85,116,117. Many of these antigens were further validated in populations
476 from Bangladesh and Nepal118 and a promising rapid diagnostic test, namely, the DPP®
477 Typhoid Assay has been developed. This assay is based on detecting S. Typhi
478 lipopolysaccharide and HlyE-specific IgA and early studies demonstrate sensitivity and
479 specificity of >90%118. Other novel typhoid diagnostic approaches currently being explored
480 include host gene signatures or metabolite signatures, which can discriminate typhoid from
481 other febrile illnesses86,119.

482 [H2] Surveillance

483 Wastewater and sero-surveillance are powerful and low-cost tools that have been used to
484 monitor community pathogen burden for several infections and are currently being
485 evaluated for measuring S. Typhi exposure and transmission within populations. In addition,
486 these approaches provide estimates of disease burden, which are not biased by care-
487 seeking behaviours and measure both symptomatic and asymptomatic infections. Studies
488 have demonstrated antibody levels to HlyE as an accurate serologic marker of acute typhoid
489 infection118,120. A multisite study used population-based serologic data to HlyE antigen
490 coupled with a new statistical modelling approach to estimate enteric fever incidence120.
491 These estimates correlated well with blood culture-based etimates of incidence but were
492 generally >100-fold higher than the unadjusted blood-culture confirmed incidence, implying
493 the rates of pathogen exposure and infection are far higher than recorded through clinical
494 surveillance. An existing challenge in serosurveillance studies of typhoid fever is that the
495 antigens presently used cannot differentiate S. Typhi from S. Paratyphi A. Anti-Vi IgG can
496 discriminate these Salmonella serovars, however its effectiveness is limited by low
497 seroconversion rates following S. Typhi infection and the prevalence of Vi antibody within
498 endemic communities. The introduction of Vi-based TCV will further complicate its use in
499 seroepidemiology, as Vi antibodies cannot distinguish active infection, immunity from
500 natural infection or vaccine-induced immunity.120,121 Environmental surveillance, which uses
501 culture or PCR-based methods to detect S. Typhi shed by infected individuals in sewage or in
502 water sources, does not have this limitation. However, the outcomes from environmental
503 surveillance for S. Typhi has been mixed18. The organism burden of S. Typhi is much lower
504 than for viral infections (for example, SARS CoV-2), which is reflected by the infrequent
505 detection of S. Typhi in wastewater samples18. Ongoing studies are being conducted to
506 ascertain if there is a correlation between environmental detection of S. Typhi and clinical
507 incidence. If this correlation is positive, two cost-effective and scalable methods that could
508 complement blood culture-based clinical surveillance will become available and expand
509 typhoid surveillance to areas without access to blood culture. A potential limitation to
510 consider, however, is that representative samples might be difficult to obtain from at-risk
511 communities that lack sewage systems.

512 [H2] Clinical manifestations

513 Typhoid fever is an outpatient disease in most areas of endemicity and generally presents as
514 undifferentiated febrile illness3. Symptoms of typhoid fever manifest 10–14 days following
515 exposure and include generalized fever and malaise, abdominal pain with or without other
516 signs such as headache, myalgias, nausea, anorexia, constipation and less commonly,
517 diarrhoea (Figure 4)106,122. The fever is classically described as step-wise (that is, gradually
518 increasing), manifesting in the first week of illness123. On clinical examination,
519 hepatosplenomegaly is observed in 29–50% of cases; diffuse abdominal tenderness and a
520 coated tongue (that is, a superficial white coating on the surface) is more common than
521 other symptoms and is observed in 56–85% of cases122. Additionally, rose-spots (a blanching
522 erythematous rash containing culturable S. Typhi) are reported in the historical literature110.
523 The antibiotic era has changed some of the clinical features historically seen in typhoid
524 fever; as patients receive appropriate antimicrobial therapy, the prevalence of
525 hepatosplenomegaly and rose spots has reduced3,124.
526 [H3] Gastrointestinal complications
527 Severe complications, such as shock, jaundice, intestinal perforation, intestinal
528 haemorrhage and encephalopathy, can occur if antimicrobial treatment is delayed or
529 inadequate36. Intestinal perforation is commonly reported as a sequalae of severe typhoid
530 infection, with the primary site of perforation occurring in the terminal ileum, resulting from
531 necrosis of infected Peyer’s patches125,126. Studies have documented increasing prevalence
532 of intestinal perforation in outbreak scenarios and in regions with increasing antimicrobial
533 resistance127. In this regard, the WHO have included guidance on the surveillance of
534 intestinal perforation, recommending all instances to be recorded in typhoid endemic
535 regions2. A systematic review of intestinal perforation in Africa found the case fatality rate
536 to be between 4.6% to 75% in included studies; however, the majority of studies (79%)
537 reported a fatality rate between 10% and 30%126 . Intestinal perforation is treated by
538 surgery, and another review estimated the mean duration of hospitalisation secondary to
539 intestinal perforation to be 18.4 days128.
540 [H3] Neurological manifestations.
541 Although rare, studies have reported numerous neurological manifestations of enteric
542 fever, including typhoid meningitis and encephalopathy129. In 2009, a large outbreak of
543 blood-culture confirmed typhoid fever with an unusually high burden of neurological
544 complications (13%) and high mortality rate (4%) was reported from the Malawi-
545 Mozambique border130. Dysarthria, ataxia, upper motor neuron signs and altered mental
546 status were identified in >40 individuals.130 Although, culturing S. Typhi directly from the
547 cerebrospinal fluid is rarely performed, cortical irritation leading to clinical symptoms is
548 hypothesized to be mediated by the typhoid toxin131,132 .
549 [H3] Other complications.
550 Systematic reviews have highlighted other complications that occur in different age-groups
551 of patients with typhoid fever. Hepatitis (36%), anaemia (71%) and leukocytosis (41%) are
552 common in children <5 years of age, whereas altered mental status (30%), signs of upper
553 respiratory tract infection (22%) and abdominal pain or tenderness (70%) are frequent in
554 school-aged children106,132. Young children, <5 years of age, are more likely to present with
555 diarrhoea than older children and adults, whereas constipation and intestinal perforations
556 are often observed in older age groups (>15 years) than children106,132. In addition,
557 respiratory symptoms (cough or bronchopneumonia) or neurologic complications (such as,
558 encephalopathy and febrile seizures) are more commonly seen in children than adults.
559 These reviews also reported geographical heterogeneity for common complications
560 associated with typhoid fever, with anaemia being more prevalent in South Asia than other
561 regions and abdominal distension, ileus and intestinal perforation more prevalent in sub-
562 Saharan Africa than the rest of the world36,106.
563 The estimated pooled prevalence of all complications (defined as any unfavourable
564 evolution of the disease) in hospitalised patients was 27% (95% CI, 21– 32%)133 with a mean
565 overall case fatality of 4.45% (95% CI 2.85–6.88%)134. The manifestation and severity of
566 typhoid fever can differ depending on the patient's age and geographical region. Children
567 bear the highest disease burden, with higher case fatality rate and complications in Africa
568 (mortality 5.4%) than in Asia (mortality 0.9%)25,36. In Africa, mortality from intestinal
569 perforation was estimated to be 19.7% compared with only 4.6% in Asia36. This reason for
570 differential mortality rates between Africa and Asia is likely to be multi-factorial. For
571 example, delays in accessing healthcare, receiving an accurate diagnosis and administering
572 appropriate treatment owing to poor healthcare infrastructure all probably contribute to
573 such differences36.

574 [H2] Chronic carriage

575 Approximately ~2–5% of acutely infected individuals are thought to develop typhoid chronic
576 carriage. However, with the usage of antimicrobials, the evolution to chronic carriage might
577 be less135,136.
578 To establish long-term carriage, organisms must enter the biliary tract either directly by
579 ascending through a malfunctioning sphincter of Oddi, or indirectly via the liver during
580 systemic infection137. Epidemiological investigations through case-control studies, and
581 ultrasound imaging in mice and humans, have shown the association between chronic
582 carriage and the development of bacterial biofilm S. Typhi on gallstones within the
583 gallbladder138-140. This association is further supported by data from different parts of the
584 world showing that prevalence of chronic carriers increase with age and are predominantly
585 female. These two characteristics are also primary risk factors for the development of
586 gallbladder pathology42,135,139.
587 Studies have shown the importance of carriage in low incidence, non-endemic settings
588 through multiple outbreaks, which have been traced to a chronic carrier often responsible
589 for food preparation141. However, the contribution of carriers to ongoing transmission
590 within endemic sites and the diagnosis of these individuals remains unclear. Stool shedding
591 of the pathogen is intermittent and at a low level, which makes detection through serial
592 stool culture both programmatically difficult and unreliable142.
593 Isolating the bacteria directly from the gallbladder is the gold standard for diagnosing
594 carriage. This procedure might be possible in individuals undergoing cholecystectomy but is
595 highly impractical at a public health level owing to the invasive nature of the procedure. The
596 duodenal string test, which involves passing a capsule into the stomach and a nylon string to
597 pass through the pylorus and duodenum, enabling the collection and subsequent culture of
598 duodenal and bile fluid, has been used historically for both the diagnosis of acute and
599 chronic typhoid143,144. However, yet again, this test is impractical at a public health level
600 owing to its invasiveness and inconvenience42.
601 Serological screening for chronic carriage using anti-Vi antibody has been successful in non-
602 endemic sites141,145, but in medium to high incidence area, where regular infection or
603 exposure to the pathogen increases the Vi capsule titre, the screening results have been
604 mixed146-148. Studies to identify novel serological markers of acute typhoid and carriage,
605 along with transcriptomic and a metabolomic profile, which could improve the prospective
606 diagnosisare underway149-151.

607 [H2] Prevention

608 [H3] Improved water, sanitation and hygiene
609 Improvements in water and sanitation infrastructure, where human waste is removed safely
610 from a population and uncontaminated drinking water is provided, has been shown to
611 reduce typhoid incidence in many developed countries.9,10 This approach often requires
612 large centralised, government-led initiatives with high levels of financial investment.
613 Typhoid incidence remains high in areas of the world that lack reliable clean water and
614 sanitation but where such infrastructure projects are challenging to deliver and maintain.
615 Evidence from Chile and Kenya has shown that in high typhoid incidence settings, improving
616 drinking water quality alone may not be sufficient to reduce disease incidence. 152,153 In
617 Chile, the irrigation of crops with untreated raw sewage was identified as a major factor of
618 maintaining typhoid transmission and, once this practice was prohibited, in combination
619 with other interventions, such as typhoid vaccine campaigns, disease incidence was
620 reduced.152,154 As demonstrated in Chile, behaviouoral change can be a feasible and
621 affordable option in reducing disease burden with improved water sources, improved basic
622 hygiene and treated water highlighted as areas that reduce disease burden after systematic
623 review.155 New approaches using point of collection disinfection technology may provide a
624 low-cost and easy to use alternative in parts of the world where water supply is intermittent
625 and faecal contamination remains a risk.156
626 [H3] Vaccine development
627 Vaccines may be a useful adjunctive strategy to WASH improvement to prevent morbidity
628 and mortality from typhoid fever. Although typhoid vaccines have been in use since the late
629 19th century, early vaccines were not fit-for-purpose for widespread deployment. For
630 example, the systemic and local side effects from the earliest heat-killed whole cell vaccines
631 rendered them unusable in young children.157,158. Subsequently, two more formulations
632 were developed; a live attenuated Ty21a vaccine and a Vi-Polysachharide (Vi-PS) vaccine. A
633 meta-analysis demonstrated a pooled efficacy of 50% for the oral live-attenuated Ty21a
634 vaccine at the 3-year follow-up159. Typically, multiple doses of attenuated vaccine are
635 required, and the capsule formation makes it difficult to administer the vaccine to children
636 younger than 6 years of age. The Vi-PS is a parenteral vaccine containing the purified
637 capsular Vi-polysaccharide antigen and studies demonstrated an efficacy of 59% for Vi-PS at
638 2 years160. Currently,Vi-PS is not licensed in children <2 years of age due to poor
639 immunogenicity. Although these vaccines have been widely used for travellers, the
640 limitations prevent their usage outside of outbreak control in low-income settings despite a
641 WHO recommendation in 2008 for their use to improve typhoid control 158.
642 [H3] Typhoid conjugate vaccines
643 A new generation of typhoid conjugate vaccines (TCV) have become available, in which the
644 Vi capsule is chemically conjugated to a protein carrier, thereby producing a T-cell-
645 dependent response with a greater and longer-lasting immunogenicity than with non-
646 conjugate vaccines, including younger children and infants from 6 months of age 161. In
647 2018, the WHO published a recommendation for the use of TCV in countries with endemic
648 typhoid, with priority given to countries with a high burden of disease, or high prevalence of
649 antimicrobial resistance, or both162. Notably, TCV was the first vaccine to be recommended
650 by the WHO based on its potential to prevent the spread of antimicrobial resistance. A
651 single dose of TCV is recommended for children from 6 months of age, introduced into
652 routine immunization schedules alongside mass catch-up campaigns from the first or
653 second year of life through to 15 years of age162.
654 Licensure of the first TCV was based on an immunogenicity and safety trial from India, 163
655 with the first vaccine efficacy data coming from adults in a non-endemic setting, as part of
656 the Oxford CHIM for typhoid.164,165 Since then, data from several phase 2 and 3 clinical trials
657 in diverse high-burden endemic settings confirm excellent safety, immunogenicity (including
658 safe co-administration with other routine immunisations) and efficacy for single-dose TCV in
659 children (Table 2).166,167 Trials conducted in >100,000 children in Nepal, Malawi and
660 Bangladesh yielded efficacy estimates of 79-85% in the first 1-2 years following receipt of
661 TCV.168, 169, 170,171 Longer-term efficacy data after >4 years of follow-up have shown an
662 overall intention-to-treat efficacy of 78% from the Malawi cohort, suggesting durable
663 protection.172
664 Notably, significant protection occurred in children <2 years of age, important for a vaccine
665 that will be introduced into routine immunisation schedules in the first 2 years of life 170 171
666
173 174.

667 The trial in Bangladesh was cluster-randomized and did not demonstrate any significant
668 additional indirect protection among non-vaccinated individuals. Vaccination campaigns
669 across a wider age-range, to include adults, might be required in some epidemiological
670 settings to achieve indirect effects.175 Nevertheless, the individual protection afforded by
671 TCVs between these three large vaccine efficacy trials, in comparable age-groups, and
672 across three very epidemiologically diverse sites is strikingly consistent.
673 In addition, data have been published from post-vaccine introduction evaluations, from
674 countries such as India,176 Pakistan177 and Zimbabwe.178 Data from Pakistan provide
675 confidence that TCV is highly effective against the XDR strain of S. Typhi, providing evidence
676 that as well as reducing the burden of typhoid fever, it will have a positive impact on
677 decreasing antimicrobial resistance.179
678 Although the safety, immunogenicity and efficacy of TCVs has been demonstrated in diverse
679 populations, TCVs alone are unlikely to eliminate typhoid fever, as evidenced by the
680 incidence rates in the vaccine groups of the trial populations. Thus, their use should be
681 viewed as an important adjunct to improvements in WASH, as the latter has successfully
682 eliminated typhoid fever in many countries around the world.9,180,181
683 [H1] Management
684 Antimicrobials have transformed typhoid from an illness that can have a mortality between
685 10 and 30% to an illness where symptoms resolve within a week with a case fatality ratio
686 <1%124. The emergence of resistance to the commonly used antimicrobials for treating
687 enteric fever have challenged this picture182. Antimicrobial resistance is associated with
688 treatment failure, an increased risk of complications and an increased potential for
689 transmission due to prolonged faecal shedding124,183,184 . Treatment choices should take
690 account of local antimicrobial resistance patterns, if known, and national guidelines where
691 available185.

692 [H2] Antimicrobial therapy

693 Most patients with enteric fever are treated with an oral antimicrobial as part of outpatient
694 management in the first week of illness and typically recover within a week. The WHO
695 Essential Medicines Expert Committee concluded on the core list of Essential Medicines List
696 that a seven-to-ten-day course of either ciprofloxacin, ceftriaxone or azithromycin should be
697 considered first-choice treatments for adults and children186. Ciprofloxacin is not a suitable
698 choice in most parts of south Asia, and some areas of sub-Saharan Africa, because of
699 widespread resistance 124,182. Azithromycin is an effective alternative drug although sporadic
700 reports of antimicrobial resistance have been reported187,188. In those admitted in hospital,
701 parenteral ceftriaxone is a safe option, particularly when resistance to other drugs is
702 uncertain. Oral chloramphenicol, amoxicillin and trimethoprim-sulphamethoxazole were
703 commonly used prior to the 1990s, but multidrug resistance to these three antimicrobials
704 emerged in the late 1980s and became widespread, preventing their usage96.
705 Systematic reviews of the comparative efficacy of chloramphenicol, the fluoroquinolones
706 (such as ciprofloxacin, ofloxacin and gatifloxacin), azithromycin and cephalosporins (such as
707 ceftriaxone and cefixime) in typhoid fever treatment have been unable to draw firm
708 conclusions on the presence or absence of important differences between the various
709 antimicrobials189-191. Evidence from most of the randomised controlled trial is of low
710 certainty owing to small trial size and methodological problems such as not double-blinded
711 and conducted >20 years ago. The lack of diagnostic sensitivity of blood culture, the paucity
712 of trials in the outpatient setting, the changing pattern of resistance over time and the lack
713 of agreed core outcome indicators are further limitations.
714 [H2] Antimicrobial resistant strains
715 The outbreak of XDR S. Typhi in Pakistan in 2016 has impacted the usefulness of ceftriaxone
716 in managing patients with typhoid192. These strains are resistant to chloramphenicol,
717 ampicillin/amoxicillin, trimethoprim-sulphamethoxazole, ciprofloxacin and
718 ceftriaxone/cefixime but susceptible to oral azithromycin and parenteral meropenem 100.
719 These infections are documented in other countries in travellers from Pakistan102.Studies
720 have also reported sporadic cases of ceftriaxone resistance distinct from those identified in
721 Pakistan193,194. Clinicians treating patients with XDR S. Typhi have found no important
722 differences in the clinical response between oral azithromycin alone, intravenous
723 meropenem alone and a combination of azithromycin and meropenem 195. Notably, the daily
724 cost of meropenem in Pakistan was 15 times more than azithromycin.

725 [H2] Combination therapy

726 Studies have confirmed that S. Typhi can reside intracellularly and extracellularly, with high
727 bacterial load in sites of the reticuloendothelial system, such as the bone marrow109,196.
728 Antimicrobials used to treat typhoid fever should target all these locations. Combining
729 azithromycin, which reaches very high intracellular concentrations but low extracellular
730 concentrations197, with a beta-lactam antimicrobial that is predominantly active in the
731 extracellular compartment has been suggested as a better option for the treatment of
732 typhoid fever. In an RCT of 105 adults with confirmed typhoid fever in Nepal, a combination
733 of azithromycin and cefixime for outpatients and azithromycin and ceftriaxone for
734 inpatients was superior to azithromycin alone, with shorter fever clearance times198 A
735 clinical trial examining the efficacy of a combination of azithromycin and cefixime in
736 suspected cases of enteric fever in south Asia is ongoing199.

737 [H2] Severe infections

738 In severe typhoid fever, supportive care such as, full intensive care provision, blood
739 transfusion in the event of gastrointestinal haemorrhage and surgery in case of intestinal
740 perforation and peritonitis, is critical to the outcome200. Following intestinal perforation,
741 secondary blood stream infection may occur due to a range of pathogens from the gut
742 lumen, requiring a repetition of blood culture and broadening of antimicrobial treatment.
743 One RCT in Indonesia demonstrated that high-dose methyl-prednisolone reduced mortality
744 in severe typhoid, characterised by altered consciousness and haemodynamic shock201.
745 Methodological issues make it difficult to draw definitive conclusions from this study and
746 further trialsare needed to address the effectiveness of prednisolone202.

747 [H2] Chronic carriers

748 A systematic review of studies of the antimicrobial treatment of chronic carriage
749 identifiedthat fluoroquinolones were effective in eradicating chronic carriage of susceptible
750 isolates after a 28-day course203 . The only double-blinded RCT performed showed an
751 eradication rate of 92% in those given a 28-day course of norfloxacin compared with 11% in
752 those given placebo. Six studies evaluated ampicillin or amoxicillin in a four-to-six-week
753 course with eradication rates ~70%. Cholecystectomy may be an option where eradication
754 has failed, particularly in the presence of structural biliary abnormalities including
755 gallstones, which may provide a protected niche for bacteria; however, this decision should
756 be weighed against the risk of surgical complications124. All these studies pre-date the
757 emergence of widespread MDR and fluroquinolone resistance, and further clinical trials, for
758 example, using azithromycin, are warranted to help guide modern management.

759 [H1] Quality of life

760 [H2] Cost of illness
761 Despite the potential acute effects and sequelae from typhoid fever, its impact on quality of
762 life is not well documented. However, a number of studies have assessed the economic
763 burden of typhoid in terms of costs to healthcare providers and to affected households in
764 low-income and middle-income countries204-208. A review of economic evidence highlights
765 the cost of hospitalisation as the most common expense reported in the literature. Costs
766 per hospitalised case range from $159 to $636 in India, $233 in Nepal and $171 in Tanzania
767 (2016 US$)209-212. Costs for treating outpatients ranged from $0 to $14.1 (2010 US$) 213.
768 Costs for treating outpatients ranged from $16 to $74 in India, and equalled $39 in Nepal
769 (2016 US$).204
770 Studies have specifically studied the cost of intestinal perforations, a complication that may
771 result from untreated typhoid or delayed access to care. For example,the additional surgical
772 costs to repair an intestinal perforation, on average, were as high as $452 in Nigeria and
773 $1,210 in India (2019 US$) 214,215. These high costs are accompanied by longer hospital stays,
774 23 days on average in Nigeria and 19 days in India, which also increase a family’s
775 expenses214,215.
776 The potential for higher cost of illness associated with MDR and XDR S. Typhi infection,
777 requiring more expensive and less available treatments than for classical S. Typhi infection ,
778 is not well documented. Data from the XDR outbreak in Pakistan between 2016 and 2018
779 suggest that the cost of an episode of typhoid from XDR S. Typhi is 2 to 4 times higher than
780 the cost of non-XDR S. Typhi infection216.
781 Owing to the difficulty in diagnosing typhoid, seeking health care can be a long and costly
782 endeavour for patients and their caregivers. Households often face indirect expenditures
783 such as transportation, loss of household income, and food and subsistence costs related to
784 seeking and receiving care, alongside direct out-of-pocket costs including diagnosis and
785 treatments, such as medication. Typhoid predominantly impacts children <15 years of age,
786 implying that a case of typhoid often results in parental absenteeism from work and a loss
787 of income for caregivers, which can cause financial consequences for families. These
788 expenses may reduce expenditures on other household spendings, which can affect
789 investments in nutrition, education and other household needs, and trigger dissaving
790 measures, resulting in long-term adverse socioeconomic impact.
791 Typhoid can represent a catastrophic cost to affected families, defined as expenses and loss
792 of revenue due to seeking care or caring for sick children and family members that
793 represents more than 40% of non-food monthly household expenditure. One study in
794 Malawi reported that, despite free access to all government medical care and minimal out-
795 of-pocket direct healthcare costs, 44% of households faced catastrophic illness costs mainly
796 related to indirect costs and 16% of households experienced illness costs that were more
797 than their total monthly income217. The median cost per case for inpatient care in patients
798 with enteric fever was also determined as catastrophic for families in studies in Bangladesh,
799 Nepal, and Pakistan209-212. Despite revealing the unfortunate societal costs involved in
800 typhoid management, cost of illness estimates are essential for evaluation of vaccine cost
801 effectiveness, to inform policy decisions (Box 2).

802 [H1] Outlook

803 Since 2010, considerable progress has been made in the development and licensure of TCVs
804 supported by robust evidence on safety and immunogenicity, innovative data on efficacy
805 from the CHIM and field efficacy data from large clinical trials conducted in diverse
806 populations at risk218. This compelling body of data has reaffirmed the WHO
807 recommendations on use of single dose TCVs in endemic settings219,220. TCV is well-tolerated
808 and may be co-administered with other childhood vaccines, facilitating its integration into
809 the WHOs Expanded Programme on Immunisation (EPI) at 9–18 months of age. In low
810 resource countries, Gavi (the Vaccine Alliance) will co-finance the introduction of TCV into
811 EPI, and fully finance single dose catch-up campaigns for all children up to 15 years of
812 age221. Country introductions have begun in Africa and Asia, however, most at-risk children
813 globally remain without protection. To this end, a coordinated multidisciplinary approach
814 that includes advocacy and communications; country support for decision-making,
815 preparation of Gavi applications and planning of vaccine delivery is essential to ensure that
816 more children are protected from this disease sooner. Additionally, an adequate stable
817 manufactured supply of prequalified vaccine is required to meet country demand.

818 In endemic areas, incorporating TCV into the routine immunisation schedule at 9 months of
819 age with an initial catch-up campaign to 15 years of age has generally been found to be
820 cost-effective213,222,223. When factoring in the indirect costs to patients, TCVs may even be
821 cost-saving.224,225

822 Two TCVs are prequalified by the WHO and are considered equally effective. Furthermore,
823 several TCVs are approved nationally or are under development226 . However, as with other
824 conjugate vaccines, robust data on relative effectiveness of different products is important
825 to provide confidence to policymakers on use of different vaccines, highlighting the
826 importance of ongoing impact studies in settings where TCV has been introduced. These
827 studies will inform the long-term TCV strategy.

828 Perhaps the most important outstanding scientific question regarding the global TCV
829 programme is the duration of protection. Although the TCV efficacy trials have shown
830 robust and durable protection against disease (~80 %)for >4 years after vaccination in pre-
831 school and school-age children,172 long term protection studies are needed for children
832 immunised with a single dose of vaccine at 9–18 months of age in the EPI schedule. Ongoing
833 long-term post-introduction effectiveness and impact studies may strengthen evidence in
834 this domain. Given the high rates of disease reported among school-age children, the need
835 for a booster prior to school entry in those vaccinated in early-life routine immunisation
836 programmes, must be assessed in Africa and Asia in areas where the vaccine is being rolled
837 out.

838 The population primarily responsible for transmission of typhoid remains unknown. A
839 cluster-randomised trial in Bangladesh in which children <16 years of age were vaccinated
840 found no evidence of indirect protection. This finding implies that the vaccine either
841 prevents clinical illness but does not prevent transmission, or that adults also contribute
842 substantially to transmission149,150. Alternatively, the complexities and biases in a cluster-
843 randomised design in an urban setting might make it impossible to detect herd effects that
844 are present. Such information could help inform whether extending vaccination to older age
845 groups might provide additional population-level benefits. Targeted vaccination of those
846 adults responsible for transmission could possibly improve typhoid control in high-burden
847 settings. Ongoing observational studies in countries implementing TCVs may provide further
848 evidence to address this question in the next 5 years.

849 Improved diagnostics are needed for clinical management of disease and to define burden
850 and inform decision-making on TCV introduction. Innovation and flexibility is needed to
851 ensure that the most disadvantaged children have access to TCV. Furthermore, without
852 accurate diagnostics, the impact of TCV might be less apparent, for example, in South Asia
853 where incidence of paratyphoid infection is substantial and symptoms are indistinguishable
854 from typhoid. Developments in paratyphoid vaccines, combined with TCV, could broaden
855 protection if shown to be effective and reduce the overall enteric fever burden further. With
856 ongoing early safety and immunogenicity studies of bivalent typhoid and paratyphoid
857 vaccines underway, a combined vaccine could be available within the next 5 years.
858 Furthermore, early phase studies combining TCV with emerging multivalent vaccines against
859 invasive non-typhoidal salmonellae, which could broaden the impact of vaccine
860 programmes are in progress.227
861 Despite the huge progress in protecting children against typhoid, ongoing transmission of
862 salmonella and other bacterial pathogens in affected populations can only be fully
863 controlled with improvements in WASH and food safety. Improving and maintaining WASH
864 requires considerable financing, structural change and political commitment, and some low-
865 income areas have experienced poor sanitation for decades. The impacts of climate change
866 may not only alter the environmental and household patterns of transmission of typhoid,
867 but also likely heighten the challenge of delivering sustained improvements in WASH. The
868 global rise of antimicrobial resistance further adds relevance and urgency to the importance
869 of vaccines. The sparsity of new antimicrobials in development also underscores the need
870 for mobilising all available means of control. The remarkable efforts in typhoid
871 immunisation programmes will help protect at-risk children in the face of these global
872 challenges.
873 Tables
874 Table 1: Case Definitions for typhoid fever disease states
Condition Definition
Acute typhoid Laboratory confirmation by culture or molecular methods of S. Typhi or
fever detection of S. Typhi DNA from a normally sterile site.

Relapse of Laboratory confirmation of S. Typhi from a normally sterile site within one
typhoid fever month of completing an appropriate course of antimicrobial treatment and
resolution of symptoms.
Chronic Evidence of shedding of S. Typhi (positive stool culture or PCR) at least 12
typhoid carrier months after finishing an appropriate course of antimicrobial treatment and the
resolution of symptoms following a laboratory-confirmed episode of acute
disease or
Two stool samples 12 months apart positive for S. Typhi.
Convalescent Evidence of shedding S. Typhi (positive stool culture or PCR) 1–12 months after
Carrier finishing an appropriate course of antimicrobial treatment and the resolution of
symptoms following a laboratory-confirmed episode of acute disease
Suspected case Fever for at least three out of seven consecutive days in an endemic area or
of typhoid following travel from an endemic area or Fever for at least three out of
seven consecutive days within 28 days of being in household contact with
a confirmed case of typhoid fever
875
876 Adapted with permission from ref 2, World Health Organisation.
877
878 Table 2: Summary of efficacy and effectiveness estimates for TCV.
Control Duration of Number Refs
Country Design Age Study period Efficacy (95% CI)
vaccine follow-up enrolled
168
Feb 2018–
18-24 months 80.7% (64.2–89.6)
Apr 2020
Malawi Individually- 9 months–
MCV-A 28,130
efficacy randomized 12 years 172
Feb 2018–
4.3 years 78.0% (66.3–86.1)
Sept 2022
171
Nov 2017–
12 months 81.6% (58.8–91.8)
Apr 2018
Individually- 9 months–
Nepal efficacy MCV-A 20,019 228
randomized 15 years
Nov 2017–
24 months 79.0% (61.9–88.5)
Feb 2020
Total protection 81% (39– 174

94.0%)
Bangladesh Cluster- JE (SA 14- 9 months– Apr 2018– Overall protection 56% (43–
17.1 months ~ 67,500
efficacy randomized 14-2) 16 years May 2020 68.0)
Indirect protection 19% (-
12–41)
Cluster- 176
India 9 months- Sept 2018– Programmatic overall
randomized NA 31 months NA
Effectiveness 14 years Mar 2021 effectiveness 56% (25–74)
Test Negative
Culture confirmed S. Typhi 229

Pakistan 6 months– Feb 2018– 95.0% (93.0% to 96.0%)

Cohort NA 23 months NA
Effectiveness 10 years Dec 2019 XDR S. Typhi 97.0% (95.0% to
98.0)
178
Zimbabwe 6months– July 2019–
Case–control NA 9 months NA 84% (57–94)
Effectiveness 15 years March 2020

879
880 Boxes
881 Box 1: Accelerating vaccine testing with CHIM.
882 Besides improving our understanding of disease pathogenesis, the CHIM also provides a
883 controlled method for testing novel vaccines at a lower cost and greater speed than large-
884 scale traditional field trials. The Oxford CHIM has performed two such trials.
885 [b1] M01ZH09 vaccine
886 The CHIM model was used to study the efficacy of an oral live attenuated vaccine, M01ZH09
887 — designed by deleting ssaV and aroC230 . The vaccine did not meet significance for
888 protective efficacybut induced strong antibody responses against lipopolysaccharide, which
889 were bactericidal. The antibodies were not associated with protection against infection;
890 however, the vaccinees demonstrated lower severity of symptoms, delayed onset of
891 infection and a lower level of bacteraemia than non-vaccinees230. Similarly, vaccination of
892 individuals with Vi-polysaccharide-containing vaccines induced bactericidal antibodies, but
893 these functional antibodies were not associated with protection from infection when these
894 individuals were challenged with S. Typhi231. Duration of bacteraemia with the antibiotic-
895 susceptible strain was longer when treated with azithromycin than ciprofloxacin232.
896 [b2] Typhoid conjugate vaccine
897 A multi-arm phase 2b study comparing a novel TCV and a WHO pre-qualified and licensed
898 Vi-polysaccharide (Vi-PS) vaccine against a control vaccine (one that has no protective
899 efficacy against S. Typhi) showed that the TCV had comparable efficacy to the existing Vi-PS
900 vaccine in the model164. Extensive analysis of class, subclass, avidity and functional
901 serological responses showed that Vi IgA levels and avidity associated with protection from
902 S. Typhi challenge, and increased anti-Vi IgG responses were associated with reduced
903 symptoms. In addition, antibody-dependent neutrophil phagocytosis was also associated
904 with protection233,234. Vaccination with TCV induced α4β7 and CCR10a+IgA+ plasma cells
905 indicating likely mucosal migration, which may be important as this is the site of invasion if
906 there is a future exposure to the organism. Moreover, in those who received TCV,
907 protection against infection was associated with the total plasma cell response235.
908
909 Box 2: Patient experience
910
911 [Au: To be able to publish these testimonials, we need to know whether you have
912 received written informed consent from the patients for the statement to be used in
913 this way. We don't need to see the consent forms to not breach confidentiality – we
914 just need you to confirm that you have the consent. We cannot publish these
915 statements if we are not sure that you have written informed consent as stated in our
916 policies:
917 https://www.nature.com/nrdp/editorial-policies#patient
918 Please confirm.]
919

920 Bashir’s experience with typhoid

921 I am a 10-year-old boy from Badin, Sindh province, Pakistan. My ten siblings and I have
922 never been to school. My father is a vegetable seller and earns about three to four dollars a
923 day – which is only enough for two meals – so we stay at home, helping him with his work or
924 playing with friends.

925 One day, while playing cricket, I found I had little energy to run. I returned home and told my
926 mother that I was feeling unwell. I rested in bed for days, but my temperature kept
927 increasing. My father took me to a nearby doctor who gave me medication and charged us
928 six dollars. Even with the medication my body was still burning like an oven. I went to
929 another doctor, who gave me a blood test and diagnosed me with typhoid. He charged us 27
930 dollars and prescribed more medication. After taking it, my condition continued to worsen. I
931 began vomiting, feeling pain in my stomach, and was unable to even take a sip of water.

932 I was taken to a hospital in Badin, despite my family not having money for transportation or
933 hospital care. There, I was told my intestine had burst and only a major surgery could save
934 my life. We did not have the money for this procedure. I cried while thinking my life was
935 about to end. An ambulance driver, who I think may be a guardian angel, suggested we
936 travel to the National Institute of Child Health in Karachi, where patients are treated at
937 almost no cost.

938 Accompanied by my family, we reached Karachi via ambulance and paid $45 for the four-
939 hour journey. I underwent surgery the same night and began my recovery. I feel like I have
940 been given another chance at life.
941
942 Figure legends
943
944 Figure 1. Global incidence of typhoid fever.
945 Incidence rates per 100,000 person-years of observation for typhoid fever, by country, in
946 2019. Highest incidence areas are shown in red, and low incidence areas in blue.
947 Reprinted with permission from Ref 32, The Institute for Health Metrics and Evaluation.
948
949
950 Figure 2: Salmonella Typhi genotype prevalence by world region.
951 This figure demonstrates the prevalence of genotypes of S. Typhi across the world.
952 Countries contributing data are shaded in beige, and are grouped by regions as defined by
953 the UN statistics division. These data are based on assumed acute cases isolated from
954 untargeted sampling frames from 2010 until 2020, with known country of origin (total
955 N=9,478 genomes).
956 Adapted from ref 57, CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
957
958
959 Figure 3: Pathogenesis of typhoid fever following pathogen ingestion.
960 A schematic figure relating the clinical presentation of typhoid fever to stages of disease
961 pathogenesis. Ingestion of S. Typhi and invasion across gut wall are typically asymptomatic
962 with an incubation period of 5-7 days. Following primary dissemination in lymph and blood,
963 a deep-seated systemic reticuloendothelial infection is established and presents with
964 secondary bacteraemia and high fever. Complications include metastatic focal tissue
965 infections. Colonisation of the gallbladder by S. Typhi, and excretion of bacteria back into
966 the gastrointestinal tract in infected bile is a hallmark of typhoid, and is the basis for long-
967 term chronic carrier state and transmission. Re-infection of Peyer’s patches from the lumen
968 may result in gastrointestinal bleeding or intestinal perforation caused by necrotic Peyer’s
969 patches. Intestinal perforation may also result in a tertiary blood stream infection with a
970 range of gut luminal enteric organisms. .
971
972
973 Figure 4: Clinical signs and symptoms of typhoid fever.
974 Typhoid fever presents predominantly with fever, headache and abdominal pain, but
975 symptoms and signs can be heterogenous and can include all organ systems.
 976 REFERENCES
977
978 1 Dougan, G. & Baker, S. Salmonella enterica Serovar Typhi and the
979 Pathogenesis of Typhoid Fever. Annual Review of Microbiology 68, 317-336,
980 doi:10.1146/annurev-micro-091313-103739 (2014).
981 2 Organisation, W. H. Typhoid: Vaccine Preventable Diseases Surveillance
982 Standards, <https://www.who.int/publications/m/item/vaccine-preventable-
983 diseases-surveillance-standards-typhoid> (2018).
984 3 Basnyat, B., Qamar, F. N., Rupali, P., Ahmed, T. & Parry, C. M. Enteric fever.
985 Bmj 372, n437, doi:10.1136/bmj.n437 (2021).
986 4 Von Drigalski, K. W. Ueber Ergebnisse bei der Bekämpfung des Typhus nach
987 Robert Koch. (1904).
988 5 Kirchhelle, C., Pollard, A. J. & Vanderslott, S. Typhoid-From Past to Future.
989 Clin Infect Dis 69, S375-s376, doi:10.1093/cid/ciz551 (2019).
990 6 Ames, W. R. & Robins, M. Age and Sex as Factors in the Development of the
991 Typhoid Carrier State, and a Method for Estimating Carrier Prevalence. Am J
992 Public Health Nations Health 33, 221-230, doi:10.2105/ajph.33.3.221 (1943).
993 7 Antillon, M., Saad, N. J., Baker, S., Pollard, A. J. & Pitzer, V. E. The
994 Relationship Between Blood Sample Volume and Diagnostic Sensitivity of
995 Blood Culture for Typhoid and Paratyphoid Fever: A Systematic Review and
996 Meta-Analysis. J Infect Dis 218, S255-s267, doi:10.1093/infdis/jiy471 (2018).
997 8 Nizamuddin, S., Khan, E. A., Chattaway, M. A. & Godbole, G. Case of
998 Carbapenem-Resistant <em>Salmonella</em> Typhi Infection, Pakistan,
999 2022. Emerging Infectious Disease journal 29, doi:10.3201/eid2911.230499
1000 (2023).
1001 9 Phillips, M. T., Owers, K. A., Grenfell, B. T. & Pitzer, V. E. Changes in
1002 historical typhoid transmission across 16 U.S. cities, 1889-1931: Quantifying
1003 the impact of investments in water and sewer infrastructures. PLoS Negl Trop
1004 Dis 14, e0008048, doi:10.1371/journal.pntd.0008048 (2020).
1005 10 Vanderslott, S., Phillips, M. T., Pitzer, V. E. & Kirchhelle, C. Water and Filth:
1006 Reevaluating the First Era of Sanitary Typhoid Intervention (1840-1940). Clin
1007 Infect Dis 69, S377-s384, doi:10.1093/cid/ciz610 (2019).
1008 11 Stanaway, J. D. et al. The global burden of typhoid and paratyphoid fevers: a
1009 systematic analysis for the Global Burden of Disease Study 2017. The Lancet
1010 Infectious Diseases 19, doi:10.1016/S1473-3099(18)30685-6 (2019).
1011 12 Crump, J. A. Progress in Typhoid Fever Epidemiology. Clin Infect Dis 68, S4-
1012 s9, doi:10.1093/cid/ciy846 (2019).
1013 13 Appiah, G. D. et al. Typhoid Outbreaks, 1989-2018: Implications for
1014 Prevention and Control. Am J Trop Med Hyg 102, 1296-1305,
1015 doi:10.4269/ajtmh.19-0624 (2020).
1016 14 Reller, M. E. et al. in 39th Annual Meeting of the Infectious Diseases Society
1017 of America. (ed IDSA) 199 (Infectious Diseases Society of America,
1018 Alexandria, VA).
1019 15 Mitscherlich, E. & Marth, E. H. in Microbial survival in the environment (eds
1020 E. Mitscherlich & E.H. Marth) 1-560 (Springer, 1984).
1021 16 Cho, J.-C. & Kim, S. J. Viable, but non-culturable, state of a green
1022 fluorescence protein-tagged environmental isolate of Salmonella Typhi in
1023 groundwater and pond water. FEMS Microbiol Lett 170, 257-264 (1999).
1024 17 Kingsley, R. A. et al. Functional analysis of Salmonella Typhi adaptation to
1025 survival in water. Environ Microbiol 20, 4079-4090 (2018).
1026 18 Andrews, J. R. et al. Environmental surveillance as a tool for identifying high-
1027 risk settings for typhoid transmission. Clin Infect Dis 71 (suppl 2), S71-S78
1028 (2020).
1029 19 Deen, J. et al. Community-acquired bacterial bloodstream infections in
1030 developing countries in south and southeast Asia: a systematic review. Lancet
1031 Infect Dis 12, 480-487 (2012).
1032 20 Reddy, E. A., Shaw, A. V. & Crump, J. A. Community acquired bloodstream
1033 infections in Africa: a systematic review and meta-analysis. Lancet Infect Dis
1034 10, 417-432 (2010).
1035 21 Marchello, C. S., Dale, A. P., Pisharody, S., Rubach, M. P. & Crump, J. A.
1036 Prevalence of community-onset bloodstream infections among hospitalized
1037 patients in Africa and Asia: a systematic review and meta-analysis.
1038 Antimicrobial agents and chemotherapy 64, e01974-01919 (2019).
1039 22 Garrett, D. O. et al. Incidence of typhoid and paratyphoid fever in Bangladesh,
1040 Nepal, and Pakistan: results of the Surveillance for Enteric Fever in Asia
1041 Project. Lancet Glob Health 10, e978-988 (2022).
1042 23 Marks, F. et al. The Severe Typhoid in Africa Program: incidences of typhoid
1043 fever in Burkina Faso, Democratic Republic of Congo, Ethiopia, Ghana,
1044 Madagascar, and Nigeria. Available at SSRN:
1045 https://ssrn.com/abstract=4292849 or
1046 http://dx.doi.org/4292810.4292139/ssrn.4292849 (2022).
1047 24 Marks, F. et al. Incidence of invasive Salmonella disease in sub-Saharan
1048 Africa: a multicentre population-based surveillance study. Lancet Glob Health
1049 5, e310-323 (2017).
1050 25 Meiring JE, e. a. Burden of enteric fever at three urban sites in Africa and
1051 Asia: a multicentre population-based study with 626,219 person-years of
1052 observation. Lancet Glob Hlth (2021).
1053 26 John, J. et al. Burden of Typhoid and Paratyphoid Fever in India. New
1054 England Journal of Medicine 388, 1491-1500, doi:10.1056/NEJMoa2209449
1055 (2023).
1056 27 Crump, J. A., Luby, S. P. & Mintz, E. D. The global burden of typhoid fever.
1057 Bull World Health Organ 82, 346-353 (2004).
1058 28 Antillón, M. et al. The burden of typhoid fever in low- and middle-income
1059 countries: a meta-regression approach. PLoS Negl Trop Dis 11, e0005376
1060 (2017).
1061 29 Mogasale, V. et al. Burden of typhoid fever in low-income and middle-income
1062 countries: a systematic, literature-based update with risk-factor adjustment.
1063 Lancet Glob Health 2, e570-580 (2014).
1064 30 Buckle, G. C., Walker, C. L. & Black, R. E. Typhoid fever and paratyphoid
1065 fever: systematic review to estimate global morbidity and mortality for 2010. J
1066 Glob Health 2, 10401 (2012).
1067 31 GBD 2017 Typhoid and Paratyphoid Collaborators. The global burden of
1068 typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of
1069 Disease Study 2017. Lancet Infect Dis 19, 369-381 (2019).
1070 32 Evaluation, I. f. H. M. a. Global Incidence of Typhoid Fever,
1071 <https://vizhub.healthdata.org/gbd-compare/> (2019).
1072 33 Crump, J. A. & Kirk, M. D. Estimating the burden of febrile illnesses. PLoS
1073 Negl Trop Dis 9, e0004040 (2015).
1074 34 Marchello, C. S., Hong, C. Y. & Crump, J. A. Global typhoid fever incidence: a
1075 systematic review and meta-analysis. Clin Infect Dis 68 (suppl 2), S105-S116
1076 (2019).
1077 35 Crump, J. A. et al. Estimating the incidence of typhoid fever and other febrile
1078 illnesses in developing countries. Emerg Infect Dis 9, 539-544,
1079 doi:10.3201/eid0905.020428 (2003).
1080 36 Marchello, C. S., Birkhold, M. & Crump, J. A. Complications and mortality of
1081 typhoid fever: A global systematic review and meta-analysis. J Infect 81, 902-
1082 910, doi:10.1016/j.jinf.2020.10.030 (2020).
1083 37 Marchello, C. S., Birkhold, M. & Crump, J. A. Complications and mortality of
1084 typhoid fever: A global systematic review and meta-analysis. J Infect 81, 902-
1085 910 (2020).
1086 38 Gibani, M. M. et al. Homologous and heterologous re-challenge with
1087 Salmonella Typhi and Salmonella Paratyphi A in a randomised controlled
1088 human infection model. PLoS Negl Trop Dis 14, e0008783,
1089 doi:10.1371/journal.pntd.0008783 (2020).
1090 39 Im, J. et al. Protection conferred by typhoid fever against recurrent typhoid
1091 fever in urban Kolkata. PLoS Negl Trop Dis 14, e0008530,
1092 doi:10.1371/journal.pntd.0008530 (2020).
1093 40 Brockett, S. et al. Associations among water, sanitation, and hygiene, and
1094 food exposures and typhoid fever in case-control studies: a systematic review
1095 and meta-analysis. Am J Trop Med Hyg 103, 1020-1031 (2020).
1096 41 Tadesse, B. T. et al. Prevention of typhoid by Vi conjugate vaccine and
1097 achievable improvements in household water, sanitation, and hygiene:
1098 evidence from a cluster-randomized trial in Dhaka, Bangladesh. Clin Infect Dis
1099 75, 1681-1687 (2022).
1100 42 Gunn, J. S. et al. Salmonella chronic carriage: epidemiology, diagnosis, and
1101 gallbladder persistence. Trends Microbiol 22, 648-655,
1102 doi:10.1016/j.tim.2014.06.007 (2014).
1103 43 Dunstan, S. J. et al. Variation at HLA-DRB1 is associated with resistance to
1104 enteric fever. Nat Genet 46, 1333-1336 (2014).
1105 44 Saad, N. J. et al. Seasonal dynamics of typhoid and paratyphoid fever. Sci
1106 Rep 8, 6870 (2018).
1107 45 Thindwa, D., Chipeta, M. G., Henrion, M. Y. R. & Gordon, M. A. Distinct
1108 climate influences on the risk of typhoid compared to invasive non-typhoid
1109 Salmonella disease in Blantyre, Malawi. Sci Rep 9, 20310,
1110 doi:10.1038/s41598-019-56688-1 (2019).
1111 46 Levy, K., Smith, S. M. & Carlton, E. J. Climate Change Impacts on
1112 Waterborne Diseases: Moving Toward Designing Interventions. Curr Environ
1113 Health Rep 5, 272-282, doi:10.1007/s40572-018-0199-7 (2018).
1114 47 Gao, Q. et al. Impact of Temperature and Rainfall on Typhoid/Paratyphoid
1115 Fever in Taizhou, China: Effect Estimation and Vulnerable Group
1116 Identification. Am J Trop Med Hyg 106, 532-542, doi:10.4269/ajtmh.20-1457
1117 (2021).
1118 48 Hickman-Brenner, F. W. & Farmer, J. J., 3rd. Bacteriophage types of
1119 Salmonella typhi in the United States from 1974 through 1981. J Clin
1120 Microbiol 17, 172-174, doi:10.1128/jcm.17.1.172-174.1983 (1983).
1121 49 Chattaway, M. A., Langridge, G. C. & Wain, J. Salmonella nomenclature in
1122 the genomic era: a time for change. Sci Rep 11, 7494, doi:10.1038/s41598-
1123 021-86243-w (2021).
1124 50 Wong, V. K. et al. Phylogeographical analysis of the dominant multidrug-
1125 resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental
1126 transmission events. Nat Genet 47, 632-639, doi:10.1038/ng.3281 (2015).
1127 51 Tanmoy, A. M. et al. Paratype: a genotyping tool for Salmonella Paratyphi A
1128 reveals its global genomic diversity. Nature Communications 13, 7912,
1129 doi:10.1038/s41467-022-35587-6 (2022).
1130 52 Kariuki, S. et al. Multiple introductions of multidrug-resistant typhoid
1131 associated with acute infection and asymptomatic carriage, Kenya. Elife 10,
1132 doi:10.7554/eLife.67852 (2021).
1133 53 Dyson, Z. A. et al. Genomic epidemiology and antimicrobial resistance
1134 transmission of <em>Salmonella</em> Typhi and Paratyphi A at three urban
1135 sites in Africa and Asia. medRxiv, 2023.2003.2011.23286741,
1136 doi:10.1101/2023.03.11.23286741 (2023).
1137 54 Wong, V. K. et al. An extended genotyping framework for Salmonella enterica
1138 serovar Typhi, the cause of human typhoid. Nature Communications 7,
1139 12827, doi:10.1038/ncomms12827 (2016).
1140 55 Dyson, Z. A. & Holt, K. E. Five Years of GenoTyphi: Updates to the Global
1141 Salmonella Typhi Genotyping Framework. The Journal of Infectious Diseases
1142 224, S775-S780, doi:10.1093/infdis/jiab414 (2021).
1143 56 Carey, M. E. et al. Global diversity and antimicrobial resistance of typhoid
1144 fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi
1145 genomes. eLife 12, e85867, doi:10.7554/eLife.85867 (2023).
1146 57 Carey, M. E. et al. Global diversity and antimicrobial resistance of typhoid
1147 fever pathogens: insights from 13,000 <em>Salmonella</em> Typhi
1148 genomes. medRxiv, 2022.2012.2028.22283969,
1149 doi:10.1101/2022.12.28.22283969 (2022).
1150 58 da Silva, K. E. et al. The international and intercontinental spread and
1151 expansion of antimicrobial-resistant Salmonella Typhi: a genomic
1152 epidemiology study. Lancet Microbe 3, e567-e577, doi:10.1016/s2666-
1153 5247(22)00093-3 (2022).
1154 59 Park, S. E. et al. The phylogeography and incidence of multi-drug resistant
1155 typhoid fever in sub-Saharan Africa. Nat Commun 9, 5094,
1156 doi:10.1038/s41467-018-07370-z (2018).
1157 60 Guevara, P. D. et al. A genomic snapshot of Salmonella enterica serovar
1158 Typhi in Colombia. PLoS Negl Trop Dis 15, e0009755,
1159 doi:10.1371/journal.pntd.0009755 (2021).
1160 61 Maes, M. et al. Whole genome sequence analysis of Salmonella Typhi
1161 provides evidence of phylogenetic linkage between cases of typhoid fever in
1162 Santiago, Chile in the 1980s and 2010–2016. PLOS Neglected Tropical
1163 Diseases 16, e0010178, doi:10.1371/journal.pntd.0010178 (2022).
1164 62 Sikorski, M. J. et al. Persistence of Rare Salmonella Typhi Genotypes
1165 Susceptible to First-Line Antibiotics in the Remote Islands of Samoa. mBio,
1166 e0192022, doi:10.1128/mbio.01920-22 (2022).
1167 63 Davies, M. R. et al. Genomic epidemiology of Salmonella Typhi in Central
1168 Division, Fiji, 2012 to 2016. Lancet Reg Health West Pac 24, 100488,
1169 doi:10.1016/j.lanwpc.2022.100488 (2022).
1170 64 Wirth, T. Massive lineage replacements and cryptic outbreaks of Salmonella
1171 Typhi in eastern and southern Africa. Nat Genet 47, 565-567,
1172 doi:10.1038/ng.3318 (2015).
1173 65 Gibani, M. M., Britto, C. & Pollard, A. J. Typhoid and paratyphoid fever: a call
1174 to action. Curr Opin Infect Dis, doi:10.1097/qco.0000000000000479 (2018).
1175 66 Johnson, R., Mylona, E. & Frankel, G. Typhoidal Salmonella: Distinctive
1176 virulence factors and pathogenesis. Cell Microbiol 20, e12939,
1177 doi:10.1111/cmi.12939 (2018).
1178 67 McClelland, M. et al. Comparison of genome degradation in Paratyphi A and
1179 Typhi, human-restricted serovars of Salmonella enterica that cause typhoid.
1180 Nat Genet 36, 1268-1274, doi:10.1038/ng1470 (2004).
1181 68 Parkhill, J. et al. Complete genome sequence of a multiple drug resistant
1182 Salmonella enterica serovar Typhi CT18. Nature 413, 848-852,
1183 doi:10.1038/35101607 (2001).
1184 69 Holt, K. E. et al. High-throughput bacterial SNP typing identifies distinct
1185 clusters of Salmonella Typhi causing typhoid in Nepalese children. BMC Infect
1186 Dis 10, 144, doi:10.1186/1471-2334-10-144 (2010).
1187 70 Hiyoshi, H., Tiffany, C. R., Bronner, D. N. & Bäumler, A. J. Typhoidal
1188 Salmonella serovars: ecological opportunity and the evolution of a new
1189 pathovar. FEMS Microbiol Rev 42, 527-541, doi:10.1093/femsre/fuy024
1190 (2018).
1191 71 Rogers, A. W. L., Tsolis, R. M. & Bäumler, A. J. Salmonella versus the
1192 Microbiome. Microbiol Mol Biol Rev 85, doi:10.1128/mmbr.00027-19 (2021).
1193 72 Bronner, D. N. et al. Genetic Ablation of Butyrate Utilization Attenuates
1194 Gastrointestinal Salmonella Disease. Cell Host Microbe 23, 266-273.e264,
1195 doi:10.1016/j.chom.2018.01.004 (2018).
1196 73 Winter, S. E. et al. The flagellar regulator TviA reduces pyroptosis by
1197 Salmonella enterica serovar Typhi. Infect Immun 83, 1546-1555,
1198 doi:10.1128/iai.02803-14 (2015).
1199 74 Pickard, D. et al. Composition, acquisition, and distribution of the Vi
1200 exopolysaccharide-encoding Salmonella enterica pathogenicity island SPI-7.
1201 J Bacteriol 185, 5055-5065, doi:10.1128/jb.185.17.5055-5065.2003 (2003).
1202 75 Ménard, S. et al. Cross-Talk Between the Intestinal Epithelium and
1203 Salmonella Typhimurium. Front Microbiol 13, 906238,
1204 doi:10.3389/fmicb.2022.906238 (2022).
1205 76 Dillon, A. & Lo, D. D. M Cells: Intelligent Engineering of Mucosal Immune
1206 Surveillance. Frontiers in Immunology 10, doi:10.3389/fimmu.2019.01499
1207 (2019).
1208 77 Watson, K. G. & Holden, D. W. Dynamics of growth and dissemination of
1209 Salmonella in vivo. Cell Microbiol 12, 1389-1397, doi:10.1111/j.1462-
1210 5822.2010.01511.x (2010).
1211 78 Hart, P. J. et al. Differential Killing of Salmonella enterica Serovar Typhi by
1212 Antibodies Targeting Vi and Lipopolysaccharide O:9 Antigen. PLoS One 11,
1213 e0145945, doi:10.1371/journal.pone.0145945 (2016).
1214 79 Waddington, C. S. et al. An outpatient, ambulant-design, controlled human
1215 infection model using escalating doses of Salmonella Typhi challenge
1216 delivered in sodium bicarbonate solution. Clin Infect Dis 58, 1230-1240,
1217 doi:10.1093/cid/ciu078 (2014).
1218 80 Waddington, C. S. et al. Advancing the management and control of typhoid
1219 fever: a review of the historical role of human challenge studies. J Infect 68,
1220 405-418, doi:10.1016/j.jinf.2014.01.006 (2014).
1221 81 Dobinson, H. C. et al. Evaluation of the Clinical and Microbiological Response
1222 to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge
1223 Model. Clin Infect Dis 64, 1066-1073, doi:10.1093/cid/cix042 (2017).
1224 82 Darton, T. C. et al. Blood culture-PCR to optimise typhoid fever diagnosis
1225 after controlled human infection identifies frequent asymptomatic cases and
1226 evidence of primary bacteraemia. J Infect 74, 358-366,
1227 doi:10.1016/j.jinf.2017.01.006 (2017).
1228 83 Blohmke, C. J. et al. Interferon-driven alterations of the host’s amino acid
1229 metabolism in the pathogenesis of typhoid fever. The Journal of Experimental
1230 Medicine 213, 1061-1077, doi:10.1084/jem.20151025 (2016).
1231 84 Darton, T. C. et al. Rapidly Escalating Hepcidin and Associated Serum Iron
1232 Starvation Are Features of the Acute Response to Typhoid Infection in
1233 Humans. PLoS Negl Trop Dis 9, e0004029, doi:10.1371/journal.pntd.0004029
1234 (2015).
1235 85 Darton, T. C. et al. Identification of Novel Serodiagnostic Signatures of
1236 Typhoid Fever Using a Salmonella Proteome Array. Front Microbiol 8, 1794,
1237 doi:10.3389/fmicb.2017.01794 (2017).
1238 86 Blohmke, C. J. et al. Diagnostic host gene signature for distinguishing enteric
1239 fever from other febrile diseases. EMBO Mol Med 11, e10431,
1240 doi:10.15252/emmm.201910431 (2019).
1241 87 Song, J., Gao, X. & Galán, J. E. Structure and function of the Salmonella
1242 Typhi chimaeric A(2)B(5) typhoid toxin. Nature 499, 350-354,
1243 doi:10.1038/nature12377 (2013).
1244 88 Del Bel Belluz, L. et al. The Typhoid Toxin Promotes Host Survival and the
1245 Establishment of a Persistent Asymptomatic Infection. PLoS Pathog 12,
1246 e1005528, doi:10.1371/journal.ppat.1005528 (2016).
1247 89 den Bakker, H. C. et al. Genome sequencing reveals diversification of
1248 virulence factor content and possible host adaptation in distinct
1249 subpopulations of Salmonella enterica. BMC Genomics 12, 425,
1250 doi:10.1186/1471-2164-12-425 (2011).
1251 90 Rodriguez-Rivera, L. D., Bowen, B. M., den Bakker, H. C., Duhamel, G. E. &
1252 Wiedmann, M. Characterization of the cytolethal distending toxin (typhoid
1253 toxin) in non-typhoidal Salmonella serovars. Gut Pathog 7, 19,
1254 doi:10.1186/s13099-015-0065-1 (2015).
1255 91 Gibani, M. M. et al. Investigation of the role of typhoid toxin in acute typhoid
1256 fever in a human challenge model. Nat Med 25, 1082-1088,
1257 doi:10.1038/s41591-019-0505-4 (2019).
1258 92 Pitzer, V. E. et al. Predicting the impact of vaccination on the transmission
1259 dynamics of typhoid in South Asia: a mathematical modeling study. PLoS
1260 Negl Trop Dis 8, e2642, doi:10.1371/journal.pntd.0002642 (2014).
1261 93 Saul, A., Smith, T. & Maire, N. Stochastic simulation of endemic Salmonella
1262 enterica serovar Typhi: the importance of long lasting immunity and the carrier
1263 state. PLoS One 8, e74097, doi:10.1371/journal.pone.0074097 (2013).
1264 94 Gibani, M. M. et al. The Impact of Vaccination and Prior Exposure on Stool
1265 Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled
1266 Human Infection Studies. Clin Infect Dis 68, 1265-1273,
1267 doi:10.1093/cid/ciy670 (2019).
1268 95 Marchello, C. S., Carr, S. D. & Crump, J. A. A Systematic Review on
1269 Antimicrobial Resistance among Salmonella Typhi Worldwide. Am J Trop Med
1270 Hyg, doi:10.4269/ajtmh.20-0258 (2020).
1271 96 Britto, C. D., Wong, V. K., Dougan, G. & Pollard, A. J. A systematic review of
1272 antimicrobial resistance in Salmonella enterica serovar Typhi, the etiological
1273 agent of typhoid. PLoS Negl Trop Dis 12, e0006779,
1274 doi:10.1371/journal.pntd.0006779 (2018).
1275 97 Bowe, F. et al. At least four percent of the Salmonella typhimurium genome is
1276 required for fatal infection of mice. Infect Immun 66, 3372-3377,
1277 doi:10.1128/iai.66.7.3372-3377.1998 (1998).
1278 98 Chau, T. T. et al. Antimicrobial drug resistance of Salmonella enterica serovar
1279 typhi in asia and molecular mechanism of reduced susceptibility to the
1280 fluoroquinolones. Antimicrobial agents and chemotherapy 51, 4315-4323,
1281 doi:10.1128/aac.00294-07 (2007).
1282 99 Day, M. R. et al. Comparison of phenotypic and WGS-derived antimicrobial
1283 resistance profiles of Salmonella enterica serovars Typhi and Paratyphi. J
1284 Antimicrob Chemother 73, 365-372, doi:10.1093/jac/dkx379 (2018).
1285 100 Qamar, F. N. et al. Antimicrobial Resistance in Typhoidal Salmonella:
1286 Surveillance for Enteric Fever in Asia Project, 2016-2019. Clin Infect Dis 71,
1287 S276-s284, doi:10.1093/cid/ciaa1323 (2020).
1288 101 Akram, J. et al. Extensively Drug-Resistant (XDR) Typhoid: Evolution,
1289 Prevention, and Its Management. Biomed Res Int 2020, 6432580,
1290 doi:10.1155/2020/6432580 (2020).
1291 102 Posen, H. J. et al. Travel-associated extensively drug-resistant typhoid fever:
1292 a case series to inform management in non-endemic regions. J Travel Med
1293 30, doi:10.1093/jtm/taac086 (2023).
1294 103 Herdman, M. T. et al. Increasingly limited options for the treatment of enteric
1295 fever in travellers returning to England, 2014-2019: a cross-sectional
1296 analytical study. J Med Microbiol 70, doi:10.1099/jmm.0.001359 (2021).
1297 104 Ashton, P. M. et al. The rapid emergence of <em>Salmonella</em> Typhi
1298 with decreased ciprofloxacin susceptibility following an increase in
1299 ciprofloxacin prescriptions in Blantyre, Malawi. medRxiv,
1300 2023.2003.2027.23287794, doi:10.1101/2023.03.27.23287794 (2023).
1301 105 Wijedoru, L., Mallett, S. & Parry, C. M. Rapid diagnostic tests for typhoid and
1302 paratyphoid (enteric) fever. Cochrane Database Syst Rev 5, Cd008892,
1303 doi:10.1002/14651858.CD008892.pub2 (2017).
1304 106 Azmatullah, A., Qamar, F. N., Thaver, D., Zaidi, A. K. & Bhutta, Z. A.
1305 Systematic review of the global epidemiology, clinical and laboratory profile of
1306 enteric fever. J Glob Health 5, 020407, doi:10.7189/jogh.05.020407 (2015).
1307 107 Aiemjoy, K. et al. Diagnostic Value of Clinical Features to Distinguish Enteric
1308 Fever From Other Febrile Illnesses in Bangladesh, Nepal, and Pakistan. Clin
1309 Infect Dis 71, S257-s265, doi:10.1093/cid/ciaa1297 (2020).
1310 108 Andrews, J. R. et al. High Rates of Enteric Fever Diagnosis and Lower
1311 Burden of Culture-Confirmed Disease in Peri-urban and Rural Nepal. J Infect
1312 Dis 218, S214-s221, doi:10.1093/infdis/jix221 (2018).
1313 109 Wain, J. et al. Quantitation of bacteria in blood of typhoid fever patients and
1314 relationship between counts and clinical features, transmissibility, and
1315 antibiotic resistance. J Clin Microbiol 36, 1683-1687,
1316 doi:10.1128/jcm.36.6.1683-1687.1998 (1998).
1317 110 Gilman, R. H., Terminel, M., Levine, M. M., Hernandez-Mendoza, P. &
1318 Hornick, R. B. Relative efficacy of blood, urine, rectal swab, bone-marrow,
1319 and rose-spot cultures for recovery of Salmonella typhi in typhoid fever.
1320 Lancet 1, 1211-1213, doi:10.1016/s0140-6736(75)92194-7 (1975).
1321 111 Mogasale, V., Ramani, E., Mogasale, V. V. & Park, J. What proportion of
1322 Salmonella Typhi cases are detected by blood culture? A systematic literature
1323 review. Ann Clin Microbiol Antimicrob 15, 32, doi:10.1186/s12941-016-0147-z
1324 (2016).
1325 112 Wain, J. et al. Specimens and culture media for the laboratory diagnosis of
1326 typhoid fever. J Infect Dev Ctries 2, 469-474, doi:10.3855/jidc.164 (2008).
1327 113 Neupane, D. P., Dulal, H. P. & Song, J. Enteric Fever Diagnosis: Current
1328 Challenges and Future Directions. Pathogens 10,
1329 doi:10.3390/pathogens10040410 (2021).
1330 114 Tennant, S. M. et al. Detection of Typhoidal and Paratyphoidal Salmonella in
1331 Blood by Real-time Polymerase Chain Reaction. Clin Infect Dis 61 Suppl 4,
1332 S241-250, doi:10.1093/cid/civ726 (2015).
1333 115 Sapkota, J. et al. Comparative Analysis of Commercially Available Typhoid
1334 Point-of-Care Tests: Results of a Prospective and Hybrid Retrospective
1335 Multicenter Diagnostic Accuracy Study in Kenya and Pakistan. J Clin
1336 Microbiol 60, e0100022, doi:10.1128/jcm.01000-22 (2022).
1337 116 Charles, R. C. et al. Immunoproteomic analysis of antibody in lymphocyte
1338 supernatant in patients with typhoid fever in Bangladesh. Clin Vaccine
1339 Immunol 21, 280-285, doi:10.1128/cvi.00661-13 (2014).
1340 117 Liang, L. et al. Immune profiling with a Salmonella Typhi antigen microarray
1341 identifies new diagnostic biomarkers of human typhoid. Sci Rep 3, 1043,
1342 doi:10.1038/srep01043 (2013).
1343 118 Andrews, J. R. et al. Plasma Immunoglobulin A Responses Against 2
1344 Salmonella Typhi Antigens Identify Patients With Typhoid Fever. Clin Infect
1345 Dis 68, 949-955, doi:10.1093/cid/ciy578 (2019).
1346 119 Näsström, E. et al. Reproducible diagnostic metabolites in plasma from
1347 typhoid fever patients in Asia and Africa. eLife 6, e15651,
1348 doi:10.7554/eLife.15651 (2017).
1349 120 Aiemjoy, K. et al. Estimating typhoid incidence from community-based
1350 serosurveys: a multicohort study. Lancet Microbe 3, e578-e587,
1351 doi:10.1016/s2666-5247(22)00114-8 (2022).
1352 121 Mylona, E. et al. The Identification of Enteric Fever-Specific Antigens for
1353 Population-Based Serosurveillance. The Journal of Infectious Diseases,
1354 doi:10.1093/infdis/jiad242 (2023).
1355 122 Parry, C. M., Hien, T. T., Dougan, G., White, N. J. & Farrar, J. J. Typhoid
1356 fever. N Engl J Med 347, 1770-1782, doi:10.1056/NEJMra020201 (2002).
1357 123 Stuart, B. M. & Pullen, R. L. Typhoid; clinical analysis of 360 cases. Arch
1358 Intern Med (Chic) 78, 629-661, doi:10.1001/archinte.1946.00220060002001
1359 (1946).
1360 124 Crump, J. A., Sjölund-Karlsson, M., Gordon, M. A. & Parry, C. M.
1361 Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial
1362 Resistance, and Antimicrobial Management of Invasive Salmonella Infections.
1363 Clin Microbiol Rev 28, 901-937, doi:10.1128/cmr.00002-15 (2015).
1364 125 Hosoglu, S. et al. Risk factors for enteric perforation in patients with typhoid
1365 Fever. Am J Epidemiol 160, 46-50, doi:10.1093/aje/kwh172 (2004).
1366 126 Birkhold, M. et al. Morbidity and mortality of typhoid intestinal perforation
1367 among children in sub-Saharan Africa 1995-2019: A scoping review. World J
1368 Surg, 1-11, doi:10.1007/s00268-020-05567-2 (2020).
1369 127 Neil, K. P. et al. A large outbreak of typhoid fever associated with a high rate
1370 of intestinal perforation in Kasese District, Uganda, 2008-2009. Clin Infect Dis
1371 54, 1091-1099, doi:10.1093/cid/cis025 (2012).
1372 128 Mogasale, V. et al. Case fatality rate and length of hospital stay among
1373 patients with typhoid intestinal perforation in developing countries: A
1374 systematic literature review. PLoS ONE 9, doi:10.1371/journal.pone.0093784
1375 (2014).
1376 129 Osuntokun, B. O., Bademosi, O., Ogunremi, K. & Wright, S. G.
1377 Neuropsychiatric manifestations of typhoid fever in 959 patients. Arch Neurol
1378 27, 7-13, doi:10.1001/archneur.1972.00490130009002 (1972).
1379 130 Lutterloh, E. et al. Multidrug-resistant typhoid fever with neurologic findings on
1380 the Malawi-Mozambique border. Clin Infect Dis 54, 1100-1106,
1381 doi:10.1093/cid/cis012 (2012).
1382 131 Britto, C. D. et al. Laboratory and molecular surveillance of paediatric
1383 typhoidal Salmonella in Nepal: Antimicrobial resistance and implications for
1384 vaccine policy. PLoS Negl Trop Dis 12, e0006408,
1385 doi:10.1371/journal.pntd.0006408 (2018).
1386 132 Britto, C., Pollard, A. J., Voysey, M. & Blohmke, C. J. An Appraisal of the
1387 Clinical Features of Pediatric Enteric Fever: Systematic Review and Meta-
1388 analysis of the Age-Stratified Disease Occurrence. Clinical Infectious
1389 Diseases: An Official Publication of the Infectious Diseases Society of
1390 America 64, 1604-1611, doi:10.1093/cid/cix229 (2017).
1391 133 Cruz Espinoza, L. M. et al. Occurrence of Typhoid Fever Complications and
1392 Their Relation to Duration of Illness Preceding Hospitalization: A Systematic
1393 Literature Review and Meta-analysis. Clinical Infectious Diseases 69,
1394 doi:10.1093/cid/ciz477 (2019).
1395 134 Al-Emran, H. M. et al. A Multicountry Molecular Analysis of Salmonella
1396 enterica Serovar Typhi With Reduced Susceptibility to Ciprofloxacin in Sub-
1397 Saharan Africa. Clin Infect Dis 62 Suppl 1, S42-46, doi:10.1093/cid/civ788
1398 (2016).
1399 135 Levine, M. M., Black, R. E. & Lanata, C. Precise estimation of the numbers of
1400 chronic carriers of Salmonella typhi in Santiago, Chile, an endemic area. J
1401 Infect Dis 146, 724-726, doi:10.1093/infdis/146.6.724 (1982).
1402 136 Khatri, N. S. et al. Gallbladder carriage of Salmonella paratyphi A may be an
1403 important factor in the increasing incidence of this infection in South Asia. Ann
1404 Intern Med 150, 567-568, doi:10.7326/0003-4819-150-8-200904210-00017
1405 (2009).
1406 137 Gonzalez-Escobedo, G., Marshall, J. M. & Gunn, J. S. Chronic and acute
1407 infection of the gall bladder by Salmonella Typhi: understanding the carrier
1408 state. Nat Rev Microbiol 9, 9-14, doi:10.1038/nrmicro2490 (2011).
1409 138 Crawford, R. W. et al. Gallstones play a significant role in Salmonella spp.
1410 gallbladder colonization and carriage. Proc Natl Acad Sci U S A 107, 4353-
1411 4358, doi:10.1073/pnas.1000862107 (2010).
1412 139 Dongol, S. et al. The microbiological and clinical characteristics of invasive
1413 salmonella in gallbladders from cholecystectomy patients in kathmandu,
1414 Nepal. PLoS One 7, e47342, doi:10.1371/journal.pone.0047342 (2012).
1415 140 Schiøler, H., Christiansen, E. D., Høybye, G., Rasmussen, S. N. & Greibe, J.
1416 Biliary calculi in chronic Salmonella carriers and healthy controls: a controlled
1417 study. Scand J Infect Dis 15, 17-19, doi:10.3109/inf.1983.15.issue-1.04
1418 (1983).
1419 141 Olsen, S. J. et al. Outbreaks of typhoid fever in the United States, 1960-99.
1420 Epidemiol Infect 130, 13-21, doi:10.1017/s0950268802007598 (2003).
1421 142 Bokkenheuser, V. DETECTION OF TYPHOID CARRIERS. Am J Public
1422 Health Nations Health 54, 477-486, doi:10.2105/ajph.54.3.477 (1964).
1423 143 Avendano, A. et al. Duodenal String Cultures: Practicality and Sensitivity for
1424 Diagnosing Enteric Fever in Children. The Journal of Infectious Diseases 153,
1425 359-362, doi:10.1093/infdis/153.2.358 (1986).
1426 144 Hoffman, S. A., Sikorski, M. J. & Levine, M. M. Chronic Salmonella Typhi
1427 carriage at sites other than the gallbladder. PLOS Neglected Tropical
1428 Diseases 17, e0011168, doi:10.1371/journal.pntd.0011168 (2023).
1429 145 Lin, F. Y. et al. Restaurant-associated outbreak of typhoid fever in Maryland:
1430 identification of carrier facilitated by measurement of serum Vi antibodies. J
1431 Clin Microbiol 26, 1194-1197, doi:10.1128/jcm.26.6.1194-1197.1988 (1988).
1432 146 Gupta, A. et al. Evaluation of community-based serologic screening for
1433 identification of chronic Salmonella typhi carriers in Vietnam. Int J Infect Dis
1434 10, 309-314, doi:10.1016/j.ijid.2005.06.005 (2006).
1435 147 Ferreccio, C. et al. [The detection of chronic Salmonella typhi carriers: a
1436 practical method applied to food handlers]. Rev Med Chil 118, 33-37 (1990).
1437 148 Lanata, C. F. et al. Vi serology in detection of chronic Salmonella typhi
1438 carriers in an endemic area. Lancet 2, 441-443, doi:10.1016/s0140-
1439 6736(83)90401-4 (1983).
1440 149 Thompson, L. J. et al. Transcriptional response in the peripheral blood of
1441 patients infected with Salmonella enterica serovar Typhi. Proc Natl Acad Sci
1442 U S A 106, 22433-22438, doi:10.1073/pnas.0912386106 (2009).
1443 150 Tran Vu Thieu, N. et al. An evaluation of purified Salmonella Typhi protein
1444 antigens for the serological diagnosis of acute typhoid fever. J Infect 75, 104-
1445 114, doi:10.1016/j.jinf.2017.05.007 (2017).
1446 151 Näsström, E. et al. Diagnostic metabolite biomarkers of chronic typhoid
1447 carriage. PLoS Negl Trop Dis 12, e0006215,
1448 doi:10.1371/journal.pntd.0006215 (2018).
1449 152 Gauld, J. S., Hu, H., Klein, D. J. & Levine, M. M. Typhoid fever in Santiago,
1450 Chile: Insights from a mathematical model utilizing venerable archived data
1451 from a successful disease control program. PLOS Neglected Tropical
1452 Diseases 12, e0006759, doi:10.1371/journal.pntd.0006759 (2018).
1453 153 Ng'eno, E. et al. Dynamic Incidence of Typhoid Fever over a 10-Year Period
1454 (2010-2019) in Kibera, an Urban Informal Settlement in Nairobi, Kenya. Am J
1455 Trop Med Hyg 109, 22-31, doi:10.4269/ajtmh.22-0736 (2023).
1456 154 Sikorski, M. J. & Levine, M. M. Reviving the "Moore Swab": a Classic
1457 Environmental Surveillance Tool Involving Filtration of Flowing Surface Water
1458 and Sewage Water To Recover Typhoidal Salmonella Bacteria. Appl Environ
1459 Microbiol 86, doi:10.1128/aem.00060-20 (2020).
1460 155 Kim, C. et al. Associations of water, sanitation, and hygiene with typhoid fever
1461 in case-control studies: a systematic review and meta-analysis. BMC Infect
1462 Dis 23, 562, doi:10.1186/s12879-023-08452-0 (2023).
1463 156 Stanaway, J. D., Atuhebwe, P. L., Luby, S. P. & Crump, J. A. Assessing the
1464 Feasibility of Typhoid Elimination. Clin Infect Dis 71, S179-s184,
1465 doi:10.1093/cid/ciaa585 (2020).
1466 157 Hejfec, L. B. RESULTS OF THE STUDY OF TYPHOID VACCINES IN FOUR
1467 CONTROLLED FIELD TRIALS IN THE USSR. Bull World Health Organ 32, 1-
1468 14 (1965).
1469 158 World Health Organization. Typhoid vaccines: WHO position paper. Wkly
1470 Epidemiol Rec 83, 49-59 (2008).
1471 159 Engels, E. A., Falagas, M. E., Lau, J. & Bennish, M. L. Typhoid fever
1472 vaccines: a meta-analysis of studies on efficacy and toxicity. Bmj 316, 110-
1473 116, doi:10.1136/bmj.316.7125.110 (1998).
1474 160 Milligan, R., Paul, M., Richardson, M. & Neuberger, A. Vaccines for
1475 preventing typhoid fever. Cochrane Database Syst Rev 5, Cd001261,
1476 doi:10.1002/14651858.CD001261.pub4 (2018).
1477 161 Goldblatt, D. Conjugate vaccines. Clin Exp Immunol 119, 1-3,
1478 doi:10.1046/j.1365-2249.2000.01109.x (2000).
1479 162 World Health Organization. Typhoid vaccines: WHO position paper – March
1480 2018. 153-172 (Geneva, Switzerland, 2018).
1481 163 Mohan, V. K. et al. Safety and immunogenicity of a Vi polysaccharide-tetanus
1482 toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults
1483 in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind,
1484 randomized controlled phase 3 study. Clin Infect Dis 61, 393-402,
1485 doi:10.1093/cid/civ295 (2015).
1486 164 Jin, C. et al. Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate
1487 vaccine in the prevention of typhoid fever using a controlled human infection
1488 model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet
1489 390, 2472-2480, doi:10.1016/S0140-6736(17)32149-9 (2017).
1490 165 Meiring, J. E., Giubilini, A., Savulescu, J., Pitzer, V. E. & Pollard, A. J.
1491 Generating the Evidence for Typhoid Vaccine Introduction: Considerations for
1492 Global Disease Burden Estimates and Vaccine Testing Through Human
1493 Challenge. Clin Infect Dis 69, S402-s407, doi:10.1093/cid/ciz630 (2019).
1494 166 Nampota, N. et al. Safety and immunogenicity of a typhoid conjugate vaccine
1495 among children aged 9 months through 12 years in Malawi: results from a
1496 randomised, double-blind, controlled trial Lancet Glob Health (2022).
1497 167 Sirima, S. B. et al. Safety and immunogenicity of co-administration of
1498 meningococcal type A and measles-rubella vaccines with typhoid conjugate
1499 vaccine in children aged 15-23 months in Burkina Faso. Int J Infect Dis 102,
1500 517-523, doi:10.1016/j.ijid.2020.10.103 (2021).
1501 168 Patel, P. D. et al. Safety and Efficacy of a Typhoid Conjugate Vaccine in
1502 Malawian Children. N Engl J Med 385, 1104-1115,
1503 doi:10.1056/NEJMoa2035916 (2021).
1504 169 Meiring, J. E. et al. Typhoid Vaccine Acceleration Consortium Malawi: A
1505 phase III, randomized, double-blind, controlled trial of the clinical efficacy of
1506 typhoid conjugate vaccine among children in Blantyre, Malawi. Clin Infect Dis
1507 68, S50-s58, doi:10.1093/cid/ciy1103 (2019).
1508 170 Colin-Jones, R. et al. Logistics of Implementing a Large-scale Typhoid
1509 Vaccine Trial in Kathmandu, Nepal. Clin Infect Dis 68, S138-s145,
1510 doi:10.1093/cid/ciy1125 (2019).
1511 171 Shakya, M. et al. Phase 3 efficacy analysis of a typhoid conjugate vaccine trial
1512 in Nepal. N Engl J Med 381, 2209-2218, doi:10.1056/NEJMoa1905047
1513 (2019).
1514 172 Patel, P. e. a. Efficacy of typhoid conjugate vaccine: final analysis of a four-
1515 year, randomised controlled trial in Malawian children. Preprint at SSRN:
1516 https://ssrn.com/abstract=4411421 (2023).
1517 173 Theiss-Nyland, K. et al. Assessing the impact of a Vi-polysaccharide
1518 conjugate vaccine in preventing typhoid infection among Bangladeshi
1519 children: A protocol for a phase IIIb trial. Clin Infect Dis 68, S74-s82,
1520 doi:10.1093/cid/ciy1107 (2019).
1521 174 Qadri, F. et al. Protection by vaccination of children against typhoid fever with
1522 a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-
1523 randomised trial. Lancet 398, 675-684, doi:10.1016/s0140-6736(21)01124-7
1524 (2021).
1525 175 Khanam, F. et al. Assessment of vaccine herd protection in a cluster-
1526 randomised trial of Vi conjugate vaccine against typhoid fever: results of
1527 further analysis. eClinicalMedicine 58, doi:10.1016/j.eclinm.2023.101925
1528 (2023).
1529 176 Hoffman, S. A. et al. Programmatic Effectiveness of a Pediatric Typhoid
1530 Conjugate Vaccine Campaign in Navi Mumbai, India. Clinical Infectious
1531 Diseases, doi:10.1093/cid/ciad132 (2023).
1532 177 Yousafzai, M. T. et al. Effectiveness of typhoid conjugate vaccine against
1533 culture-confirmed Salmonella enterica serotype Typhi in an extensively drug-
1534 resistant outbreak setting of Hyderabad, Pakistan: a cohort study. Lancet
1535 Glob Health 9, e1154-e1162, doi:10.1016/s2214-109x(21)00255-2 (2021).
1536 178 Lightowler, M. S. et al. Effectiveness of typhoid conjugate vaccine in
1537 Zimbabwe used in response to an outbreak among children and young adults:
1538 A matched case control study. Vaccine 40, 4199-4210,
1539 doi:10.1016/j.vaccine.2022.04.093 (2022).
1540 179 Nampota-Nkomba, N., Carey, M. E., Jamka, L. P., Fecteau, N. & Neuzil, K. M.
1541 Using Typhoid Conjugate Vaccines to Prevent Disease, Promote Health
1542 Equity, and Counter Drug-Resistant Typhoid Fever. Open Forum Infectious
1543 Diseases 10, S6-S12, doi:10.1093/ofid/ofad022 (2023).
1544 180 Khanam, F., Ross, A. G., McMillan, N. A. J. & Qadri, F. Toward Typhoid Fever
1545 Elimination. Int J Infect Dis 119, 41-43, doi:10.1016/j.ijid.2022.03.036 (2022).
1546 181 Nga, T. V. T., Duy, P. T., Lan, N. P. H., Chau, N. V. V. & Baker, S. The
1547 Control of Typhoid Fever in Vietnam. Am J Trop Med Hyg 99, 72-78,
1548 doi:10.4269/ajtmh.18-0035 (2018).
1549 182 Browne, A. J. et al. Drug-resistant enteric fever worldwide, 1990 to 2018: a
1550 systematic review and meta-analysis. BMC Med 18, 1, doi:10.1186/s12916-
1551 019-1443-1 (2020).
1552 183 Bhutta, Z. A. Impact of age and drug resistance on mortality in typhoid fever.
1553 Arch Dis Child 75, 214-217, doi:10.1136/adc.75.3.214 (1996).
1554 184 Parry, C. M. The treatment of multidrug-resistant and nalidixic acid-resistant
1555 typhoid fever in Viet Nam. Trans R Soc Trop Med Hyg 98, 413-422,
1556 doi:10.1016/j.trstmh.2003.10.014 (2004).
1557 185 Nabarro, L. E. et al. British infection association guidelines for the diagnosis
1558 and management of enteric fever in England. J Infect 84, 469-489,
1559 doi:10.1016/j.jinf.2022.01.014 (2022).
1560 186 Dolecek C, P. S., Basnyat B, Olliaro P. . Antibiotics for typhoid fever. In: The
1561 selection and use of essential medicines. WHO technical report series No
1562 1021,
1563 <https://apps.who.int/iris/bitstream/handle/10665/330668/9789241210300-
1564 eng.pdf?ua=1> (2019).
1565 187 Carey, M. E. et al. Spontaneous Emergence of Azithromycin Resistance in
1566 Independent Lineages of Salmonella Typhi in Northern India. Clin Infect Dis
1567 72, e120-e127, doi:10.1093/cid/ciaa1773 (2021).
1568 188 Duy, P. T. et al. The emergence of azithromycin-resistant Salmonella Typhi in
1569 Nepal. JAC Antimicrob Resist 2, dlaa109, doi:10.1093/jacamr/dlaa109 (2020).
1570 189 Effa, E. E. & Bukirwa, H. Azithromycin for treating uncomplicated typhoid and
1571 paratyphoid fever (enteric fever). Cochrane Database Syst Rev, Cd006083,
1572 doi:10.1002/14651858.CD006083.pub2 (2008).
1573 190 Effa, E. E. et al. Fluoroquinolones for treating typhoid and paratyphoid fever
1574 (enteric fever). Cochrane Database Syst Rev 2011, Cd004530,
1575 doi:10.1002/14651858.CD004530.pub4 (2011).
1576 191 Eliakim-Raz, N. et al. Efficacy and safety of chloramphenicol: joining the
1577 revival of old antibiotics? Systematic review and meta-analysis of randomized
1578 controlled trials. J Antimicrob Chemother 70, 979-996, doi:10.1093/jac/dku530
1579 (2015).
1580 192 Qamar, F. N. et al. Outbreak investigation of ceftriaxone-resistant Salmonella
1581 enterica serotype Typhi and its risk factors among the general population in
1582 Hyderabad, Pakistan: a matched case-control study. Lancet Infect Dis 18,
1583 1368-1376, doi:10.1016/s1473-3099(18)30483-3 (2018).
1584 193 Argimón, S. et al. Circulation of Third-Generation Cephalosporin Resistant
1585 Salmonella Typhi in Mumbai, India. Clin Infect Dis 74, 2234-2237,
1586 doi:10.1093/cid/ciab897 (2022).
1587 194 Samajpati, S., Pragasam, A. K., Mandal, S., Balaji, V. & Dutta, S. Emergence
1588 of ceftriaxone resistant Salmonella enterica serovar Typhi in Eastern India.
1589 Infection, Genetics and Evolution 96, 105093,
1590 doi:https://doi.org/10.1016/j.meegid.2021.105093 (2021).
1591 195 Qureshi, S. et al. Response of extensively drug resistant Salmonella Typhi to
1592 treatment with meropenem and azithromycin, in Pakistan. PLOS Neglected
1593 Tropical Diseases 14, e0008682, doi:10.1371/journal.pntd.0008682 (2020).
1594 196 Van Be Bay, P. et al. Quantitative bacterial counts in the bone marrow of
1595 Vietnamese patients with typhoid fever. Trans R Soc Trop Med Hyg 116, 736-
1596 744, doi:10.1093/trstmh/trac003 (2022).
1597 197 Pascual, A., Conejo, M. C., García, I. & Perea, E. J. Factors affecting the
1598 intracellular accumulation and activity of azithromycin. J Antimicrob
1599 Chemother 35, 85-93, doi:10.1093/jac/35.1.85 (1995).
1600 198 Zmora, N. et al. Open label comparative trial of mono versus dual antibiotic
1601 therapy for Typhoid Fever in adults. PLoS Negl Trop Dis 12, e0006380,
1602 doi:10.1371/journal.pntd.0006380 (2018).
1603 199 Giri, A. et al. Azithromycin and cefixime combination versus azithromycin
1604 alone for the out-patient treatment of clinically suspected or confirmed
1605 uncomplicated typhoid fever in South Asia: a randomised controlled trial
1606 protocol. Wellcome Open Res 6, 207,
1607 doi:10.12688/wellcomeopenres.16801.2 (2021).
1608 200 Butler, T. et al. Typhoid fever complicated by intestinal perforation: a
1609 persisting fatal disease requiring surgical management. Rev Infect Dis 7, 244-
1610 256, doi:10.1093/clinids/7.2.244 (1985).
1611 201 Hoffman, S. L. et al. Reduction of mortality in chloramphenicol-treated severe
1612 typhoid fever by high-dose dexamethasone. N Engl J Med 310, 82-88,
1613 doi:10.1056/nejm198401123100203 (1984).
1614 202 Contopoulos-Ioannidis, D. G. & Ioannidis, J. P. Claims for improved survival
1615 from systemic corticosteroids in diverse conditions: an umbrella review. Eur J
1616 Clin Invest 42, 233-244, doi:10.1111/j.1365-2362.2011.02584.x (2012).
1617 203 McCann, N., Scott, P., Parry, C. M. & Brown, M. Antimicrobial agents for the
1618 treatment of enteric fever chronic carriage: A systematic review. PLoS One
1619 17, e0272043, doi:10.1371/journal.pone.0272043 (2022).
1620 204 Luthra, K. et al. A Review of the Economic Evidence of Typhoid Fever and
1621 Typhoid Vaccines. Clin Infect Dis 68, S83-s95, doi:10.1093/cid/ciy1122
1622 (2019).
1623 205 Riewpaiboon, A. et al. Cost of illness due to typhoid Fever in pemba,
1624 zanzibar, East Africa. J Health Popul Nutr 32, 377-385 (2014).
1625 206 Bahl, R. et al. Costs of illness due to typhoid fever in an Indian urban slum
1626 community: implications for vaccination policy. J Health Popul Nutr 22, 304-
1627 310 (2004).
1628 207 Kaljee, L. M. et al. Social and Economic Burden Associated With Typhoid
1629 Fever in Kathmandu and Surrounding Areas: A Qualitative Study. J Infect Dis
1630 218, S243-s249, doi:10.1093/infdis/jix122 (2018).
1631 208 Limani, F. et al. Estimating the economic burden of typhoid in children and
1632 adults in Blantyre, Malawi: a costing cohort study. In progress. BMC Public
1633 Health (Submitted).
1634 209 Mejia, N. et al. Typhoid and Paratyphoid Cost of Illness in Nepal: Patient and
1635 Health Facility Costs From the Surveillance for Enteric Fever in Asia Project II.
1636 Clin Infect Dis 71, S306-s318, doi:10.1093/cid/ciaa1335 (2020).
1637 210 Mejia, N. et al. Typhoid and Paratyphoid Cost of Illness in Bangladesh:
1638 Patient and Health Facility Costs From the Surveillance for Enteric Fever in
1639 Asia Project II. Clin Infect Dis 71, S293-s305, doi:10.1093/cid/ciaa1334
1640 (2020).
1641 211 Mejia, N. et al. Typhoid and Paratyphoid Cost of Illness in Bangladesh:
1642 Patient and Health Facility Costs From the Surveillance for Enteric Fever in
1643 Asia Project II. Clinical Infectious Diseases 71, S293-S305,
1644 doi:10.1093/cid/ciaa1334 (2020).
1645 212 Mejia, N. et al. Typhoid and Paratyphoid Cost of Illness in Pakistan: Patient
1646 and Health Facility Costs From the Surveillance for Enteric Fever in Asia
1647 Project II. Clin Infect Dis 71, S319-s335, doi:10.1093/cid/ciaa1336 (2020).
1648 213 Bilcke, J. et al. Cost-effectiveness of routine and campaign use of typhoid Vi-
1649 conjugate vaccine in Gavi-eligible countries: a modelling study. Lancet Infect
1650 Dis 19, 728-739, doi:10.1016/s1473-3099(18)30804-1 (2019).
1651 214 Seyi-Olajide, J. O. et al. Catastrophic Healthcare Expenditure from Typhoid
1652 Perforation in Children in Nigeria. Surg Infect (Larchmt) 21, 586-591,
1653 doi:10.1089/sur.2020.134 (2020).
1654 215 Kumar, D. et al. Cost of Illness Due to Severe Enteric Fever in India. J Infect
1655 Dis 224, S540-s547, doi:10.1093/infdis/jiab282 (2021).
1656 216 Malik, A. (2019).
1657 217 Limani, F. et al. Estimating the economic burden of typhoid in children and
1658 adults in Blantyre, Malawi: A costing cohort study. PLOS ONE 17, e0277419,
1659 doi:10.1371/journal.pone.0277419 (2022).
1660 218 Birkhold, M., Mwisongo, A., Pollard, A. J. & Neuzil, K. M. Typhoid conjugate
1661 vaccine in Africa and Asia: Status of clinical evaluation and vaccine
1662 introduction. The Journal of Infectious Diseases, doi:10.1093/infdis/jiab449
1663 (2021).
1664 219 World Health, O. in Vaccine Vol. 37 (2019).
1665 220 World Health Organization. Weekly epidemiological record. 261-276 (Geneva,
1666 Switzerland, 2022).
1667 221 Gavi the Vaccine Alliance. (2017).
1668 222 Lo, N. C. et al. Comparison of Strategies and Incidence Thresholds for Vi
1669 Conjugate Vaccines Against Typhoid Fever: A Cost-effectiveness Modeling
1670 Study. J Infect Dis 218, S232-s242, doi:10.1093/infdis/jix598 (2018).
1671 223 Burrows, H. et al. Comparison of model predictions of typhoid conjugate
1672 vaccine public health impact and cost-effectiveness. Vaccine 41, 965-975,
1673 doi:10.1016/j.vaccine.2022.12.032 (2023).
1674 224 Chauhan, A. S. et al. Cost effectiveness of typhoid vaccination in India.
1675 Vaccine 39, 4089-4098, doi:10.1016/j.vaccine.2021.06.003 (2021).
1676 225 Ryckman, T. et al. Comparison of Strategies for Typhoid Conjugate Vaccine
1677 Introduction in India: A Cost-Effectiveness Modeling Study. The Journal of
1678 Infectious Diseases 224, S612-S624, doi:10.1093/infdis/jiab150 (2021).
1679 226 Carey, M. E., McCann, N. S. & Gibani, M. M. Typhoid fever control in the 21st
1680 century: where are we now? Curr Opin Infect Dis 35, 424-430,
1681 doi:10.1097/qco.0000000000000879 (2022).
1682 227 MacLennan, C. A., Stanaway, J., Grow, S., Vannice, K. & Steele, A. D.
1683 Salmonella Combination Vaccines: Moving Beyond Typhoid. Open Forum
1684 Infectious Diseases 10, S58-S66, doi:10.1093/ofid/ofad041 (2023).
1685 228 Shakya, M. et al. Efficacy of typhoid conjugate vaccine in Nepal: final results
1686 of a phase 3, randomised, controlled trial. Lancet Glob Health 9, e1561-
1687 e1568, doi:10.1016/s2214-109x(21)00346-6 (2021).
1688 229 Batool, R. et al. Effectiveness of typhoid conjugate vaccine against culture-
1689 confirmed typhoid in a peri-urban setting in Karachi: A case-control study.
1690 Vaccine 39, 5858-5865, doi:10.1016/j.vaccine.2021.08.051 (2021).
1691 230 Juel, H. B. et al. Salmonella Typhi Bactericidal Antibodies Reduce Disease
1692 Severity but Do Not Protect against Typhoid Fever in a Controlled Human
1693 Infection Model. Front Immunol 8, 1916, doi:10.3389/fimmu.2017.01916
1694 (2017).
1695 231 Jones, E. et al. A Salmonella Typhi Controlled Human Infection Study for
1696 Assessing Correlation between Bactericidal Antibodies and Protection against
1697 Infection Induced by Typhoid Vaccination. Microorganisms 9,
1698 doi:10.3390/microorganisms9071394 (2021).
1699 232 Jin, C. et al. Treatment responses to Azithromycin and Ciprofloxacin in
1700 uncomplicated Salmonella Typhi infection: A comparison of Clinical and
1701 Microbiological Data from a Controlled Human Infection Model. PLoS Negl
1702 Trop Dis 13, e0007955, doi:10.1371/journal.pntd.0007955 (2019).
1703 233 Jin, C. et al. Vi-specific serological correlates of protection for typhoid fever. J
1704 Exp Med 218, doi:10.1084/jem.20201116 (2021).
1705 234 Dahora, L. C. et al. IgA and IgG1 Specific to Vi Polysaccharide of Salmonella
1706 Typhi Correlate With Protection Status in a Typhoid Fever Controlled Human
1707 Infection Model. Front Immunol 10, 2582, doi:10.3389/fimmu.2019.02582
1708 (2019).
1709 235 Cross, D. L. et al. Vi-Vaccinations Induce Heterogeneous Plasma Cell
1710 Responses That Associate With Protection From Typhoid Fever. Front
1711 Immunol 11, 574057, doi:10.3389/fimmu.2020.574057 (2020).
1712
1713
1714 Acknowledgments
1715 [Au: If you have consent for the patient experience Box 2 and we are able to retain the
1716 Box, I suggest to add the following statement here in the Acknowledgements: "The
1717 authors thank Bashir for their contribution in Box 2." Is this OK?]
1718

1719 Author contributions

1720 [Au: I have updated this statement to match the information provided on the online
1721 tracking system. Please update here if you adjust the statement on the online
1722 system.]
1723 Introduction (M.A.G, J.E.M.); Epidemiology (M.A.G, J.A.C., B.B., F.Q., S.K., F.K., J.E.M.);
1724 Mechanisms/pathophysiology (M.A.G, K.H., A.J.P., J.E.M.); Diagnosis/screening/prevention
1725 (M.A.G, R.C., C.P., J.E.M.); Management (M.A.G, B.B., F.Q., C.P., F.K., J.E.M.); Quality of life
1726 (M.A.G, VP, J.E.M., F.D.); Outlook (M.A.G, A.J.P., K.M.N., V.P., J.E.M.); Overview of the
1727 Primer (J.E.M. and M.A.G.).
1728

1729 Competing interests

1730 The authors declare no competing interests.
1731

1732 Publisher’s note

1733 Springer Nature remains neutral with regard to jurisdictional claims in published maps and
1734 institutional affiliations.