Typhoid fever

Summary

Typhoid fever (MONDO:0005619) is a disease with 2 cohort genes (2 GWAS associations across 4 studies) and 57 clinical trials. Top therapeutic interventions include azithromycin, cefixime, and ceftriaxone.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• GWAS associations: 2
• Phenotypes (HPO): 27
• Clinical trials: 57

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	3	Europe	Validated
Annual incidence	>1 / 1000	274	South East Asia	Validated
Annual incidence	1-5 / 10 000	53	Latin America	Validated
Annual incidence	1-5 / 10 000	50	Africa	Validated
Annual incidence	1-9 / 1 000 000		North America	Validated
Annual incidence	1-5 / 10 000	15	Oceania	Validated
Annual incidence	1-9 / 1 000 000	0.2	France	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0001945	Fever	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0100785	Insomnia	Very frequent (80-99%)
HP:0000988	Skin rash	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0012733	Macule	Frequent (30-79%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001695	Cardiac arrest	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002383	Infectious encephalitis	Occasional (5-29%)
HP:0004936	Venous thrombosis	Occasional (5-29%)
HP:0006530	Abnormal pulmonary interstitial morphology	Occasional (5-29%)
HP:0012735	Cough	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	typhoid fever
Mondo ID	MONDO:0005619
EFO	EFO:0006789
MeSH	D014435
Orphanet	99745
DOID	DOID:13258
ICD-10-CM	A01.0
ICD-11	1528414070
NCIT	C35089
SNOMED CT	4834000
UMLS	C0041466
MedGen	11973
GARD	0009564
Is cancer (heuristic)	no

Also known as: typhoid · typhoid fever · typhoidal salmonellosis

Data availability: 2 GWAS associations (4 studies).

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of primarily extrinsic mechanism › infectious disease › bacterial infectious disease › primary bacterial infectious disease › salmonellosis › typhoid fever

Related subtypes (4): Salmonella gastroenteritis, invasive non-typhoidal salmonellosis, paratyphoid fever, salmonella discitis

Genetics & variants

GWAS landscape

2 GWAS associations across 4 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7765379	2e-13	MTCO3P1 - HLA-DQB3	A	4.55
rs143977447	1e-08	LINC03000 - LINC01938	A	1.29

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90018931	Sakaue S	2021	2,733	346,689	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST002693	Dunstan SJ	2014	432	2,011	Variation at HLA-DRB1 is associated with resistance to enteric fever.
GCST90018711	Sakaue S	2021	257	178,071	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST90726627	Kim HI	2026	118	43,908	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	2

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intergenic_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7765379	6	32713151	T>G	0.055	intergenic_variant	MTCO3P1 - HLA-DQB3	2e-13	Tier 4: intronic/intergenic
rs143977447	5	165219146	C>A,T		intergenic_variant	LINC03000 - LINC01938	1e-08	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 19 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HLA-DQB1	Orphanet:2073	Narcolepsy type 1
HLA-DQB1	Orphanet:477738	Pediatric multiple sclerosis
HLA-DQB1	Orphanet:703	Bullous pemphigoid
HLA-DQB1	Orphanet:83465	Narcolepsy type 2
HLA-DQB1	Orphanet:930	Idiopathic achalasia
HLA-DRB1	Orphanet:2073	Narcolepsy type 1
HLA-DRB1	Orphanet:220393	Diffuse cutaneous systemic sclerosis
HLA-DRB1	Orphanet:220402	Limited cutaneous systemic sclerosis
HLA-DRB1	Orphanet:220407	Limited systemic sclerosis
HLA-DRB1	Orphanet:3437	Vogt-Koyanagi-Harada disease
HLA-DRB1	Orphanet:397	Giant cell arteritis
HLA-DRB1	Orphanet:477738	Pediatric multiple sclerosis
HLA-DRB1	Orphanet:536	Systemic lupus erythematosus
HLA-DRB1	Orphanet:545	Follicular lymphoma
HLA-DRB1	Orphanet:703	Bullous pemphigoid
HLA-DRB1	Orphanet:747	Autoimmune pulmonary alveolar proteinosis
HLA-DRB1	Orphanet:797	Sarcoidosis
HLA-DRB1	Orphanet:83465	Narcolepsy type 2
HLA-DRB1	Orphanet:85414	Systemic-onset juvenile idiopathic arthritis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HLA-DQB1	HGNC:4944	ENSG00000179344	P01920	HLA class II histocompatibility antigen, DQ beta 1 chain	gwas
HLA-DRB1	HGNC:4948	ENSG00000196126	P01911	HLA class II histocompatibility antigen, DRB1 beta chain	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HLA-DQB1	HLA class II histocompatibility antigen, DQ beta 1 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HLA-DRB1	HLA class II histocompatibility antigen, DRB1 beta chain	A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	2	29.2×	0.001

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HLA-DQB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
HLA-DRB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lung	2
spleen	1
upper lobe of left lung	1
granulocyte	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HLA-DQB1	268	broad	marker	right lung, spleen, upper lobe of left lung
HLA-DRB1	131	tissue_specific	marker	vermiform appendix, granulocyte, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HLA-DRB1	3,448
HLA-DQB1	128

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HLA-DRB1	P01911	108
HLA-DQB1	P01920	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interferon gamma signaling	2	125.5×	4e-04	HLA-DQB1, HLA-DRB1
Translocation of ZAP-70 to Immunological synapse	1	317.2×	0.007	HLA-DRB1
Phosphorylation of CD3 and TCR zeta chains	1	271.9×	0.007	HLA-DRB1
Co-inhibition by PD-1	1	259.6×	0.007	HLA-DRB1
Generation of second messenger molecules	1	173.0×	0.008	HLA-DRB1
Downstream TCR signaling	1	64.2×	0.018	HLA-DRB1
MHC class II antigen presentation	1	44.6×	0.022	HLA-DRB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptide antigen assembly with MHC class II protein complex	2	1053.2×	3e-05	HLA-DQB1, HLA-DRB1
antigen processing and presentation of exogenous peptide antigen via MHC class II	2	543.6×	4e-05	HLA-DQB1, HLA-DRB1
positive regulation of immune response	2	481.5×	4e-05	HLA-DQB1, HLA-DRB1
positive regulation of T cell activation	2	443.5×	4e-05	HLA-DQB1, HLA-DRB1
humoral immune response	2	280.9×	7e-05	HLA-DQB1, HLA-DRB1
T cell receptor signaling pathway	2	151.8×	2e-04	HLA-DQB1, HLA-DRB1
regulation of interleukin-4 production	1	8426.0×	5e-04	HLA-DRB1
antigen processing and presentation of endogenous peptide antigen via MHC class II	1	4213.0×	8e-04	HLA-DRB1
regulation of interleukin-10 production	1	4213.0×	8e-04	HLA-DRB1
myeloid dendritic cell antigen processing and presentation	1	2808.7×	0.001	HLA-DRB1
regulation of T-helper cell differentiation	1	2106.5×	0.001	HLA-DRB1
positive regulation of CD4-positive, alpha-beta T cell activation	1	2106.5×	0.001	HLA-DRB1
immune response	2	47.1×	0.001	HLA-DQB1, HLA-DRB1
positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	1685.2×	0.001	HLA-DRB1
positive regulation of T cell mediated immune response to tumor cell	1	1203.7×	0.002	HLA-DRB1
T-helper 1 type immune response	1	936.2×	0.002	HLA-DRB1
positive regulation of memory T cell differentiation	1	936.2×	0.002	HLA-DRB1
positive regulation of monocyte differentiation	1	766.0×	0.002	HLA-DRB1
detection of bacterium	1	702.2×	0.002	HLA-DRB1
inflammatory response to antigenic stimulus	1	468.1×	0.003	HLA-DRB1
protein tetramerization	1	312.1×	0.005	HLA-DRB1
negative regulation of inflammatory response to antigenic stimulus	1	300.9×	0.005	HLA-DRB1
positive regulation of T cell mediated cytotoxicity	1	255.3×	0.005	HLA-DRB1
macrophage differentiation	1	234.1×	0.005	HLA-DRB1
negative regulation of type II interferon production	1	191.5×	0.006	HLA-DRB1
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.006	HLA-DRB1
negative regulation of T cell proliferation	1	165.2×	0.007	HLA-DRB1
epidermis development	1	105.3×	0.010	HLA-DRB1
adaptive immune response	1	42.1×	0.024	HLA-DQB1
signal transduction	1	8.0×	0.121	HLA-DRB1

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Ciprofloxacin	Approved (phase 4)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HLA-DQB1	0	0
HLA-DRB1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HLA-DRB1	17	Binding:17

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	HLA-DQB1, HLA-DRB1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HLA-DQB1	0	—
HLA-DRB1	17	—

Clinical trials & evidence

Clinical trials

Clinical trials: 57.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	13
PHASE2	12
Not specified	12
PHASE1	8
PHASE3	7
PHASE1/PHASE2	2
EARLY_PHASE1	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00125008	PHASE4	COMPLETED	Evaluation of the Vi Polysaccharide Vaccine Against Typhoid Fever
NCT00125047	PHASE4	COMPLETED	Combined Vi Vaccination and Health Education Program on the Burden of Typhoid in Childhood
NCT00131820	PHASE4	COMPLETED	Introduction of the Vi Polysaccharide Typhoid Vaccine in Hue City, Central Vietnam
NCT00131833	PHASE4	COMPLETED	Typhoid Vi Vaccine Effectiveness in Hechi, Guangxi, China
NCT01421693	PHASE4	COMPLETED	Gatifloxacin Versus Ceftriaxone in the Treatment of Enteric Fever
NCT02224040	PHASE4	UNKNOWN	Typhoid Fever: Combined vs. Single Antibiotic Therapy
NCT04154722	PHASE4	COMPLETED	Comparison of Two Drugs Regimen in Treatment of Complicated Typhoid Fever in Children
NCT04349826	PHASE4	COMPLETED	The Azithromycin and Cefixime Treatment of Typhoid in South Asia Trial (ACT-South Asia Trial)
NCT04852185	PHASE4	UNKNOWN	Evaluation of Typhoid Conjugate Vaccine Effectiveness in Ghana
NCT05119426	PHASE4	UNKNOWN	Effectiveness of a Typhoid Conjugate Vaccine in DRC
NCT05500482	PHASE4	COMPLETED	Vellore Typhoid Vaccine Impact Trial
NCT06104345	PHASE4	COMPLETED	Immune Response Elicited by Concomitant Administration of Oral Typhoid Fever (Vivotif®) and Cholera (Dukoral®) Vaccines
NCT07445282	PHASE4	COMPLETED	This Randomized Controlled Trial Evaluates the Comparative Efficacy of Intravenous Meropenem Alone Versus Intravenous Meropenem Combined With Oral Azithromycin in Children Aged 6 Months to Under 5 Years Diagnosed With Blood Culture-confirmed Extensively Drug-resistant Uncomplicated Typhoid Fever
NCT03299426	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Efficacy of Typhoid Conjugate Vaccine (Vi-TCV) Among Children Age 9 Months Through 12 Years in Blantyre, Malawi
NCT06757283	PHASE3	NOT_YET_RECRUITING	ZyVac-TCV Bangladesh Study
NCT01466387	PHASE3	COMPLETED	A Phase 3b, Randomized, Open-Label Study to Evaluate the Safety and Immunogenicity of Select Travel Vaccines When Administered Concomitantly With MenACWY in Adults
NCT01608815	PHASE3	COMPLETED	Study of a Single Dose of SP093 Typhoid Vi Polysaccharide Vaccine in Japanese Subjects
NCT03933098	PHASE3	UNKNOWN	Immune Non-inferiority and Safety of a Vi-DT Typhoid Conjugate Vaccine
NCT04204096	PHASE3	COMPLETED	Immune Equivalence Between Multi-dose and Single Dose Formulation of Vi-DT and Their Overall Safety (Phase III)
NCT04830371	PHASE2/PHASE3	COMPLETED	Non-inferiority and Safety Study of EuTCV Compared to Typbar-TCV in Healthy 6 Months-45 Years Aged Participants
NCT05771779	PHASE3	UNKNOWN	Co-administration Study of OCV, TCV and MR
NCT00342628	PHASE2	COMPLETED	Safety, Immunogenicity and Compatibility With DTP of a Typhoid Fever Vaccine in Infants
NCT00498654	PHASE2	COMPLETED	Dose Ranging Study to Determine the Safety, Reactogenicity and Immunogenicity of Typhoid Fever Vaccine (Ty800) in Healthy Adult Subjects
NCT00679172	PHASE2	COMPLETED	Immunogenicity, Safety and Tolerability of the Typhoid Fever Vaccine Candidate M01ZH09 in Healthy Adults
NCT01019083	PHASE1/PHASE2	COMPLETED	Studies of Immune Responses to Orally Administered Vaccines in Developing Country
NCT01193907	PHASE2	COMPLETED	Safety and Immunogenicity of Three Formulations of Vi-CRM197 Vaccine Against S. Typhi in Adults (18-40 Years Old)
NCT01229176	PHASE2	COMPLETED	Safety and Immunogenicity of Vi-CRM197 Vaccine Against S. Typhi in Adults, Children, Older Infants and Infants
NCT01405521	PHASE2	COMPLETED	Understanding Typhoid Disease After Vaccination
NCT01437267	PHASE2	COMPLETED	Safety and Immunogenicity of Vi-CRM197 Vaccine Against S. Typhi in Children, Older Infants and Infants
NCT01438996	PHASE2	COMPLETED	Extension Study of H01_04TP to Evaluate the Booster Response Induced by Vi-CRM197 in Adults
NCT02324751	PHASE2	COMPLETED	Vaccines Against Salmonella Typhi
NCT03527355	PHASE2	COMPLETED	Safety, Reactogenicity and Immunogenicity of Vi-DT;Typhoid Conjugate Vaccine
NCT03614533	PHASE2	COMPLETED	Typhoid Conjugate Vaccine Trial Among Children Younger Than 2 Years in Ouagadougou, Burkina Faso
NCT05475379	PHASE1/PHASE2	COMPLETED	Non-inferiority Trial of Locally Manufactured Typhoid Conjugate Vaccine ‘Typhocon’ in Bangladesh
NCT07150065	PHASE2	COMPLETED	Efficacy of Levofloxacin Versus Ciprofloxacin in the Treatment of Childhood Typhoid Fever
NCT00277147	PHASE1	COMPLETED	Salmonella Typhi Vi O-Acetyl Pectin-rEPA Conjugate Vaccine
NCT00326443	PHASE1	COMPLETED	CVD 909 Vi Prime Boost Study
NCT01123941	PHASE1	COMPLETED	Safety and Immunogenicity of Vi-CRM197 Vaccine Against S. Typhi in Adult (18-40 Years Old)
NCT02645032	PHASE1	COMPLETED	Safety and Immunogenicity of a Vi-DT Typhoid Conjugate Vaccine
NCT03312699	PHASE1	COMPLETED	Effects of Aging on Primary and Secondary Vaccine Responses

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AZITHROMYCIN	4	3
CEFIXIME	4	2
CEFTRIAXONE	4	2
MEROPENEM	4	2
ALBENDAZOLE	4	1
GATIFLOXACIN	4	1
INULIN	4	1
SECNIDAZOLE	4	1
VIBRIO CHOLERAE, LIVE ATTENUATED	4	1
ZINC SULFATE	4	1
SALMONELLA TYPHI TY2 VI POLYSACCHARIDE ANTIGEN	3	2
TYPHOID VI POLYSACCHARIDE VACCINE	3	2
MALTODEXTRIN	3	1
RABIES VACCINE	3	1
YELLOW FEVER VACCINE	3	1
ARSENIC	2	1
CHEMBL4299381	0	3