IntechOpen

Home > Books > Salmonella - Molecular Biology, Pathogenesis, and Public Health Impact

Open access peer-reviewed chapter

The Rising Crisis of Salmonella Typhimurium in Africa

Written By

Derrick A. Daah and Samuel Duodu

Submitted: 20 June 2025 Reviewed: 24 June 2025 Published: 12 September 2025

DOI: 10.5772/intechopen.1011736

Salmonella IntechOpen
Salmonella Molecular Biology, Pathogenesis, and Public H... Edited by Mihaela Laura Vica

From the Edited Volume

Salmonella - Molecular Biology, Pathogenesis, and Public Health Impact

Mihaela Laura Vica

Book Details Order Print

Chapter metrics overview

67 Chapter Downloads

View Full Metrics
Advertisement

Abstract

Non-typhoidal Salmonella (NTS) serovars globally cause self-limiting gastroenteritis in healthy humans. While the majority of NTS infections remain localized in the gut, invasive non-typhoidal Salmonella (iNTS) serovars have evolved to cause systemic disease. The major contributors of iNTS disease include Salmonella Typhimurium, Salmonella Enteritidis, and Salmonella Dublin. Notably, S. Typhimurium sequence type 313 (ST313) and its sublineages have been linked to invasive salmonellosis epidemics, especially in children and the immunocompromised in sub-Saharan Africa (sSA). Unique features of these strains include enhanced survival in host cells and signatures of genome degradation favoring their bloodstream dissemination. Although primarily localized in sSA, ST313 has been detected sporadically in South America and Europe suggesting the potential for global dissemination. The clinical challenges caused by these strains are further exacerbated by their rising antimicrobial resistance, making treatments less effective elevating their threat to public health. This review will examine the burden, biology, evolution, pathogenesis, and antimicrobial resistance of African S. Typhimurium. This will shed light on why this pathogen is a pressing public health concern emphasizing the need for continuous research to avert the possibility of global outbreaks of invasive salmonellosis.

Keywords

  • non-typhoidal salmonella (NTS)
  • invasive non-typhoidal salmonella (iNTS)
  • S. Typhimurium sequence type 313 (ST313)
  • bloodstream infection
  • multidrug resistance
  • sub-Saharan Africa

1. Introduction

Salmonella enterica constitutes the largest bacterial species under the genus Salmonella with over 2600 serovars identified [1]. The subspecies enterica consists of clinically important serovars and is broadly divided into typhoidal and non-typhoidal Salmonella (NTS). Salmonella Typhi and Paratyphi are the major typhoidal serovars causing typhoid fever in humans. They are host-specific, human restricted and transmitted via the fecal oral route. Non-typhoidal Salmonella (NTS) serovars have a wide host range and cause self-limiting enterocolitis in the majority of immunocompetent individuals [2]. In these individuals, secondary bacteremia is uncommon and estimated case fatality rates are low [3, 4]. Humans are often infected via the fecal-oral route [5, 6, 7]. NTS infections can proceed to an invasive infection in infants, children with malaria and malnutrition, and individuals with HIV infections [8]. While the global health trends between 1990 and 2021 show a marked decline in the incidence of typhoid and paratyphoid fever, infections caused by invasive non-typhoidal Salmonella (iNTS) have gradually increased during the same period. Although the incidence of typhoid and paratyphoid remains 17 times higher than that of iNTS, the latter now accounts for higher mortality and disability-adjusted life years (DALYs). The rise in iNTS disease burden underscores its significance as a cause of invasive bacterial disease worldwide [9]. Annually, approximately 500,000 cases of iNTS infection are estimated in sSA, with a mean case fatality rate of 14.5%. These figures may be underestimated due to infrequent surveillance and substantial variation in regional and national demographics [10, 11, 12, 13]. Typically, iNTS disease is not associated with diarrhea, but presents symptoms of fever, respiratory defects, and hepatosplenomegaly comparable to febrile illnesses such as malaria and typhoid fever [14, 15].

Salmonella enterica serovar Typhimurium (S. Typhimurium) is the most common cause of iNTS disease in sub-Saharan Africa (sSA) [16]. While S. Typhimurium strains globally responsible for gastroenteritis belong to multilocus sequence types (MLST) ST19 and ST34 [17], those causing bloodstream infections are strongly associated with ST313. These African-associated ST313 strains are broadly classified into distinct lineages (lineages 1 and 2) linked to multidrug resistance [18]. In many countries, ST313 strains are now resistant to commonly used first-line antibiotics such as ampicillin and chloramphenicol [19]. This resistance is believed to be a major driver of the high fatalities associated with iNTS infections [20]. Resistance to second-line antibiotics including ciprofloxacin, ceftriaxone, and azithromycin has also emerged in some African regions [21]. With treatment options narrowing, vaccine development and deployment could serve as promising alternatives. However, no licensed vaccines are currently available to prevent iNTS infections.

This review highlights the emergence and public health implications of invasive S. Typhimurium ST313 in sub-Saharan Africa. It synthesizes current knowledge on its pathogenesis and unique genomic characteristics and how it differs from classical NTS strains. Special attention is given to the role of immunosuppressive comorbidities (HIV, malaria) in facilitating the systemic spread of NTS. Additionally highlighted is the increasing antimicrobial resistance of ST313 and the slow progress in iNTS vaccine development. By bringing these elements together, the review underscores the urgency of surveillance, therapeutic innovation, and prevention strategies tailored toward the African population.

Advertisement

2. Epidemiology and burden of iNTS

In 2021, approximately 509,976 new cases of iNTS were reported worldwide. The global age-standardized incidence rate (ASIR), which adjusts for differences in population age structure to allow for fair comparisons, was 7.21 per 100,000 people. However, sSA far exceeded this global average, reflecting a disproportionate concentration of the disease burden. Western and Central sSA continued to report consistently high iNTS incidence and DALY rates. The number of new cases of iNTS in the Western regions surged to 305,959 in 2021 alone with an estimated ASIR of 47.54 per 100,000 population, which is more than six times the global average [22].

At the national level, several African countries emerged as key hotspots. Nigeria reported the highest absolute numbers in 2021, with approximately 164,230 incident cases, 21,614 deaths, and over 1.75 million DALYs attributed to iNTS. In contrast, Mali, while having a smaller total number of cases, recorded the highest rates relative to its population. Mali’s incidence rate was estimated at 107.44 per 100,000, its death rate at 16.6 per 100,000, and carried a similarly high DALY burden. These national figures highlight the geographic variability in iNTS burden within Africa and point to the need for country-specific responses.

The disease burden is highest among infants under 1 year old. This group exhibits the most elevated rates of infection, death, and DALY loss [22]. Children in this age group are particularly vulnerable due to underdeveloped immune systems and increased exposure to risk factors such as malnutrition and malaria that are widespread in many African regions.

Advertisement

3. Pathogenesis of NTS

3.1 Microbiota-mediated defense against NTS colonization

To cause disease, NTS must overcome the complex environment of the gastrointestinal tract, which is influenced by the microbiome, immune system, and dietary factors. Colonization resistance (CR), a microbiota-mediated defense process, is mediated by a range of strategies that restrict pathogen survival and proliferation within the gastrointestinal tract [23]. These include the production of antimicrobial agents such as bacteriocins and colicins, which directly inhibit pathogen growth. Physical competition for binding sites on the epithelial and mucus surfaces further prevents pathogen colonization. Additionally, the gut microbiota lowers oxygen availability in the intestine, creating conditions that suppress facultative anaerobic pathogens like NTS. Commensals also reduce pathogen fitness by competing for essential nutrients. Escherichia coli has been shown to restrict NTS infection by limiting access to electron acceptors like fumarate and carbon sources such as galactitol necessary for its proliferation [24, 25]. Recent findings have identified nociceptor sensory neurons, known for their role in detecting noxious stimuli, as important contributors to CR against NTS [26].

3.2 NTS proliferation in the gastrointestinal tract

NTS can proliferate in the large intestine when environmental conditions are favorable, and CR is not a barrier. This growth is supported by secretion systems encoded within Salmonella pathogenicity islands (SPIs). SPIs are commonly introduced into the genome via horizontal gene transfer and are subsequently integrated and stably maintained within the bacterial chromosome [27, 28, 29]. NTS utilizes the type VI secretion system (T6SS) to outcompete bacterial competitors by their elimination through dependent and independent mechanisms [30]. In the contact dependent pathway, NTS uses the T6SS to deliver toxic effector proteins directly into target cells [31]. On the other hand, in the contact independent mechanism, effectors are secreted into the extracellular medium. Through this mechanism, NTS competes for essential nutrients such as iron by producing siderophores including enterobactin and salmochelin [32]. Once these defenses are overcome, NTS multiplies rapidly, reaching high bacterial densities within the gut.

3.3 Invasion of epithelial cells by NTS

Attachment of NTS to epithelial cells is mediated by fimbrial and non-fimbrial adhesins [33]. Once attached, Salmonella employs the Trigger and Zipper mechanisms for invasion of cells. The “Trigger” mechanism, driven by T3SS-1 effectors such as SopB, SopE, and SopE2, induces dramatic actin cytoskeletal rearrangements forming membrane ruffles that lead to NTS internalization into epithelial cells [34, 35]. Additionally, the effectors SipA and SipC promote invasion by directly nucleating and bundling actin filaments [36, 37, 38]. The “Zipper” mechanism depends on the outer membrane proteins Rck and PagN. These proteins activate the phosphatidylinositol 3-kinase (PI3K) signaling cascade by binding to host receptors like EGFR. This causes cytoskeletal rearrangements that facilitate bacterial uptake [39]. However, NTS strains lacking Rck, PagN, and T3SS-1 still efficiently invade fibroblasts, epithelial, and endothelial cells, implying the presence of yet undiscovered invasion mechanisms [40].

3.4 NTS intracellular persistence and resistance to inflammatory responses

Upon infection, host cells respond by activating inflammasomes and inducing pyroptosis. This defense mechanism commences with the NAIP/NLRC4 inflammasome, which recognizes bacterial protein ligands such as flagellin and the T3SS needle protein PrgI, leading to the release of IL-18 and subsequent IFNγ production [41, 42]. NTS overcomes this response by residing within Salmonella-containing vacuoles (SCVs) intracellularly. Inhibition of autophagy, mediated by T3SS-2 effectors, additionally facilitates the intracellular survival of NTS. These effector proteins deubiquitinate SCVs, thereby reducing autophagy markers p62 and LC3 [43]. The formation of autophagosomes is further prevented by SseF and SseG, which disrupt Rab1A signaling [44] by SpvC through its phosphothreonine lyase activity [45] and by SpvB (from the pSLT plasmid), which depolymerizes the actin [46].

NTS further impairs the functions of cells of the immune system which include macrophages and dendritic cells (DC). Macrophages are crucial for phagocytosing NTS post-epithelial breach. They can exist in M1 (pathogen-killing) and M2 (tissue repair) forms [47]. The T3SS-2 effector SteE skews macrophages toward an M2 phenotype, enhancing NTS survival [48]. Macrophage-produced lactate additionally induces T3SS-2 and SteE translocation, promoting this shift [49]. DC function is also affected by NTS. The T3SS-2 effector SteD degrades mature MHC-II, impairing antigen presentation to CD4+ T cells. This disrupts dendritic cell-T cell interactions leading to a diminished T-cell response [50, 51].

Advertisement

4. Transition from NTS to iNTS

The ability of NTS to breach the intestinal epithelium and establish systemic infection is closely linked to immunosuppression as iNTS is rarely observed in otherwise healthy individuals. Consequently, current understanding of iNTS pathogenesis is largely drawn from studies involving immunocompromised populations. In this section, we explore how NTS co-infections with malaria and HIV create permissive environments for the transition of NTS to iNTS offering insights into the mechanisms underlying iNTS pathogenesis.

4.1 iNTS and malaria

Malaria and invasive non-typhoidal Salmonella (iNTS) infections are prevalent in sSA where their geographical distributions frequently coincide [52]. This risk is most prevalent in children with severe malarial anemia (SMA) [53]. In rural areas with high malaria transmission, NTS is frequently the main bacteria isolated from the bloodstream of children with Plasmodium parasitemia [54, 55]. Moreover, public health measures that reduce malaria incidence have often led to a parallel decrease in NTS bacteremia cases, an effect not consistently seen with other bacterial infections [56, 57].

4.1.1 Malaria as a cause of NTS systemic dissemination

Hemolysis is a defining characteristic of malaria infections [57]. This extensive destruction of red blood cells during malaria releases large amounts of hemoglobin and free heme, which increases the availability of iron, essential for Salmonella growth and multiplication. Macrophages ingest these damaged red cells and become overloaded with iron. This iron-rich intracellular environment within macrophages can support the survival and replication of ingested NTS [58, 59]. SMA is associated with reduced hepcidin levels, a hormone that regulates iron availability. Lower hepcidin levels allow more iron to be available within the SCV, promoting bacterial growth. This mechanism highlights how malaria indirectly supports NTS proliferation by altering iron homeostasis [60].

Gut barrier dysfunction is a mechanism facilitating the susceptibility of malaria-infected individuals to NTS infections. Sequestration of parasitized red blood cells in the gut’s microvasculature triggers inflammation, hypoxia, and disruption of tight junctions between intestinal epithelial cells. This compromises the intestinal barrier integrity causing the translocation of enteric bacteria, including NTS, from the gut lumen into the bloodstream [61, 62]. Additionally, malaria-associated deficiency of L-arginine has been linked to increased intestinal mast cell activity, histamine release, and enhanced intestinal permeability [63]. Malaria compromises the host’s ability to resist enteric pathogens by reducing gastric acidity. Studies have shown that Plasmodium yoelii infection in mice elevates gastric pH, creating a less acidic environment that facilitates the survival and colonization of S. Typhimurium in the upper gastrointestinal tract [64].

Overall epidemiological and biological evidence strongly supports a relationship where malaria increases susceptibility to iNTS disease.

4.2 iNTS and HIV

Prior to the widespread availability of antiretroviral therapy (ART) in sSA, iNTS was recognized as one of the most common causes of bloodstream infections among HIV-infected adults and children [65, 66]. Incidence rates were reported to be 20- to 100-fold higher in HIV-infected individuals compared to their HIV-uninfected counterparts in the same communities [67]. This disparity underscored HIV as a primary risk factor for invasive disease. A critical feature of iNTS in the HIV-infected population is the high rate of recurrent bacteremia, often with the same NTS strain, suggesting incomplete bacterial clearance or persistence [68].

4.2.1 HIV as a cause of systemic NTS infections

The hallmark of HIV infection is the progressive depletion and functional impairment of CD4+ T-lymphocytes [69]. These cells, particularly T-helper 1 (Th1) and T-helper 17 (Th17) subsets, are vital for effective immunity against intracellular pathogens like Salmonella. Th1 cells produce IFN-γ, a cytokine essential for activating macrophages to kill intracellular Salmonella. Th17 cells contribute to maintaining mucosal barrier integrity and recruiting neutrophils to sites of infection [70]. HIV preferentially infects and depletes Th17 cells, especially within the gut-associated lymphoid tissue (GALT), the primary site of Salmonella invasion [71]. Their loss contributes to increased intestinal permeability, facilitating the translocation of Salmonella and other microbial products from the intestinal lumen into the systemic circulation, thereby promoting bacteremia [72].

HIV infection compromises multiple macrophage functions via the depletion of Th1 cells. Macrophages from people living with HIV/AIDS (PLWH) may exhibit reduced phagocytic capacity, impaired oxidative burst, and deficient production of pro-inflammatory cytokines such as TNF-α in response to Salmonella infection [2]. Antibodies, particularly secretory IgA (sIgA) at mucosal surfaces and serum IgG, play a significant role in controlling Salmonella. HIV infection leads to B-cell dysregulation, resulting in impaired production of antibodies against various pathogens [73]. Studies have demonstrated that HIV-infected individuals often have lower levels of Salmonella-specific antibodies and reduced opsonophagocytic activity, which are critical for preventing bacteremia [74]. This defect in antibody-mediated immunity is considered a major contributor to the high incidence of iNTS.

Collectively, these immunological defects create a permissive environment for Salmonella to breach mucosal defenses, disseminate systemically, survive within host cells, and evade clearance, leading to the severe and often recurrent iNTS disease observed in PLWH.

Advertisement

5. Pathoadaptive features underpinning ST313-mediated iNTS in Africa

The burden and distribution of iNTS in Africa raises important questions about pathogen-specific factors that may amplify disease severity. While host factors are crucial in determining susceptibility to iNTS infections, they do not fully explain why only certain NTS strains cause systemic infections. Recent studies have revealed that the dominant S. Typhimurium ST313 strains circulating in sSA differ markedly from globally prevalent non-invasive strains like ST19. The following section explores these differences and how they may contribute to the unique disease profile observed in the region. Understanding how these strains differ from classical S. Typhimurium lineages is crucial to grasping the full landscape of iNTS pathogenesis.

5.1 Unique genetic composition of ST313

The enhanced systemic survival of ST313 appears tightly linked to its distinct genetic architecture. Comparative genomics has revealed that ST313 harbors numerous pseudogenes, deletions, and prophage elements absent in non-invasive strains. A defining feature of ST313 lineage 2 is the acquisition of two unique prophages—BTP1 and BTP5—which are absent from ST19 and ST313 isolates from outside Africa [75, 76]. BTP1 encodes the st313-td gene, which enhances intracellular replication in macrophages [77]. Another element, the gtrAC operon, encodes glycosyltransferases that modify the structure and length of the O-antigen (OAg), a critical determinant of resistance to antibody-mediated killing. ST313 OAg chains are typically longer, conferring serum resistance, a hallmark of systemic pathogenesis [75, 78, 79]. Furthermore, ST313 strains display a unique single nucleotide polymorphism (SNP) in the promoter of the pgtE gene, leading to its upregulation. pgtE encodes an outer membrane protease that disrupts the host complement system by degrading complement proteins, enhancing survival in serum [80]. Intriguingly, this same mutation is also present in S. Gallinarum and upregulation of pgtE has been noted during S. Typhi infection of human macrophages suggesting convergent evolution toward an invasive phenotype [81]. ST313 has undergone additional functional losses in genes associated with metabolic flexibility and gastrointestinal persistence. Inactivating mutations have been reported in genes such as allB, allP, ttdA, melR, ratB, and macAB, many of which are intact in ST19 [76, 82, 83]. These mutations likely reduce the bacterium’s ability to persist in the gut, in favor of systemic dissemination. Moreover, genes essential for iron acquisition and siderophore secretion are repressed in ST313 than in ST19 [82]. This could reflect a metabolic adaptation to iron-rich environments, such as macrophages co-infected with malaria parasites, where iron availability is increased [84].

5.2 Accumulation of pseudogenes

The gradual pseudogenization of specific genes provides further evidence of host adaptation. ST313 strains have accumulated numerous pseudogenes. In the genome of the ST313 D23580 strain, 77 pseudogenes have been observed out of which 23 are strain specific [18, 82, 85]. This mirrors patterns observed in host-adapted serovars such as S. Gallinarum, S. Typhi, and S. Paratyphi, which carry numerous pseudogenes as they shed functions unnecessary for systemic survival [86, 87, 88, 89]. One recently characterized pseudogene in ST313 is sseI, which encodes an effector of the SPI-2 type III secretion system (T3SS). In functional form, sseI promotes the inhibition of DC chemotaxis. Inactivation of sseI results in hyper-dissemination of DCs to lymph nodes in murine models, thereby facilitating systemic spread [90]. Furthermore, the downregulation of the SPI-1 effector sopE2 is commonly observed in ST313 isolates and correlates with reduced epithelial invasion [91]. Notably, sopE2 is also pseudogenized in S. Typhi [81] suggesting functional convergence with other invasive serovars. Similarly, deletions in pipD, a gene implicated in intestinal fluid accumulation, contribute to reduced intestinal inflammation in ST313 lineage 2 [83].

Advertisement

6. Transmission and reservoir dynamics of ST313

Understanding the reservoir and transmission routes of iNTS has remained a challenge since its emergence as a major cause of blood stream infections in sSA [19]. This in contrast to NTS infections that are predominantly transmitted via zoonotic and foodborne pathways [92]. Early investigations in Kenya and The Gambia failed to identify a consistent animal or environmental source for iNTS. The limited sample sizes and narrow geographic focus may have contributed to this uncertainty [93, 94]. Experimentally, ST313 has been shown to colonize the chicken gut and invade systemic sites, though less efficiently than the gastroenteritis causing NTS serovars [95]. Despite the isolation of other invasive Salmonella serovars from livestock, slaughterhouses, and retail meat, ST313 has not been detected in these samples [96]. So far, ST313 is isolated exclusively from human sources. Genomic analysis showed low diversity across isolates, consistent with host adaptation and restriction supporting a pattern of continuous human-to-human spread. The absence of environmental or animal detections, coupled with evidence of asymptomatic fecal shedding among humans, strengthens the argument for anthroponotic transmission as recently reported [97].

A clearer definition of the transmission dynamics is essential for understanding ST313 evolution and guiding public health action. If human-to-human transmission proves dominant, interventions must prioritize vaccine development, sanitation infrastructure, and identification of chronic carriers. Conversely, confirmation of an animal reservoir would necessitate strategies focused on food safety and animal vaccination. Clarifying these routes is central to designing targeted measures against iNTS infections in Africa.

Advertisement

7. The escalating antimicrobial resistance crisis of ST313 in Africa

A defining hallmark of this pathogen is its continual accumulation of antimicrobial resistance (AMR), progressively rendering treatment regimens ineffective. Geographically distinct sublineages, such as sublineage 2.2 in Malawi [98] and extensively drug resistant (XDR) ST313 strains in the DRC [99], reflect local adaptation under antibiotic pressure. Surveillance studies from Nigeria [100], Zambia [101], The Gambia [102], Mozambique [103], and Sierra Leone [104] confirm the widespread presence and expanding resistance of ST313. This section explores the resistance profile of ST313, illustrating the genetic mechanisms underpinning the evolution and the clinical challenges it poses across Africa.

7.1 Resistance to first-line antimicrobial classes

ST313 is currently resistant to all three first-line antimicrobial classes traditionally used for iNTS infections: beta-lactams (ampicillin), phenicols (chloramphenicol), and folate pathway inhibitors (trimethoprim-sulfamethoxazole) [14, 105]. Beta-lactam resistance in ST313 is largely conferred by the plasmid-encoded blaTEM-1B gene, while catA1 mediates chloramphenicol resistance. The catA gene, located on a pSTm-ST313-II.1 plasmid, encodes chloramphenicol acetyltransferase, which enzymatically inactivates the antibiotic. Resistance to trimethoprim-sulfamethoxazole is driven by the combined action of dfrA genes that encode dihydrofolate reductase and sulfonamide resistance genes (sul1, sul2). These are commonly embedded within class 1 integrons housed on IncHI1 plasmids such as pBT1 [99, 106, 107].

7.2 Resistance to second-line antimicrobial agents

In response to first-line treatment failure, clinicians shifted to fluoroquinolones (e.g., ciprofloxacin) and third-generation cephalosporins (e.g., ceftriaxone). However, ST313 isolates have evolved resistance to these agents [16, 108]. Fluoroquinolone resistance arises from point mutations in the quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC, and parE. Notably, nonsynonymous substitutions such as gyrA Ser83 → Phe and Asp87 → Asn are commonly observed in resistant isolates from Africa [99, 100]. Ceftriaxone resistance has arisen due to the acquisition and dissemination of extended-spectrum beta-lactamases (ESBLs), particularly blaCTX-M-15, often carried on IncN and IncI1 plasmids [99, 101, 107]. These mobile elements frequently co-localize with other resistance determinants, enabling co-selection and persistence of ESBL genes even in the absence of direct cephalosporin exposure.

7.3 Expansion of resistance into additional antimicrobial classes

Considering the declining efficacy of second-line agents, azithromycin has been employed as an alternative. However, resistance to macrolides is now emerging. This development is particularly evident in XDR ST313 lineages identified in the Democratic Republic of Congo (DRC). Azithromycin is often a last-resort oral antibiotic in regions with limited intravenous options. The emergence of azithromycin resistance in ST313 poses a threat to the continued use of azithromycin, which is one of the few remaining oral options for empirical treatment in children and outpatients. ST313 has also acquired resistance to aminoglycosides. Genes such as aadA1 and aadA2 encode aminoglycoside-modifying enzymes that inactivate gentamicin, streptomycin, and amikacin [99, 106]. The accumulation of these resistance determinants has led to near-total resistance to all commonly available antibiotics in some regions.

7.4 Public health implications and strategic interventions

Combating ST313’s resistance crisis demands integrated approaches. Enhanced genomic surveillance is critical for monitoring resistance patterns and informing antimicrobial policy. Stewardship programs are urgently needed to curb antibiotic misuse in human and veterinary medicine. Vaccine development against ST313 and other iNTS serovars is progressing at various stages of development [109, 110, 111]. Ultimately, addressing the AMR crisis caused by ST313 will require a One Health approach that unifies efforts across human, animal, and environmental health domains.

Advertisement

8. Vaccine progress toward elimination of ST313

The MDR phenotype of ST313 has rendered antibiotic therapy ineffective, creating an urgent need for prevention strategies. Currently, no licensed vaccines specifically targeting iNTS serovars are currently available. This is in sharp contrast to the availability of vaccines targeting typhoidal Salmonella serovars (Vi-polysaccharide conjugate vaccines) [112]. It is predicted that, without vaccination, iNTS mortality will climb significantly especially among the immunocompromised. Studies suggests that effective vaccine deployment could avert over 70% of these deaths and curb iNTS transmission [109]. The global effort to develop a vaccine against iNTS has yielded vaccine candidates, with several demonstrating compelling safety and immunogenicity in human trials. The following section will explore the merits, progress, and challenges of the leading vaccine candidates that represent the forefront of the global effort to control iNTS infections.

8.1 Live-attenuated vaccines

Live-attenuated vaccines, which utilize a weakened version of the pathogen to mimic natural infection, represent a foundational approach in Salmonella vaccinology. Its primary advantage is the ability to induce a broad spectrum of immune responses [113]. Early human studies explored strains with deletions in key virulence-regulating gene systems like phoP/phoQ [114] or those with defined auxotrophic mutations in essential metabolic pathways, such as aroC, and virulence systems, like ssaV [115]. Newer approaches, including radiation mutation enhancement technology [116] and the creation of auxotrophic live vaccines [117], have shown significant efficacy in preclinical models. Despite these advances, human clinical data for live-attenuated iNTS candidates remain limited, and their developmental pathway is currently less advanced.

8.2 Glycoconjugate vaccines

Glycoconjugate vaccines represent one of the most clinically advanced strategies in the iNTS pipeline. A leading example is the trivalent conjugate vaccine platform developed at the University of Maryland, which has progressed through multiple clinical trials. The initial candidate, CVD 1000, paired S. Typhimurium and S. Enteritidis O-antigens with the Vi polysaccharide from S. Typhi. A Phase I trial in adults confirmed its safety and ability to induce sustained IgG titers. An updated formulation, CVD 2000, advanced into Phase II pediatric trials across sSA, demonstrating age-appropriate immune responses in the target infant population [118, 119]. Another significant candidate in this class is the bivalent iNTS OAg-CRM197 vaccine, which targets the two most common iNTS serovars. In this approach, the O-antigens of S. Typhimurium and S. Enteritidis are conjugated to the non-toxic diphtheria toxoid mutant CRM197. CRM197 is a carrier protein with a history of safe and effective use in licensed pediatric vaccines [120, 121]. While their complex production and associated costs present potential barriers to access in low-resource settings, the proven ability of glycoconjugate vaccines to elicit protective immunity in infants has set a vital benchmark for all other iNTS vaccine candidates [122, 123].

8.3 Generalized modules for membrane antigens (GMMA)

Vaccines based on Generalized Modules for Membrane Antigens (GMMA) have emerged as an alternative to the glycoconjugate vaccines. GMMA are nanoparticles derived from the outer membrane of genetically engineered bacteria. They are modified to vesicles enriched with key surface antigens, including LPS (containing the O-antigen) and outer membrane proteins (OMPs), in their native conformation. GMMA vaccines possess intrinsic adjuvant properties rendering them potent immunogens, which is a key characteristic of this platform [124, 125]. GMMA vaccines have rapidly progressed into human trials. The Oxford-led SALVO trial confirmed its safety and immunogenicity in healthy adult volunteers [126]. More recently, Phase II studies in Ghana as part of the PEDVAC-iNTS consortium have shown the iNTS-GMMA vaccine demonstrates good tolerability and elicits prolonged antigen-specific IgG responses in children and infants [127, 128]. By combining potent immunogenicity with a favorable manufacturing profile, the GMMA platform is argued to be strongly positioned to deliver an effective and accessible vaccine.

8.4 Multiple antigen presentation system (MAPS)

The Multiple Antigen Presentation System (MAPS) platform offers an innovative approach to creating multivalent vaccines. This technology utilizes a dextran backbone to which multiple antigens can be attached via a high-affinity, non-covalent biotin–rhizavidin linkage. This design allows for the presentation of a diverse array of antigens in a single formulation, stimulating broad immunity [129]. A quadrivalent MAPS vaccine targeting S. Typhimurium, S. Enteritidis, S. Typhi, and S. Paratyphi A has been shown to confer broad protective immunity in preclinical models after just two doses [130]. Given the frequent co-circulation of typhoidal and iNTS serovars, multivalent vaccines are strategic in the elimination of the major causes of febrile illnesses in sSA. The global effort to develop a vaccine against iNTS has yielded a rich and advanced pipeline of candidates, with several demonstrating compelling safety and immunogenicity in human trials. The journey from a promising vaccine candidate to a widely implemented public health tool requires a clear strategic vision that addresses both regulatory and economic challenges in populations at risk.

Advertisement

9. Conclusion

The persistence of ST313 in sSA underscores the need for effective control, prevention, and policy formulation. While the burden of ST313 has been established, uncertainties remain regarding its ecological dynamics, host-pathogen interactions, and its evolution. Although current evidence suggests human-to-human transmission of ST313, the role of environmental or zoonotic reservoirs has not been adequately addressed. Many existing studies are geographically limited and lack sufficient sampling depth to definitively rule out the contribution of livestock, contaminated water sources, or foodborne pathways. Increased surveillance using One Health approach is therefore essential to clarify ST313’s transmission routes and inform multisectoral intervention strategies. Equally underexplored is the immunological response to ST313 in high-risk populations. Infants, individuals living with HIV, and patients co-infected with malaria represent the most affected groups. Studies targeting these populations are required to ensure that vaccine candidates are both immunogenic and protective. The pathogen’s ongoing evolution also demands closer attention. ST313 continues to acquire multidrug resistance while undergoing genomic adaptations associated with enhanced intracellular survival and immune evasion. However, genomic surveillance of iNTS serovars remains limited across sSA. This poses a potential danger of novel resistant or hypervirulent strains going undetected. Integrating sequencing into national and regional surveillance efforts will help guide treatment, inform vaccine development, and support public health responses. Although ST313 has been described as an African confined iNTS serovar, recent isolations in the United Kingdom, Brazil, and other non-endemic regions indicate that it is no longer geographically restricted. Timely interventions are therefore required in stemming the international spread of ST313 to mitigate the possibility of global outbreaks of iNTS infections.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

Author contributions

Both authors contributed to this summary on the rising crisis of Salmonella Typhimurium in Africa and have read and agreed to the published version of the manuscript.

Funding

This research was supported by WACCBIP, University of Ghana, which receives funding from World Bank African Centre of Excellence (WACCBIP + NCDs, Awandare).

References

  1. 1. Issenhuth-Jeanjean S, Roggentin P, Mikoleit M, Guibourdenche M, De Pinna E, Nair S, et al. Supplement 2008-2010 (no. 48) to the White–Kauffmann–Le minor scheme. Research in Microbiology. 2014;165(7):526-530
  2. 2. Hohmann EL. Nontyphoidal salmonellosis. Clinical Infectious Diseases. 2001;32:263-269
  3. 3. Voetsch AC, Gilder TJ, Angulo FJ, Farley MM, Shallow S, Marcus R, et al. FoodNet estimate of the burden of illness caused by nontyphoidal Salmonella infections in the United States. Clinical Infectious Diseases. 2004;38(Suppl. 3):127-134
  4. 4. Adak GK, Long SM, O’Brien SJ. Trends in indigenous foodborne disease and deaths. Gut. 2002;51:832-841
  5. 5. Angulo FJ. A community waterborne outbreak of salmonellosis and the effectiveness of a boil water order. American Journal of Public Health. 1997;87:580-584
  6. 6. Mishu B. Outbreaks of Salmonella enteritidis infections in the United States, 1985-1991. Journal of Infectious Diseases. 1994;169:547-552
  7. 7. Majowicz SE. The global burden of nontyphoidal Salmonella gastroenteritis. Clinical Infectious Diseases. 2010;50:882-889
  8. 8. Okoro CK, Kingsley RA, Connor TR, Harris SR, Parry CM, Al-Mashhadani MN, et al. Intracontinental spread of human invasive Salmonella typhimurium pathovariants in sub-Saharan Africa. Nature Genetics. 2012;44(11):1215-1221
  9. 9. Shi K, You T. Global trends in typhoid and paratyphoid, and invasive non-typhoidal salmonella, and the burden of antimicrobial resistance: A trend analysis study from 1990 to 2021. Frontiers in Medicine (Lausanne). 2025;12:1588507
  10. 10. Ao TT, Daugla DM, Toralta J, Ngadoua C, Fermon F, Page AL, et al. Global burden of invasive nontyphoidal Salmonella disease. Emerging Infectious Diseases. 2015;21(6):941-949
  11. 11. Stanaway JD, Parisi A, Sarkar K, Blacker BF, Reiner RC, Hay SI, et al. The global burden of non-typhoidal Salmonella invasive disease: A systematic analysis for the global burden of disease study 2017. The Lancet Infectious Diseases. 2019;19(12):1312-1324
  12. 12. Reddy EA, Shaw AV, Crump JA. Community-acquired bloodstream infections in Africa: A systematic review and meta-analysis. The Lancet Infectious Diseases. 2010;10(6):417-432
  13. 13. Hendriksen RS, Vieira AR, Karlsmose S, Lo Fo Wong DMA, Jensen AB, Wegener HC, et al. Global monitoring of Salmonella serovar distribution from the world health organization global foodborne infections network country data bank: Results of quality assured laboratories from 2001 to 2007. Foodborne Pathogens and Disease. 2011;8(8):887-900
  14. 14. Crump JA, Heyderman RS. A perspective on invasive Salmonella disease in Africa. Clinical Infectious Diseases. 2015;61:S235-S240
  15. 15. Uche IV, MacLennan CA, Saul A. A systematic review of the incidence, risk factors and case fatality rates of invasive nontyphoidal Salmonella (iNTS) disease in Africa (1966 to 2014). PLoS Neglected Tropical Diseases. 2017;11(1):1-28
  16. 16. Kariuki S, Gordon MA, Feasey N, Parry CM. Antimicrobial resistance and management of invasive Salmonella disease. Vaccine. 2015;33(S3):21-29
  17. 17. Alikhan NF, Zhou Z, Sergeant MJ, Achtman M. A genomic overview of the population structure of Salmonella. PLoS Genetics. 2018;14(4):e1007261
  18. 18. Kingsley RA, Msefula CL, Thomson NR, Kariuki S, Holt KE, Gordon MA, et al. Epidemic multiple drug resistant Salmonella typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype. Genome Research. 2009;19(12):2279-2287
  19. 19. Kariuki S, Revathi G, Kariuki N, Kiiru J, Mwituria J, Muyodi J, et al. Invasive multidrug-resistant non-typhoidal Salmonella infections in Africa: Zoonotic or anthroponotic transmission? Journal of Medical Microbiology. 2006;55(5):585-591
  20. 20. Marchello CS, Birkhold M, Crump JA, Martin LB, Ansah MO, Breghi G, et al. Complications and mortality of non-typhoidal Salmonella invasive disease: A global systematic review and meta-analysis. The Lancet Infectious Diseases. 2022;22(5):692-705
  21. 21. Tack B, Vanaenrode J, Verbakel JY, Toelen J, Jacobs J. Invasive non-typhoidal Salmonella infections in sub-Saharan Africa: A systematic review on antimicrobial resistance and treatment. BMC Medicine. 2020;18(1):212
  22. 22. He Y, Jia Q, Cai K, Xu S, Li H, Xie Q, et al. The global, regional, and national burden of invasive non-typhoidal Salmonella (iNTS): An analysis from the global burden of disease study 1990-2021. PLoS Neglected Tropical Diseases. 2025;19(4):e0012960
  23. 23. Stecher B. Establishing causality in Salmonella-microbiota-host interaction: The use of gnotobiotic mouse models and synthetic microbial communities. International Journal of Medical Microbiology [Internet]. 2021;311(3):151484. Available from: https://www.sciencedirect.com/science/article/pii/S1438422121000138 [Accessed: June 18, 2025]
  24. 24. Nguyen BD, Cuenca VM, Hartl J, Gül E, Bauer R, Meile S, et al. Import of aspartate and malate by DcuABC drives H2/fumarate respiration to promote initial Salmonella gut-lumen colonization in mice. Cell Host & Microbe. 2020;27(6):922-936.e6
  25. 25. Eberl C, Weiss AS, Jochum LM, Durai Raj AC, Ring D, Hussain S, et al. E. coli enhance colonization resistance against Salmonella typhimurium by competing for galactitol, a context-dependent limiting carbon source. Cell Host & Microbe. 2021;29(11):1680-1692.e7
  26. 26. Lai NY, Musser MA, Pinho-Ribeiro FA, Baral P, Jacobson A, Ma P, et al. Gut-innervating nociceptor neurons regulate Peyer’s patch microfold cells and SFB levels to mediate Salmonella host defense. Cell. 2020;180(1):33-49.e22
  27. 27. Hensel M. Evolution of pathogenicity islands of Salmonella enterica. International Journal of Medical Microbiology. 2004;294(2-3):95-102
  28. 28. Schmidt H, Hensel M. Pathogenicity islands in bacterial pathogenesis. Clinical Microbiology Reviews. 2004;17(1):14-56
  29. 29. Roer L, Hendriksen RS, Leekitcharoenphon P, Lukjancenko O, Kaas RS, Hasman H, et al. Is the evolution of Salmonella enterica subsp. Enterica linked to restriction-modification systems? mSystems. 2016;1(3):e00009-e00016
  30. 30. Blondel CJ, Amaya FA, Reyes-Méndez F, Soriano-Mora V, Vargas C, Parra A, et al. Deciphering the Salmonella T6SS toolkit: Two decades of research decoding a versatile bacterial weapon. Journal of Bacteriology. 2025;207(7):e00188-25
  31. 31. Coulthurst S. The type VI secretion system: A versatile bacterial weapon. Microbiology (United Kingdom). 2019;165(5):503-515
  32. 32. Mohsen Y, Tarchichi N, Barakat R, Kawtharani I, Ghandour R, Ezzeddine Z, et al. The different types of metallophores produced by Salmonella enterica: A review. Microbiology Research. 2023;14(3):1457-1469
  33. 33. Bao H, Wang S, Zhao JH, Liu SL. Salmonella secretion systems: Differential roles in pathogen-host interactions. Microbiological Research [Internet]. 2020;241:126591. Available from: https://www.sciencedirect.com/science/article/pii/S0944501320304596 [Accessed: June 18, 2025]
  34. 34. Fredlund J, Santos JC, Stévenin V, Weiner A, Latour-Lambert P, Rechav K, et al. The entry of Salmonella in a distinct tight compartment revealed at high temporal and ultrastructural resolution. Cellular Microbiology. 2018;20(4). DOI: 10.1111/cmi.12816
  35. 35. Koczerka M, Lantier I, Morillon M, Deperne J, Clamagirand CD, Virlogeux-Payant I, et al. From intestine to beyond: Salmonella entry factors display distinct transcription pattern upon infection in murine models. Open Biology. 2024;14(1):230312
  36. 36. McGhie EJ, Hayward RD, Koronakis V. Cooperation between actin-binding proteins of invasive Salmonella: SipA potentiates SipC nucleation and bundling of actin. EMBO Journal [Internet]. 2001;20(9):2131-2139. DOI: 10.1093/emboj/20.9.2131?download=true
  37. 37. Humphreys D, Davidson A, Hume PJ, Koronakis V. Salmonella virulence effector SopE and host GEF ARNO cooperate to recruit and activate WAVE to trigger bacterial invasion. Cell Host & Microbe. 2012;11(2):129-139
  38. 38. Fattinger SA, Sellin ME, Hardt WD. Salmonella effector driven invasion of the gut epithelium: Breaking in and setting the house on fire. Current Opinion in Microbiology. 2021;64:9-18
  39. 39. Barilleau E, Védrine M, Koczerka M, Burlaud-Gaillard J, Kempf F, Grépinet O, et al. Investigation of the invasion mechanism mediated by the outer membrane protein PagN of Salmonella typhimurium. BMC Microbiology. 2021;21(1):1-18
  40. 40. Rosselin M, Abed N, Virlogeux-Payant I, Bottreau E, Sizaret PY, Velge P, et al. Heterogeneity of type III secretion system (T3SS)-1-independent entry mechanisms used by Salmonella enteritidis to invade different cell types. Microbiology (N Y). 2011;157(3):839-847
  41. 41. Gram AM, Wright JA, Pickering RJ, Lam NL, Booty LM, Webster SJ, et al. Salmonella flagellin activates NAIP/NLRC4 and canonical NLRP3 inflammasomes in human macrophages. The Journal of Immunology [Internet]. 2021;206(3):631-640. DOI: 10.4049/jimmunol.2000382
  42. 42. Pandeya A, Zhang Y, Cui J, Yang L, Li J, Zhang G, et al. Inflammasome activation and pyroptosis mediate coagulopathy and inflammation in Salmonella systemic infection. Microbiological Research. 2023;275:127460
  43. 43. Mesquita FS, Thomas M, Sachse M, Santos AJM, Figueira R, Holden DW. The Salmonella deubiquitinase Ssel inhibits selective autophagy of cytosolic aggregates. PLoS Pathogens. 2012;8(6):e1002743
  44. 44. Feng ZZ, Jiang AJ, Mao AW, Feng Y, Wang W, Li J, et al. The Salmonella effectors SseF and SseG inhibit Rab1A-mediated autophagy to facilitate intracellular bacterial survival and replication. Journal of Biological Chemistry. 2018;293(25):9662-9673
  45. 45. Zhou L, Li Y, Gao S, Yuan H, Zuo L, Wu C, et al. Salmonella spvC gene inhibits autophagy of host cells and suppresses NLRP3 as well as NLRC4. Frontiers in Immunology. 2021;12:639019
  46. 46. Chu Y, Gao S, Wang T, Yan J, Xu G, Li Y, et al. A novel contribution of spvB to pathogenesis of Salmonella typhimurium by inhibiting autophagy in host cells. Oncotarget. 2016;7(7):8295
  47. 47. Brodsky IE. JAK-ing into M1/M2 polarization SteErs Salmonella-containing macrophages away from immune attack to promote bacterial persistence. Cell Host & Microbe. 2020;27(1):3-5
  48. 48. Panagi I, Jennings E, Zeng J, Günster RA, Stones CD, Mak H, et al. Salmonella effector SteE converts the mammalian serine/threonine kinase GSK3 into a tyrosine kinase to direct macrophage polarization. Cell Host & Microbe. 2020;27(1):41-53.e6
  49. 49. Wang X, Yang B, Ma S, Yan X, Ma S, Sun H, et al. Lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization. Microbiology Spectrum. 2023;11(6):e02253-23
  50. 50. Alix E, Godlee C, Cerny O, Blundell S, Tocci R, Matthews S, et al. The tumour suppressor TMEM127 is a Nedd4-family E3 ligase adaptor required by Salmonella SteD to Ubiquitinate and degrade MHC class II molecules. Cell Host & Microbe. 2020;28(1):54-68.e7
  51. 51. Cerny O, Godlee C, Tocci R, Cross NE, Shi H, Williamson JC, et al. CD97 stabilises the immunological synapse between dendritic cells and T cells and is targeted for degradation by the Salmonella effector SteD. PLoS Pathogens. 2021;17(7):e1009771
  52. 52. Feasey NA, Dougan G, Kingsley RA. Invasive non-typhoidal Salmonella disease: An emerging and neglected tropical disease in Africa. Lancet. 2012;379(9835):2489-2499
  53. 53. Bronzan RN, Taylor TE, Mwenechanya J, Tembo M, Kayira K, Bwanaisa L, et al. Bacteremia in Malawian children with severe malaria: Prevalence, etiology, HIV coinfection, and outcome. Journal of Infectious Diseases. 2007;195(6):895-904
  54. 54. Takem EN, Roca A, Cunnington A. The association between malaria and nontyphoid Salmonella bacteraemia in children in sub-Saharan Africa: A literature review. Malaria Journal. 2014;13(1):1-13
  55. 55. Mtove G, Amos B, Von Seidlein L, Hendriksen I, Mwambuli A, Kimera J, et al. Invasive salmonellosis among children admitted to a rural Tanzanian hospital and a comparison with previous studies. PLoS One. 2010;5(2):e9244
  56. 56. Scott JAG, Berkley JA, Mwangi I, Ochola L, Uyoga S, MacHaria A, et al. Relation between falciparum malaria and bacteraemia in Kenyan children: A population-based, case-control study and a longitudinal study. The Lancet. 2011;378(9799):1316-1323
  57. 57. Biggs HM, Lester R, Nadjm B, Mtove G, Todd JE, Kinabo GD, et al. Invasive Salmonella infections in areas of high and low malaria transmission intensity in Tanzania. Clinical Infectious Diseases. 2014;58(5):638-647
  58. 58. Nairz M, Schroll A, Demetz E, Tancevski I, Theurl I, Weiss G. “Ride on the ferrous wheel” - the cycle of iron in macrophages in health and disease. Immunobiology. 2015;220(2):280-294
  59. 59. Gwamaka M, Kurtis JD, Sorensen BE, Holte S, Morrison R, Mutabingwa TK, et al. Iron deficiency protects against severe Plasmodium falciparum malaria and death in Young children. Clinical Infectious Diseases. 2012;54(8):1137-1144
  60. 60. Abuga KM, Jones-Warner W, Hafalla JCR. Immune responses to malaria pre-erythrocytic stages: Implications for vaccine development. Parasite Immunology. 2021;43(2):e12795
  61. 61. Mooney JP, DonVito SM, Jahateh M, Bittaye H, Keith M, Galloway LJ, et al. ‘Bouncing back’ from subclinical malaria: Inflammation and erythrocytosis after resolution of P. falciparum infection in Gambian children. Frontiers in Immunology. 2022;13:780525
  62. 62. Taniguchi T, Miyauchi E, Nakamura S, Hirai M, Suzue K, Imai T, et al. Plasmodium berghei ANKA causes intestinal malaria associated with dysbiosis. Scientific Reports. 2015;5(1):1-13
  63. 63. Chau JY, Tiffany CM, Nimishakavi S, Lawrence JA, Pakpour N, Mooney JP, et al. Malaria-associated L-arginine deficiency induces mast cell-associated disruption to intestinal barrier defenses against nontyphoidal Salmonella bacteremia. Infection and Immunity. 2013;81:3515-3526
  64. 64. Walker GT, Yang G, Tsai JY, Rodriguez JL, English BC, Faber F, et al. Malaria parasite infection compromises colonization resistance to an enteric pathogen by reducing gastric acidity. Science Advances. 2021;7(27):eabd6232
  65. 65. Brent AJ, Oundo JO, Mwangi I, Ochola L, Lowe B, Berkley JA. Salmonella bacteremia in Kenyan children. Pediatric Infectious Disease Journal. 2006;25(3):230-236
  66. 66. Graham SM, Walsh AL, Molyneux EM, Phiri AJ, Molyneux ME. Clinical presentation of non-typhoidal Salmonella bacteraemia in Malawian children. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2000;94(3):310-314
  67. 67. Gordon MA, Banda HT, Gondwe M, Gordon SB, Boeree MJ, Walsh AL, et al. Non-typhoidal Salmonella bacteraemia among HIV-infected Malawian adults: High mortality and frequent recrudescence. AIDS. 2002;16(12):1633-1641
  68. 68. Gordon MA. Salmonella infections in immunocompromised adults. Journal of Infection. 2008;56(6):413-422
  69. 69. Février M, Dorgham K, Rebollo A. CD4 +T cell depletion in human immunodeficiency virus (HIV) infection: Role of apoptosis. Viruses. 2011;3(5):586-612
  70. 70. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE, et al. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nature Medicine [Internet]. 2008;14(4):421-428. Available from: https://www.nature.com/articles/nm1743 [Accessed: June 18, 2025]
  71. 71. Brenchley JM, Douek DC. Microbial translocation across the GI tract. Annual Review of Immunology. 2012;30:149-173
  72. 72. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Medicine. 2006;12(12):1365-1371
  73. 73. Moir S, Fauci AS. B cells in HIV infection and disease. Nature Reviews. Immunology. 2009;9(4):235-245
  74. 74. MacLennan CA, Gilchrist JJ, Gordon MA, Cunningham AF, Cobbold M, Goodall M, et al. Dysregulated humoral immunity to nontyphoidal ‘Salmonella’ in HIV-infected African adults. Science (1979). 2010;328(5977):508-512
  75. 75. Owen SV, Wenner N, Canals R, Makumi A, Hammarlof DL, Gordon MA, et al. Characterization of the prophage repertoire of African Salmonella typhimurium ST313 reveals high levels of spontaneous induction of novel phage BTP1. Frontiers in Microbiology. 2017;8:235
  76. 76. Ashton PM, Owen SV, Kaindama L, Rowe WPM, Lane CR, Larkin L, et al. Public health surveillance in the UK revolutionises our understanding of the invasive Salmonella typhimurium epidemic in Africa. Genome Medicine. 2017;9:92
  77. 77. Herrero-Fresno A, Wallrodt I, Leekitcharoenphon P, Olsen JE, Aarestrup FM, Hendriksen RS. The role of the st313-td gene in virulence of Salmonella typhimurium ST313. PLoS One. 2014;9(1):e84566
  78. 78. Kintz E, Davies MR, Hammarlof DL, Canals R, Hinton JC, Woude MW. A BTP1 prophage gene present in invasive non-typhoidal Salmonella determines composition and length of the O-antigen of the lipopolysaccharide. Molecular Microbiology. 2015;96(2):263-275
  79. 79. Onsare RS, Micoli F, Lanzilao L, Alfini R, Okoro CK, Muigai AW, et al. Relationship between antibody susceptibility and lipopolysaccharide O-antigen characteristics of invasive and gastrointestinal nontyphoidal Salmonellae isolates from Kenya. PLoS Neglected Tropical Diseases. 2015;9(3):3573
  80. 80. Hammarlöf DL, Kröger C, Owen SV, Canals R, Lacharme-Lora L, Wenner N, et al. Role of a single noncoding nucleotide in the evolution of an epidemic African clade of Salmonella. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(11):2614-2623
  81. 81. Faucher SP, Porwollik S, Dozois CM, McClelland M, Daigle F. Transcriptome of Salmonella enterica serovar Typhi within macrophages revealed through the selective capture of transcribed sequences. Proceedings of the National Academy of Sciences of the United States of America [Internet]. 2006;103:6. DOI: 10.1073/pnas.0509183103
  82. 82. Canals R, Hammarlöf DL, Kröger C, Owen SV, Fong WY, Lacharme-Lora L, et al. Adding function to the genome of African Salmonella typhimurium ST313 strain D23580. PLoS Biology. 2019;17(1):e3000059
  83. 83. Okoro CK, Barquist L, Connor TR, Harris SR, Clare S, Stevens MP, et al. Signatures of adaptation in human invasive Salmonella typhimurium ST313 populations from sub-Saharan Africa. PLoS Neglected Tropical Diseases. 2015;9(3):3611
  84. 84. Lokken KL, Stull-Lane AR, Poels K, Tsolis RM. Malaria parasite-mediated alteration of macrophage function and increased iron availability predispose to disseminated nontyphoidal Salmonella infection. Infection and Immunity. 2018;86(9):e00301-18
  85. 85. Kingsley RA, Kay S, Connor T, Barquist L, Sait L, Holt KE, et al. Genome and transcriptome adaptation accompanying emergence of the definitive type 2 host-restricted Salmonella enterica Serovar Typhimurium pathovar. MBio. 2013;4(5). DOI: 10.1128/mbio.00565-13
  86. 86. Parkhill J, Dougan G, James KD, Thomson NR, Pickard D, Wain J, et al. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature. 2001;413(6858):848-852
  87. 87. McClelland M, Sanderson KE, Clifton SW, Latreille P, Porwollik S, Sabo A, et al. Comparison of genome degradation in Paratyphi A and Typhi, human-restricted serovars of Salmonella enterica that cause typhoid. Nature Genetics. 2004;36(12):1268-1274
  88. 88. Liu WQ, Feng Y, Wang Y, Zou QH, Chen F, Guo JT, et al. Salmonella paratyphi C: Genetic divergence from Salmonella choleraesuis and pathogenic convergence with Salmonella typhi. PLoS One. 2009;4(2):e4510
  89. 89. Thomson NR, Clayton DJ, Windhorst D, Vernikos G, Davidson S, Churcher C, et al. Comparative genome analysis of Salmonella enteritidis PT4 and Salmonella gallinarum 287/91 provides insights into evolutionary and host adaptation pathways. Genome Research. 2008;18(10):1624-1637
  90. 90. Carden SE, Walker GT, Honeycutt J, Lugo K, Pham T, Jacobson A, et al. Pseudogenization of the secreted effector gene sseI confers rapid systemic dissemination of S. typhimurium ST313 within migratory dendritic cells. Cell Host & Microbe. 2017;21(2):182-194
  91. 91. Carden S, Okoro C, Dougan G, Monack D. Non-typhoidal Salmonella typhimurium ST313 isolates that cause bacteremia in humans stimulate less inflammasome activation than ST19 isolates associated with gastroenteritis. Pathogens and Disease. 2015;73(4):23
  92. 92. Chirwa EB, Dale H, Gordon MA, Ashton PM. What is the source of infections causing invasive nontyphoidal Salmonella disease? Open Forum Infectious Diseases. 2023;10:ofad086
  93. 93. Kariuki S, Revathi G, Gakuya F, Yamo V, Muyodi J, Hart CA. Lack of clonal relationship between non-typhi Salmonella strain types from humans and those isolated from animals living in close contact. FEMS Immunology and Medical Microbiology. 2002;33(3):165-171
  94. 94. Dione MM, Ikumapayi UN, Saha D, Mohammed NI, Geerts S, Ieven M, et al. Clonal differences between non-typhoidal Salmonella (NTS) recovered from children and animals living in close contact in the Gambia. PLoS Neglected Tropical Diseases. 2011;5(5):e1148
  95. 95. Parsons BN, Humphrey S, Salisbury AM, Mikoleit J, Hinton JCD, Gordon MA, et al. Invasive non-typhoidal Salmonella typhimurium st313 are not host-restricted and have an invasive phenotype in experimentally infected chickens. PLoS Neglected Tropical Diseases. 2013;7(10):1-8
  96. 96. Crump JA, Thomas KM, Benschop J, Knox MA, Wilkinson DA, Midwinter AC, et al. Investigating the meat pathway as a source of human nontyphoidal Salmonella bloodstream infections and diarrhea in East Africa. Clinical Infectious Diseases. 2021;73(7):E1570-E1578
  97. 97. Thye T, Krumkamp R, Lusingu JPA, Ofori LA, Minja DTR, Flieger A, et al. Non-typhoidal Salmonella transmission reservoirs in sub-Saharan Africa: A genomic assessment from a one health perspective. Antimicrobial Resistance and Infection Control. 2025;14(1):1-18
  98. 98. Kumwenda B, Canals R, Predeus AV, Zhu X, Kröger C, Pulford C, et al. Salmonella enterica serovar Typhimurium ST313 sublineage 2.2 has emerged in Malawi with a characteristic gene expression signature and a fitness advantage. microLife. 2024;5:uqae005
  99. 99. Van Puyvelde S, Pickard D, Vandelannoote K, Heinz E, Barbé B, de Block T, et al. An African Salmonella typhimurium st313 sublineage with extensive drug-resistance and signatures of host adaptation. Nature Communications. 2019;10(1):4280
  100. 100. Ikhimiukor OO, Oaikhena AO, Afolayan AO, Fadeyi A, Kehinde A, Ogunleye VO, et al. Genomic characterization of invasive typhoidal and non-typhoidal Salmonella in southwestern Nigeria. PLoS Neglected Tropical Diseases. 2022;16(8):e0010716
  101. 101. Yamba K, Kapesa C, Mpabalwani E, Hachaambwa L, Smith AM, Young AL, et al. Antimicrobial susceptibility and genomic profiling of Salmonella enterica from bloodstream infections at a tertiary referral hospital in Lusaka, Zambia, 2018-2019. IJID Regions. 2022;3:248-255
  102. 102. Kanteh A, Sesay AK, Alikhan NF, Ikumapayi UN, Salaudeen R, Manneh J, et al. Invasive atypical non-typhoidal Salmonella serovars in the Gambia. Microbial Genomics. 2021;7(11):000677
  103. 103. Mandomando I, MacEte E, Sigaúque B, Morais L, Quintó L, Sacarlal J, et al. Invasive non-typhoidal Salmonella in Mozambican children. Tropical Medicine and International Health. 2009;14(12):1467-1474
  104. 104. Zhao J, Lu X, Tie A, Ngegba E, Wang L, Sun L, et al. Molecular diagnostics and next-generation sequencing reveal real etiological characteristics of invasive Salmonella infection in febrile illness in Freetown, Sierra Leone. Emerging Microbes & Infections. 2022;11(1):1416-1424
  105. 105. Kalonji LM, Post A, Phoba MF, Falay D, Ngbonda D, Muyembe JJ, et al. Invasive Salmonella infections at multiple surveillance sites in the Democratic Republic of the Congo, 2011-2014. Clinical Infectious Diseases. 2015;61:S346-S353
  106. 106. Pulford CV, Perez-Sepulveda BM, Canals R, Bevington JA, Bengtsson RJ, Wenner N, et al. Stepwise evolution of Salmonella typhimurium ST313 causing bloodstream infection in Africa. Nature Microbiology. 2020 [Internet];6(3):327-338. Available from: https://www.nature.com/articles/s41564-020-00836-1 [Accessed: March 4, 2024]
  107. 107. Park SE, Pham DT, Pak GD, Panzner U, Maria Cruz Espinoza L, Von Kalckreuth V, et al. The genomic epidemiology of multi-drug resistant invasive non-typhoidal Salmonella in selected sub-Saharan African countries. BMJ Global Health. 2021;6(8):e005659
  108. 108. Feasey NA, Masesa C, Jassi C, Faragher EB, Mallewa J, Mallewa M, et al. Three epidemics of invasive multidrug-resistant Salmonella bloodstream infection in Blantyre, Malawi, 1998-2014. Clinical Infectious Diseases. 2015;61(4):363-371
  109. 109. Cassese D, Dimitri N, Breghi G. Spadafina T. Effectiveness of iNTS vaccination in sub-Saharan Africa. Scientific Reports [Internet]. 2025;15(1):3765. Available from: https://www.nature.com/articles/s41598-025-87659-4 [Accessed: May 31, 2025]
  110. 110. Emary K, Bentsi-Enchill AD, Giersing BK, Gordon M, Dale H, Chirwa EB, et al. Landscape analysis of invasive non-typhoidal Salmonella (iNTS) disease and iNTS vaccine use case and demand: Report of a WHO expert consultation. Vaccine. 2025;55:127008
  111. 111. Martin LB, Tack B, Marchello CS, Sikorski MJ, Owusu-Dabo E, Nyirenda T, et al. Vaccine value profile for invasive non-typhoidal Salmonella disease. Vaccine. 2024;42(19):S101-S124
  112. 112. World Health Organization. Typhoid vaccines: WHO position paper, march 2018 – Recommendations. Vaccine [Internet]. 2019;37(2):214-216. Available from: https://www.sciencedirect.com/science/article/pii/S0264410X18304912 [Accessed: June 19, 2025]
  113. 113. Tennant SM, Levine MM. Live attenuated vaccines for invasive Salmonella infections. Vaccine. 2015;33(Suppl 3):36-41
  114. 114. Angelakopoulos H, Hohmann EL. Pilot study of phoP/phoQ-deleted Salmonella enterica serovar Typhimurium expressing Helicobacter pylori urease in adult volunteers. Infection and Immunity. 2000;68:2135-2141
  115. 115. Hindle Z, Chatfield SN, Phillimore J, Bentley M, Johnson J, Cosgrove CA, et al. Characterization of Salmonella enterica derivatives harboring defined aroC and ssaV mutations by immunization of healthy volunteers. Infection and Immunity. 2002;70:3457-3467
  116. 116. Ji HJ, Jang AY, Song JY, Ahn KB, Han SH, Bang SJ, et al. Development of live-attenuated Salmonella typhimurium vaccine strain using radiation mutation enhancement technology (R-MET). Frontiers in Immunology. 2022;13:931052
  117. 117. Garcia P, Moscoso M, Fuentes-Valverde V, Rodicio MR, Herrera-Leon S, Bou G. A highly-safe live auxotrophic vaccine protecting against disease caused by non-typhoidal Salmonella typhimurium in mice. Journal of Microbiology, Immunology, and Infection. 2023;56:324-336
  118. 118. Maryland U. Salmonella conjugates CVD 1000: Study of responses to vaccination with trivalent invasive Salmonella disease vaccine. 2021. Available from: https://clinicaltrials.gov/study/NCT03981952
  119. 119. Maryland U. Salmonella conjugates CVD 2000: Study of responses to vaccination with trivalent Salmonella conjugate vaccine. 2022. Available from: https://clinicaltrials.gov/study/NCT05525546
  120. 120. Tontini M, Berti F, Romano MR, Proietti D, Zambonelli C, Bottomley MJ, et al. Comparison of CRM197, diphtheria toxoid and tetanus toxoid as protein carriers for meningococcal glycoconjugate vaccines. Vaccine. 2013;31(42):4827-4833
  121. 121. Shinefield HR. Overview of the development and current use of CRM197 conjugate vaccines for pediatric use. Vaccine. 2010;28(27):4335-4339
  122. 122. Rondini S, Lanzilao L, Necchi F, O’Shaughnessy CM, Micoli F, Saul A, et al. Invasive African Salmonella typhimurium induces bactericidal antibodies against O-antigens. Microbial Pathogenesis. 2013;63:19-23
  123. 123. Rondini S, Micoli F, Lanzilao L, Gavini M, Alfini R, Brandt C, et al. Design of glycoconjugate vaccines against invasive African Salmonella enterica serovar Typhimurium. Infection and Immunity. 2015;83(3):996-1007
  124. 124. Micoli F, Rondini S, Alfini R, Lanzilao L, Necchi F, Negrea A. Comparative immunogenicity and efficacy of equivalent outer membrane vesicle and glycoconjugate vaccines against non-typhoidal Salmonella. Proc Natl Acad Sci USA. 2018;115(42):10428-10433
  125. 125. Micoli F, Alfini R, Benedetto R, Necchi F, Schiavo F, Mancini F. GMMA is a versatile platform to design effective multivalent combination vaccines. Vaccines (Basel). 2020;8:540
  126. 126. Hanumunthadu B, Kanji N, Owino N, Silva C, Robinson H, White R, et al. Salmonella vaccine study in oxford (SALVO) Trial TVOC. BMJ Open. 2023;13:72938
  127. 127. Spadafina T. PEDVAC-iNTS starts a Phase 2 Clinical Trial of a Vaccine Against Invasive Non-Typhoidal Salmonellosis, iNTS-GMMA in Ghana [Internet]. 2024. Available from: https://pedvac-ints.eu/pedvac-ints-starts-a-phase-2-clinical-trial-of-a-vaccine-against-invasive-non-typhoidal-salmonellosis-ints-gmma-in-ghana/ [Accessed: June 19, 2025]
  128. 128. Skidmore PD, Canals R, Ramasamy MN. The iNTS-GMMA vaccine: A promising step in non-typhoidal Salmonella vaccine development. Expert Review of Vaccines. 2023;22(9):918-920
  129. 129. Malley R, Lu YJ, Sebastian S, Zhang F, Willer DO. Multiple antigen presenting system (MAPS): State of the art and potential applications. Expert Review of Vaccines. 2024;23:196-204
  130. 130. Boerth EM, Gong J, Roffler B, Thompson CM, Song B, Malley SF, et al. Induction of broad immunity against invasive Salmonella disease by a quadrivalent combination Salmonella MAPS vaccine targeting Salmonella enterica serovars Typhimurium, Enteritidis, Typhi, and Paratyphi A. Vaccines (Basel). 2023;11:1671

Written By

Derrick A. Daah and Samuel Duodu

Submitted: 20 June 2025 Reviewed: 24 June 2025 Published: 12 September 2025

© 2025 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Continue reading from the same book

View All

Your cart

Discounts available on purchase of multiple copies. View rates

Subtotal €0.00

Local taxes (VAT) are calculated in later steps, if applicable.

Support: orders@intechopen.com