Current perspectives on invasive nontyphoidal Salmonella disease

Purpose of review We searched PubMed for scientific literature published in the past 2 years for relevant information regarding the burden of invasive nontyphoidal Salmonella disease and host factors associated with nontyphoidal Salmonella infection and discuss current knowledge on vaccine development. The following search terms were used: Salmonella, non typhoidal/nontyphoidal, NTS, disease, bloodstream infection, invasive, sepsis/septicaemia/septicemia, bacteraemia/bacteremia, gastroenteritis, incidence, prevalence, morbidity, mortality, case fatality, host/risk factor, vaccination, and prevention/control. Recent findings Estimates of the global invasive nontyphoidal Salmonella disease burden have been recently updated; additional data from Africa, Asia, and Latin America are now available. New data bridge various knowledge gaps, particularly with respect to host risk factors and the geographical distribution of iNTS serovars. It has also been observed that Salmonella Typhimurium sequence type 313 is emergent in several African countries. Available data suggest that genetic variation in the sequence type 313 strain has led to increased pathogenicity and human host adaptation. A bivalent efficacious vaccine, targeting Salmonella serovars Typhimurium and Enteritidis, would significantly lower the disease burden in high-risk populations. Summary The mobilization of surveillance networks, especially in Asia and Latin America, may provide missing data regarding the invasive nontyphoidal Salmonella disease burden and their corresponding antimicrobial susceptibility profiles. Efforts and resources should be directed toward invasive nontyphoidal Salmonella disease vaccine development.


INTRODUCTION
Salmonella enterica serovar Typhi (S. Typhi) and the various pathovars of S. Paratyphi are commonly referred to as typhoidal Salmonella serovars. These agents are restricted to human hosts. Salmonella serovars that fall outside of this group are typically referred to as the nontyphoidal Salmonella (NTS) serovars and are considered to have the potential to interact with human and nonhuman hosts [1 && ]. Poor access to improved water supplies and adequate sanitation facilities, combined with growing urbanization, favor the transmission of NTS serovars through food or water sources and contact with animals [2

KEY POINTS
Global estimates suggest 3.4 million iNTS illnesses and 618 316 iNTS disease-related deaths per year.
The most common iNTS serovars are S. Enteritidis, S. Dublin, S. Typhimurium; of particular concern is the S. Typhimurium ST313 variant.
Vietnam from 2013 to 2015 identified an overall NTS-associated bacterial positivity rates of 27.5% (11/40 bacteremia cases) in children and 11.7% (7/60 bacteremia cases) in adults [35]. Limited iNTS prevalence (20/12 940 bacteremia patients) and a 25% case fatality were reported among bacteremic patients hospitalized from 2009 to 2013 in Bangladesh [36]. A longitudinal study of communityacquired bacteremia in hospitalized children conducted in Malaysia from 2001 to 2011 found an iNTS prevalence of 16.2% (36/222), with most NTS isolated from infants below 1 year of age [37]. A surveillance study from Colombia investigated a sample of 4010 S. Enterica isolates collected from blood and feces samples and found that 32.5% were S. Typhimurium, 28.2% were S. Enteritidis, and 2.9% were S. Dublin cases over a 6-year period [38]. These numbers are considerably lower than those reported from Asia and sub-Saharan Africa. Notably, S. Typhimurium ST313 variants have been isolated from humans and poultry in Brazil [39]. On the basis of the investigations of Almeida et al. [39], the organisms identified appear genetically distinct from the ST313 variants isolated in sub-Saharan Africa.

HOST-ASSOCIATED FACTORS
Common factors contributing to iNTS disease include extremes in age, the occurrence of immunosuppressive conditions, and other underlying comorbidities (e.g., diabetes, cancer, and cardiovascular diseases) [40]. In addition, climatic conditions such as increased rainfall or drought that can result in food scarcity, leading to malnutrition and increased transmission of malaria parasites are factors that may favor the transmission of NTS organisms [7 && ]. Particularly in Africa, the association of iNTS disease with malnutrition (OR 1. 44 ]. In comparison to other S. Typhimurium types (e.g., ST19), the genomically degraded ST313 may cause systemic infections and induce a lower inflammatory reaction in the intestine, exerted by evasion mechanisms from the immune response [43,44]. The genomic degradation includes the downregulation of gene expression involved in active cell invasion through effector proteins [43,44]. The reduced activation of macrophages is assumed to be caused by lower flagellin expression [43,44]. The survival time and replication rate were found to be more efficient in the investigated ST313 isolates compared with ST19 [43,44]. Therefore, the ST313 phenotype appears to become closer to that of typhoidal Salmonella, suggesting analogical adaptation toward a more invasive phenotype in humans [  [46] found stabilizing effects on the gastrointestinal microbiome associated with the ingestion of probiotics in mice, which may improve the functionality of the intestinal barrier.

VACCINE DEVELOPMENT
Effective vaccines preventing iNTS disease are likely to differ inherently from those protecting against S. Typhi infections. Studies from Africa have shown that naturally acquired antibodies against NTS correspond with a reduced risk of iNTS disease [47,48]. Several vaccine candidates targeting S. Typhimurium and S. Dublin are currently under development, some of which may provide protection against both serovars. The current status of iNTS vaccine considerations has been described in a recent review [49 && ]: several potential iNTS vaccines are under development, including live-attenuated, subunit-based, and recombinant antigen-based substances. Both humoral and cellular immunities are likely required to achieve full protection against iNTS disease. Liveattenuated vaccines provide both types of immune response; however, they may pose a risk for immunocompromised individuals [41 && ]. Inactivated iNTS vaccines may induce humoral immunity only and suppress NTS during the acute phase of infection, but are likely not to achieve systematic clearance in infected individuals [41 && ]. The lack of disease burden data from Asia and South America, coupled with the enormous number of NTS serovars, and the role of alternate prevention measures (i.e., access to improved water and sanitation and food safety) have contributed to a delay and a lack of investment in the development of iNTS disease vaccines.
Previously, when animals were considered to be the only reservoir of NTS organisms, the implementation of hygiene and safety measures along a regulated and appropriate food chain was thought to be sufficient for the reduction of iNTS transmission. However, with the speculation that humans may be a growing alternative reservoir for ST313 [50], the development and deployment of iNTS disease vaccines appear to be a more viable solution. However, iNTS disease vaccines would not only require considerable funding to progress existing vaccine candidates, but also will require parallel vaccine deployment strategies to identify appropriate target age groups, schedules, formulations, and potential vaccine adjuvants.
An iNTS disease vaccine would need to be administered in infants to ensure protection before the peak occurrence of disease. This strategy, however, poses the challenge of combining iNTS and S. typhi vaccines, as the peak disease incidence for typhoid (5-8 years of age) is later than that for iNTS disease [51], except in highly endemic areas. A potential byproduct after the widespread use of a bivalent iNTS vaccine conferring protection against S. Typhimurium and S. Enteritidis would be serovar replacement by other Salmonella variants, such as S. Dublin. Such a serotype replacement was observed following the MenAfriVac campaign, when large populations in the African meningitis belt were vaccinated against Neisseria meningitidis serotype A and other serotypes subsequently emerged [52][53][54]. Another consideration would be a combined iNTS disease/malaria vaccine; this approach may be particularly prudent, given that malaria is associated with the severity of iNTS disease. Such a vaccine would then be tailormade for sub-Saharan Africa, but may be less applicable for low and nonendemic malaria regions (i.e., Brazil) [39]. This would potentially suggest the need to develop an independent, nonmalaria-combined vaccine that is applicable to all iNTS endemic regions.

CONCLUSION
iNTS is a major public health issue in sub-Saharan Africa. ST313 appears to be better adapted to humans than other S. Typhimurium, is associated with an increased disease severity, and has acquired an MDR phenotype. Observations of the Brazilian ST313 lead to some insights on this serotype that are also relevant for Africa. First, ST313 has the ability to arise in new locations independently and does not appear to be confined to sub-Saharan Africa. The fact that some Brazilian ST313 isolates exhibit different antimicrobial susceptibility profiles in comparison to African variants suggests that iNTS disease has the potential to evolve de novo outside of Africa, which may result in new and unlinked epidemics. Improvement in water and sanitation, a reduction in malaria incidences and malnutrition and improved management of HIV infections should additionally prevent iNTS disease from becoming an even bigger global health threat. However, the rapid emergence of ST313, the possible de-novo occurrence and spread of the future MDR and pathogenic variants place iNTS disease increasingly on the vaccine development agenda. Now is also a prime time to invest in enhanced iNTS disease surveillance. This enhanced surveillance is particularly important in Asia and Latin America, and is required to assess the actual extent of disease in these locations. Typhoid fever should be used as an example, when, despite the availability of vaccines, a lack of appropriate disease burden data stalled the global commitment, resulting in limited vaccine uptake and dampened efforts to develop conjugated vaccines. The persistence of typhoid fever culminated in the evolution of a highly antimicrobial resistant S. Typhi genotype (H58), which is spreading globally [55].