The genus Salmonella has over 2500 different serovars: Salmonella enterica serovar Typhi and Salmonella enterica serovars Paratyphi A and B (and uncommonly Paratyphi C), that cause enteric fevers, and many non-typhoidal Salmonella (NTS) serovars that cause invasive disease (iNTS), and diarrheal disease (dNTS). iNTS has been recognized as a major cause of bacteremia in sub-Saharan Africa. Children with HIV infection, malaria and malnutrition, and immunocompromised adults with HIV are at high risk. iNTS usually presents as a febrile illness, frequently without gastrointestinal symptoms in both young adults and children, leading to severe, extra-intestinal, invasive bacteremia. 

The Institute for Health Metrics and Evaluation (IHME) estimates of the global burden of disease from iNTS in 2019 are 594,000 cases, 79,000 deaths and 6.11 million global DALYs.¹ The mean all-age case-fatality rate was 14.5%, with higher estimates (41.8%) among people living with HIV.²

The incidence rate is highest in sub-Saharan Africa, and in those under 5 years of age. Host factors such as malnutrition and co-infection with malaria and HIV contribute to the higher burden of iNTS disease in the developing world compared to industrialized countries. Data gaps remain in fully understanding the full burden of iNTS disease, including geographic diversity, host risk factors, transmission, long term sequelae etc. Diarrheal disease caused by NTS serovars is more prevalent and is usually considered to be mild and self-limiting, but the burden has yet to be well characterized. Preliminary analysis from IHME estimated that 73.9 million cases of dNTS occurred in 2019, resulting in 61,600 deaths. The combined burden of iNTS and dNTS in DALYs is found to be substantial in children under 5.

Non-typhoidal Salmonella serovars Enteritidis and Typhimurium account for the majority of all human NTS isolates reported globally. Multi-drug resistance is common and resistance to ceftriaxone and fluoroquinolones is emerging.  One subtype of iNTS, Salmonella enterica var Typhimurium, ST313, is highly prevalent in sub-Saharan Africa and is associated with multi-drug resistance, making vaccine against NTS an important public health priority.

The NTS vaccine development pipeline includes live-attenuated, subunit-based, and recombinant antigen-based candidates. Both humoral response and cellular immune responses are likely to be required to protect against iNTS disease, as indicated from immuno-epidemiological studies and animal studies. Development of a bivalent NTS vaccine would be required to protect against the predominant serovars S. Typhimurium and S. Enteritidis, or a multivalent vaccine that combines with another enteric vaccine, such as a typhoid conjugate vaccine, to ease delivery.

Several iNTS vaccines are currently in preclinical or early clinical phase of development. Before 2019, the only candidate being tested in humans was a live attenuated vaccine candidate WT05. Although WT05 has displayed good tolerability and elicited high anti-lipopolysaccharide (LPS) antibody responses in some healthy human volunteers, the candidate has not progressed further due to the prolonged fecal shedding of bacteria.  Glycoconjugate vaccines against iNTS are also being developed, in order to generate a protective antibody response against the surface polysaccharide, the Core O-PolySaccharides (COPS) in NTS serovars. Coupling with a protein carrier flagellin FliC engages CD4+ T-cell help and enhances polysaccharide immunogenicity. A trivalent iNTS-typhoid conjugate (iNTS COPS:FliC coupled with a Vi-tetanus toxoid typhoid conjugate vaccine) is currently in Phase 1. 

Another promising approach is the use of outer membrane vesicles (OMVs) as a vehicle to deliver iNTS O-Ag (O-antigen, the main polysaccharide component of the Gram-negative LPS). A low-cost, scalable, standardized manufacturing system for producing GMP-quality OMVs, referred to as Generalized Modules for Membrane Antigens (GMMA) has been developed.  A GMMA-based bivalent vaccine against the African invasive S. Typhimurium and S. Enteritidis will enter clinical Phase 1 soon. There are also plans to combine this GMMA-based iNTS candidate with a Vi-CRM197 typhoid conjugate vaccine. Multiple other vaccines, including live attenuated vaccine and outer membrane protein-based vaccines, are in pre-clinical development.

Field efficacy studies would be needed to provide the first indication of efficacy for iNTS candidates, as unlike typhoid, there is no Controlled Human Infection Model (CHIM) model available to test proof of concept of these vaccine candidates. It is also unclear if these vaccine candidates will be protective against both gastroenteritis and invasive NTS disease, but the evidence on typhoid, paratyphoid A and NTS (iNTS/dNTS) disease burden has led to interests in developing a multivalent “pan-Salmonella” vaccine that is broadly protective against Salmonella disease. In 2021, WHO has organized a stakeholder consultation to discuss the product development strategy for broadly protective salmonella vaccines, as a first step to develop an iNTS vaccine development roadmap and WHO Preferred Product Characteristics (PPCs).

Updated April 30, 2022

References:

1) Institute for Health Metrics and Evaluation (IHME). GBD 2019 Cause and Risk Summary: Invasive non-typhoidal Salmonella (iNTS). Accessed 6th October 2021. Seattle, USA: IHME, University of Washington.

2) 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. Lancet Infect Dis. 2019 Sep 24;19(12):1312–24. pmid:31562022