Invasive non-typhoidal Salmonella disease in the vaccine-development era: diagnostic blind spots, antimicrobial resistance, genomic transmission, and prevention

SUMMARY Invasive non-typhoidal Salmonella (iNTS) disease is a severe bloodstream and focal invasive infection caused by non-typhoidal serovars of Salmonella enterica , especially S . Typhimurium and S . Enteritidis. Its clinical importance is disproportionate to its routine visibility because disease often presents as undifferentiated fever, sepsis, meningitis, severe anaemia-associated deterioration, recurrent bacteraemia, or focal infection, while definitive recognition depends on blood or other sterile-site microbiology. Global estimates indicate substantial mortality, but the true incidence remains uncertain because blood-culture access, prior antimicrobial exposure, specimen volume, and surveillance intensity vary widely. The vaccine-development era has intensified the need for a unified clinical microbiology framework. Prevention of invasive disease requires host-risk recognition, laboratory-confirmed endpoints, antimicrobial susceptibility testing, lineage-aware genomic surveillance, reservoir assessment, and post-introduction systems able to detect residual disease, breakthrough infection, non-target serovars, lineage shifts, and resistant invasive clones. This narrative review synthesizes the clinical, immunological, genomic, diagnostic, antimicrobial resistance, and vaccine era evidence relevant to iNTS control. Emphasis is placed on immune evasion, macrophage survival, T-cell dysfunction, immunosuppressed hosts, diagnostic blind spots, treatment under uncertainty, and the integration of laboratory systems with surveillance and prevention policy.