In sub-Saharan Africa, systematic surveillance of young children with suspected invasive bacterial disease has revealed non-typhoidal Salmonella (NTS) as a major pathogen exhibiting high case fatality. As the burden of Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae has been decreased with successful vaccine implementation, NTS has become the predominant invasive bacterial pathogen in children aged <5 years. Most invasive NTS (iNTS) disease in endemic regions is caused by two serovars, S. Typhimurium and S. Enteritidis. My research investigated phylogenetic changes associated with a recent increase in the relative proportion of iNTS caused by S. Enteritidis in Bamako, Mali. Through comparative genomics, homologs of tetracycline resistance and arsenic utilization genes were identified to be associated with isolates obtained after the serovar shift. These findings were validated through laboratory assays and provide initial steps towards identifying evolutionary pressures associated with the shift in serovars. While NTS is believed to be acquired orally via contaminated food/water, studies have failed to identify the reservoir of infection or vehicles of transmission. This precludes the use of food chain interventions, but conversely has fostered the development of vaccines to prevent iNTS disease. We developed a Markov chain model to estimate the potential impact of NTS vaccination programs in Bamako utilizing age-specific demographic and hospital surveillance data for iNTS disease in children aged <5 years, and assuming vaccine coverage and efficacy similar to the existing Hib vaccine. The outcomes of interest were annual iNTS hospitalizations and deaths in children <5 years, with and without a NTS vaccine. Per the model, high coverage/high efficacy iNTS vaccination programs would drastically diminish iNTS disease except among infants age <8 weeks. The public health impact of NTS vaccination shifts as disease burden, vaccine coverage, and serovar distribution vary. S. Enteritidis exhibits a higher case fatality rate than S. Typhimurium, so the public health burden of the disease is increasing as it emerges as the dominant serovar causing iNTS. Our model demonstrates that implementing an iNTS vaccine through an analogous strategy to the Hib vaccination program in Bamako would markedly reduce cases and deaths due to iNTS among the pediatric population.