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Multi-drug-resistant (MDR) <i>Acinetobacter baumannii</i> is an opportunistic pathogen associated with hospital-acquired infections. Due to its environmental persistence, virulence, and limited treatment options, this organism causes both increased patient mortality and incurred healthcare costs. Thus, prophylactic vaccination could be ideal for intervention against MDR <i>Acinetobacter</i> infection in susceptible populations. In this study, we employed immunoinformatics to identify peptides containing both putative B- and T-cell epitopes from proteins associated with <i>A. baumannii</i> pathogenesis. A novel <i>Acinetobacter</i> Multi-Epitope Vaccine (AMEV2) was constructed using an <i>A. baumannii</i> thioredoxin A (TrxA) leading protein sequence followed by five identified peptide antigens. Antisera from <i>A. baumannii</i> infected mice demonstrated reactivity to rAMEV2, and subcutaneous immunization of mice with rAMEV2 produced high antibody titer against the construct as well as peptide components. Immunization results in increased frequency of IL-4-secreting splenocytes indicative of a Th2 response. AMEV2-immunized mice were protected against intranasal challenge with a hypervirulent strain of <i>A. baumannii</i> and demonstrated reduced bacterial burden at 48 h. In contrast, all mock vaccinated mice succumbed to infection within 3 days. Results presented here provide insight into the effectiveness of immunoinformatic-based vaccine design and its potential as an effective strategy to combat the rise of MDR pathogens.