Review Mapping Global Prevalence of Acinetobacter baumannii and Recent Vaccine Development to Tackle It Chaoying Ma and Siobhán McClean * School of Biomolecular and Biomedical Sciences, University College Dublin, Belfield, D04 V1W8 Dublin 4, Ireland; [email protected] * Correspondence: [email protected] Abstract: Acinetobacter baumannii is a leading cause of nosocomial infections that severely threaten public health. The formidable adaptability and resistance of this opportunistic pathogen have hampered the development of antimicrobial therapies which consequently leads to very limited treatment options. We mapped the global prevalence of multidrug-resistant A. baumannii and showed that carbapenem-resistant A. baumannii is widespread throughout Asia and the Americas. Moreover, when antimicrobial resistance rates of Acinetobacter spp. exceed a threshold level, the proportion of A. baumannii isolates from clinical samples surges. Therefore, vaccines represent a realistic alternative strategy to tackle this pathogen. Research into anti-A. baumannii vaccines have enhanced in the past decade and multiple antigens have been investigated preclinically with varying results. This review summarises the current knowledge of virulence factors relating to A. baumannii–host interactions and its implication in vaccine design, with a view to understanding the current state of A. baumannii vaccine development and the direction of future efforts. Keywords: Acinetobacter baumannii; antimicrobial resistance; ESKAPE; virulence factors; vaccines; immune response Citation: Ma, C.; McClean, S. Mapping Global Prevalence of Acinetobacter baumannii and Recent Vaccine Development to Tackle It. 1. Introduction Vaccines 2021, 9, 570. https:// Acinetobacter baumannii is an opportunistic gram-negative coccobacillus that demon- doi.org/10.3390/vaccines9060570 strates exquisite survival under various environmental conditions and intrinsic resistance to routinely prescribed antibiotics [1]. Multidrug-resistant (MDR) A. baumannii strains Academic Editor: Ernesto S. Nakayasu are now prevalent worldwide, with the highest percentage of carbapenem resistance of over 90% being reported in the Mediterranean region, imposing serious burdens on health- Received: 20 April 2021 care systems. The vast majority of A. baumannii isolates arise in medical institutions and Accepted: 22 May 2021 Published: 1 June 2021 are closely associated with nosocomial infections, particularly in patients receiving in- tensive care and in immunocompromised individuals. Ventilator-associated pneumonia Publisher’s Note: MDPI stays neutral (VAP), central line-associated bloodstream infections (BSI), urinal tract infections (UTI), with regard to jurisdictional claims in and meningitis are the most common clinical manifestations [2]. Unfortunately, the lack published maps and institutional affil- of efficacious treatments has led to high crude mortality ranging from 40% to 80% for iations. infections occurring in sterile sites [3–6]. In 2017, the World Health Organization (WHO) listed carbapenem-resistant A. baumannii as a critical priority, for which, new antibiotics are urgently needed [7]. In addition, once nosocomial outbreaks of A. baumannii occur, it is difficult to thoroughly eradicate from the environment due to its remarkable resistance to disinfectants and its capacity to rapidly develop tolerance to these antibacterial agents, Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. contributing to prolonged colonisation and transmission [8]. Therefore, vaccination of This article is an open access article susceptible individuals is likely to be a more effective intervention for the prevention of distributed under the terms and A. baumannii infections. Compared with other nosocomial pathogens such as Pseudomonas conditions of the Creative Commons aeruginosa, Staphylococcus aureus, and Clostridium difficile, the search for vaccines against Attribution (CC BY) license (https:// A. baumannii is in its infancy [9]. Over the last decade, increased research efforts have creativecommons.org/licenses/by/ concentrated on identifying potential virulence factors, clarifying host–pathogen interac- 4.0/). tions, and developing vaccines against this exquisitely resilient pathogen. In this review, Vaccines 2021, 9, 570. https://doi.org/10.3390/vaccines9060570 https://www.mdpi.com/journal/vaccines Vaccines 2021, 9, x FOR PEER REVIEW 2 of 25 concentrated on identifying potential virulence factors, clarifying host–pathogen interac- tions, and developing vaccines against this exquisitely resilient pathogen. In this review, we describe these advances and also provide a comprehensive appraisal of the relevant microbiology, epidemiology, and antibiotic resistance of A. baumannii. Vaccines 2021, 9, 570 2 of 25 The genus Acinetobacter currently comprises more than 60 validly named species [10]. It has been classified in the family Moraxellaceae, within the order Pseudomonadales, and the weclass describe Gammaproteobacteria these advances and also providesince 1991 a comprehensive [11]. The appraisalwhole ofgenome the relevant of A. baumannii (strain microbiology,ATCC 17978) epidemiology, was first and sequenced antibiotic resistance in 2007 of byA. Smith baumannii et. al. [12]. However, its unambiguous identificationThe genus Acinetobacter in routinecurrently diagnostic comprises laborato more thanries 60 has validly long named been species hindered [10]. as A. baumannii is It has been classified in the family Moraxellaceae, within the order Pseudomonadales, and thephenotypically class Gammaproteobacteria similar to, since and 1991 phylogenetically [11]. The whole genome close of to,A. baumanniiseveral other(strain Acinetobacter species ATCC(Figure 17978) 1). wasThe first A. sequencedcalcoaceticus in 2007–A. by baumannii Smith et al. [(Acb)12]. However, complex its unambiguous consists of six valid species: A. identificationbaumannii, inA. routine calcoac diagnosticeticus (formerly laboratories hasAcinetobacter long been hindered genomic as A. species baumannii 1),is A. nosocomialis (for- phenotypically similar to, and phylogenetically close to, several other Acinetobacter species (Figuremerly1 ).Acinetobacter The A. calcoaceticus genomic–A. baumannii species(Acb) 13TU) complex [13], consists A. pittii of six (formerly valid species: Acinetobacter genomic A.species baumannii 3) ,[13],A. calcoaceticus A. seifertii(formerly (formerlyAcinetobacter Acinetobactergenomic genomic species 1), A.species nosocomialis ‘close to 13TU’) [14], and (formerlythe mostAcinetobacter recentlygenomic added species A. lactucae 13TU) [13 (formerly], A. pittii (formerly AcinetobacterAcinetobacter NB14,genomic synonymous with A. species 3) [13], A. seifertii (formerly Acinetobacter genomic species ‘close to 13TU’) [14], anddijkshoorniae the most recently) [10,15 added–17]A.. lactucaeWhile (formerlyA. calcoaceticusAcinetobacter is nonNB14,-pathogenic, synonymous with the other five members A.are dijkshoorniae all clinically)[10,15 relevant–17]. While andA. calcoaceticus are frequentlyis non-pathogenic, identified the otherin a fivebroad members sense as A. baumannii, or areA. allbaumannii clinically relevantgroup, and in areclinical frequently microbial identified identification. in a broad sense The as A. dominant baumannii, species among the or A. baumannii group, in clinical microbial identification. The dominant species among theclinically clinically isolated isolated A. A. baumannii baumanniigroup group vary vary with region with [region18,19], but [18,19] from, a but clinical from a clinical perspec- perspective,tive, A. baumanniiA. baumannii isis the the most most virulent virulent [5,20 [5,20]]. Figure 1. Phylogenetic1. Phylogenetic analysis analysis of the Acb of complex. the Acb The phylogenycomplex. tree The was phylogeny inferred with tree MEGA was X inferred with MEGA on a Clustal W alignment of the 16S rRNA in the selected type strains. The maximum likelihood- X on a Clustal W alignment of the 16S rRNA in the selected type strains. The maximum likelihood- kimura 2-parameter (ML-K2) model was used. Moraxella osloensis was chosen as an outgroup. Strain nameskimura and 2 their-parameter corresponding (ML GenBank-K2) model accession was numbers used. Moraxella are listed in osloensis Table S1, Supplementary was chosen as an outgroup. Strain Materials.names andA. oleivorans their correspondinghas also been catalogued GenBank into the accession Acb group innumbers some studies are [21 listed–23], though in Table S1, Supplementary itsMaterials. name has not A. yetoleivorans been validated. has also been catalogued into the Acb group in some studies [21–23], though 2.itsA. name baumannii has notIs Ubiquitous yet been validated. Acinetobacter spp. are ubiquitous organisms and the first isolate, described as Mi- crococcus2. A. baumannii calcoaceticus isback Ubiquitous in 1911, was from soil [24]. Their widely distributed natural reservoirs occupy nearly all environmental niches including waterbodies, soil, mines, crude oil, sewage,Acinetobacter sludge, solid spp. surfaces, are rawubiquitous meat, cheese, organisms milk, unprocessed and the vegetables, first isolate, human described as Micro- skin,coccus wild calcoaceticus animals, livestock, back fish, in shrimps,1911, was plants, from and soil nectar [24]. [25]. Their The natural widely habitats distributed natural res- ofervoirsA. baumannii occupy, however, nearly are all still environmental poorly defined as itniches is almost inc exclusivelyluding isolatedwaterbodies,