A Glimpse on Outer Membrane Vesicles as Vaccine Candidates

Abstract

DescriptionRecently it becomes increasingly evident that actively release of membrane-derived vesicles from cellular surfaces is conserved in all domains of life, including eukaryotes, archaea, Gram-positive and Gram-negative bacteria. For the latter case these spherical structures originate from the outer membrane (OM) and are consequently referred to as outer membrane vesicles (OMVs). Notably, all Gramnegative bacteria that have been investigated so far are able to naturally release OMVs [1,2]. Although OMV formation seems to be a common feature of Gram-negative bacteria the knowledge of their biological roles and biogenesis remains very limited. The hypothesized functions range from simple waste dumps to delivery vehicles for virulence factors (e.g. toxins), degradation enzymes (e.g. toxins and proteases), DNA to enable horizontal gene transfer or signaling molecules for intra-and inter-species communication (e.g. quorum sensing signaling molecules) [3,4]. OMVs range from 10-300 nm in diameter and consist mainly of OM components, such as phospholipids, OM proteins, and lipooligosaccharide (LOS) or lipopolysaccharide (LPS). Additionally, OMVs contain periplasmic components, which are trapped in the lumen of OMVs during the vesiculation process [5]. Hence, OMVs are basically non-living facsimiles of the bacterial cell surface, naturally containing multiple native surface-exposed antigens as well as immunostimulatory molecules [1,6]. Based on their aforementioned immunogenic potency and on positive examples of the OMV-derived vaccines against serogroup B Neisseria meningitides, we initiated several projects over the last years to analyze the potential of OMVs derived from human Gram-negative pathogens as vaccine candidates [7][8][9][10][11][12]. This concise communication summarizes our recent findings in the emerging research field of OMVs as vaccine candidates including immunization studies against human gastrointestinal pathogens (e.g. V. cholerae and ETEC) as well as human and veterinarian respiratory tract pathogens (e.g. Pasteurellaceae family members).For example, we comprehensively characterized OMVs derived from V. cholerae as a new approach for an effective vaccine candidate against cholera [7][8][9][10]13]. As it turns out OMVs exhibit several advantages compared to other vaccines. For example, OMVs are highly stable, even at room temperature, and highly immunogenic without requirements of additional adjuvants [7][8][9]. Thus, a cold chain or accessory buffer solutions are unlikely to be required for the OMV vaccine candidate. In addition, OMV donor strains can be genetically modified to secrete altered OMVs. We successfully applied this strategy to isolate OMVs from a LPS acyltransferase mutant strain, demonstrating that reduction of OMV endotoxicity can be achieved without diminishing the immunogenic potential by genetic modification resulting in underacylated lipid A [10]. Overall, we demonstrated the induction of a specific, long-lasting, high-titer, protective immune response upon mucosal immuniz...