Bacterial-Derived Outer Membrane Vesicles are Potent Adjuvants that Drive Humoral and Cellular Immune Responses

Abstract

Discovery and development of novel adjuvants that can improve existing or next generation vaccine platforms have received considerable interest in recent years. In particular, adjuvants that can elicit both humoral and cellular immune responses would be particularly advantageous because the majority of licensed vaccines are formulated with aluminum hydroxide (alum) which predominantly promotes antibodies. We previously demonstrated that bacterial-derived outer membrane vesicles (OMV) possess inherent adjuvanticity and drive antigen-specific antibody and cellular immune responses to OMV components. Here, we investigated the ability of OMVs to stimulate innate and adaptive immunity and to function as a stand-alone adjuvant. We show that OMVs are more potent than heat-inactivated and live-attenuated bacteria in driving dendritic cell activation in vitro and in vivo. Mice immunized with OMVs admixed with heterologous peptides generated peptide-specific CD4 and CD8 T cells responses. Notably, OMV adjuvant induced much greater antibody and B cell responses to co-delivered ovalbumin compared to the responses elicited by the adjuvants alum and CpG DNA. Additionally, pre-existing antibodies raised against the OMVs did not impair OMV adjuvanticity upon repeat immunization. These results indicate that vaccines adjuvanted with OMVs elicit robust cellular and humoral immune responses, supporting further development of OMV adjuvant for use in next-generation vaccines.

An Outer Membrane Vesicle-Adjuvanted Oral Vaccine Protects Against Lethal, Oral Salmonella Infection

“…Typhimurium adjuvanted with B. pseudomallei OMVs to determine if oral immunization could elicit protective mucosal immunity against Salmonella . The addition of the OMVs can mimic a live bacterium to stimulate the immune response [ 14 ]. Indeed, B. pseudomallei OMVs have recently been shown to behave like and elicit similar protection to a live-attenuated vaccine [ 37 ].…”

“…Administration of OMVs to other mucosal surfaces would be beneficial in defining their adjuvant role and whether they are capable of inducing both humoral and cellular immunity at any site or if this phenomenon is gut specific. In this study, we used B. pseudomallei OMVs based on previous literature showing their safety and efficacy both as a vaccine and an adjuvant [ 13 , 14 , 37 ]. Overall, this study highlights the first time that B. pseudomallei OMVs have been employed to adjuvant an oral vaccine.…”

“…OMVs from other species, such as Burkholderia pseudomallei , have been used as a vaccine platform against infection with various Burkholderia species and have been shown to produce both humoral and cell-mediated immune responses [ 10 , 11 , 12 ]. B. pseudomallei OMVs have also been shown to be safe and effective in mice and rhesus macaques [ 13 ] and have recently been shown to function as a potent adjuvant [ 14 ]. Unlike alum, OMVs, like those from Vibrio cholerae , are able to be given directly at a mucosal surface and induce long-term local and systemic immune responses [ 15 ].…”

GMMA-Based Vaccines: The Known and The Unknown

“…It is known that OMV are able to drive DC maturation. Indeed, native OMV derived from the facultative-intracellular bacterium Burkholderia pseudomallei were shown to favor DC maturation and activation both in vitro and in vivo in a mouse model (57). Moreover, Schetters et al demonstrated that the LPS present on OMV was able to induce, through the myeloid differentiation primary response 88 (Myd88) adapter protein, maturation of human monocyte-derived DCs, murine bone marrow-derived DCs and CD11c+ splenic DCs (58).…”

“…It is known that OMV are able to drive DC maturation. Indeed, native OMV derived from the facultative-intracellular bacterium Burkholderia pseudomallei were shown to favor DC maturation and activation both in vitro and in vivo in a mouse model ( 57 ). Moreover, Schetters et al.…”