Outer Membrane Vesicle Vaccines from Biosafe Surrogates Prevent Acute Lethal Glanders in Mice

Abstract

Burkholderia mallei is a host-adapted Gram-negative mammalian pathogen that causes the severe disease glanders. Glanders can manifest as a rapid acute progression or a chronic debilitating syndrome primarily affecting solipeds and humans in close association with infected animals. In USA, B. mallei is classified as one of the most important bacterial biothreat agents. Presently, there is no licensed glanders vaccine available for humans or animals. In this work, outer membrane vesicles (OMVs) were isolated from three attenuated biosafe bacterial strains, Burkholderia pseudomallei Bp82, B. thailandensis E555, and B. thailandensis TxDOH and used to vaccinate mice. B. thailandensis OMVs induced significantly higher antibody responses that were investigated. B. mallei specific serum antibody responses were of higher magnitude in mice vaccinated with B. thailandensis OMVs compared to levels in mice vaccinated with B. pseudomallei OMVs. OMVs derived from biosafe strains protected mice from acute lethal glanders with vesicles from the two B. thailandensis strains affording significant protection (>90%) up to 35 days post-infection with some up to 60 days. Organ loads from 35-day survivors indicated bacteria colonization of the lungs, liver, and spleen while those from 60 days had high CFUs in the spleens. The highest antibody producing vaccine (B. thailandensis E555 OMVs) also protected C57BL/6 mice from acute inhalational glanders with evidence of full protection.

Deletion of Two Genes in Burkholderia pseudomallei MSHR668 That Target Essential Amino Acids Protect Acutely Infected BALB/c Mice and Promote Long Term Survival

“…route. We wanted to evaluate these candidates as potential vaccines similar to outer membrane vesicle (OMV) vaccines in which we could characterize protective host humoral and cell-mediated immune responses induced by our whole-cell candidate strains, in addition to still evaluate their attenuation [56][57][58]. In the OMV vaccine studies the particulate OMV were vaccinated s.c. into mice, and vaccinated mice were subsequently challenged by aerosol or intranasal (i.n.)…”

The Peptidoglycan-associated lipoprotein Pal contributes to the virulence of Burkholderia mallei and provides protection against lethal aerosol challenge

“…Fortunately, the genetic, virulence, and disease similarities between B. mallei and B. pseudomallei suggest the feasibility of devising medical countermeasures that protect against both organisms. This premise is supported by studies showing that antibodies against in vivo expressed Burkholderia antigens [ 19 ], vaccination with Burkholderia live attenuated strains [ 19 , 20 ] and outer membrane vesicles [ 21 , 22 ], and polysaccharide-based vaccines [ 23 , 24 ] provide cross-species protection in animal models of melioidosis and glanders.…”

The autotransporter protein BatA is a protective antigen against lethal aerosol infection with Burkholderia mallei and Burkholderia pseudomallei

“…Hence, there is concern that Burkholderia LAS might establish chronic infection, especially in immunocompromised individuals (a growing population in today’s society and risk group for glanders and melioidosis). Capsule [48], [49], [50], LPS [20], [21], [51], and outer membrane vesicles [22], [23], [52], [53] have been investigated as subunit vaccines and showed excellent protection against acute lethal challenge. However, production of these vaccines requires large-scale culture of pathogenic organisms under BSL3 containment and conjugation of capsule and LPS to a carrier to optimize immunogenicity.…”

“…The genetic, biochemical, and virulence similarities between B. mallei and B. pseudomallei , and the marked resemblance of the disease they cause, supports the feasibility of developing countermeasures that protect against both organisms. This belief is supported by studies demonstrating that passive transfer of antibodies against in vivo expressed Burkholderia antigens provides protection in mice against lethal challenge with B. pseudomallei and B. mallei [19], and subunit vaccines containing Burkholderia exopolysaccharides [20], [21] and outer membrane vesicles [22], [23] elicit cross-species immunity in glanders and melioidosis infection models.…”