Burkholderia pseudomallei Capsular Polysaccharide Conjugates Provide Protection against Acute Melioidosis

Abstract

bBurkholderia pseudomallei, the etiologic agent of melioidosis, is a CDC tier 1 select agent that causes severe disease in both humans and animals. Diagnosis and treatment of melioidosis can be challenging, and in the absence of optimal chemotherapeutic intervention, acute disease is frequently fatal. Melioidosis is an emerging infectious disease for which there are currently no licensed vaccines. Due to the potential malicious use of B. pseudomallei as well as its impact on public health in regions where the disease is endemic, there is significant interest in developing vaccines for immunization against this disease. In the present study, type A O-polysaccharide (OPS) and manno-heptose capsular polysaccharide (CPS) antigens were isolated from nonpathogenic, select-agent-excluded strains of B. pseudomallei and covalently linked to carrier proteins. By using these conjugates (OPS2B1 and CPS2B1, respectively), it was shown that although high-titer IgG responses against the OPS or CPS component of the glycoconjugates could be raised in BALB/c mice, only those animals immunized with CPS2B1 were protected against intraperitoneal challenge with B. pseudomallei. Extending upon these studies, it was also demonstrated that when the mice were immunized with a combination of CPS2B1 and recombinant B. pseudomallei LolC, rather than with CPS2B1 or LolC individually, they exhibited higher survival rates when challenged with a lethal dose of B. pseudomallei. Collectively, these results suggest that CPSbased glycoconjugates are promising candidates for the development of subunit vaccines for immunization against melioidosis.

Antibodies against In Vivo -Expressed Antigens Are Sufficient To Protect against Lethal Aerosol Infection with Burkholderia mallei and Burkholderia pseudomallei

“…While the constitutively expressed capsule and LPS are lead vaccine targets for B. mallei and B. pseudomallei (110)(111)(112)(113)(114), the results of our passive-transfer experiments with adsorbed immune serum demonstrate the protective value of antigens selectively expressed in vivo during vaccination with the batA KO mutant. The data show that a single dose of immune serum depleted of antibodies binding to whole B. mallei bacteria cultured in vitro provides significant protection against lethal challenge during acute and chronic infection (Fig.…”

“…The ELISA data in Fig. S5 in the supplemental material demonstrate that this treatment effectively removed antibodies against antigens constitutively expressed in vitro, including capsular polysaccharides and LPS, which are the most abundant molecules on the surface of the organism and lead targets for vaccine development in the field (110)(111)(112)(113)(114). Remarkably, the adsorbed serum, which was completely depleted of antibodies binding to laboratory-grown bacteria, retained the ability to protect against lethal aerosol exposure to WT B. mallei ATCC 23344 at a level that was comparable to that of IgG antibodies purified from whole immune serum ( Fig.…”

Vaccines for the Prevention of Melioidosis and Glanders

“…For example, type O-polysaccharide and CPS antigens covalently linked to carrier proteins demonstrated high IgG titers and protected mice from a lethal i.p. B. pseudomallei challenge [59, 60]. Furthermore, it was demonstrated that mice co-administrated with a capsular polysaccharide (CPS) glycoconjugate and the promising subunit antigen, LolC, exhibited higher survival rates following lethal challenge compared to single administration [59].…”

Use of Reverse Vaccinology in the Design and Construction of Nanoglycoconjugate Vaccines against Burkholderia pseudomallei

“…However, B. pseudomallei and B. mallei are BSL3 pathogens, making the isolation of antigenic components (e.g., LPS) difficult. To avoid these complications, many researchers have turned to excluded strains of B. pseudomallei or the avirulent B. thailandensis for LPS isolation (15,20,32). Importantly, the structure of B. thailandensis LPS has been shown to be nearly identical to that of B. pseudomallei and is able to protect against lethal B. pseudomallei challenge (32,33).…”

“…In fact, previous studies have shown that proteins alone can provide significant, albeit incomplete, protection against Burkholderia challenge (11)(12)(13)(14). However, more recent studies have shown that when immunogenic proteins are incorporated in a glycoconjugate vaccine in conjunction with the highly antigenic Burkholderia lipopolysaccharide (LPS) or capsular polysaccharide (CPS), a more robust immune response is generated (15)(16)(17)(18). Our lab has previously demonstrated that the incorporation of a glycoconjugate with the surface of a gold nanoparticle can enhance the immune response and increase protection in a murine model of inhalational glanders, a disease caused by the closely related host-adapted pathogen B. mallei (17).…”