Evaluation of a biodegradable microparticulate polymer as a carrier for Burkholderia pseudomallei subunit vaccines in a mouse model of melioidosis

Abstract

Melioidosis, a potentially lethal disease of humans and animals, is caused by the soil-dwelling bacterium Burkholderia pseudomallei. Due to B. pseudomallei's classification as a Tier 1 Select Agent, there is substantial interest in the development of an effective vaccine. Yet, despite decades of research, no effective target, adjuvant or delivery vehicle capable of inducing protective immunity against B. pseudomallei infection has been identified. We propose a microparticulate delivery vehicle comprised of the novel polymer acetalated dextran (Ac-DEX). Ac-DEX is an acid-sensitive biodegradable carrier that can be fabricated into microparticles (MPs) that are relatively stable at pH 7.4, but rapidly degrade after phagocytosis by antigen presenting cells where the pH can drop to 5.0. As compared to other biomaterials, this acid sensitivity has been shown to enhance cross presentation of subunit antigens. To evaluate this platform as a delivery system for a melioidosis vaccine, BALB/c mice were vaccinated with Ac-DEX MPs separately encapsulating B. pseudomallei whole cell lysate and the toll-like receptor (TLR) 7/8 agonist resiquimod. This vaccine elicited a robust antibody response that included both Th1 and Th2 immunity. Following lethal intraperitoneal challenge with B. pseudomallei 1026b, vaccinated mice demonstrated a significant delay to time of death compared to untreated mice. The formulation, however, demonstrated incomplete protection indicating that lysate protein offers limited value as an antigen. Nevertheless, our Ac-DEX MPs may offer an effective delivery vehicle for a subunit B. psuedomallei vaccine.

Novel multi-component vaccine approaches for Burkholderia pseudomallei

“…B. pseudomallei produces OMVs that contain numerous protective proteins, such as OmpA, and surface polysaccharides, such as LPS and CPS. The formulation showed significant but incomplete protection against a lethal challenge in mice [60]. Protection was associated with the induction of both antibody and cellular-mediated immune responses.…”

“…Synthetic microparticles composed of acetylated dextran have also been used to encapsulate a B. pseudomallei cell lysate. The formulation showed significant but incomplete protection against a lethal challenge in mice [60]. However, the microparticle platform could potentially be enhanced with different antigens and/or adjuvant combinations.…”

Vaccines for the Prevention of Melioidosis and Glanders

“…This suggests that a sterilizing immunity was achieved in a fraction of immunized mice. When this platform was expanded to a more traditional day 0 and 14 prime and boost with a 28-day challenge, somewhat similar trends in survival were observed, indicating that perhaps these formulations could be used effectively in a more rapid timeframe, such as post-exposure prophylaxis [73]. Although the vaccine lead to incomplete protection, likely due to lack of discrete antigens, Ac-DEX represents a novel delivery vehicle for a subunit vaccine against melioidosis.…”

“…Ac-DEX MPs have been previously shown to enhance cross-presentation of subunit antigens leading to protection in an anthrax vaccine model [71, 72]. In a model against acute melioidosis, BALB/c mice were vaccinated subcutaneously with free whole killed B. pseudomallei cell lysate (antigen) and Ac-DEX MPs encapsulating the adjuvant resiquimod (TLR 7/8 agonist) [73]. One of the two studies presented followed a rapid immunization/challenge schedule (vaccination on day 0, boost on day 7, followed by challenge on day 14).…”

“…Resiquimod MPs co-delivered with soluble lysate as the antigen elicited robust Th1- and Th2-type immune responses leading to significant delay to time of death (88% at day 14) compared to empty MP-treated mice when given a lethal i.p. B. pseudomallei challenge; however, only 16% of mice survived past 26 days post-challenge [73]. Additionally, B. pseudomallei was not detected in the liver and blood of several surviving mice (2/4) following lethal challenge in the lysate with resiquimod MP group.…”