Serum antibody profiling identifies vaccine-induced correlates of protection against aerosolized ricin toxin in rhesus macaques

Abstract

Inhalation of the biothreat agent, ricin toxin (RT), provokes a localized inflammatory response associated with pulmonary congestion, edema, neutrophil infiltration, and severe acute respiratory distress. The extreme toxicity of RT is the result of the toxin’s B chain (RTB) promoting rapid uptake into alveolar macrophages and lung epithelial cells, coupled with the A chain’s (RTA) potent ribosome-inactivating properties. We previously reported that intramuscular vaccination of rhesus macaques with a lyophilized, alum-adsorbed recombinant RTA subunit vaccine (RiVax®) was sufficient to confer protection against a lethal dose of aerosolized RT. That study implicated RT-specific serum IgG, toxin-neutralizing activity (TNA), and epitope-specific responses as being associated with immunity. However, it was not possible to define actual correlates of protection (COP) because all vaccinated animals survived the RT challenge. We addressed the issue of COP in the current study, by vaccinating groups of rhesus macaques with RiVax® following the previously determined protective regimen (100 µg on study days 0, 30 and 60) or one of two anticipated suboptimal regimens (100 µg on study days 30 and 60; 35 µg on study days 0, 30, and 60). Two unvaccinated animals served as controls. The animals were challenged with ~5 × LD50s of aerosolized RT on study day 110. We report that all vaccinated animals seroconverted prior to RT challenge, with the majority also having measurable TNA, although neither antibody levels nor TNA reached statistical significance with regard to a correlation with protection. By contrast, survival correlated with pre-challenge, epitope-specific serum IgG levels, derived from a competitive sandwich ELISA using a panel of toxin-neutralizing monoclonal antibodies directed against distinct epitopes on RiVax®. The identification of a species-neutral, competitive ELISA that correlates with vaccine-induced protection against RT in nonhuman represents an important advance in the development of medical countermeasures (MCM) against a persistent biothreat.

Identification and Biological Evaluation of a Novel Small-Molecule Inhibitor of Ricin Toxin

“…The existing therapeutic options for ricin mainly consist of vaccines, neutralizing antibodies, and small-molecule inhibitors. Although the RiVax ® and RVEc TM vaccines are currently undergoing phase I clinical trials [30,31], there are still limitations to their use. These vaccines demonstrate a good anti-ricin effect only on the premise of early prophylactic vaccination, and the activation of the immune response has a limited duration, requiring frequent booster injections [32].…”

Surface Bio‐engineered Polymeric Nanoparticles

“…The diversity of such threatening agents and their varying degrees of infectivity and transmissibility rendered their detection highly challenging. [ 201 ] Established detection methods such as genome sequencing, [ 202 ] enzyme‐linked immunosorbent assay (ELISA), [ 203 ] and polymerase chain reaction (PCR) [ 204 ] are being continuously developed to overcome these challenges. However, these methods are typically used only after a diagnosis of the pathogen is suspected by a clinician.…”