RESUMO
Safe and effective adjuvants are needed for many vaccines with limited commercial appeal, such as vaccines to infrequent (orphan) diseases or to neglected and poverty-related diseases. Here we found that three nonproprietary liposome formulations containing monophosphoryl lipid A each induced 3-fold to 5-fold increased titers of binding and neutralizing antibodies to anthrax protective antigen compared to aluminum hydroxide-adsorbed antigen in monkeys. All vaccinated monkeys were protected against lethal challenge with aerosolized Ames strain spores.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra Antraz/imunologia , Lipossomos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/efeitos adversos , Animais , Antraz/prevenção & controle , Vacinas contra Antraz/efeitos adversos , Anticorpos Antibacterianos/sangue , Anticorpos Neutralizantes/sangue , Lipossomos/efeitos adversos , Macaca mulatta , Doenças dos Primatas/prevenção & controle , Análise de SobrevidaRESUMO
The US Army utilizes pralidoxime (2-PAM) for the reactivation of OP-inhibited AChE. While 2-PAM effectively reactivates acetylcholinesterase (AChE) in the body, it does not cross the blood-brain barrier (BBB) at therapeutically relevant levels. To address this problem of central nervous system AChE reactivation, novel sugar-oxime conjugates were utilized. These 'sugar-oximes' would potentially be transported across the BBB because they contain a sugar moiety which would be recognized by the facilitative glucose transporters. Eight previously reported, but understudied sugar-oximes, as well as six novel sugar-oximes were synthesized, and their ability to reactivate both human red blood cell AChE and plasma butyrylcholinesterase poisoned with DFP, paraoxon, sarin and VX were tested. The results show that the novel sugar-oxime 13c was more active than the other compounds with a reactivation potential similar to 2-PAM. The sugar-oxime 8b had low toxicity with a LD(50) of 1,590 mg/kg from a single IM dose in the guinea pig and >2,000 mg/kg IP in the mouse. Histopathological analysis showed that there were no apparent differences in hippocampus, heart, liver, kidney sciatic nerve, or skeletal muscle between treated and untreated animals. These results show that sugar-oximes can be effective reactivators and suggest that high treatment doses may be possible.