We conducted studies with mice, rats, and monkeys which demonstrated the ability of glucan to induce either nonspecific or specific enhancement of host resistance to infectious diseases. Intravenous pretreatment of mice with glucan significantly enhanced the survival of mice challenged with either Venezuelan equine encephalomyelitis (VEE) virus or Rift Valley fever virus. Pretreatment was beneficial when initiated 3 days before challenge with VEE virus and 7 days before challenge with Rift Valley fever virus. Treatment of mice after VEE challenge did not increase their survival compared with controls. Glucan pretreatment of rats provided increased resistance to both intraperitoneal and low-dose aerosol challenges with virulent Francisella tularensis when the glucan was given intravenously, but not when it was administered intranasally. In contrast, intranasal glucan pretreatment enhanced the survival of mice when they were challenged by aerosol with Pseudomonas pseudomallei, whereas intravenous glucan pretreatment did not increase survival. mice given glucan combined with a marginally immunogenic dose of VEE vaccine were more resistant to homologous virus challenge than were mice given either Freund complete adjuvant plus vaccine or vaccine alone. Similarly, both primary and secondary VEE antibody titers in cynomolgus monkeys given glucan with VEE vaccine were significantly greater than titers in vaccine controls.
Abstract. Tyzzer's disease (bacillus piliformis infection) was diagnosed in a young guinea pig killed because of diarrhea and poor condition. There was necrosis and inflammation of the colon, cecum and ileum. Typical B . piliformis were in intestinal epithelial cells. Spirochetes were in large numbers in intestinal crypts and were often adjacent to the intracellular B . pilifbrrnis. Extracellular B . piliformis occasionally were surrounded by spirochetes.
Polyriboinosinic·polyribocytidylic acid [poly(I)·poly(C)] stabilized with poly-
l
-lysine and carboxymethylcellulose [poly(ICLC)] has been previously shown to be a compound with marked adjuvant activity when given in high doses with inactivated Venezuelan equine encephalomyelitis (VEE) virus vaccine. This study investigated the effects of much lower doses of poly(ICLC) on the magnitude and kinetics of the primary and secondary humoral antibody responses of rhesus monkeys to inactivated VEE virus vaccine. Monkeys given a single injection of vaccine developed very low neutralizing antibody titers, whereas those given adjuvant plus vaccine had 30- to 100-fold-higher titers which remained elevated for longer than 6 months. Low doses of poly(ICLC) given with VEE virus vaccine resulted in a profound but transient increase in priming of secondary antibody responses to the antigen. In contrast, the administration of poly-
l
-lysine and carboxymethylcellulose alone without the poly(I)·poly(C) component of the complex had no adjuvant effect on antibody responses of monkeys to VEE virus vaccine. The temporal development of antibody by class (immunoglobulin M-immunoglobulin G) in monkeys given two injections of adjuvant-vaccine was not different from that with vaccine alone. Serial hematological and clinical chemistry determinations on monkeys given single or multiple doses of poly(ICLC) with vaccine were not different from values in monkeys given vaccine alone.
Tilorone analog 11,567 (BDD) was demonstrated to immunopotentiate Formalin-inactivated Venezuelan equine encephalomyelitis (VEE) TC-83 vaccine in mice and monkeys. The dosage of BDD required for adjuvant effects was different in mice and monkeys. In monkeys, primary and secondary antibody responses were increased (4-and 12-fold greater titers, respectively) when 10 mg/kg of BDD was given with VEE vaccine; however, 100 mg/kg of BDD had no adjuvant effect. Mice given 62 or 250 mg/kg of BDD with undiluted vaccine developed 3-and 4-fold greater antibody titers, respectively, than vaccine controls. The immunopotentiation effect of BDD was most dramatically demonstrated when graded doses (7 to 500 mg/kg) were given with a marginally antigenic dose of VEE vaccine (diluted 1:4). The BDD-vaccine combination induced antibody production, while vaccine administered without adjuvant did not. Antibody titers were significantly higher when 125 (P
Studies were conducted in mice, hamsters, sheep, and two species of nonhuman primates which demonstrate the adjuvant activity of a new metabolizable lipid emulsion with marginally immunogenic doses of Formalin-inactivated viral vaccines. The lipid base consists of highly refined peanut oil emulsified in aqueous vaccines with glycerol and lecithin. Hamsters and mice inoculated with lipid emulsion plus western or Venezuelan equine encephalitis vaccine were significantly more resistant than vaccinated controls to lethal homologous virus challenge. Sheep given one dose of lipid emulsion plus Rift Valley fever vaccine developed significantly higher antibody titers than control sheep receiving only vaccine. Cynomolgous monkeys inoculated with lipid emulsion plus Rift Valley fever vaccine developed 16-fold greater peak primary and 20-fold greater secondary antibody titers than those of vaccine controls. Similar lipid emulsion-Rift Valley fever studies in rhesus monkeys resulted in 37- and 300-fold increases in primary and secondary titers, respectively, compared with monkeys given vaccine alone. Neither the sequence of combining antigen with lipid nor the exact ratio of aqueous phase to lipid phase affected the survival of Venezuelan equine encephalitis-vaccinated mice challenged with homologous lethal virus. This lipid formulation has several advantages over other water-in-oil adjuvants for potential use in humans. The components are metabolizable or normal host constituents, it is easily emulsified with aqueous vaccines by gentle agitation, and it is relatively nonreactogenic in recipients.
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