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Biomedical subjects

J C Sadoff

Publications and source records attributed to J C Sadoff.

At least 55 records · Page 3Linked to original sources
PubMed1993

Immunotherapy of tularemia: characterization of a monoclonal antibody reactive with Francisella tularensis.

An IgM monoclonal antibody (mAb) recognized surface antigens specific to Francisella tularensis wild-type (Schu4) and live vaccine strain (LVS), and reacted with both in ELISA and slide agglutination tests. This mAb also reacted with LVS microorganisms in tissues of infected mice as assessed by an indirect fluorescence technique. Western blot analysis showed the mAb to react with antigens associated with F. tularensis LPS.

Animals↗
PubMed1993

The efficacy of combination immunotherapy in experimental Pseudomonas sepsis.

Immunotherapy has been shown to be an effective adjuvant in the management of septic shock. A neutropenic rat model of septic shock induced by infection with Pseudomonas aeruginosa 12.4.4 (Fisher immunotype 6) was used to determine the relative efficacy of single, double, and triple combination immunotherapy. A Pseudomonas O serotype-specific, opsonophagocytic monoclonal antibody (MAb), polyclonal J5 antiserum, and a MAb directed against tumor necrosis factor-alpha (TNF) were studied as single therapy and in combination. The combination of all three immunotherapeutic agents resulted in a 77% survival rate (33/43 animals). This level of protection was superior to that achieved with any combination of two antibody treatments (50%-60% survival; P = .029) or single antibody therapy (25%-43% survival; P < .001) or compared with a control group (0/25 survivors; P < .0001). Immunotherapy directed against multiple steps of the septic process is more active than single or double antibody regimens and may offer an improved approach to the adjunctive treatment of septic shock.

Animals↗
PubMed1993

Safety and immunogenicity of the oral, whole cell/recombinant B subunit cholera vaccine in North American volunteers.

A newly formulated, oral, inactivated whole cell plus recombinant B subunit (WC/rBS) cholera vaccine was evaluated in US military personnel. In the first study, 74 subjects were given two doses 14 days apart. In the second study, 186 subjects were randomized into four groups; two groups received vaccine with either full (4 g) or half (2 g) strength bicarbonate buffer, and two groups received either full or half strength buffer without vaccine. Mild gastrointestinal symptoms were associated with full buffer (P = .02) but not with the vaccine. In the first study, 36% of all subjects and 55% with low prevaccination titers (< 1:40) had a > or = 2-fold rise in vibriocidal antibody level; > 80% of subjects developed a 4-fold rise in anti-cholera toxin (CT) titers. Post-vaccination IgA and IgG anti-CT titers were approximately 1.5-fold higher among persons receiving full strength buffer (P = .05). The WC/rBS vaccine is safe and immunogenic in North Americans, although some mild gastrointestinal symptoms occur with the high concentration of buffer necessary to protect the B subunit from gastric acid denaturation. Prior immunity to cholera conferred by parenteral vaccine decreased vibriocidal antibody response.

Administration, Oral↗
PubMed1993

Humoral immune responses in volunteers immunized with irradiated Plasmodium falciparum sporozoites.

Volunteers immunized with gamma-irradiated Plasmodium falciparum sporozoites serve as the gold standard for protective immunity against mosquito-borne malaria transmission and provide a relevant model for studying protective immune effector mechanisms. During a 7-12 month period, we immunized four volunteers via the bites of irradiated, infected mosquitoes. Following these exposures to attenuated sporozoites, all four volunteers developed antibodies to sporozoites as measured by an immunofluorescence assay and by an enzyme-linked immunosorbent assay using the circumsporozoite (CS) protein repeat-based molecule R32LR as capture antigen. Three volunteers also developed antibodies against the nonrepeating (flanking) regions of the CS protein; the level of these antibodies paralleled the serum activity to inhibit sporozoite invasion of hepatoma cells in vitro. These three volunteers were protected against malaria transmitted by the bites of five infected mosquitoes. Two of these protected volunteers received additional immunizing doses of irradiated sporozoites and were subsequently protected against challenge with a heterologous P. falciparum clone. No detectable fluctuations were observed in circulating levels of tumor necrosis factor, interferon-gamma, or interleukin-6 during the course of this study. Analysis of the humoral and cellular immune responses of these protected volunteers is expected to yield important clues to additional targets of immunity against the pre-erythrocytic stages of malaria parasites.

Adult↗
PubMed1992

Safety, immunogenicity, and efficacy of a Plasmodium falciparum vaccine comprising a circumsporozoite protein repeat region peptide conjugated to Pseudomonas aeruginosa toxin A.

Twenty-one malaria-naive volunteers were immunized with a vaccine consisting of a 22-kDa recombinant peptide (R32LR), derived from the repeat region of Plasmodium falciparum circumsporozoite (CS) protein, covalently coupled to detoxified Pseudomonas aeruginosa toxin A. Nineteen volunteers received a second dose of vaccine at 8 weeks, and eighteen received a third dose at 8 to 12 months. The vaccine was well tolerated, with only one volunteer developing local discomfort and induration at the site of injection which limited function for 48 h. The geometric mean anti-CS immunoglobulin G antibody concentration 2 weeks after the second dose of vaccine was 10.6 micrograms/ml (standard deviation = 3.0 micrograms/ml). Eleven volunteers (52%) developed anti-CS antibody levels of greater than 9.8 micrograms/ml, the level measured in the one volunteer protected against P. falciparum challenge after immunization with the alum-adjuvanted recombinant protein R32tet32 in a prior study. Three separate experimental challenges were conducted with 10 volunteers 2 to 4 weeks after the third dose of vaccine. The four best responders, on the basis of antibody levels (6 to 26 micrograms/ml), were challenged with two infected-mosquito bites, but only one of four immunized volunteers and one of three malaria-naive controls became parasitemic. In a second challenge study using five infected-mosquito bites as the challenge dose, three of three malaria-naive control volunteers and two of three immunized volunteers developed malaria. The third vaccine was apparently completely protected. In the third and last challenge, three of three controls and five of five vaccinees became infected. Sera obtained on the days of challenge inhibited sporozoite invasion of hepatocytes variably in vitro (range, 45 to 90% inhibition), but the degree of inhibition did not correlate with protection. Although antibody against the CS repeat region may protect some individuals against experimental challenge, this protection cannot be predicted from antibody levels by current in vitro assays. The functionality and fine specificity of anti-CS antibody are probably critical determinants.

ADP Ribose Transferases↗
PubMed1992

Safety, immunogenicity, and efficacy in monkeys and humans of invasive Escherichia coli K-12 hybrid vaccine candidates expressing Shigella flexneri 2a somatic antigen.

A live, oral Shigella vaccine, constructed by transfer of the 140-MDa invasiveness plasmid from Shigella flexneri 5 and the chromosomal genes encoding the group- and type-specific O antigen of S. flexneri 2a to Escherichia coli K-12, was tested in humans. Designated EcSf2a-1, this vaccine produced adverse reactions (fever, diarrhea, or dysentery) in 4 (31%) of 13 subjects who ingested a single dose of 1.0 x 10(9) CFU, while at better-tolerated doses (5.0 x 10(6) to 5.0 x 10(7) CFU), it provided no significant protection against challenge with S. flexneri 2a. A further-attenuated aroD mutant derivative, EcSf2a-2, was then tested. Rhesus monkeys that received EcSf2a-2 in three oral doses of ca. 1.5 x 10(11) CFU experienced no increase in gastrointestinal symptoms compared with a control group that received an E. coli K-12 placebo. Compared with controls, the vaccinated monkeys were protected against shigellosis after challenge with S. flexneri 2a (60% efficacy; P = 0.001). In humans, EcSf2a-2 was well tolerated at inocula ranging from 5.0 x 10(6) to 2.1 x 10(9) CFU. However, after a single dose of 2.5 x 10(9) CFU, 4 (17%) of 23 subjects experienced adverse reactions, including fever (3 subjects) and diarrhea (209 ml) (1 subject), and after a single dose of 1.8 x 10(10) CFU, 2 of 4 subjects developed dysentery. Recipients of three doses of 1.2 to 2.5 x 10(9) CFU had significant rises in serum antibody to lipopolysaccharide (61%) and invasiveness plasmid antigens (44%) and in gut-derived immunoglobulin A antibody-secreting cells specific for lipopolysaccharide (100%) and invasiveness plasmid antigens (60%). Despite its immunogenicity, the vaccine conferred only 36% protection against illness (fever, diarrhea, or dysentery) induced by experimental challenge (P = 0.17). These findings illustrate the use of an epithelial cell-invasive E. coli strain as a carrier for Shigella antigens. Future studies must explore dosing regimens that might optimize the protective effects of the vaccine while eliminating adverse clinical reactions.

Adolescent↗
PubMed1991

Human cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein.

Cytotoxic T lymphocytes (CTL) against the circumsporozoite (CS) protein of malaria sporozoites protect against malaria in rodents. Although there is interest in developing human vaccines that induce CTL against the Plasmodium falciparum CS protein, humans have never been shown to produce CTL against any Plasmodium species protein or other parasite protein. We report that when peripheral blood mononuclear cells (PBMC) from three of four volunteers immunized with irradiated P. falciparum sporozoites were stimulated in vitro with a recombinant vaccinia virus expressing the P. falciparum CS protein or a peptide including only amino acids 368-390 of the P. falciparum CS protein [CS-(368-390)], the PBMC lysed autologous Epstein-Barr virus-transformed B cells transfected with the P. falciparum CS protein gene or incubated with CS-(368-390) tricosapeptide. Activity was antigen specific, genetically restricted, and dependent on CD8+ T cells. In one volunteer, seven peptides reflecting amino acids 311-400 were tested, and, as in B10.BR mice, CTL activity was only associated with the CS-(368-390) peptide. Development of an assay for studying human CTL against the CS and other malaria proteins and a method for constructing target cells by direct gene transfection provide a foundation for studying the role of CTL in protection against malaria.

Amino Acid Sequence↗
PubMed1991

Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group.

BACKGROUND: HA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia. METHODS: To evaluate the efficacy and safety of HA-1A, we conducted a randomized, double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection. The patients received either a single 100-mg intravenous dose of HA-1A (in 3.5 g of albumin) or placebo (3.5 g of albumin). Other interventions, including the administration of antibiotics and fluids, were not affected by the study protocol. RESULTS: Of 543 patients with sepsis who were treated, 200 (37 percent) had gram-negative bacteremia as proved by blood culture. For the patients with gram-negative bacteremia followed to death or day 28, there were 45 deaths among the 92 recipients of placebo (49 percent) and 32 deaths among the 105 recipients of HA-1A (30 percent; P = 0.014). For the patients with gram-negative bacteremia and shock at entry, there were 27 deaths among the 47 recipients of placebo (57 percent) and 18 deaths among the 54 recipients of HA-1A (33 percent; P = 0.017). Analyses that stratified according to the severity of illness at entry showed improved survival with HA-1A treatment in both severely ill and less severely ill patients. Of the 196 patients with gram-negative bacteremia who were followed to hospital discharge or death, 45 of the 93 given placebo (48 percent) were discharged alive, as compared with 65 of the 103 treated with HA-1A (63 percent; P = 0.038). No benefit of treatment with HA-1A was demonstrated in the 343 patients with sepsis who did not prove to have gram-negative bacteremia. For all 543 patients with sepsis who were treated, the mortality rate was 43 percent among the recipients of placebo and 39 percent among those given HA-1A (P = 0.24). All patients tolerated HA-1A well, and no anti-HA-1A antibodies were detected. CONCLUSIONS: HA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia.

Antibodies, Monoclonal↗
PubMed1991

Efficacy trial of a parenteral gonococcal pilus vaccine in men.

A randomized, placebo-controlled, double-blind efficacy trial of a purified gonococcal pilus vaccine composed of a single pilus type was tested in 3123 men and 127 women volunteers. Either 100 micrograms of vaccine or a placebo was given intradermally on day 1 and day 14. Each group was evenly matched with respect to age, sex, prior history of a sexually transmitted disease, sexual exposure during the study and attrition from the study. None of the women volunteers acquired gonorrhoea during the trial. In the male volunteers, 108 vaccine and 102 placebo recipients acquired gonorrhoea 15 days or later after the initial immunization. Vaccines developed a sustained ELISA antibody response to homologous and heterologous pili, but the latter titres were approximately 40% as high as the homologous pilus antibody rises. There were, however, no increases in inhibition of attachment antibody (IEA) titres. Local antibodies (semen) against homologous and heterologous strains were also elicited (ELISA). The vaccine was safe and did not alter the clinical expression of disease. This gonococcal pilus vaccine composed of a single pilus type failed to protect men against gonococcal urethritis.

Adult↗
PubMed1991

Human immunization with Pgh 3-2 gonococcal pilus results in cross-reactive antibody to the cyanogen bromide fragment-2 of pilin.

In 1983, a gonococcal pilus vaccine failed to show protection in a large, placebo-controlled, double-blind field trial. The epitopic response to this vaccine was investigated in a random subgroup of 20 vaccine recipients. Using Western blot analysis of the immunizing pilus and its cyanogen bromide (CNBr) fragments, IgG antibody to pilin was detected before immunization in all individuals. Preexistent antibody to the CNBr-2 and CNBr-3 fragments of pilin was detected in 65% and 5% of individuals, respectively. Pilus immunization resulted in a vigorous response to the CNBr-2 fragment in 100% of the individuals tested; only 33% developed antibody to the CNBr-3 fragment. Absorptions of postimmunization sera with different gonococcal strains resulted in either complete or partial removal of antibody to the CNBr-2 fragment. In the context of an unsuccessful vaccine trial, these results suggest that antibody to the CNBr-2 fragment of pilin may not be protective.

Adult↗
PubMed1991

Safety and immunogenicity of Escherichia coli O18 O-specific polysaccharide (O-PS)-toxin A and O-PS-cholera toxin conjugate vaccines in humans.

O-specific polysaccharide (O-PS) isolated from serotype 18 Escherichia coli lipopolysaccharide (LPS) was covalently coupled to either Pseudomonas aeruginosa toxin A (TA) or or cholera toxin (CT). The conjugates were nontoxic and nonpyrogenic. The conjugates were well tolerated on parenteral administration to human volunteers, with only mild, transient local reactions reported. Immunization engendered an IgG antibody response to both the O-PS and carrier protein. Anti-LPS antibody promoted the uptake and killing of an E. coli O18 strain bearing the K1 capsule by human polymorphonuclear leukocytes, which was complement dependent. Antibody to carrier protein neutralized the activity of native TA or CT in cell culture assays. Passively transferred IgG isolated from the serum of immunized donors provided a significant (P less than .01) degree of protection against fatal experimental E. coli O18 sepsis in mice. This study illustrates the potential use of such conjugates as vaccines against E. coli extraintestinal infections.

ADP Ribose Transferases↗
PubMed1991

Production and characterization of a human hyperimmune intravenous immunoglobulin against Pseudomonas aeruginosa and Klebsiella species.

A hyperimmune globulin for intravenous use (H-IVIG) was prepared from the plasma of donors immunized with Pseudomonas aeruginosa and Klebsiella vaccines. H-IVIG preparations contained substantially higher IgG antibody levels to all nine P. aeruginosa vaccine antigens and to 22 of the 24 Klebsiella vaccine antigens than did commercial IVIG. The H-IVIG was more effective at promoting the opsonophagocytic killing of P. aeruginosa and Klebsiella vaccine serotype strains than normal IVIG. The H-IVIG neutralized greater than 20 times more toxin A than commercial IVIG. Only the H-IVIG offered significant protection against Klebsiella K2 sepsis. The H-IVIG provided significantly better protection against six of the eight P. aeruginosa vaccine serotypes than normal IVIG when compared in a murine burn wound sepsis model. The H-IVIG also protected mice against an Enterobacter aerogenes challenge, whereas normal IVIG was ineffective.

Animals↗
PubMed1991

Efficacy of antilipopolysaccharide and anti-tumor necrosis factor monoclonal antibodies in a neutropenic rat model of Pseudomonas sepsis.

Monoclonal antibodies (MAb) directed against bacterial lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF) provide partial protection in experimental models of septic shock. To determine if additional benefit accrues from a combination of anti-TNF and anti-LPS MAb in the treatment of septic shock, a neutropenic rat model was developed to study active infection with Pseudomonas aeruginosa 12.4.4. Animals were treated intravenously with an irrelevant MAb (group 1); anti-TNF MAb (group 2); MAb directed against P. aeruginosa 12.4.4 LPS (group 3); or a combination of anti-TNF and anti-LPS MAb (group 4). None of the control animals in group 1 survived the 7-d period of neutropenia (0/16). In contrast, the survival rate was 44% in group 2 (P less than 0.02); 37% in group 3 (P less than 0.05); and 75% in group 4 (P less than 0.0002). The combination of monoclonal antibodies provided greater protection than either MAb given alone (P less than 0.05). Serum TNF levels during infection were significantly greater in groups 1 and 3 (20.1 +/- 3.3 U, mean +/- SE) than in groups 2 and 4 (0.9 +/- 0.8 U, P less than 0.0001). These results indicate that a combination of monoclonal antibodies to LPS and TNF have additive benefit in experimental Pseudomonas aeruginosa sepsis. This immunotherapeutic approach may be of potential utility in the management of serious, gram-negative bacterial infection in neutropenic patients.

Animals↗
PubMed1990

Preparation of proteosome-based vaccines. Correlation of immunogenicity with physical characteristics.

In order to facilitate the use of proteosome-based vaccines, we have identified and analyzed the parameters that affect their immunogenicity. As a model system we used synthetic peptides (LCF6) containing sequences from the immunodominant (NANP)n tandem repeat region of the P. falciparum circumsporozoite protein, hydrophobically complexed to multimeric protein preparations (proteosomes) of meningococcal outer membrane proteins (OMP), since we have previously shown that high levels of anti-(NANP)n IgG can be elicited in mice by use of this novel adjuvant system (Lowell et al., 1988a). We have now examined these preparations by velocity sedimentation and measured their ability to elicit an IgG response in mice. Velocity sedimentation of freshly mixed OMP and LCF6, without dialysis, produced a limited number of small complexes, whereas dialysis of the mixture for 4 d yielded heterogeneously sized complexes that became more homogeneous when the dialysis was carried out for 7 or 10 days. The most homogeneous of these peptide-proteosome complexes (those dialyzed for 10 days) induced substantial levels of anti-(NANP)n IgG in mice, and shorter periods of dialysis resulted in vaccines that induced proportionately lower titers. Analysis of a series of preparations with varying LCF6: OMP ratios (w/w) showed that the degree of peptide substitution of the proteosomes was inversely proportional to the rate of sedimentation of the complexes and that there exists an optimal degree of lipopeptide complexing to the proteosomes. Our results suggest that the parameters affecting the immunogenicity of the peptide-proteosome complexes are: (i) hapten density, and (ii) size of the complex. Furthermore, sedimentation analysis of peptide-proteosome immunogens may serve as a rapidly performed assay of immunogenic potency.

Adjuvants, Immunologic↗
PubMed1990

Efficacy of a monoclonal antibody directed against tumor necrosis factor in protecting neutropenic rats from lethal infection with Pseudomonas aeruginosa.

A monoclonal antibody directed against murine tumor necrosis factor-alpha (TNF) was studied in a neutropenic rat model to determine its efficacy in protecting animals from lethal infection with Pseudomonas aeruginosa. Anti-TNF monoclonal antibody at a dose of 20 mg/kg given intravenously at 0 and 120 h resulted in a 53% survival rate (8/15) compared with no survival in control animals (0/15) (P less than .005). The combination of anti-TNF monoclonal antibody and oral ciprofloxacin at a suboptimal dose of 2.5 mg/kg/day resulted in a 100% survival rate in neutropenic animals (16/16), while ciprofloxacin alone produced only a 67% survival rate (10/15) during the 7-day period of neutropenia (P less than .05). Thus anti-TNF monoclonal antibody alone or in addition to antimicrobial agents improved survival in neutropenic animals after infection with P. aeruginosa.

Agranulocytosis↗