Search PubMed⌕ Search

Biomedical subjects

J B Robbins

Publications and source records attributed to J B Robbins.

At least 55 records · Page 3Linked to original sources
PubMed1997

Unchanged efficacy of a pertussis toxoid vaccine throughout the two years after the third vaccination of infants.

BACKGROUND: In a previously reported double blind efficacy trial of a pertussis toxoid vaccine, 3450 infants were randomized to receive diphtheria-tetanus toxoids with or without pertussis toxoid at 3, 5 and 12 months of age. Efficacy against pertussis as defined by the World Health Organization was 71% from 30 days after the third vaccination with an average follow-up of 17.5 months. We now report efficacy for an additional 6 months of open follow-up. METHODS: Parents were contacted monthly by a nurse. If a participant or a family member coughed for > or = 7 days, a nasopharyngeal sample and paired sera were obtained. RESULTS: Efficacy during this open follow-up period was 77% (95% confidence intervals, 66 to 85%) based on 29 and 110 cases fulfilling the WHO definition of pertussis in vaccinated and control children, respectively. Efficacy against household exposure was 76% (95% confidence intervals, 51 to 91%). Pertussis in vaccinated children had a significantly shorter duration than pertussis in control children. Determination of pertussis toxin antibodies in paired sera with enzyme-linked immunosorbent assay had a lower diagnostic sensitivity in vaccinated (45%) than in control (92%) children, while determination of antibodies against filamentous hemagglutinin (not included in the vaccine) was highly sensitive for diagnosing pertussis in both groups (100 and 90%, respectively). CONCLUSIONS: A monocomponent pertussis toxoid vaccine induces significant protection against pertussis for at least 2 years after the third injection. To obtain an unbiased estimate of vaccine efficacy it is important to determine antibodies against an antigen that is not included in the vaccine.

Antibodies, Bacterial↗
PubMed1997

Detoxified lipooligosaccharide from nontypeable Haemophilus influenzae conjugated to proteins confers protection against otitis media in chinchillas.

Detoxified-lipooligosaccharide (dLOS)-protein conjugates from nontypeable Haemophilus influenzae (NTHi) elicited a significant rise of anti-LOS antibodies with bactericidal activity in rabbits (X.-X. Gu, C.-M. Tsai, T. Ueyama, S. J. Barenkamp, J. B. Robbins, and D. J. Lim, Infect. Immun. 64:4047-4053, 1996). In this study, we evaluated whether vaccination with the conjugates would protect against NTHi otitis media in chinchillas. Fifty-eight chinchillas received three subcutaneous or intramuscular injections of dLOS-conjugated tetanus toxoid, dLOS-conjugated high-molecular-weight proteins from NTHi, or saline (control) in Freund's adjuvant and then were challenged by intrabullar inoculation with 140 CFU of NTHi. All vaccinated animals responded with elevated serum titers of anti-LOS antibody, and 49% (19 of 39) demonstrated bactericidal activity against the homologous strain. Otitis media with culture-positive NTHi effusions developed in all 19 controls and 56% (22 of 39) of the vaccinated animals during a period of 21 days (P < 0.001). Bacterial counts of the middle ear effusions were lower in the vaccine groups than in the controls (P < 0.01). The incidences of infection in the unchallenged ear or inner ear were 26 or 28% in the vaccine groups and 53 or 58% in the controls (P < 0.05). The signs of infection observed by otoscopy were less severe in the vaccine groups than in the controls. There was no significant difference between the two vaccine groups. These data indicate that active immunization with LOS-based conjugates reduces the incidence of NTHi-induced otitis media.

Animals↗
PubMed1997

Synthesis and immunological properties of Vi and di-O-acetyl pectin protein conjugates with adipic acid dihydrazide as the linker.

The Vi capsular polysaccharide of Salmonella typhi, a licensed vaccine for typhoid fever in individuals > or = 5 years old, induces low and short-lived antibodies in children, and reinjection does not elicit booster responses at any age. Its immunogenicity was improved by binding Vi to proteins by using N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP) as a linker. Similar findings were observed with the structurally related, di-O-acetyl derivative of pectin [poly-alpha(1-->4)-D-GalpA] designated OAcP. Protein conjugates of Vi and OAcP were synthesized by carbodiimide-mediated synthesis with adipic acid dihydrazide (ADH) as the linker. Hydrazide groups were introduced into proteins (bovine serum albumin or recombinant Pseudomonas aeruginosa exoprotein A) by treatment with ADH and 1-ethyl-3(3-dimethylaminopropyl carbodiimide (EDC). The resultant adipic acid hydrazide derivatives (AH-proteins), containing 2.3 to 3.4% AH, had antigenic and physicochemical properties similar to those of the native proteins. The AH-proteins were bound to Vi and OAcP by treatment with EDC. The immunogenicity of Vi or OAcP, alone or as protein conjugates, was evaluated in young outbred mice and guinea pigs by subcutaneous injection of 2.5 and 5.0 microg, respectively, of polysaccharide, and antibodies were measured by enzyme-linked immunosorbent assay. All conjugates were significantly more immunogenic than Vi or OAcP alone and induced booster responses with 5- to 25-fold increases of antibodies. Vi conjugates were significantly more immunogenic than their OAcP analogs. A carboxymethyl derivative of yeast beta-glucan enhanced the anti-Vi response elicited by an OAcP conjugate but had no effect on the immunogenicity of Vi or of OAcP alone. Vi and OAcP conjugates synthesized by this scheme will be evaluated clinically.

Adipates↗
PubMed1996

The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines.

The development of Haemophilus influenzae type b (Hib) conjugate vaccines has led to the virtual elimination of systemic infections caused by that pathogen, has provided insights into the pathogenesis of and immunity to other capsulated bacteria, and has contributed to the development of new vaccines. Meningitis, a common and serious infection of children, and other infections caused by Hib have been virtually eliminated in countries that have achieved widespread vaccination with Hib conjugates, including the United States, Canada, the United Kingdom, Iceland, Scandinavia, France, and Germany. Hib conjugates have also been shown to be highly effective in developing countries. The principles derived from the use of these vaccines, along with studies of other capsulated pathogens, should allow the rapid inclusion of new polysaccharide-based conjugates into routine vaccination schedules of infants, and should help to realize further reductions in serious systemic infectious diseases.

Animals↗
PubMed1996

Hypothesis: how licensed vaccines confer protective immunity.

By examining experience with evaluation of licensed vaccines we theorize that a critical level of serum IgG confers protection against infectious diseases by killing or inactivating the inoculum. We found that efficacy is reliably predicted by measurement of serum antibodies elicited by vaccines, that serum IgG antibodies alone account for the protection conferred by passive immunization, that vaccine-induced "herd" immunity is best explained by inactivation of the inoculum on epithelial surfaces by serum antibodies and that serum antibodies induced by active immunization will neither treat disease symptoms nor eliminate the pathogen. If valid, this theory should facilitate research because knowledge of the pathogenesis of the disease symptoms may not be essential for vaccine development.

Animals↗
PubMed1996

Immunogenicity, efficacy and serological correlate of protection of Salmonella typhi Vi capsular polysaccharide vaccine three years after immunization.

The protective efficacy and immunogenicity of Vi capsular polysaccharide vaccine against typhoid fever was measured 3 years after its administration in a double-blind randomized trial. Vaccine efficacy was not significantly different during each year of the trial and was 55% (95% CI: 30-71%) over the 3 year period. In a case-control study at 3 years after vaccination, recipients of Vi had higher levels of Vi antibodies than controls, as measured by radio-immunoassay (GMT 1.28 vs 0.76 microgram ml-1, P = 0.0004) and by passive haemagglutination assay (GMT 10.46 vs 3.52, P = 0.0001). The serological correlate of protection has been estimated using the relative risks of typhoid fever in the 2 groups and the relative ratio of antibody levels. The estimated protective level is 1 microgram ml-1 suggesting that at a mean age of 9 years, 64% of vaccinates and 40% of controls had protective antibody against typhoid fever in this endemic area.

Adolescent↗
PubMed1996

Synthesis, characterization, and immunologic properties of detoxified lipooligosaccharide from nontypeable Haemophilus influenzae conjugated to proteins.

Nontypeable Haemophilus influenzae (NTHi) is an important cause of otitis media in children and of pneumonitis in adults with depressed resistance. Lipooligosaccharide (LOS) is a major surface antigen of NTHi and elicits bactericidal and opsonic antibodies. We prepared detoxified LOS (dLOS) protein conjugates from NTHi for use as experimental vaccines. LOS from NTHi 9274 was treated with anhydrous hydrazine and had its toxicity reduced to clinically acceptable levels. dLOS was bound to tetanus toxoid (TT) or high- molecular-weight proteins (HMPs) from NTHi through a linker of adipic acid dihydrazide to form dLOS-TT or dLOS-HMP. The molar ratio of the dLOS to protein carriers ranged from 26:1 to 50:1. The antigenicity of the conjugates was similar to that of the LOS alone as determined by double immunodiffusion. Subcutaneous or intramuscular injection of the conjugates elicited a 28- to 486-fold rise in the level of immunoglobulin G antibodies in mice to the homologous LOS after two or three injections and a 169- to 243-fold rise in the level of immunoglobulin G antibodies in rabbits after two injections. The immunogenicity of the conjugates in mice and rabbits was enhanced by formulation with monophosphoryl lipid A plus trehalose dimycolate. In rabbits, conjugate-induced LOS antibodies induced complement-mediated bactericidal activity against the homologous strain 9274 and prototype strain 3189. These results indicate that a detoxified LOS-protein conjugate is a candidate vaccine for otitis media and pneumonitis caused by NTHi.

Animals↗
PubMed1996

Safety and immunogenicity of investigational Shigella conjugate vaccines in Israeli volunteers.

The safety and immunogenicity of investigational conjugates, composed of the O-specific polysaccharides of Shigella sonnei and Shigella flexneri type 2a covalently bound to Pseudomonas aeruginosa recombinant exoprotein A (rEPA), were evaluated in 192 Israeli soldiers. None had significant local reactions or fever. Fourteen days after injection, 90% of S. sonnei-rEPA recipients and 73 to 77% of S. flexneri-rEPA recipients had a fourfold or greater increase in serum immunoglobulin G (IgG) and IgA anti-lipopolysaccharide (anti-LPS) levels; at 2 years, these remained higher than at prevaccination (P < 0.01). There was a fourfold or greater increase in IgM anti-LPS in 20% of vaccinees at 2 weeks, but levels returned to prevaccination values at 6 to 12 months. IgG was the highest and most sustained class of LPS antibodies. Reinjection at day 42 did not boost antibody levels. Eighteen of 23 (78%) who received S. sonnei-rEPA and 13 of 19 (68%) who received S. flexneri-rEPA. had significant IgA-secreting cell responses. Significant IgG antibody-secreting cell responses were detected in 19 of 23 (83%) and 11 of 19 (58%) volunteers following vaccination with S. sonnei-rEPA and S. flexneri 2a-rEPA, respectively. On the basis of these data, further evaluation of the Shigella conjugates for protective efficacy in field trials in Israel was started.

Adolescent↗
PubMed1996

Synthesis, characterization, and immunological properties in mice of conjugates composed of detoxified lipopolysaccharide of Salmonella paratyphi A bound to tetanus toxoid with emphasis on the role of O acetyls.

Salmonella paratyphi A, the second most common cause of enteric fever in Southeast Asia, is a habitant of and a pathogen for humans only. Lipopolysaccharides (LPS) are both essential virulence factors and protective antigens for systemic infections caused by groups A, B, C, and D nontyphoidal salmonellae. The O-specific polysaccharide of S. paratyphi A is composed of a trisaccharide, -->2-alpha-D)-Manp-(1-->4)-alpha-L-Rhap-(1-->3)-alpha-D-Galp -(1-->, with a branch of D-paratose from the C-3 of alpha-D-mannose, and the C-3 of beta-L-rhamnose is partially O acetylated (C. G. Hellerqvist, B. Lindberg, K. Samuelsson, and A. A. Lindberg, Acta Chem. Scand. 25:955-961, 1971). On the basis of data from our investigational vaccines for enteric bacterial pathogens, including group B salmonellae (D. C. Watson, J. B. Robbins, and S. C. Szu, Infect. Immun. 60:4679-4686, 1992), conjugates composed of the detoxified LPS of S. paratyphi A bound to tetanus toxoid (TT) were prepared by several schemes. LPS was detoxified with acetic acid or with hydrazine; the latter removed O acetyls from the O-specific polysaccharide. The detoxified polysaccharides were activated with cyanogen bromide (CNBr) or with 1-cyano-4-dimethylaminopyridinium tetratfluoroborate (CDAP) and bound to TT with or without a spacer. Solutions of 2.5 microgram of saccharide, alone or as a conjugate, were injected subcutaneously into young mice, and LPS and TT antibodies were measured by enzyme-linked immunosorbent assaying. A conjugate synthesized with higher-molecular-weight O-SP elicited the highest anti-LPS levels. Only conjugates with O acetyls elicited serum immunoglobulin G anti-LPS with bactericidal activity. There were no statistically significant differences between LPS antibody levels elicited by conjugates synthesized with or without a spacer. The conjugate with O-specific polysaccharide activated by CDAP and bound to TT without a spacer elicited the highest level of TT antibodies. Clinical evaluation (if S. paratyphi A conjugates is planned.

Acetylation↗
PubMed1996

Safety and immunogenicity of Staphylococcus aureus type 5 capsular polysaccharide-Pseudomonas aeruginosa recombinant exoprotein A conjugate vaccine in patients on hemodialysis.

Seventeen volunteers with ESRD on hemodialysis, negative for infection with HIV or hepatitis B and C and not receiving immunosuppressive therapy, were injected two times 6 wk apart with 25 micrograms of Staphylococcus aureus Type 5 capsular polysaccharide-Pseudomonas aeruginosa exoprotein A (rEPA) conjugate. Controls were healthy adults, 18 to 44 yr old, injected previously with the same vaccine. None of the patients had fever or significant elevations in their SGOT or SGPT attributable to the vaccine. Two vaccinees had transient induration > 1 cm in diameter at the injection site. The preimmunization geometric mean (GM) Type 5 antibody levels of the ESRD patients and controls were similar. Type 5 antibody levels of the three major immunoglobulin (lg) classes rose at 2 and 6 wk after immunization (P < 0.001 for lgG, P < 0.005 for lgM, and P = 0.0001 for lgA). Reimmunization at 6 wk did not elicit a booster response. At 6 months, the GM lgG level of the patients was approximately 50% of that of the healthy volunteers and 14 of 17 had a more than fourfold higher antibody level than the preimmune value. The GM lgM level, in contrast, declined to the preimmunization value. Vaccine-induced Type 5 antibodies had opsonophagocytic activity. There was a slight increase of lgG antibodies to the heterologous S. aureus Type 8 polysaccharide (P < 0.01) that was sustained at 6 months. The S. aureus Type 5-rEPA vaccine is safe and immunogenic in ESRD patients, and evaluation of its effectiveness against S. aureus bacteremia in this at-risk group is planned.

ADP Ribose Transferases↗
PubMed1995

Synthesis of a pentasaccharide fragment of Polysaccharide II of Mycobacterium tuberculosis.

Stereocontrolled, stepwise synthesis of decyl glycosides of alpha-(1-->2)-linked di- to pentaglucosides (1-5) is described; these constitute fragments of Polysaccharide II of Mycobacterium tuberculosis. Phenyl 3,4,6-tri-O-acetyl-2-O-benzyl-1-thio-alpha-D- glucopyranoside (7) was used as the single key intermediate, obtained from 1,3,4,6-tetra-O-acetyl-2-O-benzyl-beta-D-glucopyranose (6) and PhSSiMe3. Halogenolysis of 7 afforded the isolated beta bromide (10) and beta chloride (13). Solvolysis of 10 with decanol without heavy metal salts gave decyl 3,4,6-tri-O-acetyl-2-O-benzyl-alpha-D-glucopyranoside (14) in a highly stereoselective reaction, in high yield. Subsequent, iterative hydrogenolytic removal of the O-benzyl group and glycosylation with the beta-chloride 13 under catalysis by silver salts afforded the protected di- to penta-saccharide glycosides 16, 19, 21, and 23, which were conventionally deblocked.

Carbohydrate Conformation↗
PubMed1995

A placebo-controlled trial of a pertussis-toxoid vaccine.

BACKGROUND: Although many whole-cell vaccines have been effective in preventing pertussis, these vaccines are difficult to standardize and can produce side effects. In Sweden, pertussis became endemic during the 1970s despite vaccination. Because of its limited efficacy, the Swedish-made whole-cell vaccine was withdrawn in 1979. METHODS: To evaluate the efficacy of an acellular vaccine consisting of pertussis toxin inactivated by hydrogen peroxide (pertussis toxoid), we conducted a randomized, double-blind, placebo-controlled trial in Sweden. Infants were vaccinated with either diphtheria and tetanus toxoids alone (DT toxoids, 1726 infants) or diphtheria, tetanus, and pertussis toxoids (DTP toxoids, 1724 infants) at 3, 5, and 12 months of age. RESULTS: There were no serious reactions. With the pertussis vaccine there were slightly more local reactions than with the DT toxoids alone, but the rates of postvaccination fever were the same. The main period of surveillance, which began 30 days after the third vaccination, continued for a median of 17.5 months. There were 312 cases of pertussis (72 in the DTP-toxoids group and 240 in the DT-toxoids group) that met the clinical criterion (paroxysmal cough lasting > or = 21 days) and laboratory criteria for pertussis as defined by the World Health Organization. The efficacy of this acellular vaccine was 71 percent (95 percent confidence interval, 63 to 78 percent). The recipients of DTP toxoids who had pertussis had cough of shorter duration than the recipients of DT toxoids, and fewer had whooping and vomiting. The vaccine efficacy after two doses was 55 percent (95 percent confidence interval, 12 to 78 percent), on the basis of 14 cases in the DTP-toxoids group and 31 in the DT-toxoids group that met the definition of the World Health Organization. CONCLUSIONS: A pharmacologically inert, acellular pertussis-toxoid vaccine that is easily standardized is safe and confers substantial protection against pertussis.

Diphtheria Toxoid↗