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At least 217 records · Page 12Linked to original sources
PubMed2004

Bivalent Fv antibody fragments obtained by substituting the constant domains of a fab fragment with heterotetrameric molybdopterin synthase.

The antibody Fv fragment is the smallest functional unit of an antibody but for practical use, the VH/VL interface requires stabilization, which is usually accomplished by a peptide linker that joins the two variable domains to form a single chain Fv fragment (scFv). An alternative format to scFv is proposed that (i) allows stabilization of the Fv fragment, and (ii) restores the bivalency of the antibody as a pseudo-F(ab')2 format. This new antibody fragment was constructed by replacing the CHI and CL domains of the Fab fragment with heterotetrameric molybdopterin synthase (MPTS). We found that this format, named MoaFv, improved significantly the cytoplasmic expression of the Fv as a soluble protein in BL21 or Origami Escherichia coli strains. This MoaFv format is expressed as a homogeneous heterotetrameric protein with a Mr value of 110 kDa containing two functional binding sites as revealed by active site titration. In its native condition at 37 degrees C or in the presence of urea, this format was nearly as stable as the corresponding scFv, indicating that non-covalent interactions between the MPTS subunits can replace the covalent peptide linker in scFv. Finally, this MoaFv construct could be a useful format when bivalency is desirable to improve the functional avidity.

Base Sequence↗
PubMed2005

A bivalent conjugate vaccine in the treatment of biochemically relapsed prostate cancer: a study of glycosylated MUC-2-KLH and Globo H-KLH conjugate vaccines given with the new semi-synthetic saponin immunological adjuvant GPI-0100 OR QS-21.

GPI-0100 is a semi-synthetic saponin with modifications designed to augment stability and diminish toxicity. Two batches of GPI-0100 (the second with higher purity) were tested with doses ranging between 100 and 5000 microg in groups of five treated prostate cancer patients who had no evidence of disease except for rising PSA levels. GPI-0100 was mixed with a bivalent vaccine containing the glycolipid Globo H and the glycosylated mucin MUC2 conjugated to keyhole limpet hemocyanin (KLH). All doses were well tolerated and antibody titers against Globo H and MUC-2 escalated with the increasing dose levels. At the 5000 microg dose level in this patient population, toxicity remained minimal with only occasional grade II local toxicity at vaccination sites and occasional sporadic grade I elevations in ALT. Compared with a subsequent trial with the same bivalent vaccine plus QS-21 at the maximal tolerated dose of 100 microg, the 5000 microg dose of GPI-0100 produced comparable antibody titers.

Adjuvants, Immunologic↗
PubMed2005

The changing epidemiology of meningococcal meningitis after introduction of bivalent A/C polysaccharide vaccine into school-based vaccination programs in Egypt.

BACKGROUND: The strategy recommended by the World Health Organization (WHO) to curtail outbreaks of meningococcus in Africa is enhanced surveillance with administration of oily chloramphenicol as well as vaccination when incidence thresholds are exceeded. The role of capsular polysaccharide meningococcal vaccine in outbreak prevention has been the subject of considerable debate. The Egyptian Ministry of Health and Population initiated a school-based vaccination program with bivalent A/C capsular polysaccharide vaccine in 1992. This investigation reviews data on meningococcal meningitis in Egypt comparing years before and after introduction of the vaccine. METHODS: This is a retrospective review of several sources to examine the rates and serogroups of meningococcal meningitis before and after the introduction of the meningococcal A/C vaccine in Egypt. FINDINGS: Between 1967 and 1991, outbreaks of meningococcal disease were documented with a periodicity of 8 years in Egypt. However, there has not been an outbreak since 1991 and over the same period, there has also been a progressive decline in the baseline incidence of meningococcus. Also, a shift from a serogroup A to serogroup B predominance in meningococcal disease was noted during the study period. These data suggest that there has been an alteration in the epidemiology of meningococcal disease in Egypt that coincided with the implementation of the school-based vaccination program. INTERPRETATION: Routine use of the bivalent A/C meningococcal vaccine may be an alternative for the control and prevention of meningococcal disease in high-risk areas including the "meningitis belt".

Egypt↗
PubMed2006

Optimisation of secretion of recombinant HBsAg virus-like particles: Impact on the development of HIV-1/HBV bivalent vaccines.

The hepatitis B surface antigen (HBsAg) assembles into virus-like particles (VLPs) that can be used as carrier of immunogenic peptides for the development of bivalent vaccine candidates. It is shown here that by respecting certain qualitative features of mammalian preS1 and preS2 protein domains upstream of HBsAg, foreign sequences can be inserted in their place while maintaining efficient secretion of VLPs. A polyepitope bearing HIV-1 epitopes restricted to the HLA-A*0201 class I allele was optimised for secretion as an HBsAg fusion protein by counterbalancing the generally hydrophobic class I epitopes with hydrophilic spacers, eliminating epitopes bearing cysteine residues, limiting the number of internal methionine residues to a minimum and adopting Homo sapiens codon usage. The optimised HIV-1 polyepitope-HBsAg recombinant protein with up to 138 residues assembled into efficiently secreted recombinant VLPs. DNA immunisation in HLA-A*0201 and HLA-A*0201/HLA-DR1 transgenic mice resulted in the recovery of humoral response against the carrier and enhanced levels of HIV-1 specific CD8(+) T lymphocyte activation. Efficient self-assembly of recombinant HBsAg VLPs opens up the possibility of making efficient bivalent HBV/HIV vaccine candidates, which is particularly apposite given that the two viruses are frequently associated.

AIDS Vaccines↗
PubMed1984

Equilibrium theory for the clustering of bivalent cell surface receptors by trivalent ligands. Application to histamine release from basophils.

For certain cell types, the cross-linking of bivalent cell surface receptors by multivalent ligands is an important biochemical step in the transmission of information across the cell's membrane to its interior. The formation of cell surface receptor-ligand aggregates has been shown to "turn on" and "turn off" particular cell responses. It has been hypothesized that very large aggregates generate signals that small aggregates cannot. This hypothesis has not been rigorously tested as yet, in part because of a lack of quantitative information about aggregate sizes. Here we develop a general equilibrium theory for the clustering of bivalent receptors by trivalent ligands. In addition to predicting the concentrations of receptor-ligand aggregates of all possible sizes, we show that a range of ligand concentrations exists at which extremely large aggregates, i.e., superaggregates, form on the cell surface. The formation of a superaggregate corresponds to a sol-gel phase transition, and we study this transition in some detail. For the biologically interesting case of histamine release by basophils, we show, using realistic parameter values, that such transitions should occur when the cells are from highly allergic individuals. We prescribe in detail experimental conditions under which such transitions should occur. These conditions can be used as a guide to test whether or not large aggregates provide signals to cells that small aggregates do not.

Animals↗
PubMed1994

Theory for measuring bivalent surface binding kinetics using total internal reflection with fluorescence photobleaching recovery.

Total internal reflection with fluorescence photobleaching recovery (TIR-FPR) is a method for experimentally examining coupled diffusion and reaction kinetics at surfaces. In a previous work (Thompson et al. 1981. Biophys. J. 33:435-454), a theoretical basis for interpreting TIR-FPR data was described for monovalent ligands that undergo a reversible reaction with monovalent surface sites in a single step. Here, the theory for TIR-FPR has been extended to two different surface binding mechanisms that involve sequential, bivalent surface attachment. Methods for obtaining the intrinsic surface association and dissociation kinetic rates from measured fluorescence photobleaching recovery curves are described. The new theory should be applicable to the association of bivalent protein ligands such as antibodies with supported planar model membranes.

Animals↗
PubMedDate not supplied

Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial.

BACKGROUND: Vaccination against the most common oncogenic human papillomavirus (HPV) types, HPV-16 and HPV-18, could prevent development of up to 70% of cervical cancers worldwide. We did a randomised, double-blind, controlled trial to assess the efficacy, safety, and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types, associated cervical cytological abnormalities, and precancerous lesions. METHODS: We randomised 1113 women between 15-25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0 month, 1 month, and 6 month schedule in North America and Brazil. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and for vaccine safety and immunogenicity. FINDINGS: In the according-to-protocol analyses, vaccine efficacy was 91.6% (95% CI 64.5-98.0) against incident infection and 100% against persistent infection (47.0-100) with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95.1% (63.5-99.3) against persistent cervical infection with HPV-16/18 and 92.9% (70.0-98.3) against cytological abnormalities associated with HPV-16/18 infection. The vaccine was generally safe, well tolerated, and highly immunogenic. INTERPRETATION: The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.

Adolescent↗
PubMed2006

Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial.

BACKGROUND: Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions. Our aim was to assess the long-term efficacy, immunogenicity, and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes. METHODS: We did a follow-up study of our multicentre, double-blind, randomised, placebo-controlled trial reported in 2004. We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine (0.5 mL; n=393) or placebo (n=383). We assessed HPV DNA, using cervical samples, and did yearly cervical cytology assessments. We also studied the long-term immunogenicity and safety of the vaccine. FINDINGS: More than 98% seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase. We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints: incident infection, 96.9% (95% CI 81.3-99.9); persistent infection: 6 month definition, 94.3 (63.2-99.9); 12 month definition, 100% (33.6-100). In a combined analysis of the initial efficacy and extended follow-up studies, vaccine efficacy of 100% (42.4-100) against cervical intraepithelial neoplasia (CIN) lesions associated with vaccine types. We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31. The vaccine has a good long-term safety profile. INTERPRETATION: Up to 4.5 years, the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe, and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions. There is also evidence of cross protection.

Adult↗
PubMed2000

On the mechanism of action of thiamin enzymes in the presence of bivalent metal ions.

Results on the interactions between the bivalent metal ions Zn2+, Cd2+, Hg2+, Co2+, Ni2+ and 'active aldehyde' thiamin derivatives are reviewed. The techniques used in these studies include spectroscopic methods, i.e., IR-Raman, UV-Vis, multidimensional and multinuclear NMR in solution and in solid state, and X-ray crystal structure determinations. More recently, potentiometric studies on thiamin pyrophosphate and 2-(alpha-hydroxyethyl)thiamin in combination with NMR and EPR techniques were also undertaken. All these studies lead to useful conclusions on the mechanism of action of thiamin enzymes in the presence of bivalent metal ions.

Cations, Divalent↗
PubMed2002

Bivalency of plasminogen monoclonal antibodies is required for plasminogen bridging to fibrin and enhanced plasmin formation.

Binding of plasminogen to fibrin and cell surfaces is essential for fibrinolysis and pericellular proteolysis. We used surface plasmon resonance and enzyme kinetic analyses to study the effect of two mAbs (A10.2, CPL15) on plasminogen binding and activation at fibrin surfaces. A10.2 is directed against the lysine-binding site (LBS) of kringle 4, whereas CPL15 recognises a region in kringle 1 outside the LBS. In the presence of CPL15 and A10.2 mAbs, binding of plasminogen (K(d)=1.16+/-0.22 micromol/l) to fibrin was characterised by a mAb concentration-dependent bell-shaped isotherm. A progressive increase in the concentration of mAbs at the surface was also detected, and reached a plateau corresponding to the maximum of plasminogen bound. These data indicated that at low mAb concentration, bivalent plasminogen-mAb-plasminogen ternary complexes are formed, whereas at high mAb concentration, a progressive shift to monovalent plasminogen-mAb binary complexes is observed. Plasmin formation in the presence of mAbs followed a similar bell-shaped profile. Monovalent Fab fragments of mAb A10.2 showed no effect on the binding of plasminogen, confirming the notion that a bivalent mAb interaction is essential to increase plasminogen binding and activation at the surface of fibrin.

Antibodies, Monoclonal↗
PubMedDate not supplied

Evaluation of bivalent live attenuated influenza A vaccines in children 2 months to 3 years of age: safety, immunogenicity and dose-response.

1126 children, 2 months to 3 years old, received a single intranasal dose of 10(4), 10(6), or 10(7) TCID50 of cold adapted (ca) A/Kawasaki/9/86 (H1N1) and A/Beijing/352/89 (H3N2) or placebo, in a double blind, placebo-controlled, safety and immunogenicity trial. No reactogenicity attributable to vaccine was demonstrated. A single bivalent 10(6) or 10(7) dose produced high rates of seroconversion to H1N1 (77%) and H3N2 (92%) in seronegative children > 6 months old; serologic responses were lower to H1N1 (P < 0.001) and H3N2 (P = 0.01) in younger infants. A single 10(6) dose of bivalent ca influenza A vaccine can be immunogenic in children, but response is age dependent.

Antibodies, Viral↗
PubMed1999

Protection against experimental infection with group B streptococcus by immunization with a bivalent protein vaccine.

Group B streptococcus (GBS), a bacterium with polysaccharide capsule, is the major cause of sepsis and meningitis in early infancy. Recent work has indicated that immunity to GBS infection can be elicited by the surface proteins Rib and alpha, either of which is expressed by most GBS strains causing invasive infections. Here we show that a bivalent vaccine, composed of purified Rib and alpha mixed with aluminum hydroxide (alum), an adjuvant accepted for human use, elicits an antibody response to each of the two antigens. Moreover, the bivalent vaccine was found to protect against experimental infection with GBS strains representing the four classical serotypes. Our results represent an encouraging step towards the development of a human GBS vaccine based on pure protein antigens.

Animals↗
PubMed1999

Neisseria meningitidis serogroup C polysaccharide and serogroup B outer membrane vesicle conjugate as a bivalent meningococcus vaccine candidate.

Neisseria meningitidis serogroup C polysaccharide (PS C) was conjugated to serogroup B outer membrane vesicles (OMV) in order to test the possibility of obtaining a bivalent group B and C meningococcus vaccine. The conjugate and controls were injected intraperitoneally into groups of ten mice with boosters on days 14 and 28 after the primary immunization. The following groups were used as control: (i) PS C; (ii) PS C plus OMV; (iii) OMV; and (iv) saline. The serum collected on days 0, 14, 28 and 42 were tested by enzyme-linked immunosorbent assay (ELISA) for PS C and OMV, and by complement mediated bactericidal assay against serogroups B and C. ELISA for PS C as well as bactericidal titres against serogroup C meningococci of the conjugated vaccine increased eight-fold (ELISA) and 32 fold (bactericidal) after 42 days in comparison with the PS C control group. ELISA for OMV and bactericidal titre against serogroup B meningococci of the conjugate showed no significant difference in comparison with the OMV containing controls. Furthermore, Western Blot assay of the conjugate immune serum did not bind OMV class four protein which is related to the complement dependent antibody suppressor. The results indicate that the PS C-OMV conjugate could be a candidate for a bivalent vaccine toward serogroups B and C meningococci.

Animals↗
PubMed2001

Amino acids and peptides. Part 39: a bivalent poly(ethylene glycol) hybrid containing an active site (RGD) and its synergistic site (PHSRN) of fibronectin.

Fibronectin contains the active sequence Arg-Gly-Asp (RGD), along with its synergic site Pro-His-Ser-Arg-Asn (PHSRN). However, the PHSRN peptide does not show synergic activity when it is mixed with the RGD peptide, indicating that a spatial array between RGD and PHSRN in fibronectin may be necessary for synergic activity. Here, we have used an amino acid type poly(ethylene glycol) derivative (aaPEG) to design a bivalent PEG hybrid of fibronectin active peptides. We prepared the aaPEG hybrid peptides PHSRN-aaPEG, aaPEG-RGD, and PHSRN-aaPEG-RGD, and tested their biological activity. Whereas aaPEG-RGD promoted cell spreading activity, PHSRN-aaPEG had no activity. The PHSRN-aaPEG-RGD hybrid strongly promoted cell spreading compared with aaPEG-RGD. These results suggest that the PHSRN sequence in the PHSRN-aaPEG-RGD molecule synergistically enhances the cell spreading activity of the RGD sequence, and that the bivalent aaPEG hybrid method may be useful for conjugating functionally active peptides.

Amino Acid Motifs↗
PubMed2003

Bivalent biogenic amine reuptake inhibitors.

A series of aryltropane-based bivalent ligands was prepared and investigated for binding potency and for their ability to inhibit reuptake of human dopamine, serotonin and norepinephrine transporters. The bivalent ligand 4, comprised of linking an aryltropane by an octamethylene spacer showed high efficacy for the human dopamine transporter and had a discrimination ratio of 130.

Adrenergic Uptake Inhibitors↗
PubMed2002

Gene optimization is necessary to express a bivalent anti-human anti-T cell immunotoxin in Pichia pastoris.

The bivalent anti-human anti-T cell immunotoxin A-dmDT390-bisFv(G(4)S) was developed for treatment of T cell leukemia, autoimmune diseases, and tolerance induction for transplantation. The multi-domain structure of the bivalent immunotoxin hinders efficient production in Escherichia coli and most eukaryotes are sensitive to the toxin. However, Pichia pastoris has a tolerance to levels of DT (diphtheria toxin) that were previously observed to intoxicate wild type eukaryotic cells, including Saccharomyces cerevisiae. This tolerance has permitted the optimization of the secreted expression of A-dmDT390-bisFv(G(4)S) in P. pastoris under the control of AOX1 (alcohol oxidase 1) promoter. The original DNA sequence of A-dmDT390-bisFv(G(4)S) was not expressed in P. pastoris because of several AT-rich regions, which induce an early termination of transcription. After DNA rebuilding for abolishing AT-rich regions and codon optimization, the immunotoxin could be expressed up to 10mg/L in the shake flask culture. No differences in the expression levels of immunotoxin were observed by using different secretional signal sequences, Mut(s) (methanol utilization slow phenotype) or Mut(+) (methanol utilization plus phenotype) phenotypes. Buffered complex medium (pH 7.0) having 1% casamino acids provided the highest expression in shake flask culture and PMSF (phenylmethylsulfonyl fluoride) in the range of 1 to 3mM further improved the expression level presumably by inhibiting protein degradation. The immunotoxin was purified by DEAE (diethylaminoethyl) Sepharose ion exchange chromatography and Protein L affinity chromatography. The immunotoxin purified from P. pastoris culture was as fully functional as that expressed in a toxin resistant mutant CHO (Chinese hamster ovary) cell line. Our results demonstrate that P. pastoris is an ideal system for expression of toxin-based fusion proteins.

Animals↗
PubMed2004

Efficacy of a bivalent vaccine against eel diseases caused by Vibrio vulnificus after its administration by four different routes.

Vulnivaccine, a vaccine against vibriosis caused by Vibrio vulnificus serovar E (formerly biotype 2), confers acceptable levels of protection to eels after its administration by prolonged immersion in three doses. Recently, a new pathogenic serovar, named serovar A, has been isolated from vaccinated eels in a Spanish freshwater eel farm. The main objective of this work was to design a bivalent vaccine, and to study its effectiveness against the two pathogenic serovars. With this aim, eels weighing around 20 g were immunised with the bivalent vaccine by oral and anal intubation, intraperitoneal injection (i.p.) and prolonged immersion. The overall results indicated that: (i) the new vaccine delivered by oral and anal intubation induced protection levels higher than 80%, to that achieved after i.p. vaccination; (ii) oral and anal vaccination induced a significant systemic and mucosal immune response; (iii) the protection after vaccination by whichever routes was related to antibody titres in plasma; (iv) mucosal and systemic compartments showed different kinetics of antibody production; (v) evidence for passive transfer of antibodies from plasma to gut mucus were found after i.p. and anal vaccination, and finally, (vi) vaccination did not enhance the production of lysozyme, in plasma or mucus. In conclusion, this new vaccine is effective in protecting eels against vibriosis caused by the two eel-pathogenic serovars of V. vulnificus, the oral delivery system is a promising way which may be used in intensive culture facilities during the whole growth period of eels.

Anguilla↗