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At least 19 recordsLinked to original sources
PubMed1985

Carrier-induced epitopic suppression, a major issue for future synthetic vaccines.

Synthetic antigens have been shown, in experimental models, to induce protective immunity against a variety of pathogens. These studies have demonstrated that, due to their low immunogenicity, these synthetic antigens required conjugation to carrier molecules. Therefore, the choice of appropriate carriers for human immunization by future synthetic vaccines is a major issue. Tetanus toxoid is generally considered to be an effective potential carrier devoid of side-effects. However, the present study performed in mice with two synthetic vaccine models demonstrates that the immune response against the synthetic epitopes conjugated to tetanus toxoid can be suppressed by pre-existing immunity against this same carrier. Because most humans have been exposed to this antigen, this effect may have important implications for the development of synthetic vaccines.

Animals↗
PubMed1983

Synthetic vaccines.

Synthetic vaccines are designed with the help of computer-graphics programs. These displays generated by Arthur J. Olson of the Research Institute of Scripps Clinic show a method whereby parts of a viral protein that are on the surface of a virus, and therefore accessible to antibodies, can be identified. The backbone of the surface domain of the protein on the outer shell of the tomato bushy-stunt virus is displayed (1) on the basis of coordinates determined by Stephen C. Harrison of Harvard University and his colleagues. A single peptide of the protein is picked out in yellow, with the side chains of its component amino acids indicated in atomic detail (2). The peptide is enlarged and a sphere representing a water molecule is displayed (3). The sphere is rolled around the peptide to generate a map of the surface accessible to water (4); it does so, following an algorithm developed by Michael L. Connolly, by placing a dot at each point of its closest contact with the peptide, taking account of the sphere's own van der Waals radius (zone of influence, in effect) and that of each atom of the peptide and the rest of the protein. A similar-dot-surface map is generated to show what parts of the peptide are still accessible to water when three copies of the protein are associated in an array on the surface of the virus (5) and when four such arrays (out of 60) are in position on the outer surface of the virus (6).

Animals↗
PubMed2005

Use of biodegradable PLGA microspheres as a slow release delivery system for the Boophilus microplus synthetic vaccine SBm7462.

The synthetic anti-Boophilus microplus vaccine SBm7462 derived from the tick intestinal protein, Bm86, induced a protective immune response when emulsified in saponin and used in cattle. Using a mice model, and with the objective of improving the vaccine by continual peptide release, it was encapsulated in PLGA 50:50 microspheres and inoculated in BALB/c mice to assess the immunological response by detection of anti-peptide IgGs. Comparative studies were made with the peptide emulsified in saponin and with another synthetic vaccine, and the microsphere/peptide was characterized for efficiency of encapsulation, in vitro release profile, morphology, size, peptide integrity after encapsulation and stability in different pHs. The findings showed that saponin enhances a better immune response from SBm7462 and that the PLGA 50:50 microspheres are suitable for use with this peptide.

Animals↗
PubMed1999

Peptide and carbohydrate vaccines in relapsed prostate cancer: immunogenicity of synthetic vaccines in man--clinical trials at Memorial Sloan-Kettering Cancer Center.

Men with rising prostate-specific antigen (PSA) levels after primary therapies such as prostatectomy or radiotherapy represent a unique group for whom no standard treatment option exists. A variety of approaches including expectant monitoring, dietary modification, hormonal therapy, and alternative medicines have shown an impact on the rate of increase in PSA, but the overall effect on survival remains controversial. At Memorial Sloan-Kettering Cancer Center, we have focused our treatment approach on this cohort of patients in a series of phase I monovalent carbohydrate and glycoprotein-conjugate vaccine trials using the patients' immune system to generate an antitumor response. These synthetic vaccines are conjugated to keyhole limpet hemocyanin (KLH) and given with the immunologic adjuvant QS21 as five subcutaneous vaccines over 26 weeks. All patients generated specific high-titer immunoglobulin M (IgM) and/or IgG antibodies, some of which were able to mediate complement lysis. Preliminary data suggest that these vaccines may impact on the rate of increase in posttreatment PSA slopes compared with pre-PSA values. The impact of vaccine therapy on the PSA slope and its effect on the time to radiographic progression are the current focus of a forthcoming phase II trial. Vaccines may offer an alternative treatment option for the patient who has relapsed early following primary therapies.

Antibody Formation↗
PubMed1987

Induction of biologically active antibodies by a polyvalent synthetic vaccine constructed without carrier.

Four synthetic peptides that copy fragments of two bacterial antigens (Streptococcus pyogenes M protein and diphtheria toxin), one viral antigen (hepatitis B surface antigen), and one parasitic antigen (circumsporozoite protein of Plasmodium knowlesi) were covalently bound within the same construct. This totally synthetic polyvalent administered to mice with Freund complete adjuvant or in saline with murabutide (an adjuvant-active muramyl peptide) elicited high levels of antibodies which, in certain cases, were shown to be biologically active. The results indicated that these antibodies recognized specifically the four peptides. None of the epitopes were immunodominant. It was also demonstrated that the association of several peptides enhanced their respective immunogenicities as compared with those of their homopolymers. Finally, this study shows that a totally synthetic vaccine administered in saline with a synthetic adjuvant can be immunogenic in the absence of a protein carrier.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

Synthetic immunomodulators and synthetic vaccines.

Efforts have been made for several years to obtain well-defined, nontoxic adjuvants and antigens which could be used for human vaccination and immunostimulation. Among synthetic adjuvants, MDP represents one of the most studied family of compounds. This molecule is the minimal active structure of whole Mycobacteria and has been shown to be endowed with numerous biological activities. MDP is adjuvant active, increases nonspecific resistance against infectious challenges and, under certain conditions, increases resistance against tumor grafts. Moreover, MDP has other pharmacological properties such as pyrogenic and somnogenic activities. Several hundred MDP derivatives have been synthetized and some of the biological activities have been dissociated. One MDP derivative presently under clinical trials has been shown to be adjuvant active but is devoid of pyrogenicity. The mechanisms of activity of these MDP and derivative molecules will be discussed. More recently, synthetic antigens which are copies of natural epitopes, have been shown to induce protective antibodies against bacterial or viral pathogens. These synthetic antigens conjugated to synthetic carriers or to synthetic adjuvants such as MDP, may permit the preparation of totally synthetic vaccines.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Protective anti-sporozoite antibodies induced by a chemically defined synthetic vaccine.

Chemically defined synthetic polymers, known as multiple antigen peptide systems (MAPs) represent an effective and novel approach for engineering peptide-based vaccines. Ten different mono and diepitope MAP models, containing different arrangements and stoichiometry of functional B and/or T helper epitopes from the circumsporozoite protein of Plasmodium berghei were used to immunize mice. High titers of antibody and protective immunity against sporozoite challenge were elicited by MAPs containing T and B epitopes arranged in tandem and in equimolar amounts. These results indicate that MAPs may serve as a basis for developing subunit vaccines to induce high levels of antibodies against sporozoites.

Amino Acid Sequence↗
PubMed1997

Interaction of the receptor binding domains of Pseudomonas aeruginosa pili strains PAK, PAO, KB7 and P1 to a cross-reactive antibody and receptor analog: implications for synthetic vaccine design.

The four synthetic peptide antigens, PAK 128-144, PAO 128-144, KB7 128-144 and P1 126-148, correspond in amino acid sequence to the C-terminal receptor binding regions of four strains (PAK, PAO, KB7, P1) of Pseudomonas aeruginosa pilin. The NMR solution structures of the trans forms of the peptides show conserved beta-turns which have been implicated in antibody and receptor recognition. The interactions between these peptides and a cross-reactive monoclonal antibody, PAK-13, have been studied using two-dimensional (1)H NMR spectroscopy in order to map the antigenic determinants recognized by the antibody. Residues for which spectral changes were observed upon antibody binding differed from peptide to peptide but were mostly confined to one or both of the turn regions and to the hydrophobic pockets. Conformational changes in the beta-turns and hydrophobic pockets of these peptides upon antibody binding were also monitored by examination of the pattern of nuclear Overhauser effects (NOEs) versus transferred nuclear Overhauser effects (TRNOEs) for the free versus the bound peptides. Although TRNOEs developed strongly between side chain resonances in the hydrophobic pockets of the peptides, no additional backbone TRNOEs were observed in the presence of antibody, suggesting no major conformational changes in the secondary structures of the peptides upon binding. This implies a flexible antibody combining site, a feature which is discussed with respect to cross-reactivity, strain specificity, and the design of a synthetic peptide vaccine effective against a broad spectrum of P. aeruginosa strains. The binding of the PAK peptide to a disaccharide receptor analog, (beta GalNAc(1-4)beta Gal), was also studied using (1)H NMR in order to map the "adhesintope" recognized by the receptor. Spectral changes observed in the peptide spectrum with the binding of receptor were similar to those seen for the binding of antibody, suggesting that the epitope recognized by the antibody is structurally coincident with the adhesintope recognized by the receptor. The relevancy of this result is discussed with respect to immunogenicity versus pathogenicity, and the proper design of a vaccine which could prevent the mutational escape of the pathogen away from the host's defence systems.

Amino Acid Sequence↗
PubMed1990

The conformational restriction of synthetic vaccines for malaria.

The effectiveness of synthetic vaccines is dependent upon the chance event that antibodies formed against largely disordered peptides can bind native protein surfaces which are often ordered. To improve on this situation, new methods are being developed for the conformational restriction of synthetic peptides. Cognate peptide sequences often form predictable secondary structures in proteins characterized by distinct hydrogen-bonding patterns. These weak hydrogen bonds have now been replaced with covalent mimics to conformationally restrict selected peptides to the Type 1 reverse turn and alpha helix. Potential uses for this chemistry are discussed in the context of malaria vaccines. The peptide component of a Plasmodium falciparum sporozoite vaccine, acetyl-(ASN-ALA-ASN-PRO)3-NH2 has been conformationally analysed using two-dimensional nuclear magnetic resonance spectroscopy. These studies are consistent with the formation of transiently ordered turnlike structures which provide a guide for the design and synthesis of a conformationally restricted synthetic vaccine. To assess the effects of conformational restriction and chemical modification on the sporozoite vaccine, ASN side-chains were linked around proline with ethylene bridges. Polyclonal antibodies to this shaped peptide show a strong cross-reaction with living sporozoites.

Animals↗
PubMed2001

Exploiting conformationally constrained peptidomimetics and an efficient human-compatible delivery system in synthetic vaccine design.

Peptide and protein mimetics are potentially of great value in synthetic vaccine design. The mimetics should function by stimulating the immune system to produce antibodies that recognize the intact parasite. Also the mimetics should be presented to the immune system in a way that leads to efficient antibody production. Here we investigate the application of cyclic peptidomimetics presented on immunopotentiating reconstituted influenza virosomes (IRIVs), a form of antigen delivery that is licensed already for human clinical use, in synthetic vaccine design. We focus on the central (NPNA)(n) repeat region of the circumsporozoite (CS) protein of the malaria parasite Plasmodium falciparum as a model system. Cyclic peptidomimetics of the NPNA repeats were incorporated into both an IRIV and (for comparison) a multiple-antigen peptide (MAP). Both IRIV and MAP delivery forms induced mimetic-specific humoral immune responses in mice, but only with the mimetic-IRIV preparations did a significant fraction of the elicited antibodies cross-react with sporozoites. The results demonstrate that IRIVs are a delivery system suitable for the efficient induction of antibody responses against conformational epitopes by use of cyclic template-bound peptidomimetics. Combined with combinatorial chemistry, this approach may have great potential for the rapid optimization of molecularly defined synthetic vaccine candidates against a wide variety of infectious agents.

Animals↗
PubMed1989

Affinity consideration in the design of synthetic vaccines intended to elicit antibodies.

As a model for synthetic vaccines BALB/c mice were injected with a large cyanogen bromide cleaved fragment of horse cytochrome c, containing residues 1-80 of the 104 residue long polypeptide chain; then individual B cells specific for the peptide were challenged in vitro in splenic fragment cultures, with either the fragment or intact cytochrome c, both coupled to hemocyanin. The splenic environment in which the B cells were cultured contained hemocyanin-primed T cells, which provided equivalent T cell help for both the peptide and protein immunogens. In two experiments, intact cytochrome c-hemocyanin activated a total of only five peptide-primed B cells, compared to 66 that were activated by the peptide-hemocyanin conjugate. Furthermore, antibodies from the few cells that appeared to be activated by the protein did not bind the native protein with appreciable affinity in competitive ELISA. Of the mAbs elicited by the peptide, 51 were shown to have detectable affinity for native cytochrome c, but their affinity was dramatically less than that previously observed for antibodies elicited by protein-primed B cells and also less than that for the peptide. Thus, although the Ig receptors on many of the peptide-primed B cells did bind the protein to some extent, most such B cells were not activated. These results demonstrate that, in the development of synthetic vaccines, the affinity of a protein for peptide-primed antibodies (Ig receptors) is an important criterion to be considered. Qualitative examination of the binding of an anti-peptide antibody to a protein antigen, especially in denaturing conditions such as Western blots or in potentially denaturing conditions such as ELISA, is not an accurate indication of the efficacy of the peptide to prime B cells that can be activated upon challenge from the native protein.

Animals↗
PubMed1991

Studies on the humoral immune response to a synthetic vaccine against Plasmodium falciparum malaria.

A synthetic vaccine against the asexual blood stages of P. falciparum, the SPf 66 synthetic hybrid polymer, composed of peptides derived from three merozoite membrane proteins as well as one peptide from the sporozoite CS protein, has been developed by our group and tested in different protection assays in Aotus monkeys as well as in human volunteers. This study evaluates the humoral immune response induced by the SPf 66 protein vaccination in adult human volunteers from the Colombian Pacific coast as follows: determination of specific IgG antibody levels against SPf 66 by FAST-ELISA after each immunization; analysis of antibody reactivity with P. falciparum schizont lysates by immunoblots; and determination of the in vitro parasite growth inhibition. A clear boosting effect, dependent on time and dose, was observed in the antibody production kinetics. These antibodies also specifically recognize three proteins of the P. falciparum schizont lysate corresponding to the molecular weights of the proteins from which the amino acid sequence was derived. These sera were also capable of markedly inhibiting in vitro parasite growth.

Adolescent↗
PubMed1987

A synthetic vaccine constructed by copolymerization of B and T cell determinants.

Synthetic vaccines are based on the identification of short peptide sequences responsible for inducing a protective immune response. These sequences could contain B and/or T cell determinants. In this study, we have examined the recognition by B and T mouse lymphocytes of several synthetic peptides corresponding to regions of a bacterial and two viral proteins. These include a streptococcal S-34 peptide, H(99-121) and two other synthetic hepatitis B virus surface peptides. A lymph node proliferation assay was employed to detect T cell determinants. Limiting dilution analysis was used to estimate the frequency of clonal precursor B cells specific for an antigenic determinant. This study indicates that the synthetic hepatitis B virus surface peptides are recognized by B cells but not by T cells, whereas the S-34 peptide possesses both B and T epitopes. The copolymerization of the B determinant H(99-121) with S-34 has conferred immunogenicity to the H(99-121) peptide. After copolymerization, the synthetic hybrid molecule retained the S-34 T epitope and acquired a new determinant recognized by T cells. These results demonstrate that synthetic vaccines could be constructed by appropriate selection and organization of B and T determinants.

Animals↗
PubMed1989

[Synthetic vaccines for immunization against infection with hepatitis B virus].

The paper informs on the present state of preparation of a vaccine against infection with the hepatitis B virus, using techniques of genetic engineering. Synthesis of immunogenic peptides derived from the structure of HBaAg amino acids stimulated the administration of several oligopeptides derived from the structure of HBsAg. Experiments with the decapeptide derived from the S-portion of HBsAg revealed that also a small peptide, when administered with adjuvants, is immunogenic, Synthesis of HBsAg protein in a culture of Saccharomyces cerevisiae was already tested clinically and proved to be an effective vaccine. It will be probably also possible to prepare the vaccine by formation of the anti-idiotype, induced by HBsAg anti Ig. The authors' own observation revealed that the administration of anti HBsAg immunoglobulin (Hepaga) causes in rabbits the formation of a component which reacts in serum by the RIA technique as HBsAg.

Animals↗
PubMed1990

Studies in owl monkeys leading to the development of a synthetic vaccine against the asexual blood stages of Plasmodium falciparum.

During the development of a synthetic vaccine for human use against the asexual blood stages of Plasmodium falciparum, monkey trials were performed to assess safety, immunogenicity, and protectivity. We determined the minimal infective dose of the P. falciparum FVO strain, the kinetics of the immune response induced by vaccination with the synthetic peptide mixture (S7 + S12 + S17) or the synthetic hybrid polymeric protein SPf66, and the induction of protective immunity against the experimental challenge with 2 P. falciparum strains. A clear boosting effect was observed, determined by the increased antibody titers against synthetic peptides S7, S12, S17, and SPf66, and by improvement in the protective immune response against the challenge. These studies suggest that either the peptide mixture or the synthetic hybrid polymeric protein are excellent choices for the development of a vaccine against P. falciparum.

Amino Acid Sequence↗