Some unanswered questions about vaccination.
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Antigenic Variation↗
Biomedical subjects
F Brown
Publications and source records attributed to F Brown.
Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.
The synthesis of 15 methyl or unsubstituted 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles additionally substituted with a 1-azabicyclo[2.2.2]octan-3-yl group is described. The potency and efficacy of these compounds as muscarinic ligands were determined in radioligand binding assays using [3H]oxotremorine and [3H]quinuclidinyl benzilate. Potency and efficacy were found in compounds in which the azole moiety was attached to the azabicyclic ring either through a carbon atom or a nitrogen atom. Electrostatic potential maps of both the C-linked and the novel N-linked series of compounds were calculated. A relationship between position and depth of the electrostatic minima relative to the azabicyclic ring and the potency and efficacy of the compounds was determined.
Animals↗
Independent effect of various facial mimetic muscles on the nasolabial fold.
The independent effect of the contraction of various facial mimetic muscles on the nasolabial fold was defined through study of cadaver dissections. The four major lip elevator muscles were identified and the effect of traction of these muscles on the nasolabial fold was studied. This study identified the levator alae muscle (levator labii superioris alaeque nasi) as the primary facial muscle responsible for creating the medial nasolabial fold. The levator labii superioris muscle was found to define the middle nasolabial fold. These two facial muscles may be significant in the etiology of the prominent nasolabial fold that occurs with aging.
Aged↗
Characterization of neutralizing antibodies to bovine enterovirus elicited by synthetic peptides.
Six synthetic peptides corresponding to regions of bovine enterovirus (BEV), strain VG-5-27, elicited antibodies in mice which reacted with the virus in various assays. These antibodies have been characterised on the basis of their ability to (1) neutralize the virus, (2) bind to the intact virus particle in an immunoprecipitation test, (3) react with the denatured viral proteins, and (4) give immunofluorescent staining of virus infected cells. We have also determined the proportion of antipeptide antibody which binds to the virus in each case. All of the sera immunoprecipitated the virus and neutralized its activity to varying extents. Two of the sera specific for VP 1 sequences failed to react with denatured VP 1 whereas all the other antisera reacted with their respective parental proteins. All of the sera reacted with VG-5-27 infected cells in an immunofluorescence test. The proportion of antibodies to each peptide recognizing intact virus was variable and did not appear to correlate with neutralizing activity. In addition, the ability of each of the sera to react with and neutralize three other strains of the virus was analysed. With one of these strains significant cross-neutralization was observed.
Amino Acid Sequence↗
New approaches to vaccination against foot-and-mouth disease.
The economically important foot-and-mouth disease has been successfully controlled in Western Europe by comprehensive immunization using killed vaccine. The author discusses the wisdom of abandoning this policy, and outlines research into alternative vaccines using recombinant DNA technology, in particular using synthetic peptides.
Animals↗
Correlations between the conformations elucidated by CD spectroscopy and the antigenic properties of four peptides of the foot-and-mouth disease virus.
The conformational features of four related antigenic peptides (A, B, C and USA) from the foot-and-mouth disease virus (FMDV) (VP1; 141-160 of serotype A, subtype 12), assessed by CD, were found to correlate with the serological properties of these peptides. The CD spectra of the four peptides, obtained under cryogenic and solvent titration conditions, were consistent with three conformational components (a left-handed extended helix, an alpha-helix and a 3(10) helix) for peptides A and C and four components (a beta-turn of type II, an alpha-helix, a gamma-turn and a 3(10) helix) for peptides B and USA. The amino acid substitutions at positions 148 and 153, which distinguish the peptides, are therefore responsible for both their conformational and antigenic differences.
Amino Acid Sequence↗
Designing future vaccines.
Vaccination is one of the major preventive measures against infectious diseases. With the exception of the hepatitis B vaccine, the vaccines in use today are produced from the infectious agents themselves, either by attenuation or inactivation. Although these products have been successful in controlling many diseases, there are several reasons why efforts are being made to improve their quality. In addition there are some infectious diseases for which vaccines are not available because the causal agents cannot be grown in sufficient quantities. New approaches will be required to obtain effective vaccines against these diseases. In this paper, these approaches to the design of new vaccines are described using hepatitis B, rabies and foot-and-mouth disease as examples.
Animals↗
Vaccines.
Much progress has been made towards reaching an understanding of immune responses at the molecular level. This has provided much needed information for identifying the antigens which will afford protection against diseases such as rabies, malaria, whooping cough, hepatitis and acquired immune deficiency syndrome, and for presenting them to the immune system.
Animals↗
Comparison of azabicyclic esters and oxadiazoles as ligands for the muscarinic receptor.
The link between the cognitive deficit associated with Alzheimer type dementia and the loss of cholinergic function in the disease provides a basis for examining muscarinic agonists as potential therapeutic agents. This paper describes the design and synthesis of novel azabicyclic methyl esters as ligands for the muscarinic receptor. Replacement of the methyl ester by a 3-methyl-1,2,4-oxadiazole ring produces potent metabolically more stable muscarinic agonists capable of penetrating the central nervous system. These compounds generally show improved affinity relative to the corresponding methyl esters. 3-Methyl-1,2,4-oxadiazole 7b has an affinity 4 times that of acetylcholine. Receptor affinity is discussed in relation to the size and geometry of the azabicyclic ring and the electronic properties of the heteroaromatic ring.
Aminoquinolines↗
Immunological evaluation of the multiple antigen peptide (MAP) system using the major immunogenic site of foot-and-mouth disease virus.
The multiple antigenic peptide (MAP) system for presenting epitopes to the immune system has been studied with an immunogenic foot-and-mouth disease virus (FMDV) peptide comprising amino acids 141-160 of protein VP1. Neutralizing antibody responses known to protect guinea-pigs against challenge infection were obtained with a single inoculation of 0.8-4 micrograms of peptide, presented as an octamer or a tetramer, whereas 20 micrograms of a dimer were required to evoke a similar level of antibody. A monomeric preparation did not elicit measurable levels of neutralizing antibody at doses up to 20 micrograms. The octameric MAP was also immunogenic using an aluminum hydroxide adjuvant. Antibodies elicited by the octameric, tetrameric and dimeric constructs differed qualitatively in their reaction with sequences within the 141-160 peptide. Those against the octamer reacted poorly with peptides within the 141-160 sequence, whereas those elicited by the tetramer and dimer reacted preferentially with the peptides covering the N-terminal region. The levels of neutralizing antibody obtained with the octamer and tetramer compare favourably with those obtained when the FMDV peptide is attached to carrier proteins but are lower than those obtained when it is presented as part of a peptide-hepatitis B virus core particle. Nevertheless, the ability to elicit protective levels of neutralizing antibody without the use of a carrier protein would be a distinct advantage in the development of synthetic peptide vaccines.
Adjuvants, Immunologic↗
An overview of the inactivation of FMDV and the implications when residual virus is present in vaccines.
Most foot-and-mouth disease (FMD) vaccines are prepared by inactivating the virus with acetylethyleneimine or binary ethyleneimine. However, formaldehyde is still used by some manufacturers despite the well-documented evidence that inactivation with this reagent is not a linear or first-order reaction. Recent German work provides clear evidence that almost all the outbreaks in Western Europe in recent years have been caused by viruses closely related to strains which were isolated more than 20 years ago and are used for the production of vaccines. Moreover, with one exception, all the vaccines connected with the outbreaks were prepared by formaldehyde inactivation. The implications of these outbreaks are both immediate and longer term. The immediate effect is that they severely disrupt trading in meat and dairy products. The longer term effect has been the decision to abandon vaccination in Western Europe. This could have serious implications as trading with Eastern European countries will be expected to increase in the immediate future.
Animals↗
A CD strategy for the study of polypeptide folding/unfolding. A synthetic foot-and-mouth disease virus immunogenic peptide.
The circular dichroism spectrum of the 20-residue immunogenic peptide from the foot-and-mouth disease virus (VP1; 141-160 of serotype A, subtype 12) was solvent- and temperature-dependent. Careful solvent titration revealed two isodichroic points and plateaux consistent with stepwise unfolding of specific stable conformations. Variable temperature studies in cryogenic solvents and urea perturbation were consistent with the existence of three conformational moieties, the left-handed extended helix, the alpha-helix, and the 3(10) helix. The number of residues in each helix was confirmed by CD spectral simulations. The strategy described here can be used to determine the components of a conformational equilibrium and their statistical weights, to study peptide folding and unfolding and to determine the bioactive conformation(s) of linear peptides. The conclusions were supported by 2D-NMR studies. A new mechanism for the stabilization of left-handed extended helices and destabilization of alpha-helices by urea is proposed. The structure of the peptide as resolved by CD spectroscopy is of particular significance since the conformation of this antigenic sequence in situ has so far not been solved by X-ray crystallography.
Amino Acid Sequence↗
Structural and serological evidence for a novel mechanism of antigenic variation in foot-and-mouth disease virus.
Changes resulting in altered antigenic properties of viruses nearly always occur on their surface and have been attributed to the substitution of residues directly involved in binding antibody. To investigate the mechanism of antigenic variation in foot-and-mouth disease virus (FMDV), variants that escape neutralization by a monoclonal antibody have been compared crystallographically and serologically with parental virus. FMDVs form one of the four genera of the Picornaviridae. The unenveloped icosahedral shell comprises 60 copies each of four structural proteins VP1-4. Representatives from each of the genera have similar overall structure, but differences in the external features. For example, human rhinovirus has a pronounced 'canyon' that is proposed to contain the cell attachment site, whereas elements of the attachment site for FMDV, which involves the G-H loop (residues 134-160) and C-terminus (200-213) of VP1, are exposed on the surface. Moreover, this G-H loop, which is a major antigenic site of FMDV, forms a prominent, highly accessible protrusion, a feature not seen in other picornaviruses. It is this loop that is perturbed in the variant viruses that we have studied. The amino acid mutations characterizing the variants are not at positions directly involved in antibody binding, but result in far-reaching perturbations of the surface structure of the virus. Thus, this virus seems to use a novel escape mechanism whereby an induced conformational change in a major antigenic loop destroys the integrity of the epitope.
Antibodies, Monoclonal↗
From Jenner to genes--the new vaccines.
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Adjuvants, Immunologic↗
Synthetic peptides as potential vaccines against foot-and-mouth disease.
Advances made in our knowledge of the structure of foot-and-mouth disease virus have enabled us to identify a fragment, consisting of 20 amino acids, of one of the four proteins of the particle, which elicits neutralizing antibodies in experimental animals and in cattle and pigs. The fragment has been synthesised chemically by Merrifield's solid phase method and biochemically as part of different fusion proteins. The level of the immune response to the peptide, which depends critically on the way it is presented, affords protection against experimental challenge and holds out promise for its future as a vaccine.
Amino Acid Sequence↗
"Instant-mix" whole brain photon with neutron boost radiotherapy for malignant gliomas.
From July 1985 through March 1987, 44 consecutive patients with supratentorial, nonmetastatic anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with whole brain photon irradiation with concomitant neutron boost at the University of Chicago. All patients had biopsy proven disease and surgery ranged from biopsy to total gross excision. Whole brain photon radiation was given at 1.5 Gy per fraction, 5 days weekly for a total dose of 45 Gy in 6 weeks. Neutron boost radiation was prescribed to a target minimum dose that included the pre-surgical CT tumor volume plus 1 cm margin. Neutrons were administered 5-20 minutes prior to photon radiation twice weekly and a total dose of 5.2 Gyn gamma was administered over 6 weeks. Median follow-up was 36 months. The median survival was 40.3 months for anaplastic astrocytoma (10 patients) and 11 months for glioblastoma multiforme (34 patients) and 12 months for the overall group. Variables that predicted longer median survival included histology (AA vs. GBM), age (less than or equal to 39 years vs. older), and extent of surgery (total gross or partial excision vs. biopsy) whereas tumor size and Karnofsky performance status did not have a significant influence. The median survival of the anaplastic astrocytoma group was better than expected compared to the RTOG 80-07 study (a dose-finding study of similar design to this study) and historical data. Reasons for this are discussed.
Adult↗
The structure of foot-and-mouth disease virus: implications for its physical and biological properties.
The structure of foot-and-mouth disease virus has been solved at a resolution of 2.9 A by X-ray diffraction techniques. The overall structural organisation of the particle is similar to that seen in other picornaviruses but there are several unique features. Many of these help to explain its characteristic physical and biological properties. In particular the canyon or pit found at the surface of other picornaviruses is lacking, which has important implications for cell attachment and the process of infection. Also there are 60 large disordered protrusions at the surface corresponding to the major antigenic site. This disorder is of particular interest in relation to the striking ability of linear synthetic peptides to induce protective immunity against foot-and-mouth disease.
Animals↗
Expression in yeast of amino-terminal peptide fusions to hepatitis B core antigen and their immunological properties.
Hepatitis B core protein (HBcAg) is a potent antigen that gives both a T-cell-dependent and a T-cell-independent antibody response. It has been shown that a foreign epitope can be fused to the amino terminus of HBcAg without affecting particle integrity, and that the resulting chimaeric cores retain the immunogenicity of the foreign epitope. Here we describe the efficient expression in yeast of two different chimaeric cores, carrying epitopes of Foot and Mouth Disease Virus (FMDV) or human chorionic gonadotrophin (hCG), which are candidates for FMD and contraceptive vaccines, respectively. These cores could not be produced in E. coli in soluble form but were expressed to high levels in yeast. We constructed a yeast expression vector that allows rapid production of different chimaeric cores by cloning in cassettes encoding foreign epitopes. Both FMDV and hCG-cores were shown to present the epitopes at the surface of the particles. The FMDV-cores produced in yeast were efficient inducers of neutralising antibodies in guinea-pigs after one low dose.
Amino Acid Sequence↗