The antibody response to hepatitis B surface antigen (anti-HBs) induced in 25 recipients of a recombinant hepatitis B vaccine derived from yeast was compared with that induced in 25 recipients of a vaccine prepared from hepatitis B surface antigen (HBsAg) derived from plasma. Anti-HBs affinity and specificity were compared using assays of antibody affinity with two different antigens, a complex of the major polypeptide of HBsAg (p25; molecular weight 25000 daltons) covalently linked to its glycosylated form (gp3O) prepared from native purified HBsAg, and a cyclical synthetic peptide representing amino acid residues 139-147 of the major polypeptide of HBsAg and known to represent a major part of an a determinant. There was no difference in anti-HBs affinity or molar antigen binding sites of the antibody measured with either antigen between the two groups. All subjects in both groups produced antibody that bound to the gp3O/p25 complex antigen, whereas 22 of the recipients of the plasma derived vaccine compared with 24 of those receiving the yeast derived vaccine produced antibodies that bound to the cyclical synthetic peptide 139-147. These results support the finding of similar levels of anti-HBs, measured by commercial solid phase radioimmunoassay, in the two vaccine groups after three doses of vaccine.These results show no significant difference in the quantity, quality, or specificity of the anti-HBs response induced by the recombinant hepatitis B vaccine and the plasma derived hepatitis B vaccine.
There is considerable current interest in the development of techniques for the precise manipulation of the immune response resulting in either enhancement or suppression. In the context of responses to infectious agents, the use of molecules representing single defined epitopes able to substitute for antigen (i.e., surrogate antigens) would provide considerable advantages over the use of the native antigen (I-5). Two types of reagent could potentially fulfill this role, the first is a synthetic peptide antigen, and the second an internal image antiidiotype mAb. Because of the development of the technique of solid-phase peptide synthesis and methods for the prediction of potential antigenic determinants of complex antigens, it is now possible to synthesize peptides representing these antigenic determinants. An internal image antiidiotype is the hypervariable region of an antiidiotype that behaves as a surface determinant on the antigen with respect to recognition by antibody. A number of such polyclonal reagents have been developed, including rabbit antiidiotypic antibodies specific for an interspecies crossreactive idiotype on antibodies to hepatitis B surface antigen (6), but monoclonal internal image antiidiotypes appear to offer considerable advantages (7-13).Over 200 million individuals are persistently infected with the hepatitis B virus (HBV), 1 presenting a major risk of transmission via contaminated blood and blood products. In addition exposure to HBV is associated with the development of hepatocellular carcinoma late in life. Hepatitis B is a particularly appropriate system in which to investigate the potential of surrogate antigenic epitopes for immunization. Vaccine development has been hindered however, as the virus cannot be grown in vitro, and standard virological techniques of detecting neutralizing antibody are not available. The currently licensed hepatitis B vaccines are therefore derived by extensive purification of the outer surface antigen of the virus (HBsAg), which is present in excess in the plasma of human HBV carriers (14). New, alternative sources of HBsAg include antigen expressed in yeast by recombinant DNA technology (15). It is clearly established (16) that This work was supported by the Wellcome Trust, the British Technology Group, and the Medical Research Council.Abbreviations used in this paper: HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.J. EXl'. MEt).
Human IgG subclasses differ in their biologic functions and are restricted as specific antibodies to certain Ag. The basis for this restriction is unknown but in order to characterize it further, we obtained serum preparations containing one single subclass by using subclass-specific mAb in affinity chromatography. Subsequently we determined the affinity of antibodies in the four IgG subclasses for gp30/p25, a hepatitis B surface Ag (HBsAg) complex, for a nine-amino acid cyclical peptide representing residues 139 to 147 of HBsAg, and for a peptide representing residues 126 to 140 of the hepatitis B virus pre-S2 region and the relative avidity of IgG1 and IgG2 antibodies for purified pneumococcal polysaccharide type 3. Affinities to the HBsAg showed a clear pattern of decreasing affinity in the order IgG1 greater than IgG2 greater than IgG3 greater than IgG4 both in sera from vaccinated and from naturally infected individuals. The relative avidities of antibodies to the polysaccharide Ag had a reverse pattern, IgG2 greater than IgG1. In individuals with or without Ig H chain gene deletions where the anti-HBsAg response was restricted to one subclass, the affinity was similar to that observed for the same subclass in sera from individuals who in addition possessed high or low affinity antibodies of other subclasses.
Background Biologic therapy has significantly improved treatment for UC, but nearly two-thirds of patients attenuate the response. Additional therapeutic modalities are therefore needed to address the underlying pathophysiology of UC. Faecal microbiota transplant (FMT) is an emerging therapy for the treatment of UC, but several randomised controlled trials have shown variable efficacy of FMT, and the microbial mechanisms responsible for clinical response are not well understood. Therefore, using samples from our pilot FMT study (Jacob, V, et al. Inflamm. Bowel Dis. 2017), we aim to identify the core transferable microbiota (CTM) in UC patients responsive to FMT therapy and to define the therapeutic mechanism of these strains in pre-clinical models. Methods IBD disease activity scores were used to define a clinical response. Metagenomic sequencing of a donor, recipient, and 4-week post-FMT faecal samples was performed to define the CTM. Strain-level transferability was defined using the StrainFinder algorithm. To define the transferable immune-reactive microbiota (TIM), IgA-seq was performed on a donor, recipient, and 4-week post-FMT faecal samples. TIM strains were isolated from faecal samples and gnotobiotic mouse models were used to evaluate their impact on mucosal immunity and mouse models of colitis. Results Here, we defined a CTM associated with clinical response to FMT for UC. Strain-level tracking of the CTM confirmed that clinical response correlated with strain transferability. In addition, we defined a core TIM by IgA-seq that correlated with clinical response. In humanised mouse models, these TIM were found to induce IgA in a T-cell independent manner. Colonisation of germ-free mice with a core TIM strain of Odoribacter induced IL-10-dependent, RORgt+/Foxp3+ iTreg cells and reduced the severity of transfer T-cell colitis in mono-colonised RAG−/− mice. Conclusion Our data highlight an immune-reactive, core transferable microbiota in responders to FMT for UC. Using pre-clinical mouse models of colitis, we define the mechanistic impact of these TIM in shaping mucosal immunity and guiding the response to UC. This work provides a framework for the rational selection of TIM for microbial-therapy in IBD.
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