Hepatitis B: a scientific success story (almost).
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Animals↗
Biomedical subjects
R H Purcell
Publications and source records attributed to R H Purcell.
Prevention of perinatal acquisition of hepatitis B virus carriage using vaccine: preliminary report of a randomized, double-blind placebo-controlled and comparative trial.
Hepatitis B is a serious disease of global significance. In developing countries, hepatitis B virus (HBV) infection and its sequelae rank among the public health problems of highest priority. Infants born to mothers who are chronic carriers of HBV are at particularly high risk of acquiring infection and becoming chronic HBV carriers. The efficacy of hepatitis B vaccine alone in preventing the transmission of HBV to infants born to HBV carrier mothers was determined in a double-blind placebo-controlled trial. Infants received plasma-derived vaccine at birth, 1 month, and 6 months of age. Of 180 infants born to hepatitis B surface antigen (HBsAg)-positive mothers, equal numbers received National Institute of Allergy and Infectious Disease (NIAID) vaccine, Beijing Institute of Vaccine and Serum (BIVS) vaccine, and placebo. The cumulative seroconversion to the vaccines at 1 year of age was 95% and 75%, respectively. Vaccine efficacy as measured by the prevention of HBsAg-positive events was 88% for the NIAID vaccine and 51% for the BIVS vaccine. Vaccine efficacy was similar among infants born to hepatitis Be antigen-positive mothers. Because of the low efficacy of the BIVS vaccine, an additional group of 28 infants was given vaccine and hepatitis B immune globulin at birth. The resulting efficacy was 83%. The results of this trial indicate that hepatitis B vaccine alone can substantially reduce perinatally acquired HBV infection and the resulting chronic carrier state.
Carrier State↗
Prevention of hepatitis B virus carriage of infants using HBV vaccine in Shanghai. Preliminary report of a randomized double-blind placebo-controlled trial.
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Carrier State↗
Experimental infection of chimpanzees with the HBsAg-associated delta (delta) agent: an ultrastructural study.
Characteristic cytoplasmic membranous structures and intranuclear aggregates of particles similar to those reported in non-A, non-B hepatitis were observed by electron microscopy in the liver biopsies of chimpanzees inoculated with human serum, infectious for the delta agent. The ultrastructural changes were maximal during the intrahepatic production of the delta antigen, but were detected also independently of delta-Ag expression. The ultrastructural analogies provide further evidence that delta has properties distinct from HBV.
Alanine Transaminase↗
Activation of human peripheral blood B cells following immunization with hepatitis B surface antigen vaccine.
To further evaluate the human immune response to hepatitis B surface antigen (HBsAg), we used an enzyme-linked immunosorbent assay to measure the in vitro production of antibody to HBsAg in normal individuals following booster immunization with the HBsAg vaccine. Following booster immunization, cells spontaneously secreting antibody to HBsAg were present in the peripheral blood. The specific antibody production was first detectable 4 days after booster immunization. The peak of specific antibody production was on Day 6, with resolution of the response by Day 9. The presence of these spontaneously secreting cells in the peripheral blood precedes the rise in serum antibody levels to HBsAg. The antibody secretion does not require the presence of accessory cells and is not enhanced by pokeweed mitogen, suggesting that these cells are quite advanced in the B-cell maturation sequence. The significance of these observations is discussed. Understanding the human immune response to HBsAg vaccine should provide insights into the immune regulatory abnormalities associated with disease states characterized by chronic hepatitis B antigenemia, including cryoglobulinemia, polyarteritis nodosa, and chronic hepatitis.
Adult↗
Hepatitis delta virus infection of the liver.
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Animals↗
Transmission of the hepatitis B virus-associated delta agent to the eastern woodchuck.
delta agent of human origin was inoculated into four woodchucks chronically infected with woodchuck hepatitis virus (WHV). The animals developed delta infections with serologic patterns similar to those previously observed in human and chimpanzee infections. delta antigen was detected transiently in serum and liver and was followed by seroconversion to anti-delta antibody. Analogous to the chimpanzee model of delta infection, serum and hepatocyte markers of WHV were suppressed in the woodchuck during acute delta infection. The suppression of WHV DNA in serum was evident only during the time of delta-antigen positivity, while the inhibition of other WHV markers was more protracted. The delta antigen in woodchuck sera circulated as an internal component of a particle similar in size to the human delta particle (36-nm diameter) and was encapsidated by the woodchuck hepatitis virus surface antigen; delta antigen from infected woodchuck and chimpanzee livers had similar biophysical properties. Histologic analysis showed that experimental delta infection is associated with a transient acute hepatitis in woodchucks and loss of hepatocytes carrying WHV antigens. The lesions differed from the conspicuous hepatitis associated with reappearance of WHV replication. Hepatitis B-like viruses, therefore, appear to provide the requisite helper functions for delta replication and the woodchuck represents a useful model for study of the virology and pathology of the delta agent.
Animal Diseases↗
Delta hepatitis agent: structural and antigenic properties of the delta-associated particle.
Delta agent (delta) was serially passaged to a second and third hepatitis B surface antigen (HBsAg) carrier chimpanzee, using as inoculum the peak delta antigen (delta Ag) serum of an animal previously infected with human serum. The characteristics of serially transmitted delta Ag were similar to those described in first-passage animals. It was consistently detected before the development of anti-delta, in association with a 35- to 37-nm subpopulation of HBsAg particles and a unique low-molecular-weight (5.5 X 10(5)) RNA. RNase susceptibility of the delta-associated RNA and release of delta Ag activity upon treatment of delta-associated particles with detergent revealed that this particle is organized into a virion-like form with the RNA and delta Ag as internal components within a coat of HBsAg. Surface determinants of the delta-associated particle other than HBsAg were not detected by radioimmunoprecipitation experiments, using sera of humans and chimpanzees convalescent from delta hepatitis. The HBsAg-associated particle is the "candidate agent" of delta hepatitis.
Animals↗
Core antigen and antibody in woodchucks after infection with woodchuck hepatitis virus.
The woodchuck hepatitis virus is a naturally occurring hepatitis B-like virus that infects the eastern woodchuck. Direct immunofluorescence staining for woodchuck hepatitis virus core antigen in liver biopsies demonstrated the presence of this antigen in 14 of 17 chronically infected woodchucks, and in 8 of 10 woodchucks undergoing acute infections. Fluorescent localization of woodchuck hepatitis virus core antigen was typically cytoplasmic, and this was confirmed further by electron microscopy. Experimental infection with woodchuck hepatitis virus was achieved in four of four woodchucks inoculated with serum from chronic carrier woodchucks. All infected animals developed a self-limited disease characterized by seroconversion to antibodies against the major viral antigens (core and surface antigens); naturally acquired acute infection demonstrated a similar course. A chimpanzee seronegative for all markers of hepatitis B virus developed a subclinical infection after inoculation with woodchuck hepatitis virus.
Animals↗
In vitro antigen-induced antibody responses to hepatitis B surface antigen in man. Kinetic and cellular requirements.
In this report we define the parameters of the human immune response after immunization with hepatitis B vaccine. 2 wk after booster immunization, there is significant spontaneous secretion of antibody to hepatitis B surface antigen (anti-HBs IgG), which is not further augmented by stimulation with antigen or pokeweed mitogen (PWM). By 4 wk there is little spontaneous secretion of specific antibody, and low doses of antigen or PWM produce significant increases in the amount of anti-HBs IgG produced. By 8 wk the peripheral blood mononuclear cells are refractory to stimulation by antigen, but anti-HBs IgG is produced in response to PWM. 0.5 yr or more after the last immunization, some individuals will manifest an antigen-induced specific antibody response. This induction of anti-HBs IgG by hepatitis B surface antigen (HBsAg) is monocyte- and T cell-dependent. Note that there is a dichotomy in the T cell response to HBsAg. The specific antibody response is clearly T cell dependent, but no in vitro T cell proliferative response to HBsAG could be demonstrated in the immunized individuals. Although the precise reason for the absent proliferative response to HBsAg despite well-established humoral immunity has not been determined, there was no evidence to suggest nonspecific suppression by HBsAg or the presence of an adherent suppressor cell population. The ability to evaluate antigen-induced, antigen-specific responses to HBsAg will be useful in defining the unique interaction between the human immune response and this clinically important viral agent.
Adult↗
Cell-mediated immunity to hepatitis B surface antigen in man.
An aqueous preparation of hepatitis B virus (HBV) vaccine was used as an intradermal skin test antigen to assess delayed hypersensitivity to hepatitis B surface antigen (HBsAg). Thirty-five persons were tested including 10 individuals seronegative for all HBV markers, 10 positive for HBsAg (chronic carriers) and 15 positive for antibody to HBsAg (anti-HBs), five of whom had received the HBV vaccine. All patients were also studied for lymphocyte blastogenic responses to phytohaemagglutinin, concanavalin A, pokeweed mitogen and purified HBsAg. Only one individual had a positive delayed skin test reaction to HBsAg. This person had received the HBV vaccine and had high titres of anti-HBs in serum. However, neither this individual nor any other subject exhibited a positive lymphocyte blastogenic response to HBsAg in vitro. Thus, delayed hypersensitivity skin test reactivity to HBsAg was not detected after natural infection with HBV and was rarely present in hyperimmunized individuals. In vitro assays of immune responsiveness failed to demonstrate cellular immunity to HBsAg even in hyperimmunized persons. These studies provide no evidence that cell-mediated immunity to HBsAg plays a role in the immunopathogenesis of acute or chronic type B hepatitis.
Carrier State↗
A dot hybridisation assay for detection of rotavirus.
A "dot" hybridisation technique for the detection of rotavirus in stools and other biological materials is described. The assay is based on the in-situ hybridisation of labelled single-stranded RNA probes, obtained by in-vitro transcription of rotavirus particles, to heat-denatured rotavirus RNA immobilised on nitrocellulose membranes. The method is highly specific and allows for the detection of as little as 8 pg of viral RNA. Its use for the detection of rotavirus in stool suspensions and rectal swabs obtained from children with diarrhoea may facilitate epidemiological studies of rotavirus gastroenteritis.
Child↗
Molecular cloning and characterization of hepatitis A virus cDNA.
Double-stranded cDNA was synthesized from hepatitis A virus (HAV) RNA and inserted into the Pst I site of pBR322. Restriction endonuclease digestion and cross-hybridization of fragments yielded a map of overlapping cloned cDNAs that included at least 99% of the viral genome. Molecular clones containing HAV cDNA were identified by hybridizing cloned cDNA to electrophoretically resolved RNA from uninfected and HAV-infected tissue culture cells. Cloned cDNA probes specifically hybridized to RNA from infected cells, and the predominant species identified had the characteristic genomic length of picornaviral RNA (approximately equal to 7,500 nucleotides). A partial sequence from the 3' end of the genome revealed 414 bases in an open reading frame followed by two closely spaced stop codons, a 60-base noncoding region, and a tract of poly(A).
Amino Acid Sequence↗
Chemically synthesized peptides of hepatitis B surface antigen duplicate the d/y specificities and induce subtype-specific antibodies in chimpanzees.
Synthetic peptides, predicted from the nucleotide sequence of the S gene of hepatitis B virus were analyzed in terms of the established specificities of the hepatitis B surface antigen. The analysis indicated that the group-specific alpha antigen is composed of at least three nonoverlapping sequences and that a relatively hydrophilic region of the surface antigen protein, spanning amino acid residues 110-137, specifies the major d and y subtype system. The d/y subtype appears to depend on changes in one or more variable amino acids at positions 127, 131, and 134 of the hepatitis B surface antigen protein. Peptide 49 (consisting of amino acid sequences of the y subtype for the region 110-137), coupled to a carrier protein and mixed with an adjuvant, stimulated a brisk anti-y response in chimpanzees, the relevant model of human response to hepatitis B virus immunization and infection. Experimental challenge with homologous hepatitis B virus resulted in a pattern of partial protection. The results offer promise for the application of chemically synthesized peptides as vaccines in the prophylaxis of hepatitis B virus disease.
Amino Acid Sequence↗
Use of and interpretation of results using inocula of hepatitis B virus with known infectivity titers.
The infectivity of three inocula (subtypes ayw, adr, and adw) of hepatitis B virus was evaluated by intravenous inoculation of 54 chimpanzees. End-point infectivity titers were 10(-7.5) (ayw), 10(-8.0) (adr), and 10(-7.0) (adw). In contrast, the end-point titers for detection of hepatitis B surface antigen by radioimmunoassay were 10(-4) (ayw), 10(-4) (adr), and 10(-5) (adw). The mean incubation period for infections transmitted by each dilution of each of the inocula was inversely proportional to the amount of infectious virus in the dilution, but substantial overlap was observed among proximate dilutions. The severity of hepatitis in the chimpanzees differed among the inocula, but it was unrelated to the amount of virus inoculated. Thus, conclusions about the infectivity of hepatitis B virus after inactivation based on titers of hepatitis B surface antigen or on the inverse relationship between the incubation period and the end-point infectivity titer must be made with caution.
Animals↗
IgM antibody responses to hepatitis B surface antigen in recipients of hepatitis B virus vaccine.
Both total anti-HBs and specific IgM anti-HBs were assayed in sequential serum specimens from five healthy volunteers receiving a primary immunization with the HBV vaccine. Four of the five subjects developed anti-HBs in the six-week period following primary immunization. Anti-HBs was first detectable between days 4 and 21 after initiation of vaccination. Specific IgM anti-HBs was detectable in all four patients who responded to the initial inoculation. This antibody was often present before anti-HBs was detectable by the conventional RIA. However, the titers of IgM anti-HBs were invariably low, and this antibody response was short lived (less than 21 days). The lack of a vigorous and sustained IgM antibody response to HBsAg has also been noted after infection with HBV [1, 2]. This observation is in marked contrast to the magnitude of IgM response to hepatitis B core antigen, which is detectable in high titers during acute HBV infection and persists for months to years after the disease has resolved [2, 3]. The significance of the weak IgM antibody response to HBsAg during both immunization with HBV vaccine and HBV infection is not known but may be related to the relatively low immunogenicity of HBsAg. This weak IgM antibody response may play a role in the propensity of persons with HBV infection to develop the chronic HBsAg carrier state.
Antibodies, Viral↗
Nuclear antigen detected in hepatoma cell lines containing integrated hepatitis B virus DNA.
We identified, by anticomplement immunofluorescence, a nuclear antigen (hepatitis B virus-associated nuclear antigen [HBNA]) in two human hepatoma cell lines containing integrated hepatitis B virus DNA but not in three hepatoma cell lines lacking it. The antigen resembled neoantigens associated with the oncogenesis of certain papovaviruses, adenoviruses, and herpesviruses. Antibody to the antigen (anti-HBNA) was found in 7.3% of hepatitis B surface antigen-positive sera from patients with hepatocellular carcinoma but not in surface antigen-negative sera. The staining of HBNA was characterized by two patterns, reticular nuclear fluorescence and nucleolar fluorescence. The expression of HBNA did not parallel the production of extracellular hepatitis B surface antigen. Treatment of cells with proteinase K, RNase, DNase, or cycloheximide significantly diminished the staining of HBNA.
Animals↗
Inactivation of hepatitis B virus and non-A, non-B hepatitis by chloroform.
To determine whether a non-A, non-B hepatitis agent contained essential lipids, we extracted with chloroform a dilution of human plasma that contained approximately 10(4) chimpanzee infectious doses of non-A, non-B hepatitis virus and then tested for infectivity in chimpanzees. In addition, we treated a serum containing hepatitis B virus in the same way. Both of these samples were also sham extracted as controls. Known chloroform-sensitive and chloroform-resistant viruses were added directly to the hepatitis-containing serum or plasma as internal controls or to fetal calf serum as external controls and were assayed for infectivity in vitro after chloroform extraction or sham extraction. All infectivity of the diluted plasma that contained at least 10(4) chimpanzee infective doses of non-A, non-B hepatitis agent and all infectivity of the serum that contained 10(3.5) chimpanzee infective doses of hepatitis B virus were destroyed by chloroform. The chloroform-sensitive control viruses were completely inactivated, but the chloroform-resistant control viruses lost less than 0.5 log10 of infectivity. Sham-extracted non-A, non-B hepatitis agent-containing plasma was shown to maintain its infectivity in chimpanzees that had initially been inoculated with the chloroform-extracted plasma. Thus, both hepatitis type B and non-A, non-B hepatitis appear to be caused by viruses that can be inactivated by a lipid solvent.
Animals↗