Ulla Hellström

Antibody responses to preS components after immunization of children with low doses of BioHepB.

BioHepB is a recombinant, hepatitis B vaccine derived from a mammalian cell line and containing HBs as well as preS1 and preS2 antigens, in their glycosylated and non-glycosylated forms. The vaccine was administered intramuscularly to 18 children aged 5 months to 11 years at 0, 1 and 6 months. One hundred percent seroconversion and seroprotection rates were achieved after primary and secondary immunization with the 2.5 microg doses of BioHepB. Ten out of the 18 children (56%) responded with the appearance of anti-preS1 and/or anti-preS2 antibodies in circulation, when analyzed 1, 2, 6, 7 and 12 months after the initiation of vaccination. In comparison with the emergence of the anti-HBs response, early (month 2, after two injections) or late (month 7, after three injections) peak responses were noted for the kinetics of anti-preS1 and anti-preS2 production during the course of immunization, demonstrating that the anti-preS1 and anti-preS2 responses are differently regulated, compared with the anti-HBs response. At month 6, just prior to the final injection, BioHepB caused significantly higher anti-HBs responses (GMT) in preS1-reactive children than in children without preS1 antibodies (P<0.005). Moreover, a significantly higher, anti-HBs response in GMT was also noted for anti-preS2-reactive children compared with anti-preS2-negative children (P<0.05). These findings demonstrated that recognition of the preS epitopes contained in the experimental preS1/preS2/S vaccine is accompanied by a more rapid onset and pronounced antibody response to the S-gene-derived protein in healthy children.

Circulating Cholera Antitoxin Memory Cells in the Blood One Year after Oral Cholera Vaccination in Humans

Oral vaccination with the combined B subunit/whole cell cholera vaccine generates antitoxin memory cells that could be isolated from peripheral blood for at least 1 year after immunization. These memory cells were triggered by antigen in vitro to produce antitoxin in the presence of autologous T cells and monocytes. Antitoxin‐producing peripheral blood lymphotes (PBL) were found in 4 out of 5 previously vaccinated subjects. IgA and IgM isotypes dominated the momery response. The antigen‐dose dependency and requirement for a specific ratio of T to B cells for activation of the memory cells in vitro implies T‐cell control of antitoxin responses. These antitoxin memory cells in peripheral blood (and corresponding antibacterial memory cells) might represent it pool of circulating cells that on renewed exposure to cholera rapidly produce protective antibody in the gut and thus might have a central role in the long‐term protection against reinfection and disease seen in convalescents from cholera.

Impact of a vaccination campaign on adult immunity to diphtheria

OBJECTIVES to raise the level of immunity to diphtheria in the adult population of Stockholm by a vaccination campaign. The rationale behind the campaign, conducted during 1995-1996, was the re-emergence of epidemic diphtheria in the countries of the former Soviet Union and earlier surveys of immunity to diphtheria showing low levels of protection in adults. DESIGN AND MAIN OUTCOME MEASURES the impact of the vaccination campaign was measured by recording the age and sex of vaccinees, the type and number of vaccine doses given and any side-effects. The effect on immunity was evaluated in 1998-1999 by measuring the neutralising antibodies in blood samples from 1863 inhabitants, chosen by random stratified sampling. Vaccines and vaccinations: three doses of diphtheria (D) or diphtheria-tetanus (DT) vaccine were given to those without documented previous vaccination; others received a booster dose. The DT vaccine, with the D component purified before toxoiding, contained 15 Lf of D and 7.5 Lf of T per ml, and was given in 0.5 ml doses for the two priming doses and 0.25 ml as booster. RESULTS 184969 doses of D or DT vaccine were given to 99939 individuals. Of the vaccinees, 65% were 50 years of age or older and 60% were women. The highest rates of reported local reactions were 1.8-5.4% and of systemic reactions, such as fever, 0.2-0.8%. The campaign resulted in a significant increase in antitoxin concentrations in the age cohorts targeted, and especially in women, less well protected than men. CONCLUSIONS a vaccination campaign, targeting the adult part of a population, can result in a major improvement in immunity to diphtheria with only a few and minor side-effects with a DT vaccine where the D component was purified prior to toxoiding. Extending national immunisation programmes to include adults would, however, seem preferable.

Demonstration of an association between detection of IgG antibody reactivity towards the C-terminal region of the preS1 protein of hepatitis B virus and the capacity to respond to interferon therapy in chronic hepatitis B

Background and Aim:  The treatment of hepatitis B virus (HBV) remains complex, with somewhat unpredictable responses. The aim of this study was to determine the predictive value of the pretreatment presence of circulatory antibodies towards a synthetic peptide mimicking the amino acids 94–117 of the preS1 protein of HBV and the capacity to respond to alpha‐inteferon (IFN‐alpha) treatment.

Modulation of Serum Interleukin-18 Concentrations and Hepatitis B Virus DNA Levels During Interferon Therapy in Patients with Hepatitis B e-Antigen-Positive Chronic Hepatitis B

The aim of this study was (1) to determine plasma values of interleukin-18 (IL-18) in patients with different clinical manifestations of hepatitis B (HB) and (2) to analyze the correlation between presence of circulatory levels of IL-18 and levels of HB virus (HBV) DNA during interferon-alpha (IFN-α)-induced HBe seroconversion in patients with chronic HB (CHB). The IL-18 levels in serum did not significantly differ between healthy control subjects (99 ± 25 pg/mL), HB-immune patients (85 ± 33), and asymptomatic carriers of HB surface antigen (144 ± 44 pg/mL). In contrast, anti-HBe (HBV DNA <10⁴ copies/mL, 555 ± 248, P < 0.05), anti-HBe (HBV DNA >10⁴ copies/mL, 280 ± 85, P < 0.05), and HBe-antigen-reactive (373 ± 108, P < 0.0001) patients with symptomatic CHB had significantly elevated levels in circulation compared with healthy control subjects (99 ± 25 pg/mL). An inverse correlation was found between serum HBV DNA copies and IL-18 levels during therapy (r = -0.54, P < 0.001). We consistently observed an IFN-α-induced suppression of viral replication, which was followed by the alanine aminotransferase (ALT) flare. There was a significant increase in IL-18 production after the ALT flare, where the peak of IL-18 preceded or coincided with the time of HBe seroconversion in patients who cleared the virus. These results suggest that IL-18 is involved in the pathogenesis of CHB and that IFN-α therapy can augment the production of IL-18 in patients with CHB.

Regulation of the immune response to hepatitis B virus and human serum albumin. III: Induction of anti-albumin antibody secretion in vitro by C-gene-derived proteins in peripheral B cells from chronic carriers of HBsAg

The circulatory pool of B cells from the majority (11/13) of chronic hepatitis B surface antigen (HBsAg) carriers contained sensitized B cells with the capacity to secrete IgG antibodies with specificity for human serum albumin (HSA), when stimulated with E, coli‐derived core protein at low concentrations in vitro. The IgG anti‐USA secretion was dependent upon and regulated by T cells, and optimal secretion was obtained at T/B‐cell ratios of 1.0–4.0, varying for different individuals. The level of anti‐HSA secretion was higher for patients with on‐going viral replication as assessed by hepatitis B virus (HBV)‐DNA in serum. Culture supernatants containing anti‐HSA antibodies also contained anti‐HBc antibodies, as detected by enzyme‐linked immunosorbent assay (ELISA) where the solid phase was charged with E. coli‐derived core protein, or the synthetic peptides corresponding to the 75–84 and 132–147 sequences in the C region of HBV, In contrast, IgG anti‐HBc (E. coli‐derived), but no anti‐MSA or anti‐HBc 75–84, 132–147 antibodies, were detected at similar T/B‐cell ratios in cell cultures from 56 individuals with naturally acquired immunity to hepatitis B. These data indicate that peripheral B cells from the majority of HB‐immune donors are sensitized lo unique (e.g. non‐albumin associated) structures in the nucleocapsid of HBV, while B cells in the majority of chronic HBsAg carriers are sensitized to linear C‐gene‐derived structures in association with the host ‘self’ ‐component HSA.