Tolerance and immunogenicity of the simultaneous administration of virosome hepatitis A and yellow fever vaccines.

BACKGROUND: The purpose of this study was to evaluate the tolerance and immunogenicity of a hepatitis A vaccine using immunopotentiating reconstituted influenza virosomes (IRIV) as adjuvant when administered simultaneously with a yellow fever vaccine (YFV). METHOD: An open prospective trial with two parallel groups was conducted with 105 volunteers to study the effect of these vaccinations on the anti-hepatitis A virus (HAV) antibody response. Half of the volunteers (53) received one dose of IRIV-HAV vaccine (Epaxal) and one dose of live attenuated YFV (Stamaril) on the same day at two different sites. Fifty-six volunteers were given a single injection of IRIV-HAV as a control group. Anti-HAV titers were measured at days 14, 28, months 3, 12, 13, and 24 using a standardized test (Enzymun test Anti-HAV). Neutralizing yellow fever antibodies were measured at days 14 and 28 for the YFV recipients. Regarding vaccine tolerance, the volunteers were asked to record all their adverse reactions on a standard report sheet for the 6 days following the immunization. RESULTS: Seroconversion rates for HAV were 88% after 14 days and 100% after 4 weeks. There was no statistically significant difference between the two groups every time the titers were checked (IRIV-HAV vs HAV only: D14: 81 vs 101; D28: 275 vs 368; M3: 153 vs 169; M12: 117 vs 226; geometrical mean titers (GMT) in mIU/mL). However, lower titers were found among male volunteers, and were not attributable to YFV administration. The seroconversion rates for YFV were 90% after 14 days and 96% after 4 weeks. No serious general side-effects and only mild local reactions were reported. The administration of a booster of IRIV-HAV at 12 months resulted in a 24-fold increase in GMT. CONCLUSION: When needed, the simultaneous administration of the IRIV-HAV and YFV is immunogenic, safe and well-tolerated, as volunteers seroconverted to both antigens, with no cross-interference.

Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients.

The safety and immunogenicity of a commercial trivalent subunit influenza vaccine and an experimental virosome-formulated influenza vaccine were evaluated among geriatric patients in a double-blind, randomized manner. The virosome vaccine was produced by incorporating hemagglutinin (HA) into the membrane of liposomes composed of phosphatidylcholine. Both vaccines elicited a significant (P < 0.01) rise in the geometric mean anti-HA antibody titer to all three vaccine components 1 month after immunization. However, significantly (P < 0.005) more subjects vaccinated with the virosome preparation mounted a more than fourfold rise to the A/Singapore and A/Beijing strains compared with those who received subunit vaccine. The percentage of patients who attained protective levels (anti-HA titer > or = 40) of anti-A/Beijing antibody was also significantly (P < 0.005) higher in the virosome group. Subjects who possessed non-protective baseline antibody levels to the A/Singapore and A/Beijing strains were more likely (P < 0.005-0.030) to achieve protective levels after immunization with the virosome vaccine than with the subunit vaccine. Of particular clinical significance was the fact that 68.4% of subjects immunized with the virosome vaccine attained protective levels of antibody to all three vaccine components versus 38% for the subunit vaccine (P = 0.010).

Immunogenicity and protectivity of a new liposomal hepatitis A vaccine.

In this study we investigated a new liposomal hepatitis A vaccine (Epaxal) developed by the Swiss Serum and Vaccine Institute clinically and immunologically using a one dose priming schedule and a booster injection after 1 year. This vaccine contains formalin inactivated hepatitis A virus particles attached to phospholipid vesicles together with influenza virus haemagglutinin. Two doses of the vaccine were administered at months 0 and 12 in 117 volunteers. Blood samples were drawn at days-7, 14 and 28 and after 6, 12 and 13 months, local and systemic reactions were monitored by means of questionnaires. Immunogenicity was evaluated as usual by the determination of anti-HAV from the collected sera using the ELISA technique. In order to evaluate the protective efficacy of the vaccine induced antibodies a sample of 25 sera mainly from vaccinees showing low ELISA titres was additionally analysed by means of a virus NT. The vaccine was excellently tolerable and highly immunogenic. Seroconversion evaluated by ELISA was 97 and 99%, respectively, 14 and 28 days after the first dose and 100% after the second dose. NT titres were well correlated with ELISA titres and showed similar seroconversion rates even in the early phase of immunization. The results of this study show that with two doses of the liposomal hepatitis A vaccine administered at months 0 and 12 early protection within 14 days and long lasting immunity can be achieved.

Immunogenicity and adverse effects of inactivated virosome versus alum-adsorbed hepatitis A vaccine: a randomized controlled trial.

Immunogenicity and adverse effects of a novel inactivated hepatitis A vaccine based on virosomes (IRIV-HAV) was compared with a standard vaccine adsorbed to aluminium (Al-HAV). Seronegative volunteers (n = 301) were randomly allocated to one injection of IRIV-HAV or to two injections of Al-HAV, followed by a booster injection at 12 months. Two hundred and ninety-eight (99%) completed the first month and 215 (71%) could be evaluated at 1 year. Geometric mean antibody concentrations at days 0, 14 and at 12 months were similar in the two vaccine groups. Lower antibody concentrations were recorded with IRIV-HAV at day 28 (P < 0.0001) and at 13 months (P = 0.02). Seroconversion to protective antibody levels, however, was similar (98% at day 28, 94% at 12 months, 100% at 13 months). Local adverse effects were reported in 17% with IRIV-HAV but in 66% with Al-HAV (P < 0.0001) after the initial vaccination and in 32% and 42% following the booster vaccination (P = 0.05). In conclusion, IRIV-HAV may provide similar protection but cause less local adverse effects.

[Immune response to a single dose of a novel kind of hepatitis A vaccine following splenectomy]. / Immunantwort einer Einzeldosis eines neuartigen Hepatitis-A-Impfstoffes nach Splenektomie.

BASIC PROBLEM AND OBJECTIVE: The immune response to parenteral antigens is reduced in persons without spleen. The seroconversion rate was measured after application of a new type of vaccine against hepatitis A (immunopotentiating reconstituted influenza virus virosome [IRIV]) in patients who had undergone a splenectomy after trauma. PATIENTS AND METHODS: 26 patients (23 men and 3 women, mean age 34.9 +/- 9.7 [25-65] years) with anti-hepatitis A virus (HAV) antibody titres < 20 mIU/ml (maximally 17 mIU/ml) were given a single dose of 0.5 ml of the IRIV hepatitis A vaccine 1 to 14 (mean 9.4) years after splenectomy. Immediately after the immunisation and 14 and 28 days afterwards anti-HAV titres were determined. A titre rise to < 20 mIU/ml was counted as seroconversion. At the first and last titre measurement immunoglobulins, neopterin and beta-microglobulin levels were also measured as additional markers. RESULTS: The seroconversion rate was 69.2% (18/26) after 14 days (geometric titre mean: 39 mIU/ml) and rose to 88.5% (23/26) after 28 days (geometric titre mean 74 mIU/ml). Seroconversion occurred in the three nonresponders after a second dose of the vaccine. All measurements of the immunological markers were within normal limits. CONCLUSION: A single dose of a new type of vaccine against hepatitis A confers adequate protection even in those persons who had a splenectomy.

Antifungal prophylaxis in bone marrow transplant.

The benefits of fungal prophylaxis with fluconazole in BMT patients appear to outweigh the risks of a possible increase in colonization and infection by C. krusei or T. glabrata. Disseminated fungal infections caused by C. tropicalis and C. albicans have a 38.8% mortality rate, and these infections may be prevented by the prophylactic use of fluconazole. C. krusei and T. glabrata infections generally do not contribute to increased mortality, and most patients infected by these organisms recover after appropriate antifungal therapy. The use of amphotericin B as prophylaxis may have some efficacy. One retrospective study found low-dose amphotericin B therapy to be effective in preventing Candida infections, but results from a placebo-controlled, randomized prospective trial with 0.1 mg/kg/d failed to support this claim. Low-dose amphotericin B prophylaxis (0.1-0.25 mg/kg/d) shows promise against aspergillosis, an opportunistic infection associated with high morbidity and mortality. The literature suggests the possible value of using oral or intravenous fluconazole 200-400 mg/d or intravenous amphotericin B 0.1-0.25 mg/kg/d as antifungal prophylaxis in patients after autologous or allogeneic BMT. Many questions remain unanswered, however. These studies described the potential decrease in morbidity and mortality of BMT patients with the use of either fluconazole or amphotericin B, but it is not known whether all patients after BMT or only those at high risk of fungal infection may benefit from prophylaxis. Optimal dosing of either antifungal agent has not been defined in the studies. Clinicians should be aware of the possible increase in colonization by less pathogenic fungal species, such as C. krusel and T. glabrata, when prescribing fluconazole prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and immunogenicity of a V3 loop synthetic peptide conjugated to purified protein derivative in HIV-seronegative volunteers.

OBJECTIVES: To develop a peptide-based model for a preventive vaccine for HIV-1 infection. DESIGN: Phase I trial in HIV-1-seronegative volunteers. PARTICIPANTS: Adult healthy subjects HIV-1-antibody-seronegative in an enzyme-linked immunosorbent assay, screened for tuberculin [purified protein derivative (PPD)] reactivity with 2 tuberculin units PPD-administered intradermally. INTERVENTIONS: Submicrogram doses of a PPD conjugate with a peptide of the primary neutralizing domain (PND) of HIV-1MN (PPD-MN-PND) were administered intradermally to tuberculin skin-test-positive and -negative volunteers. RESULTS: Antibodies to the MN-PND were measured after two immunizations in 10 out of 11 PPD skin-test-positive volunteers. After the fourth immunization high-affinity antibodies were detected, which persisted for over 1 year. High titers of MN-PND-specific immunoglobulin (Ig) G and IgA were detected in the serum and saliva of all volunteers tested. Serum antibodies were cross-reactive with PND peptide from some other HIV-1 strains but neutralized only the HIV-1MN prototype. Human leukocyte antigen (HLA)-B7-restricted MN-PND-specific cytotoxic T lymphocytes (CTL) were also detected. CONCLUSIONS: The PPD-MN-PND vaccine at submicrogram doses is safe and immunogenic in PPD skin-test-positive healthy adult volunteers. Long lasting humoral immune responses in the serum and saliva were possibly accompanied by HLA-B7-restricted CTL responses. This is a vaccine prototype that can be rapidly and inexpensively modified to include other peptide epitopes. It is especially suitable for use in a worldwide multibillion Bacillus Calmette-Guérin (BCG)-primed or tuberculosis-exposed population at risk for HIV-1 infection.

Inactivated virosome hepatitis A vaccine.

Immunopotentiating reconstituted influenza virosomes (IRIV) are efficient carrier systems for small virion particles such as hepatitis A virus (HAV). We evaluated immunogenicity and tolerability of an IRIV-HAV vaccine and the effectiveness of a booster by immunising 104 healthy HAV seronegative volunteers. A single dose was highly immunogenic, since 98% of volunteers had seroconverted after 2 weeks. Anti-HAV titres remained high, with 100% seroconversion rate 1 year later, when the booster was given. The vaccine was effective, with a 22-fold increase in geometric mean titres 1 month later. No serious adverse reactions were observed.

Time course of hepatitis A antibody production after active, passive and active/passive immunisation: the results are highly dependent on the antibody test system used.

Two commercially available automated test systems for hepatitis A antibody, HAVAB IMX (Abbott) and ENZYMUN Anti-HAV (Boehringer) were evaluated in a study of active, passive and active/passive immunisation against hepatitis A. The inactivated hepatitis A vaccine Epaxal Berna and the hepatitis A immunoglobulin preparation Globuman were products of the Swiss Serum and Vaccine Institute. Although both hepatitis A antibody test kits were standardised with the same international WHO standard hepatitis A immunoglobulin preparation, divergent results were obtained for the level of circulating hepatitis A antibody after vaccination. One month after the vaccination the mean geometric antibody titres were 315 mIU/ml after active, 253 mIU after active/passive and 22 mIU after passive immunisation when measured with the Enzymun assay. In the same sera 70 mIU/ml after active, 60 mIU after active/passive and 18 mIU after passive immunisation could be detected with the IMX test. Antibody avidity studies could not explain the differences obtained by the two test methods. The neutralization test is the standard method for the estimation of protection against hepatitis A. This test is not suitable for large series of serum samples, and enzyme immunoassays are indispensable for vaccination studies. To be suitable for monitoring antibody development in phase I and II clinical trials as well as in postmarketing studies, EIA tests for hepatitis A antibodies must be commercially available and of known sensitivity. The Enzymun anti-HAV test developed by Boehringer Mannheim (Germany) offers the possibility to measure antibody titres around the protective level of 20 mIU/ml which is reached by the passive immunisation with immunoglobulin preparations or within two weeks after active vaccination with an inactivated hepatitis A vaccine. The Abbott IMX test system is more useful for the detection of natural infections by the hepatitis A virus.

Immunopotentiating reconstituted influenza virus virosome vaccine delivery system for immunization against hepatitis A.

Hepatitis A virus (HAV) was purified from MRC-5 human diploid cell cultures, inactivated with formalin, and evaluated for safety and immunogenicity in humans. Three vaccine formulations were produced: (a) a fluid preparation containing inactivated HAV, (b) inactivated HAV adsorbed to Al(OH)3, and (c) inactivated HAV coupled to novel immunopotentiating reconstituted influenza virosomes (IRIV). IRIV were prepared by combining phosphatidylcholine, phosphatidylethanolamine, phospholipids originating from the influenza virus envelope, influenza virus hemagglutinin, and neuraminidase. The HAV-IRIV appeared as unilamellar vesicles with a diameter of approximately 150 nm when viewed by transmission electron microscopy. Upon intramuscular injection, the alum-adsorbed vaccine was associated with significantly (P < 0.01) more local adverse reactions than either the fluid or IRIV formulations. 14 d after a single dose of vaccine, all the recipients of the IRIV formulation seroconverted (> or = 20 mIU/ml) versus 30 and 44% for those who received the fluid and alum-adsorbed vaccines, respectively (P < 0.001). The geometric mean anti-HAV antibody titer achieved after immunization with the IRIV-HAV vaccine was also significantly higher (P < 0.005) compared with the other two vaccines.

Safety and immunogenicity of a booster dose of Vibrio cholerae CVD 103-HgR live oral cholera vaccine in Swiss adults.

Adult volunteers received a booster dose (4 x 10(8) CFU) of attenuated Vibrio cholerae CVD 103-HgR oral vaccine 15 or 24 months after primary immunization. The immune response was modest, presumably due to rapid clearance of the vaccine strain by a primed immune system.

Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues.

PURPOSE: Subclinical hypothyroidism is found in about 7.5% of females and in about 3% of males. It appears to be a risk factor for atherosclerosis and for coronary heart disease and can affect various other target organs. The morbidity and clinical significance of subclinical hypothyroidism are controversial. Therefore, we evaluated the metabolic impact of progressive thyroid failure in patients with various degrees of hypothyroidism compared with control subjects. PATIENTS AND METHODS: We investigated 86 female patients with the whole spectrum of subclinical hypothyroidism (n = 69) and of overt hypothyroidism (n = 17) and 52 euthyroid women as controls. All subjects underwent full medical and endocrine evaluations (including measurements of thyrotropin [TSH], TSH beta- and alpha-subunits, and prolactin before and after oral administration of thyrotropin-releasing hormone [TRH]) as well as lipid profiles and different tests of peripheral thyroid hormone action. All hypothyroid patients were divided into five categories according to disease severity: grades I to III (subclinical hypothyroidism, with normal thyroxine [T4] levels) and grades IV and V (overt hypothyroidism, with diminished T4). RESULTS: In grade I subclinical hypothyroidism (basal TSH below 6 mU/L), we found significant changes in the clinical index (p less than 0.05), apoprotein A-I level (p less than 0.05), and stimulated prolactin level after oral TRH (p less than 0.001). The findings were similar in grade II (TSH 6 to 12 mU/L). Further changes could be demonstrated in grade III (TSH above 12 mU/L) with a definite elevation of ankle reflex time (p less than 0.001), serum myoglobin level (p less than 0.01), and, to a lesser extent, creatine kinase (p greater than 0.1). The mean low-density lipoprotein cholesterol (LDL-C) level showed an increase of 18%, which was not significant because of marked individual variations (p = 0.15). The frequency of elevated LDL-C levels was definitely higher in patients with grade III disease compared with the controls (42.9% versus 11.4%, p less than 0.05) and with patients with grades I and II disease. Total cholesterol, triglycerides, apoprotein B, and the systolic time intervals (pre-ejection period, corrected for heart rate [PEPc]) were clearly elevated only in overt hypothyroidism (grades IV and V) (p less than 0.01). CONCLUSION: Subclinical hypothyroidism has significant effects on some peripheral target organs at an early stage (grades I and II), but affects LDL-C, skeletal muscle, and myocardial contractility only at a later stage (grades III, IV, and V). Our data of elevated LDL-C in grade III subclinical hypothyroidism provide a likely pathophysiologic explanation for the reported association of coronary heart disease with this syndrome. The impact of increased prolactin secretion, observed in subclinical hypothyroidism, on gonadal function and infertility has yet to be clarified. Therapy with thyroxine should be recommended in at least some patients with subclinical hypothyroidism. Patients with high TSH levels (above 12 mU/L) will require treatment because of the metabolic effects on several target organs. Before treatment is advocated in all patients with subclinical hypothyroidism, the benefits and long-term side effects of thyroid hormone therapy should be clarified by prospective studies in larger groups of patients.

[Does isolated TSH elevation need treatment? Study of risk factors for the development of manifest hypothyroidism]. / Ist eine isolierte TSH-Erhöhung behandlungsbedürftig? Untersuchung der Risikofaktoren für die Entwicklung einer manifesten Hypothyreose.

Isolated elevations of basal TSH levels are frequently observed in the general population. In a prospective study we analyzed the spontaneous evolution of thyroid function over time in such patients. The mean observation period was 5.4 (0.5-12) years. During the follow-up period 20% of these patients developed overt hypothyroidism. The risk of developing hypothyroidism was determined primarily by the initial TSH value and an additive effect was found for the thyroid antibodies and the thyroidal reserve (delta-T3) after TRH stimulation (Cox proportional hazard model). The cumulative risk for overt hypothyroidism after 10 years was only 22% for a mean TSH level of 12 mU/l for patients with negative thyroid antibodies and a good thyroidal reserve (low-risk), but increased to 63% for patients with positive antibodies and impaired T3 reserve (high-risk). Therefore, patients with isolated elevation of TSH can be divided into two subgroups according to the results of TSH, antibody status and T3 reserve: (1) In the "low-risk group" with good prognostic factors the patients should be followed up by periodic laboratory testing only (TSH, FT4, every 2-3 years). (2) In the "high-risk group" with clearly abnormal parameters, however, frequent controls are mandatory (every 6-12 months) or treatment with thyroxine may be indicated.

Randomized double-blind placebo controlled trial to evaluate the safety and immunogenicity of the live oral cholera vaccine strain CVD 103-HgR in Swiss adults.

A randomized, double-blind, placebo controlled trial was conducted in 50 healthy Swiss adults to assess the safety and immunogenicity of the live oral attenuated cholera vaccine candidate strain Vibrio cholerae CVD 103-HgR (classical, Inaba). A single dose of 5 x 10(8) viable CVD 103-HgR organisms, administered in a buffered liquid formulation, was well tolerated as compared with individuals who received an equivalent amount of heat-killed Escherichia coli K-12 placebo. Eighty-eight percent of subjects receiving CVD 103-HgR mounted a significant (greater than fourfold) rise in Inaba vibriocidal titre while 68% did so for the heterologous Ogawa serotype. The magnitude of the vibriocidal antibody response (as measured by peak geometric mean titre and by fold-rise in titre over baseline) was greater for the homologous Inaba serotype. Nineteen out of 25 volunteers (76%) responded with a significant (p less than 0.05) rise in serum antitoxin levels. No vaccinee who received the E. coli K-12 placebo mounted a significant rise in either vibriocidal or antitoxin antibody levels. These results corrobrate the safety and immunogenicity of CVD 103-HgR in healthy adult volunteers.

[Carbimazole therapy in Basedow's disease: therapy results in individual dosage adjustment]. / Carbimazol-Therapie beim Morbus Basedow: Therapieerfolg bei individueller Dosisanpassung.

We analyzed the results of 85 treatments with carbimazol in 71 patients with Graves' disease. The initial dose ranged from 45 to 60 mg/day, which was gradually reduced to the lowest possible maintenance dose; the mean treatment period was 17 months. All patients achieved euthyroid function after 12 weeks at the latest. Normalization of the pituitary TSH-reserve occurred late (after 6-12 months in most cases). 60% of the patients treated for the first time (n = 58) and 59% of the whole group remained in remission. The maintenance dose of carbimazol had no effect on the rate of remission. It is interesting to note that in 66% of the patients a very low dose (less than or equal to 5 mg/day) was fully effective and resulted in a remission rate of 54%. Therefore, the dose should always be reduced individually. Relapses occurred within the first year after the end of treatment in 77% of the cases, but were also observed after 2-3 years. Hence follow-up should be continued after cessation of therapy.

Assessment of antithyroglobulin and antimicrosomal autoantibodies in patients with autoimmune thyroid disease: comparison of haemagglutination assay, enzyme-linked immunoassay and radioligand assay.

Four different assay systems for detection of antithyroglobulin (T-Ab) and thyroid antimicrosomal autoantibodies (M-Ab) were evaluated: two passive haemagglutination assays (PHA), an enzyme-linked immunoassay (ELISA) and a radioligand assay (RLA). Antibody levels measured with these methods correlated well (T-Ab: r = 0.72 to 0.88; M-Ab: r = 0.63 to 0.84; p less than 0.0001). However, when the results of the measured samples were classified as normal, slightly elevated and pathological, only 40-50% of the samples showed congruous results in all tests; 60-70% agreed in PHA and ELISA, whereas 80 to 90% corresponded in the two PHAs. RLA and ELISA gave more frequently positive results for T-Ab and negative results for M-Ab than the PHAs. Despite the lower sensitivity of the quantitative methods for M-Ab detection, they depicted more readily small changes after thyroxine treatment than the PHAs. We suggest that differences in autoantibody levels found with different methods may be due to autoantibody heterogeneity.

[Study of the long-term effects of amiodarone on thyroid function using ultrasensitive TSH measurements. Preliminary report]. / Untersuchung der Amiodaron-Langzeitwirkung auf die Schilddrüsenfunktion mit Messung des ultrasensitiven TSH. Vorläufige Mitteilung.

The results of a prospective study of basal ultrasensitive TSH concentrations in patients during long-term treatment over 12 months with amiodarone are reported. 2 patients (3%) developed hypothyroidism, whereas no case of hyperthyroidism was observed. A significant increase in FT4 with a simultaneous decrease in T3 was demonstrated at every periodic investigation during amiodarone therapy. In most patients ultrasensitive TSH values stayed within the normal range and showed no significant alteration during treatment. A slow decline in TSH during therapy was observed in a subgroup of patients with completely euthyroid initial TSH concentrations. This TSH decrease reached statistical significance after 12 months' therapy. FT4 showed pathological results in 35% of all determinations at any time during the study, T3 in 27%, and TSH in only 17%. In conclusion, a new steady-state of thyroid tests is attained during treatment with amiodarone and most patients maintain a euthyroid function state. Assessment of ultrasensitive TSH can be recommended as a primary screening test for evaluation of thyroid function in patients under amiodarone therapy.

[Therapy resistance of amiodarone-induced hyperthyroidism]. / Therapieresistenz einer Amiodaron-induzierten Hyperthyreose.

The case of a 77-year-old patient who suffered from clinically severe and persistent hyperthyroidism induced by amiodarone is described. Amiodarone-associated hyperthyroidism is a rare (1-5%) but potentially severe complication. Its treatment presents a serious problem. The newer forms of treatment of this specific type of hyperthyroidism with prednisone and perchlorate are described. Under a combined therapy with thionamide drugs, prednisone and perchlorate euthyroidism could be achieved only after months. We propose a simple diagnostic procedure during amiodarone therapy based on the determination of basal ultrasensitive TSH enabling early recognition of amiodarone-associated hyperthyroidism. Thus, with well defined cardiac criteria for therapy with amiodarone as well as early assessment of thyroid dysfunction the incidence of this potentially severe complication can be reduced.