Zoltan Vajo

Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009–10 influenza season: a multicentre, randomised controlled trial

BACKGROUND With the ongoing 2009 pandemic of influenza A H1N1, development of pandemic influenza vaccines has generated much interest. We investigated the safety and immunogenicity of a whole-virion, inactivated, adjuvanted pandemic H1N1 vaccine in adult and elderly volunteers, given without or simultaneously with the 2009-10 seasonal trivalent influenza vaccine. METHODS This prospective, randomised study was undertaken in two centres in Hungary. 355 participants, including 203 adults (18-60 years) and 152 elderly people (>60 years), were assigned by stratified randomisation to either 0.5 mL of the pandemic vaccine (Fluval P, a monovalent vaccine with 6 microg haemagglutinin per 0.5 mL content and aluminium phosphate gel adjuvant; n=178) or 0.5 mL of the pandemic vaccine and 0.5 mL of the seasonal trivalent vaccine (Fluval AB, a trivalent inactivated whole-virion influenza vaccine; n=177). All vaccinations were done by specific study personnel, who did not take part in the assessment of safety or immunogenicity. Co-primary objectives were safety and immunogenicity by haemagglutinin inhibition testing. All analyses were done according to a pre-established analysis plan. This study is registered with ClinicalTrials.gov, number NCT01010893. FINDINGS Two participants receiving the pandemic vaccine only (group 1) and one receiving pandemic and seasonal vaccines (group 2) were lost to follow-up. Participants in both groups developed antibody responses against the pandemic influenza A H1N1 virus (group 1: seroconversion for adults 74.3%, 95% CI 64-6-82.4 and for elderly people 61.3%, 49.1-72.4; group 2: 76.8%, 67.2-84.7 and 81.8%, 71.4-89.7, respectively). Single doses of 6 microg fulfilled European Union and US licensing criteria for interpandemic and pandemic influenza vaccines. Simultaneously, participants in group 2 developed the immune responses needed for licensing for all three seasonal strains in the seasonal vaccine for the 2009-10 season. All adverse events were rare, mild, and transient; the most frequent were pain at injection site (eight cases in group 1 vs 18 in group 2) and fatigue for 1-2 days after vaccination (three vs five cases). INTERPRETATION The present pandemic vaccine is safe and immunogenic in healthy adult and elderly patients, and needs low doses and only one injection to trigger immune responses to comply with licensing criteria. It can be safely co-administered with the 2009-10 seasonal influenza vaccine. FUNDING Omninvest, Hungary.

Postmenopausal hormone replacement improves proteinuria and impaired creatinine clearance in type 2 diabetes mellitus and hypertension

Objective To determine whether hormone replacement therapy can reverse established renal microvascular damage in type 2 diabetes and hypertension.

Hormone replacement therapy reduces mean 24-hour blood pressure and its variability in postmenopausal women with treated hypertension

Background: The rate and severity of hypertension increase dramatically after menopause. Complications seem to be more frequent and marked in hypertensive patients with greater blood pressure (BP) variability, and antihypertensive treatment does not easily reduce this variability. The effect of hormone replacement therapy (HRT) on BP and its variability is not well understood in moderate to severe hypertension, but estrogen may have calcium channel‐blocking properties. Cardiovascular events occur more frequently in the morning, likely in part because of a rise in BP. Design: We prospectively studied 34 postmenopausal women with treated hypertension (mean age = 53 years) and receiving a cyclic combination of estradiol and norgestrel for 19 weeks with 24‐h ambulatory BP monitoring. Results: Mean daily BP and its variability decreased significantly with HRT (149.3 ± 6.1 mm Hg vs. 140.3 ± 8.5 mm Hg [p < 0.001]; diastolic: 95.4 ± 4.7 mm Hg vs. 92.4 ± 7.2 mm Hg [p < 0.05]). There was also a significant decrease in the early morning BP values after HRT (154.0 ± 6.9 mm Hg vs. 145.6 ± 11.0 mm Hg [p < 0.001]; diastolic: 98.0 ± 4.8 mm Hg vs. 95.1 ± 10.0 mm Hg [p < 0.05]). Subjects who were taking calcium channel blockers (n = 11) had only half the reduction in 24‐h systolic BP compared with those who were not taking calcium channel blockers (5.3 mm Hg vs. 10.5 mm Hg), and the reduction in those who were taking calcium channel blockers failed to reach statistical significance. Conclusions: Our results demonstrate that HRT may have a role in decreasing the severity of hypertension, and the mechanism of its action might be through calcium channels. (Menopause 2000;7:31‐35.

Inactivated whole virus influenza A (H5N1) vaccine.

To the Editor: Avian influenza viruses of the H5N1 subtype represent a potential source of the next pandemic (1,2). Our goal was to determine the safety and immunogenicity of a newly developed vaccine in humans. The vaccine was produced by the same method as the interpandemic influenza vaccine “FluvalAB” used in Hungary for the past 11 years (3,4). The method has been validated by meeting the requirements of the European Agency for the Evaluation of Medicinal Products (EMEA) related to interpandemic influenza vaccines each year since 1995, and by having been administered in humans in a total of >15 million cases (5). The virus strain (NIBRG-14), a reverse genetics–derived 2:6 reassortant between A/Viet Nam/1194/2004 (H5N1) and PR8, was obtained from the National Institute for Biologic Standards and Control, London. It is one of the reference viruses indicated as suitable for use in a mock-up vaccine by the Committee for Medicinal Products for Human Use (6). Hens’ egg–grown, formaldehyde-inactivated, whole virus vaccine, developed and produced by the Omninvest Ltd. (Budapest, Hungary), was used. The vaccine contained 6 μg hemagglutinin per dose (as determined by single radial immundiffusion test) in 0.5-mL ampules. Purity was assessed by endotoxin content (determined by chromogenic endotoxin assay, using a modified limulus amoebocyte lysate and a synthetic color-producing substrate), which was considered acceptable in concentrations <0.1 IU/mL. The amount of ovalbumin was determined by ELISA, which was considered satisfactory in concentrations <10 ng/mL. Aluminum phosphate was used as adjuvant, in the amount of 0.31 mg Al per ampule; 0.1 mg/mL merthiolate was added as preservative. A total of 146 healthy volunteers >18 years of age (mean ± SD 42.07 ± 12.62 years). were enrolled in the study. Sixty-five male and 81 female volunteers participated. The sample size was chosen to exceed the requirement of 50 patients per group set by the European guidelines for yearly influenza vaccine trials (5). The sponsor was the National Public Health and Medical Officer Service, Budapest, Hungary. The injection administered 0.5 mL of vaccine intramuscularly. The injection was not repeated. Serum antibody titers were measured by hemagglutination inhibition (HI) by using chicken erythrocytes, following standard procedures (7). Because the protective titer for influenza virus A (H5N1) infections is unknown, immunogenicity was assessed according to the European Medicines Agency criteria related to interpandemic influenza vaccines (Table) (5). Table Immunogenicity findings of whole-virus influenza vaccine trial, Hungary*† None of the study participants displayed measurable levels of HI antibodies before vaccination. According to EMEA requirements, both male and female groups met 2 independent criteria for immunogenicity 21 and 90 days after vaccination (Table). In 15.7% of the participants, adverse reactions in the form of local pain at the injection site occurred within the first 48 hours; these reactions disappeared within 1 day. No other local reactions, such as injection site induration, erythema, swelling, warmth, or ecchymosis, were noted. No systemic reaction (fever, malaise, headache, shivering) was detected. No serious adverse events were observed. These results are in line with the 11-year experience using the interpandemic vaccine produced by Omninvest Ltd. by the same method, where a similar safety profile has been seen after >15 million vaccinations in humans. This is the first study that reports that an inactivated whole virus vaccine with an aluminum phosphate adjuvant system against influenza A (H5N1) was safe and immunogenic in humans after only 1 injection. This study reports the lowest effective dose used to cause immune response. Other trials used much higher maximum doses and required 2 injections 21 or 28 days apart (8–10). Using the lowest possible amount of the antigen and fewer injections is essential for increasing the production capacity of vaccine manufacturers in a pandemic (2). Using 1, instead of 2, injections will shorten the time needed to develop immune response by 3–4 weeks. Unlike previous studies on influenza A (H5N1) vaccines that reported only data from 21, 28, or 56 days after the final vaccination (8–10), we report data up to 90 days. The lower dose and fewer injections required to trigger an immune response can be at least partially explained by using a whole virus vaccine and an aluminum phosphate adjuvant system. The use of a different adjuvant system than ours may have influenced the results of other trials (9,10). Other investigators used a modified HI method with horse erythrocytes, which are known to be more sensitive for influenza A (H5N1) subtype than the conventionally used turkey or chicken erythrocytes (8,9). Thus, if horse erythrocytes had been used in our study, the vaccine would likely have been even more immunogenic. This study found fewer, less frequent, and milder side effects than did other trials of influenza A (H5N1) vaccines published so far (8–10). This could possibly be explained by the smaller dose used. Also, the endotoxin content of 0.1 IU/mL in our vaccine was much smaller then the allowed amount of 100 IU/mL by standards (5). We report an inactivated whole virus vaccine that is safe and immunogenic in healthy adults and that requires a low dose and only 1 injection to trigger an immune response. We are conducting trials in elderly persons and children.

Increased intra-abdominal fat may lower HDL levels by increasing the fractional catabolic rate of Lp A-I in postmenopausal women

High-density lipoprotein (HDL) particles without apolipoprotein A-II (Lp A-I) may be more anti-atherogenic than HDL with apo A-II (Lp A-I/AII) and Lp A-I is reported selectively to be reduced in cases of intra-abdominal obesity. We explored the mechanisms of this reduction by studying the turnover of Lp A-I and Lp A-I/A-II in postmenopausal women well characterized for total body, regional and sub-regional adiposity by body mass index (BMI), truncal girth ratio, and abdominal magnetic resonance imaging (MRI), respectively. We tested for possible cause-effect relationships by measuring inter-correlations among these variables. Intra-abdominal fat area correlated strongly and positively with the fractional catabolic rate (FCR) of Lp A-I (r=0.98, P=0.003). Intra-abdominal fat only showed a non-significant trend toward correlation with the FCR of Lp A-I/A-II (r=0.84, P=0.07), and had no correlation with the production or transport rate (TR) of either Lp A-I or Lp A-I/A-II (r=0.48 and 0.02, respectively, P>0.1). Subjects were studied both with and without estrogen replacement, allowing exploration of a possible interaction of adiposity with estrogen effects on HDL turnover. Response of HDL turnover to estrogen did not correlate with adiposity, except for a parameter of waist to hip ratio (WHR), which predicted the increase in LP A-I TR with estrogen (r=0.84, P=0.04). We conclude that intra-abdominal fat may lower HDL levels by increasing the FCR of Lp A-I, suggesting a mechanism by which central adiposity may be proatherogenic.

Safety and immunogenicity of a prepandemic influenza A (H5N1) vaccine in children.

Background: The avian influenza A (H5N1) virus is considered to be a potential cause of the next influenza pandemic. Children may be particularly vulnerable to the pandemic virus, and they may react differently than adults to vaccines. We report the results of the first clinical trial of an H5N1 vaccine in children. Methods: Twelve healthy children (mean age ± SD: 12.73 ± 2.77 years) received a single dose of 6 μg of the inactivated whole virus vaccine Fluval. Twenty-one days after vaccination, immunogenicity was assessed by hemagglutination inhibition and microneutralization assays. Safety information was collected for 180 days. Results: No side-effects were observed, and the vaccine fulfilled all applicable U.S. and European immunogenicity criteria for licensure. The post/prevaccination geometric mean titer ratio was 16.95, the rate of seroconversion was 75% and the rate of seroprotection was also 75% 21 days after vaccination. Conclusions: We confirmed our earlier findings of the present vaccine in adults showing encouraging safety and immunogenicity properties in children. Studies with the present vaccine in elderly subjects are underway.

A Single-Dose Influenza A (H5N1) Vaccine Safe and Immunogenic in Adult and Elderly Patients: an Approach to Pandemic Vaccine Development

ABSTRACT With the ongoing pandemic of influenza A (H1N1) virus infection and the threat of high fatality rates for recent human cases of infection with highly pathogenic H5N1 strains, there has been considerable interest in developing pandemic vaccines. Here we report a randomized multicenter dose-finding clinical trial of a whole-virion, inactivated, adjuvanted H5N1 vaccine in adult and elderly volunteers. Four hundred eighty patients were randomly assigned to receive one or two doses of 3.5 μg of the vaccine or one dose of 6 or 12 μg. The subjects were monitored for safety analysis, and serum samples were obtained to assess immunogenicity by hemagglutination inhibition and microneutralization tests. The subjects developed antibody responses against the influenza A (H5N1) virus. Single doses of ≥6 μg fulfilled EU and U.S. licensing criteria for interpandemic and pandemic influenza vaccines. Except for occasional injection site pain, malaise, and fever, no adverse events were observed. We found that the present vaccine is safe and immunogenic in healthy adult and elderly subjects and requires low doses and, unlike any other H5N1 vaccines, only one injection to trigger immune responses which comply with licensing criteria. A vaccine using the same methods as those described in this report, but based on a wild-type swine-origin 2009 (H1N1) influenza A virus isolate from the United States (supplied by the CDC), has been developed and is currently being tested by our group.

Facial and dental appearance of Williams syndrome

Williams syndrome is a genetic condition, which predominantly occurs as a sporadic disorder, although some families have been reported showing autosomal dominant inheritance with varying penetrance. The incidence of Williams syndrome is estimated to be one in 20 000–50 000 live births, and it consists of supravalvular aortic stenosis, characteristic dysmorphic facial features named “elfin face” (wide mouth with long phyltrum and …

Impaired β2-adrenergic agonist–induced venodilation in Indians of Asian origin

Vascular responsiveness to infusions of vasoactive substances varies between ethnic groups. Indians of Asian origin are a rapidly growing ethnic group in the United States but have not been extensively studied. We sought to determine whether there was any difference in venous responsiveness to a local infusion of vasoactive substances between Indians of Asian origin and white subjects.

Cutaneous granuloma and uveitis caused by a tattoo.

A 24-year-old male with red tattoos developed ocular pain and blurred vision three years after having been tattooed. The patient also noticed redness and itching in the area of the tattooed skin (Fig. 1). The rest of the history and physical examination was unremarkable. Routine laboratory screening tests were within normal limits, with the exception of a mildly elevated white blood cell count (11,6 G/L). Chest X-ray examination and CT scan were within normal limits. Ophthalmological examination revealed panuveitis of the right eye with keratic precipitates, several firm posterior synechiae, infiltrated vitreous, and acute iridocyclitis of the left eye with ciliary congestion, flare and cells in the anterior chamber, and keratic precipitates (Figs. 2, 3). Histological examination of the lesion confirmed granulomatous reaction in the tattooed skin. Excision of the inflamed tattoo, administration of topical and systemic steroid (40 mg/day of prednisolone orally and 0,5% prednisolone acetate eye drops (2 drops twice daily) and cyclosporin (150 mg/day orally for 4 weeks) resulted in remarkable improvement in visual acuity and cure of the uveitis. All medications were discontinued, and the patient has been asymptomatic since. To our knowledge, the coexistence of uveitis and tattoo granulomas has only been reported once in the English language medical literature by Rorsman et al. [1]. According to their suggestion, tattoo granulomas and uveitis may be a special granulomatous hypersensitivity syndrome induced by cobalt [1]. As with their three cases, our patient also had no signs of systemic sarcoidosis and developed the ophthalmologic symptoms delayed after having had his skin tattooed.