We conclude that the proposed vaccination with hu-EGF was well tolerated and that antibody titers against self EGF were developed. The results of this trial may be useful in the design of new clinical trials with higher dose immunization protocols and using more effective adjuvants.
ContextCurrent drugs for chronic hepatitis B therapy have a poor efficacy in terms of post-treatment sustained viral suppression and generate important side effects during and after therapy. Therapeutic vaccination with HBV antigens is an attractive alternative to test.ObjectiveEvaluating the efficacy of a therapeutic vaccine candidate (designated NASVAC) containing both hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) versus pegylated interferon (Peg-IFN) in naïve chronic hepatitis B patients.Design, setting, participantsAn open phase III, randomised and treatment controlled clinical trial was conducted in a total of 160 CHB patients, allocated into two groups of 80 patients each to receive NASVAC or Peg-IFN. The vaccine formulation comprised 100 μg of each HBsAg and HBcAg, and was administered in 2 cycles of 5 doses. The control group received 48 subcutaneous injections of Peg-IFN alfa 2b, 180 μg per dose, every week, for 48 consecutive weeks.Main outcome measureThe primary outcome measure was in relation with the proportion of patients showing reduction of the viral load under the limit of detection (250 copies/mL) after 24 weeks of treatment completion.ResultsSustained control of HBV DNA was significantly more common in NASVAC group (p<0.05) at 24 weeks of follow up. NASVAC-induced increases of alanine aminotransferases (ALT) were detected in 85% patients after 5 nasal vaccinations, although seen in only 30% of patients receiving Peg-IFN. At the end of treatment (EOT) antiviral effect was comparable in both NASVAC and Peg-IFN groups. Clearance of Hepatitis B e antigen (HBeAg) was also more frequent in NASVAC group compared to Peg-IFN recipients. A lower progression to cirrhosis was found in NASVAC group compared to Peg-IFN group.ConclusionNasvac induced a superior reduction of the viral load under the limit of detection compared to Peg-IFN treatment. It is a safe and efficacious finite alternative of antiviral treatment for CHB patients.Trial registrationClinicalTrials.gov NCT 01374308.
This study examined if a series of epidermal growth factor (EGF) local infiltrations can enhance the healing process of complicated diabetic wounds. Twenty-nine in-hospital patients with diabetic neuropathic or ischaemic lesions with high risk of amputation were treated in a non controlled pilot study conducted at the National Institute of Angiology, Havana. Lesions, classified as Wagner's grade 3 or 4, included ulcers > or = 20 cm2 for > or = 25 days or amputation residual bases > or = 30 cm2 for > or = 15 days, healing refractory despite comprehensive wound care. EGF (25 microg) intralesional infiltrations (approximately 250 microl of a 25 microg/ml solution/injection point) were performed thrice weekly up to the eighth week. Wound closure was monitored during the treatment and recurrence examined for a year following discharge from hospital. Eighty-six per cent of the patients treated showed a productive granulation at infiltration session 8. Histological examination at this point indicated a substantial wound matrix transformation, granulation tissue cell repopulation and angiogenesis. Of the 29 patients treated, amputation was prevented in 17 (58.6%) of them who completed 24 infiltration sessions. They averaged 71.1 +/- 18.3% of reepithelisation during a mean in-hospital period of 66.5 +/- 4.9 days. Wound recurrence after 1 year of follow-up appeared in only one patient. Preliminary evidences suggest that EGF intralesional infiltrations may be effective in reducing diabetic lower limb amputation.
Dengue virus (DENV) infects an estimated 400 million people every year, causing prolonged morbidity and sometimes mortality. Development of an effective vaccine has been hampered by the lack of appropriate small animal models; mice are naturally not susceptible to DENV and only become infected if highly immunocompromised. -cell response to viral infection, compared to a weak response in IFNAR؊/؊ mice. Furthermore, mice lacking IFNAR on either CD11c ؉ or LysM ؉ cells were also sufficiently immunocompetent to raise a protective immune response to a candidate subunit vaccine against DENV-2. These data demonstrate that mice with conditional deficiencies in expression of the IFNAR represent improved models for the study of DENV immunology and screening of vaccine candidates. IMPORTANCEDengue virus infects 400 million people every year worldwide, causing 100 million clinically apparent infections, which can be fatal if untreated. Despite many years of research, there are no effective vaccine and no antiviral treatment available for dengue. Development of vaccines has been hampered in particular by the lack of a suitable small animal model. Mouse models used to test dengue vaccine are deficient in interferon (IFN) type I signaling and severely immunocompromised and therefore likely not ideal for the testing of vaccines. In this study, we explored alternative models lacking the IFN receptor only on certain cell types. We show that mice lacking the IFN receptor on either CD11c-or LysM-expressing cells (conditional IFNAR mice) are susceptible to dengue virus infection. Importantly, we demonstrate that conditional IFN receptor knockout mice generate a better immune response to live virus and a candidate dengue vaccine compared to IFNAR mice and are resistant to subsequent challenge. D engue virus (DENV, a member of the Flaviviridae family, is a mosquito-borne pathogen that infects approximately 400 million people every year (1, 2). Each of the four DENV serotypes causes a spectrum of clinical symptoms ranging from mild fever to potentially fatal manifestations of dengue shock syndrome. DENV causes an acute infection with high fever, which usually resolves after 5 to 7 days. At this time, most patients have cleared the high virus load. Intriguingly, however, this is also the time point when some patients start to develop vascular leakage, which, if untreated, can lead to a collapse of the metabolism and organ failure. The frequency, severity, and geographical spread of cases has increased over the past decades (3, 4), and DENV infection is now considered a leading cause of morbidity in the tropics.There are no effective treatments for dengue fever, and the development of a vaccine has been hampered by the lack of suitable small animal models. Wild-type (wt) mice are not susceptible to infection with field strains of DENV, and while viral replication in these animals can be forced by intracranial injections of hightiter mouse-adapted DENV strains, the resulting clinical disease bears little resemblance to dengue fev...
A dengue vaccine should induce long-lasting, simultaneous protection to the four dengue viruses while avoiding the immune enhancement of viral infection. Domain III of the dengue envelope protein has been implicated in receptor binding, and is also the target of specific neutralizing antibodies. Domain III has emerged as a promising region for a subunit vaccine candidate. Here, we review the current state of knowledge on vaccine candidates based on domain III. Due to the results obtained concerning the immune response and protection in mice and monkeys, particular attention is paid to the chimeric protein domain III fused to p64k of Neisseria meningitidis.
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