Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice.

Prion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform (PrPSc). In humans, there are sporadic, genetic and infectious etiologies, with sporadic Creutzfeldt-Jakob disease (sCJD) being the most common form. Currently, no treatment is available for prion diseases. Cellular cholesterol is known to impact prion conversion, which in turn results in an accumulation of cholesterol in prion-infected neurons. The major elimination of brain cholesterol is achieved by the brain specific enzyme, cholesterol 24-hydroxylase (CYP46A1). Cyp46A1 converts cholesterol into 24(S)-hydroxycholesterol, a membrane-permeable molecule that exits the brain. We have demonstrated for the first time that Cyp46A1 levels are reduced in the brains of prion-infected mice at advanced disease stage, in prion-infected neuronal cells and in post-mortem brains of sCJD patients. We have employed the Cyp46A1 activator efavirenz (EFV) for treatment of prion-infected neuronal cells and mice. EFV is an FDA approved anti-HIV medication effectively crossing the blood brain barrier and has been used for decades to chronically treat HIV patients. EFV significantly mitigated PrPSc propagation in prion-infected cells while preserving physiological PrPC and lipid raft integrity. Notably, oral administration of EFV treatment chronically at very low dosage starting weeks to months after intracerebral prion inoculation of mice significantly prolonged the lifespan of animals. In summary, our results suggest that Cyp46A1 as a novel therapeutic target and that its activation through repurposing the anti-retroviral medication EFV might be valuable treatment approach for prion diseases.

Induction of humoral immune response in piglets after perinatal or post-weaning immunization against porcine circovirus type-2 or keyhole limpet hemocyanin.

The objective of this study was to test the hypothesis that porcine circovirus type-2 (PCV2) vaccination is efficacious when administered in the first week of life. Three groups of pigs were vaccinated with Circumvent either early (at the end of week 1), late (at the end of week 4), or not at all. All 3 groups were later challenged intranasally with PCV2 (at the end of week 5). Two other groups were immunized with keyhole limpet hemocyanin (KLH) as a novel antigen at the end of either week 1 or week 4. Weight, PCV2 genome copy number in serum and saliva, anti-KLH antibody titer, and serum PCV2-neutralizing antibodies were measured weekly. Early PCV2 vaccination or KLH antigen exposure resulted in earlier humoral responses that were slower to develop than in older piglets, yet converged with the responses to later vaccination within 5 wk. Both groups of vaccinated piglets had periods of higher PCV2-neutralizing antibody titers and lower viral levels shortly after weaning and PCV2 challenge, thus supporting the recent labelling of 1 Canadian PCV2 vaccine for use in week 1 and suggesting that early PCV2 vaccination can reduce piglet handling without compromising vaccine efficacy.

L'objectif de la présente étude était de vérifier l'hypothèse que la vaccination contre le circovirus porcin de type 2 (CVP2) est efficace lorsqu'administrée durant la première semaine de vie. Trois groupes de porcs ont été vaccinés avec Circumvent soit hâtivement (à la fin de la semaine 1), tardivement (à la fin de la semaine 4), ou pas du tout. Les trois groupes ont plus tard été inoculés par voie intranasale avec CVP2 (à la fin de la semaine 5). Deux autres groupes ont été immunisés avec de l'hémocyanine de patelle (KLH) à titre de nouvel antigène à la fin de soit la semaine 1 ou la semaine 4. Le poids, le nombre de copies du génome de CVP2 dans le sérum et la salive, le titre d'anticorps anti-KLH, et le titre d'anticorps sériques neutralisants CVP2 ont été mesurés à chaque semaine. La vaccination tôt contre CVP2 ou l'exposition à l'antigène KLH a donné des réponses humorales plus hâtives qui étaient plus lentes à se développer que chez les porcs plus vieux, mais qui convergeaient vers les réponses de la vaccination tardive à l'intérieur d'un délai de 5 sem. Les deux groupes de porcelets vaccinés avaient des périodes de titres d'anticorps neutralisants contre CVP2 plus élevés et des charges virales plus basses peu de temps après le sevrage et le challenge avec CVP2, soutenant ainsi l'étiquetage récent d'un vaccin canadien contre CVP2 pour utilisation dans la semaine 1 et suggérant qu'une vaccination tôt contre CVP2 peut réduire la manipulation des porcelets sans compromettre l'efficacité du vaccin.(Traduit par Docteur Serge Messier).

Concomitant administration of a virosome-adjuvanted hepatitis a vaccine with routine childhood vaccines at age twelve to fifteen months: a randomized controlled trial.

BACKGROUND: The objectives of this trial were to test for noninferiority of a virosomal hepatitis A virus (HAV) vaccine (Epaxal) coadministered with routine childhood vaccines compared with Epaxal given alone and to an alum-adjuvanted HAV vaccine (Havrix Junior) coadministered with routine childhood vaccines. METHODS: Healthy children 12- to 15-month-old were randomized to receive either a pediatric dose (0.25 mL) of Epaxal coadministered with DTPaHibIPV, oral polio vaccine, and measles-mumps-rubella vaccine (n = 109; group A), or Epaxal given alone (n = 105; group B), or Havrix Junior coadministered with DTPaHibIPV, oral polio vaccine, and measles-mumps-rubella vaccine (n = 108; group C). A booster dose was given 6 months later. Anti-HAV antibodies were tested before and 1 month after each vaccination. Safety was assessed for 1 month after each vaccination. Solicited adverse events were assessed for 4 days after each vaccination. RESULTS: : HAV seroprotection rates (> or =20 mIU/mL) at 1 and 6 months after first dose were: A: 94.2% and 87.5%, B: 92.6% and 80.0%, C: 78.2% and 71.3%, respectively (A versus C: P < 0.001 and P = 0.017 at month 1 and 6, respectively). The respective geometric mean concentrations were: A: 51 and 64 mIU/mL, B: 49 and 59 mIU/mL, C: 33 and 37 mIU/mL (A versus C: P < 0.001 at both time points). All groups achieved 100% seroprotection after the booster dose. The geometric mean concentrations after the booster dose were 1758, 1662, and 1414, for groups A, B and C, respectively (A versus C: P = 0.15). No clinically significant reduction in immune response to all concomitant vaccine antigens was seen. All vaccines were well tolerated. CONCLUSIONS: : Coadministration of pediatric Epaxal with routine childhood vaccines showed immunogenicity and safety equal to Epaxal alone as well as to Havrix Junior. After first dose, Epaxal was significantly more immunogenic than Havrix Junior.