Estimated research and development costs of rotavirus vaccines

Diseases like rotavirus afflict both upper- and lower-income countries, but most serious illnesses and deaths occur among the latter. It is a vital public health issue that vaccines for these types of global diseases can recover research and development (R&D) costs from high-priced markets quickly so that manufacturers can offer affordable prices to lower-income nations. Cost recovery depends on how high R&D costs are, and this study attempts to replace high, unverified estimates with lower, more verifiable estimates for two new vaccines, RotaTeq (Merck) and Rotarix (GlaxoSmithKline or GSK), based on detailed searches of public information and follow-up interviews with senior informants. We also offer a new perspective on “cost of capital” as a claim for recovery from public bodies. Our estimates suggest that companies can recover all fixed costs quickly from affluent markets and thus can offer these vaccines to lower-income countries at prices they can afford. Better vaccines are a shared project between companies and public health agencies; greater transparency and consistency in reporting of R&D costs is needed so that fair prices can be established.     

Localization and characterization of val‐opsin isoform‐expressing cells in the brain of adult zebrafish

In addition to vision, light information is used to regulate a range of animal physiology. Such nonimage‐forming functions of light are mediated by nonvisual photoreceptors expressed in distinct neurons in the retina and the brain in most vertebrates. A nonvisual photoreceptor vertebrate ancient long opsin (VAL‐opsin) possesses two functional isoforms in the zebrafish, encoded by valopa and valopb, which has received little attention. To delineate the neurochemical identities of valop cells and to test for colocalization of the valop isoforms, we used in situ hybridization to characterize the expression of the valop genes along with that of neurotransmitters and a neuropeptide known to be present at the sites of valop expression. Double labeling showed that the thalamic valop population coexpresses valopa and valopb. All the thalamic valop cells overlapped with a GABAergic cell mass that continues from the anterior nucleus to the intercalated thalamic nucleus. A novel valopa cell population found in the superior raphe was serotonergic in nature. A valopb cell population in the Edinger‐Westphal nucleus was identified as containing thyrotropin‐releasing hormone. Valopb cells localized in the hindbrain intermediate reticular formation were noncholinergic in nature (nonmotorneurons). Thus, the presence of valop cell populations in different brain regions with coexpression of neurotransmitters and neuropeptides and the colocalization of valop isoforms in the thalamic cell population indicate regulatory and functional complexity of VAL‐opsin in the brain of the zebrafish. J. Comp. Neurol. 522:3847–3860, 2014. © 2014 Wiley Periodicals, Inc.     

In silico identification of anthropogenic chemicals as ligands of zebrafish sex hormone binding globulin

Anthropogenic compounds with the capacity to interact with the steroid-binding site of sex hormone binding globulin (SHBG) pose health risks to humans and other vertebrates including fish. Building on studies of human SHBG, we have applied in silico drug discovery methods to identify potential binders for SHBG in zebrafish (Danio rerio) as a model aquatic organism. Computational methods, including; homology modeling, molecular dynamics simulations, virtual screening, and 3D QSAR analysis, successfully identified 6 non-steroidal substances from the ZINC chemical database that bind to zebrafish SHBG (zfSHBG) with low-micromolar to nanomolar affinities, as determined by a competitive ligand-binding assay. We also screened 80,000 commercial substances listed by the European Chemicals Bureau and Environment Canada, and 6 non-steroidal hits from this in silico screen were tested experimentally for zfSHBG binding. All 6 of these compounds displaced the [³H]5α-dihydrotestosterone used as labeled ligand in the zfSHBG screening assay when tested at a 33 μM concentration, and 3 of them (hexestrol, 4-tert-octylcatechol, and dihydrobenzo(a)pyren-7(8H)-one) bind to zfSHBG in the micromolar range. The study demonstrates the feasibility of large-scale in silico screening of anthropogenic compounds that may disrupt or highjack functionally important protein:ligand interactions. Such studies could increase the awareness of hazards posed by existing commercial chemicals at relatively low cost.     

Shingles vaccine

Importance of the field: Herpes zoster or shingles is a condition with the potential to result in severe debilitation. It affects approximately 10 – 30% of the population. Until recently there were only treatments to shorten the duration and lessen the symptoms of herpes zoster, but no practical or approved method of prevention for susceptible immunocompetent adults. The live attenuated zoster vaccine (Zostavax^®, Merck & Co., Inc.) is effective in preventing shingles in individuals 60 years of age and older and recommended by the Center for Disease Control's (CDC) Advisory Committee for Immunization Practices (ACIP).

Areas covered in this review: Literature related to the live attenuated zoster vaccine is reviewed from its beginnings in the early 1970s through to the present.

What the reader will gain: Background information on herpes zoster and up to date information on the live attenuated zoster vaccine including pharmacology, efficacy and safety are covered. New areas of research in zoster vaccination are also discussed.

Take home message: The live attenuated zoster vaccine is an effective and well-tolerated method of preventing zoster and the potentially debilitating sequelae and is recommended for immunocompetent patients 60 years of age and older. Ongoing clinical trials are investigating new means of effective prevention.     

The antifertility and antiadrenergic actions of thiocarbamate fungicides in laying hens

The effects of the thiocarbamate fungicides, thiram, ziram, ferbam, maneb, and zineb, on norepinephrine synthesis by laying hens were investigated. Inhibition experiments with dopamine beta-hydroxylase purified from chicken adrenals indicated that thiram, ziram, and ferbam are potent competitive inhibitors with the substrate the substrate ascorbate. Maneb and zineb were without effect at comparable concentrations. Experiments investigating the interaction of thiram, ziram, and ferbam with cupric ions suggested that these compounds probably inhibit the enzyme by complexing the fully oxidized copper at its active site. Maneb and zineb also complexed cupric ions in solution and thus their failure to inhibit is not due to their inability to complex copper. When tested in vivo, thiram, ziram, and ferbam at po doses of 2.5 mg/kg or greater significantly reduced the conversion of radioactive dopa, given systemically, to brain norepinephrine. Since they did not affect the uptake of radioactive dopa by the brain or its subsequent decarboxylation within the brain to yield dopamine, these three compounds inhibit cerebral dopamine beta-hydroxylase in vivo. In contrast maneb and zineb at a po dose of 20 mg/kg had no significant effect on brain norepinephrine synthesis. Previously published results (Weppelman et al., Biol. Reprod. 23, 40-46, 1980) demonstrated that thiram, ziram, and ferbam (but not maneb or zineb) have antifertility action in laying hens. The correlation between this action and inhibition of dopamine beta-hydroxylase suggests that the antifertility effects of thiram, ziram, and ferbam might result from their antiadrenergic action. The observation that all doses of thiram in the diet which caused significant antigonadal action when fed to laying hens for 1 week also significantly decreased central and peripheral stores of norepinephrine supports this conclusion.     

Effect of halothane inhalation on orotic acid uptake and uridine incorporation into mouse liver RNA

Repeated exposure of mice to an oxygen-halothane atmosphere (99.1, v/v) caused the liver wt and RNA content to increase about 30 per cent. When RNA was labeled with radioactive orotic acid during this time, the labeling of RNA decreased about 50 per cent. The RNA precursor pool was not affected by halothane treatment. It could be demonstrated that the application of the anesthetic hampered the uptake of orotic acid from the blood into liver cells. Using radioactive uridine, this effect could not be observed. The study demonstrates that unexpected side effects of drugs might complicate the interpretation of results.     

Treatment of compulsive rituals with visual screening: A case study with long-term follow-up

The present study reports on the use of visual screening, a mildly aversive response suppression procedure, as a treatment for reducing compulsive behaviors in a four and one-half year-old developmentally disabled boy. Two distinct patterns of compulsive responding were observed: repetitive (stereotyped) shoe-related behaviors and a ritualistic shoe-related act. The effect of visual screening on repetitive shoe-related responses was initially evaluated in a laboratory setting under A-B-A-B-B¹ experimental conditions and systematically extended to the classroom setting in multiple baseline fashion. Visual screening was also contingently applied as treatment for the shoe-related ritual, with the effects analyzed using a similar multiple baseline format across hospital residential unit and natural home settings. Results of the study indicated that visual screening was an effective treatment for suppressing both forms of the subject's compulsive responding and that it was an easily learned and administered procedure from both staff and parent perspectives. Follow-up data across 12 months were obtained and indicated that the effect of treatment was exceptionally durable.     

Impact of rotavirus vaccine on paediatric rotavirus hospitalisation and intussusception in New Zealand: A retrospective cohort study

BackgroundRotavirus results in a significant burden of hospitalisations and deaths globally. Rotavirus vaccine has been used in New Zealand since July 2014. The aim of this study was to assess the safety and effectiveness of RotaTeq® vaccine in New Zealand between 2006 and 2016.MethodsA national cohort study of 723,695 children aged less than 6 years was carried out using linked administrative datasets. Study outcomes were hospitalisation for intussusception, rotavirus, and all-cause gastroenteritis. Intussusception hospitalisation rates were calculated from 2006 to 2016, and rotavirus and all-cause gastroenteritis hospitalisation rates from 2011 to 2016. We examined the effect of RotaTeq® vaccination on rotavirus and all-cause gastroenteritis hospitalisation rates using Poisson regression. Adjusted incidence rate ratios controlled for sex, year of birth, ethnicity, socioeconomic deprivation, and district health board area.ResultsSignificant reductions in the incidence of rotavirus hospitalisation were seen in all age groups, ethnicities, and deprivation following the introduction of RotaTeq®. There was a 92.6% reduction in hospitalisation incidence in the vaccinated cohort (p < 0.0001). There was also a 48% reduction in all-cause gastroenteritis hospitalisation incidence in the vaccinated cohort (p < 0.0001). The average annual intussusception rate in children aged less than 3 years was 26.2 per 100,000, with no significant change over time (p = 0.847).ConclusionsIn New Zealand the introduction of RotaTeq® resulted in a significant reduction in rotavirus hospitalisation, and a halving in all-cause gastroenteritis hospitalisation. There has been no change in the overall incidence of intussusception or clear change in patterns of cases, although intussusception cases did occur within risk period immediately post vaccine.     

Public health impact of Rotarix vaccination among commercially insured children in the United States

BackgroundThis study (NCT01915888) assessed public health impact of Rotarix, GSK [RV1] vaccination.MethodsChildren born between 2007–2011 were identified from Truven Commercial Claims and Encounters Databases and observed until earlier of plan disenrollment or five years old. Children receiving one or two doses of RV1 during the vaccination window were assigned to incomplete and complete vaccination cohorts, respectively. Children without rotavirus (RV) vaccination (RV1 OR RotaTeq, Merck & Co., Inc. [RV5]) were assigned to the unvaccinated cohort. Claims with International Classification of Disease 9th edition (ICD-9) codes for diarrhea and RV infections were identified. First RV episode incidence, RV-related and diarrhea-related healthcare resource utilization were compared. Multivariate Poisson regression with generalized estimating equations was used to generate 95% confidence intervals (CIs) around incidence rate ratios (IRR) between cohorts while adjusting for gender, age and calendar year. Mean costs for first RV and diarrhea episodes were calculated with adjustment for gender and birth year; bootstrapping was used to determine statistically significant differences between cohorts.ResultsIncidence of first RV episodes was significantly reduced in complete and incomplete vaccination cohorts compared to the unvaccinated cohort (IRR = 0.17 [95%CI: 0.09–0.30] and IRR = 0.19 [95%CI: 0.06–0.58], respectively). RV-related inpatient, outpatient and emergency room (ER) visits were significantly lower for complete vaccination versus unvaccinated cohort. Diarrhea-related inpatient and ER visit rates were significantly lower for complete vaccination versus unvaccinated cohorts; outpatient rates were similar. RV-related and diarrhea-related resource utilization rates were significantly lower or no different for incomplete vaccination versus unvaccinated cohort. Compared with unvaccinated children, adjusted mean cost for first RV episode and first diarrhea episode per 1000 persons was $11,511 (95%CI: $9855-$12,024) and $46,772 (95%CI: $26,268-$66,604) lower, respectively, for completely vaccinated children.ConclusionsRV1 vaccination confers benefits in reduction of RV incidence, RV- and diarrhea-related healthcare resource utilization, and RV- and diarrhea-related healthcare costs.