Utilisation of Chimeric Lyssaviruses to Assess Vaccine Protection against Highly Divergent Lyssaviruses.

Lyssaviruses constitute a diverse range of viruses with the ability to cause fatal encephalitis known as rabies. Existing human rabies vaccines and post exposure prophylaxes (PEP) are based on inactivated preparations of, and neutralising antibody preparations directed against, classical rabies viruses, respectively. Whilst these prophylaxes are highly efficient at neutralising and preventing a productive infection with rabies virus, their ability to neutralise other lyssaviruses is thought to be limited. The remaining 15 virus species within the lyssavirus genus have been divided into at least three phylogroups that generally predict vaccine protection. Existing rabies vaccines afford protection against phylogroup I viruses but offer little to no protection against phylogroup II and III viruses. As such, work involving sharps with phylogroup II and III must be considered of high risk as no PEP is thought to have any effect on the prevention of a productive infection with these lyssaviruses. Whilst rabies virus itself has been characterised in a number of different animal models, data on the remaining lyssaviruses are scarce. As the lyssavirus glycoprotein is considered to be the sole target of neutralising antibodies we generated a vaccine strain of rabies using reverse genetics expressing highly divergent glycoproteins of West Caucasian Bat lyssavirus and Ikoma lyssavirus. Using these recombinants, we propose that recombinant vaccine strain derived lyssaviruses containing heterologous glycoproteins may be a suitable surrogate for wildtype viruses when assessing vaccine protection for the lyssaviruses.

Systematic review of the clinical efficacy of vaginal progesterone for luteal phase support in assisted reproductive technology cycles.

Vaginal progesterone via capsule, gel or tablet is the most common route for luteal phase support (LPS) in Europe. Although there is a wealth of data comparing products used at other stages of assisted reproductive technology cycles, there is a lack of systematically identified evidence comparing the wide range of vaginal progesterone products. This systematic review queried the MEDLINE, Embase and Cochrane Library databases on 30 June 2016 to identify head-to-head randomized controlled trials (RCTs) comparing the efficacy or safety of vaginal progesterone preparations (Crinone, Cyclogest, Lutigest or Utrogestan Vaginal) for LPS in assisted reproductive technology cycles. Of 1914 results, 18 RCTs were included. No significant difference in clinical pregnancy rate was identified in comparisons of Utrogestan Vaginal with Crinone. Utrogestan Vaginal and Lutigest were non-inferior to Crinone in ongoing pregnancy rate comparisons. Differences in patient-reported perineal irritation with Crinone and Lutigest were not significantly different to Cyclogest. In studies comparing varying timing or dosage of Utrogestan Vaginal or Crinone, no significant differences were observed. These results suggest Crinone, Cyclogest, Lutigest and Utrogestan Vaginal represent equally safe and effective choices of vaginal progesterone for LPS in assisted reproductive technology cycles. Future quantitative analyses could provide further support for these findings.

Long-term retention rates for antiepileptic drugs: A review of long-term extension studies and comparison with brivaracetam.

Antiepileptic drug (AED) retention rates are frequently reported in the literature and used to inform clinical decision-making, but methodological differences in the determination of retention rates make comparisons between trials difficult. Open-label extension (OLE) studies of AEDs in patients with focal epilepsy were identified from the literature. Retention calculation methods were reviewed, and published AED retention rates qualitatively compared with corresponding data for brivaracetam (BRV), a synaptic vesicle protein 2A ligand. The search identified 40 publications (corresponding to 17 studies of nine AEDs: eslicarbazepine, gabapentin, lacosamide, levetiracetam, oxcarbazepine, perampanel, pregabalin, topiramate and zonisamide) meeting eligibility criteria for inclusion in the review. Three methodologies to estimate retention rate were identified, which differed in whether patients randomised to placebo in the preceding randomised controlled trials (RCTs) were included or analysed separately, and whether retention was measured from the start of the OLE or of active treatment exposure. The most robust, conservative approach included all patients and measured retention from start of active treatment exposure, whether during the blinded RCT or at the start of the OLE (placebo RCT patients). Data using this method was available for five AEDs in this review, including BRV. The corresponding BRV 52week retention rate (modal doses 50-200mg/day; therapeutic range) was 69.8% (63.3-66.7% for other AEDs at this time point). No statistical indirect comparison was performed, as study populations were clinically heterogeneous. To avoid inconsistencies in methodologies, and allow comparison between AEDs when OLE data are the only long-term data available, retention rate analyses would benefit from the development of consistent reporting standards and guidelines.

Lyssaviruses and bats: emergence and zoonotic threat.

The continued detection of zoonotic viral infections in bats has led to the microbial fauna of these mammals being studied at a greater level than ever before. Whilst numerous pathogens have been discovered in bat species, infection with lyssaviruses is of particular significance from a zoonotic perspective as, where human infection has been reported, it is invariably fatal. Here we review the detection of lyssaviruses within different bat species and overview what is understood regarding their maintenance and transmission following both experimental and natural infection. We discuss the relevance of these pathogens as zoonotic agents and the threat of newly discovered viruses to human populations.

Rabies virus vaccines: is there a need for a pan-lyssavirus vaccine?

All members of the lyssavirus genus are capable of causing disease that invariably results in death following the development of clinical symptoms. The recent detection of several novel lyssavirus species across the globe, in different animal species, has demonstrated that the lyssavirus genus contains a greater degree of genetic and antigenic variation than previously suspected. The divergence of species within the genus has led to a differentiation of lyssavirus isolates based on both antigenic and genetic data into two, and potentially a third phylogroup. Critically, from both a human and animal health perspective, current rabies vaccines appear able to protect against lyssaviruses classified within phylogroup I. However no protection is afforded against phylogroup II viruses or other more divergent viruses. Here we review current knowledge regarding the diversity and antigenicity of the lyssavirus glycoprotein. We review the degree of cross protection afforded by rabies vaccines, the genetic and antigenic divergence of the lyssaviruses and potential mechanisms for the development of novel lyssavirus vaccines for use in areas where divergent lyssaviruses are known to circulate, as well as for use by those at occupational risk from these pathogens.