Optimising Immunogenicity with Viral Vectors: Mixing MVA and HAdV-5 Expressing the Mycobacterial Antigen Ag85A in a Single Injection

The Bacillus Calmette - Guerin (BCG) vaccine provides a critical but limited defense against Mycobacterium tuberculosis (M.tb). More than 60 years after the widespread introduction of BCG, there is an urgent need for a better vaccine. A large body of pre-clinical research continues to support ongoing clinical trials to assess whether viral vectors expressing M.tb antigens that are shared by BCG and M.tb, can be used alongside BCG to enhance protection. A major focus involves using multiple unique viral vectors to limit anti-vector immunity and thereby enhance responses to the insert antigen delivered. The successful introduction of viral vector vaccines to target M.tb and other pathogens will be reliant on reducing the costs when using multiple vectors and inhibiting the development of unwanted anti-vector responses that interfere with the response to insert antigen. This study examines methods to reduce the logistical costs of vaccination by mixing different viral vectors that share the same insert antigen in one vaccine; and whether combining different viral vectors reduces anti-vector immunity to improve immunogenicity to the insert antigen. Here we show that a homologous prime-boost regimen with a mixture of MVA (Modified Vaccinia virus Ankara) and Ad5 (human adenovirus type 5) vectors both expressing Ag85A in a single vaccine preparation is able to reduce anti-vector immunity, compared with a homologous prime-boost regimen with either vector alone. However, the level of immunogenicity induced by the homologous mixture remained comparable to that induced with single viral vectors and was less immunogenic than a heterologous Ad5 prime-MVA-boost regimen. These findings advance the understanding of how anti-vector immunity maybe reduced in viral vector vaccination regimens. Furthermore, an insight is provided to the impact on vaccine immunogenicity from altering vaccination methods to reduce the logistical demands of using separate vaccine preparations in the field.     

Effects of ovariectomy of the dogfish Scyliorhinus canicula L. on circulating levels of androgen and oestradiol and on pituitary gonadotrophin content

Levels of androgens and oestradiol in dogfish, Scyliorhinus canicula , plasma, measured by radioimmunoassay, decrease markedly after ovariectomy (OVX). The magnitude and latency of these responses varies according to length of captivity preceding the operation and the time of year at which ovariectomy is performed. Androgens are cleared more rapidly than oestradiol from plasma following OVX, and levels of both steroids are reduced after laparotomy (LAP) in November but not in March. An extract of ventral lobes of the dogfish pituitary induces a significant increase in the circulating androgen levels in LAP fish but not in OVX fish, indicating that the ovary is the major site of androgen production in response to stimulation by dogfish gonadotrophin. Intramuscular injections of oestradiol benzoate (2.5 mg per fish) into LAP fish produce a significant reduction in the gonadotrophin content of the pituitary ventral lobe, measured in the quail testicular cell bioassay, when compared to LAP and unoperated controls. However, no significant changes in the gonadotrophin content of the ventral lobe were seen five days after OVX in June.     

Elimination of African Onchocerciasis: Modeling the Impact of Increasing the Frequency of Ivermectin Mass Treatment

The African Programme for Onchocerciasis Control (APOC) is currently shifting its focus from morbidity control to elimination of infection. To enhance the likelihood of elimination and speed up its achievement, programs may consider to increase the frequency of ivermectin mass treatment from annual to 6-monthly or even higher. In a computer simulation study, we examined the potential impact of increasing the mass treatment frequency for different settings. With the ONCHOSIM model, we simulated 92,610 scenarios pertaining to different assumptions about transmission conditions, history of mass treatment, the future mass treatment strategy, and ivermectin efficacy. Simulation results were used to determine the minimum remaining program duration and number of treatment rounds required to achieve 99% probability of elimination. Doubling the frequency of treatment from yearly to 6-monthly or 3-monthly was predicted to reduce remaining program duration by about 40% or 60%, respectively. These reductions come at a cost of additional treatment rounds, especially in case of 3-monthly mass treatment. Also, aforementioned reductions are highly dependent on maintained coverage, and could be completely nullified if coverage of mass treatment were to fall in the future. In low coverage settings, increasing treatment coverage is almost just as effective as increasing treatment frequency. We conclude that 6-monthly mass treatment may only be worth the effort in situations where annual treatment is expected to take a long time to achieve elimination in spite of good treatment coverage, e.g. because of unfavorable transmission conditions or because mass treatment started recently.     

A Novel Piggybac Transposon Inducible Expression System Identifies a Role for Akt Signalling in Primordial Germ Cell Migration

In this work, we describe a single piggyBac transposon system containing both a tet-activator and a doxycycline-inducible expression cassette. We demonstrate that a gene product can be conditionally expressed from the integrated transposon and a second gene can be simultaneously targeted by a short hairpin RNA contained within the transposon, both in vivo and in mammalian and avian cell lines. We applied this system to stably modify chicken primordial germ cell (PGC) lines in vitro and induce a reporter gene at specific developmental stages after injection of the transposon-modified germ cells into chicken embryos. We used this vector to express a constitutively-active AKT molecule during PGC migration to the forming gonad. We found that PGC migration was retarded and cells could not colonise the forming gonad. Correct levels of AKT activation are thus essential for germ cell migration during early embryonic development.     

Regional co-ordinator for haemophilia in domiciliary practice.

The North-east Thames Region has appointed a nursing sister to co-ordinate the organisation of care for haemophiliacs in the region. As a result of the appointment, facilities for home treatment have expanded rapidly. Several associate centres providing care to haemophiliacs have been set up around the region in addition to the four main haemophilia centres, which are all in the south-west corner of the region. As well as providing support and supervision of patients on home treatment, the co-ordinator helps to place haemophiliac children in suitable schools, maintains the regional register of haemophiliacs, and has a more general role in ensuring that services are available where they are needed throughout the region.     

Catchment areas in general practice and their relation to size and quality of practice and deprivation: a descriptive study in one London borough.

OBJECTIVE: To relate the sizes of general practice catchment areas in one London borough to list size, deprivation payments, medical staffing, and locally and nationally recognised measures of quality. DESIGN: Study of general practice catchment area maps. SETTING: London borough of Lambeth. SUBJECTS: 60 out of the 71 general practices in Lambeth. MAIN OUTCOME MEASURES: Practice catchment area size with corrections for numbers of doctors and patients. RESULTS: Catchment area size varied greatly between practices, showing an almost 150-fold difference between the largest and smallest practices. This size differential was even more marked when the size of the catchment area was corrected for the number of general practitioners in the practice, where a 300-fold difference was found. Substantial differences existed between practices in each of the four locally assigned quality bands. The weakest practices had catchment areas three times as large as those of the strongest practices. When corrected for medical staffing, the difference was eight times as great. A calculated measure of patient dispersion showed that the practice population of the strongest practices was four times as densely clustered as that of the weakest practices, whose patients were more widely geographically dispersed. CONCLUSIONS: Large variations exist in the size of catchment areas of inner city practices even when corrected for numbers of doctors and patients. These differences are associated with variations in quality of care.