MRC CiC successful applicants 2015

  • Lymphatic Filariasis Surveillance System

Lead: Dr Lisa Reimer (Liverpool School of Tropical Medicine)

Current lymphatic filariasis surveillance strategies require blood collection from hundreds of community members and waiting for children to develop patent infections in order to establish recent exposure.

Xenomonitoring (detection of filarial DNA in mosquitoes) would allow for real-time detection and rapid response compared to the current strategy, however the costs and expertise involved are prohibitive for LF programmes. We are developing a tool to collect, concentrate and filter filarial DNA from wild mosquitoes.

This innovative, low cost approach has been informed by our preliminary work on mosquito behaviour and filariasis diagnostics. Our xenomonitoring tool directly responds to the emerging need of LF elimination programmes to rapidly and sensitively detect LF resurgence.

 

  • Exploring phosphodiesterase inhibitors as future antimalarial drugs

Lead: Dr David Baker (London School of Hygiene and Tropical Medicine)

Drug resistance is a major concern for the effective treatment and control of malaria worldwide. It is therefore imperative that the drug discovery pipeline remains productive and new chemical entities are progressed to form components of future combination treatments.

Our previous work has shown that certain phosphodiesterase inhibitors (PDEi) can block development of blood stage and sexual development of the most lethal form of malaria parasite, Plasmodium falciparum. In collaboration with Pfizer we have recently identified new PDEi with a much higher potency, but with inadequate pharmacokinetic properties.

This MRC Confidence in Concept Scheme grant will support a partnership between the London School of Hygiene & Tropical Medicine (LSHTM), Salvensis, Pfizer, GSK and the Liverpool School to screen a larger number of PDEi chemotypes to identify those which combine potent antimalarial effects with stronger pharmacokinetic properties. PDEi are used to treat a number of human disorders and we view them as promising potential antimalarials.

 

  • Pre-clinical protective efficacy of novel Chagas vaccine candidates: A final step towards clinical application

Lead: Professor Arturo Reyes Sandoval (University of Oxford)

Chagas disease (caused by Trypanosoma cruzi) remains a leading neglected tropical disease in the Americas, associated with 546,000 disability adjusted life years and 10,300 annual deaths.

Approximately 7.5 million people are living with Chagas disease, mostly in impoverished regions of Central and South America, although thousands of T. cruzi-infected individuals also live in the United States, Spain and elsewhere in southern Europe. Development of an efficacious vaccine would represent a major contribution to improving public health throughout this globally important region.

The team lead by Prof. Arturo Reyes-Sandoval in Oxford is developing a Chagas vaccine using replication-deficient viral vectors. Cellular immune responses have been assessed and the candidates have shown to be highly immunogenic, stimulating the development of high frequencies of antigen-specific T cells. Supported by a CiC grant, we have started a collaboration with Prof. John Kelly at the LSHTM to assess efficacy of our vaccine using an infection model recently developed in Prof. Kelly’s lab.

We aim to merge two technological platforms to support the development of a protective Chagas vaccine candidate suitable for human use.

 

  • The whole blood phagocytosis assay: a near patient test to promote a personalised approach to immunomodulatory therapy

Lead: Dr Jamie Rylance (Liverpool School of Tropical Medicine)

Severe infection (sepsis) kills 37000 people in the UK annually. Even with appropriate antibiotic treatment, mortality remains high. New treatments will target the immune response to infection, rather than the bugs causing it.

To identify people who will benefit most, and to enable such drugs to be used effectively, we need a new and relevant test of immune function.Our whole blood assay measures the capacity of neutrophils (a type of white blood cell) to engulf and kill bacteria. These cells are the first cellular line of defence against blood-bourne infection.

This research grant will allow us to test its applicability to real-world situations. By trialing the assay in patients with sepsis, and those without, we expect to refine the test to the point it is clinically robust and useful to doctors. This will pave the way to accelerated development of new treatments for sepsis.

 

  • Formulation of ceftriaxone into nanoparticles to improve intracellular penetration and hasten intracellular killing of Salmonellae

Lead: Dr Nick Feasey (Liverpool School of Tropical Medicine)

Typhoid fever is responsible for an estimated 225,000 deaths/year. Resistance to standard antimicrobials is commonly seen, making ceftriaxone the first-line agent in many settings, however ceftriaxone penetrates the intracellular compartment more slowly than ciprofloxacin and is associated with prolonged fever clearance times and high relapse rates. 

Formulation of ceftriaxone into nanoparticles offers the potential to enhance intracellular delivery, thus improving its efficacy. Preliminary data has demonstrated we can formulate ceftriaxone into nanoparticles without reducing in-vitro activity.

In this study, we will be collaborating with Blueberry Therapeutics on an evaluation of nano-formulations of ceftriaxone, comparing them against standard ceftriaxone using the Operetta High Content Imaging System to determine intracellular clearance of S. Typhi. 

 

  • Evaluation of Plasmodium falciparum SPECT-1 as a novel pre-erythrocytic vaccine candidate

Lead: Dr Ahmed Salman (University of Oxford)

PfSPECT-1 which induces high level efficacy mediated by antibodies is more protective in mice than PfCSP, which has been the leading sporozoite vaccine antigen for decades.

We will compare the immunogenicity and efficacy of PfSPECT-1 as a vaccine candidate in several forms, particularly as virus-like particles in adjuvant, aiming to provide a promising new vaccine candidate. We anticipate identification of a VLP malaria vaccine candidate based on PfSPECT-1 that generates high level efficacy in mice against challenge with transgenic P. berghei sporozoites encoding the same antigen. This will use a production system that is compatible with Good Manufacturing Practice biomanufacture and show adequate yield and purity for further development.

In addition we will aim to demonstrate durable efficacy, and also higher level (additive) efficacy with liver-stage vaccine candidates and with the R21 VLP based on the circumsporozoite protein. PfSPECT-1 might be the easiest to develop as it would only need to double the efficacy of RTS,S alone to be a very useful option. 

 

  • A One Health Approach to MERS-CoV Vaccines for Camels and Humans

Lead: Dr George Warimwe (University of Oxford)

Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging zoonosis that is highly prevalent in camels and causes life-threatening respiratory disease in humans. No licensed camel or human vaccines are currently available for MERS-CoV.

Here, utilising a chimpanzee adenovirus platform with an established safety profile in camels and humans, we will develop a MERS-CoV vaccine for deployment in both these species.

We aim to demonstrate induction of high titre neutralizing antibody and protective efficacy against MERS-CoV in camels, thus providing proof-of-concept for further development of a deployable product for use in camels and in subsequent human clinical trials.

 

  • Development of 2D and 3D in vitro dynamic/flow infection models for drug evaluation against Leishmania 

Lead: Professor Simon Croft (London School of Hygiene and Tropical Medicine)

This proposal focuses on in vitro models for evaluation of novel chemical entities (NCEs) against the intracellular stage of the parasite that causes leishmaniasis.

The project aims to develop novel 2D and 3D dynamic/flow models of the Leishmania intracellular amastigote stage within macrophage populations. We aim to simulate the in vivo situation as closely as possible and seek to demonstrate that this approach is more predictive of the in vivo activity in rodent models. 

Initially, the project will focus on L. major and skin models of infection. We will also provide a different approach to determining the selectiveindex of NCEs as the models will also evaluate cytotoxicity.

 

  • Field diagnostic kits for insecticide resistance

Lead: Dr Mark Paine (Liverpool School of Tropical Medicine)

Project description: TBA

 

  • Towards the generation of safe 8-aminoquinolines: Development of Quantitative structure activity/quantitative structure property (QSAR/QSPR) relationships of primaquine analogs to accurately predict redox potentials

Lead: Professor Giancarlo Biagini (Liverpool School of Tropical Medicine)

Project description: TBA

 

  • Design and development of commercial diagnostic assays for chikungunya and dengue virus diagnosis

Lead: Professor Luis Cuevas (Liverpool School of Tropical Medicine)

Dengue (DENV) and Chikungunya (CHIKV) are viral pathogens transmitted by infected Aedes mosquitoes and a major public health problem worldwide. DENV can cause dengue haemorrhagic fever (DHF) and shock syndrome (DSS) and CHIKV leads to long lasting aches and pains, polyarthralgia. The diseases share many clinical signs, and are difficult to differentiate without laboratory confirmation. However, despite millions of cases occurring each year, < 3% of cases are confirmed, as only the first few patients during an outbreak are tested for surveillance purposes and subsequent cases are assumed to be due to the same virus. Differentiation would help direct treatment.

Although CHIKV used to be limited to Africa, Asia and the Indian subcontinent, it has recently spread to the Americas, making it more difficult to differentiate the infections using epidemiological data. There is thus a need for low cost, sensitive and specific diagnostics for timely clinical management, improved surveillance and in the near future monitoring the new DENV vaccines.

 Our team will develop low cost CHIKV and DENV RT-qPCR assays for surveillance and simplified molecular assays for near-patient testing. These novel diagnostics will facilitate patient management, improve surveillance and facilitate monitoring the imminent implementation of the new DENV vaccines.

 

  • Redevelopment of a promising vaccine candidate for Crimean-Congo Haemorrhagic Fever virus (CCHFv) into a markerless MVA vector suitable for commercial development

Lead: Professor Roger Hewson (Public Health England)

An experimental vaccine against Crimean-Congo Haemorrhagic Fever virus (CCHFv) developed at PHE - Porton Down is effective at protecting mice from an otherwise lethal infection of this highly pathogenic virus CCHFV.

The vaccine is based on a recombinant orthopox virus backbone; this currently includes makers useful to its construction but which are expected to be superfluous to its protective efficacy. 

This project will further develop the vaccine into a more suitable candidate for commercialisation and clinical trials by modifying it into a markerless orthopox platform. The redeveloped vaccine will then be compared with the original vaccine to ensure efficacy.

 

 

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