Cluster 3 - Vaccine Development Cross Cutting Supporting Activities
WP3.1 Comparative evaluation, concept development
The target product profile for an envisaged EMVDA supported product will: 1) prevent clinical malaria caused by all polymorphic variants of P. falciparum, 2) target children under five years of age in endemic areas, 3) use a non-frozen safe vaccine, 4) be administered intra muscularly., 5) not interfere with Expanded Program of Immunisation (EPI) delivered vaccines, 6) provide more than six months clinical efficacy, and 7) induce an immune response, which has no adverse effects on subsequent exposure to infection. The project has developed a harmonised immunisation protocol to allow for comparison between different vaccinations strategies. The immunogenicity will first be assessed in mice or rabbits because of the need for large amounts of antibodies. Immunogenicity tests will include IgG subclass determination, reactivity with parasite protein and reactivity in the growth-inhibition assays described below. The External Scientific Advisory Committee (ESAC) will, from the start of the project, assist in the design of the concept and the modus operandi of EMVDA's entire preclinical and clinical assays package.
A full and detailed review of all the EMVDA vaccination strategies will be carried out. With recommendations from the ESAC all projects will be ranked based on their potential to deliver a product within the timescale of the EMVDA project. Funding will be contingent on successful achievement of milestones and deliverables, recommendations from ESAC reviews, EMVDA vaccine potential addressing the target profile, and availability of adequate funding.
Work Package Leader: EVI
WP3.2 Comparative pre-clinical and clinical ELISA, IFA and GIA
To measure immune responses and assess safety, mice and rabbits will be used in accordance with regulatory requirements; the latter because of the need for large amounts of antibodies. Rhesus monkeys might be enrolled if need arises to address specific questions. Only products that have been characterised to appropriate biochemical and antigenic levels will be tested. The WP offers a unique opportunity for a better understanding of the relationship between pre-clinical and clinical studies. Furthermore, it also ensures optimal use is made of animal resources, a vital ethical requirement, as the required detailed planning and organisation, use of shared controls etc., can be assured. The specialised immune response and biological efficacy assays will be carried out at the UEDIN and BPRC, continuing a successful collaboration to establish joint European centres at which critical comparative assays can be undertaken under masked, unbiased evaluation protocols. The assays involve the use of malaria parasites in synchronised cultures for invasion blocking, in vitro growth inhibition, and inhibition of proteolytic processing assays. ELISA and microscopic immunofluorescence assays will also be used to assess antibody titre following immunisations, plus qualitative and quantitative assessments of antibody recognition of antigenically diverse isolates of P. falciparum.
To determine whether natural antibody responses to the current antigens of this project are related to protection from clinical malaria the Afro Immuno Assay (AIA) project was initiated. The aim of this project is to develop and introduce standardised immunological assays that will: (1) form part of a set of criteria for the validation of promising malaria vaccine candidate antigens and, (2) provide essential baseline information for clinical trials. A set of standardised ELISA assays that measure humoral immune responses - including IgG subclasses to malaria antigens - has been developed, and used to examine whether specific antibody responses correlate to the immune status of the populations studied. Depending on the outcome and on ESAC recommendations, selected studies will be continued and new studies with new partners initiated. In particular further development and standardisation of the Antibody Dependent Cytotoxic Inhibition assay (ADCI), for use in the field, as a possible marker of the acquisition of clinical malaria immunity is foreseen.
Work Package Leader: BPRC
WP3.3. Optimisation and standardisation of an ADCI assay[nim1]
The ADCI assay investigates the inhibition of parasite cultures’ multiplication by the combined presence of parasite antibodies and monocytes. It is thus important to 1) control the preparation of monocytes used in the assay, 2) standardise and preferably automate quantification of growth inhibition, and 3) control the preparation of test samples.
To date a robust assay that can readily be implemented in different labs has not been established for ADCI, even though this assay was first published more than twenty years ago. This work package will define and standardise the basic parameters of an ADCI-type assay that can contribute to selection between candidate vaccines to be undertaken in close collaboration with other global initiatives (if any) to standardise ADCI. This assay will then be implemented independently in at least two labs to provide the Consortium with decision making tools.
Work Package Leader: BPRC
WP3.4. Comparison of human challenge models for protective efficacy for blood stage vaccines
Evaluation of vaccine efficacy by using Experimental Human Malaria Infection (EHMI) has strong added value. Such challenges are relatively cheap, and are carried out under safe controlled conditions, and could provide a more solid ethical basis for testing candidate vaccines in endemic countries, should protection be found. Hundreds of volunteers have been experimentally infected by the bite of five infected mosquitoes and treated with anti-malarial drugs when thick blood smear became positive. EHMI has been shown to be instrumental for testing pre-eythrocytic vaccines. Parasite multiplication rate is the key parameter for asexual stage vaccine efficacy, which implies that parasitaemia should be followed over a sufficiently lengthy period. Parasitaemia can be obtained by either mosquito bite (sporozoite inoculation) or by i.v. injection of P. falciparum Infected Red Blood cells (RBC).
The objectives are harmonisation of EHMI, comparative evaluation of parasite multiplication by infected mosquito bites versus direct i.v. injection of infected RBC and comparative evaluation of protection by infected mosquito bites versus direct i.v. injection of infected RBC.
Work Package Leader: RUNMC
WP3.5. EMVDA PhD programme
This work package concerns research and innovation effort elements of the PhD programme. The aim is to enrol eight students, each associated with one or more of the project work packages, at minimum two partner laboratories involved in individual PhD projects. In order to ensure capacity development both in Europe and low income countries, and to contribute positively towards future North-South partnerships, some of the fellowships are specifically for low income countries’ scientists, whereby they will be associated with the AMANET third party performer institutions. Although nominally associated with a specific work package, the PhD programme encourages students to undertake work in more than one partner institution, including placement with the Small and Medium-sized Enterprise (SME) partners involved. This mobility is seen as an important aspect of the training programme. There are eight fellowships each for 3.5 years duration. In the event a specific project is terminated, students will be allowed to continue their studies as originally proposed, or where appropriate - and where it does not prejudice the student – switch to another project. Management of the PhD programme is under the control of the Coordinator and the programme has been implemented in collaboration with the European Molecular Biology Laboratory (EMBL), who report directly to the Steering Committee. All students report on their work at the annual meetings of the EMVDA project. Students receive an annual stipend equivalent to EMBL students. Students may receive support for up to 3.5 years.
Work Package Leader: EVI
WP3.6. EMVDA Industrial training
This work package concerns research and innovation effort elements of African industrial training efforts. A key aim of this WP is to deliver measurable capacity development in terms of industrial training for AMANET third party performers. It is envisaged that two to three African scientists will be awarded up to one year scholarships allowing them to enrol in appropriate hands-on training programmes organised by ETNA.
Work Package Leader: AMANET
WP3.7 EMVDA's annual research conference
The annual conference is the principle opportunity for the consortium to meet in its entirety. It serves several purposes: 1) it is the mechanism whereby the consortium establishes links, disseminates knowledge and develops innovative research proposals between EMVDA members, in the form of presentations, posters and workshops representing all aspects of EMVDA activity, including the PhD programme and African industrial training efforts; 2) annual monitoring, in line with the EC requirements, is arranged to coincide with the annual conference. The annual conference focuses on the ongoing monitoring of active work packages through the project leaders and management committee. Evaluation is ongoing. Initial first year evaluations are followed by a further detailed evaluation at month 18 to determine which WPs progress. Subsequent evaluation and monitoring occur annually in line with the EC review timetable. All meetings involve the ESAC and EC representative; 3) the annual conference is timed once to coincide with the EviMalaR conference to provide opportunities to share information and develop closer alignment between the two EC-funded projects.
Work Package Leader: EVI