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FP7

E PIAF Report Summary

Project reference: 242131
Funded under: FP7-HEALTH

Periodic Report Summary 3 - E PIAF (Enhanced Protective Immunity Against Filariasis)

Project Context and Objectives:
Enhanced Protective immunity Against Filarial Infections
HEALTH-2009-4.3.1-1 Contract 242131

Summary description of project

The prime objective of E PIAF (http://filaria.eu/) was identification and testing of candidates for inclusion in a vaccine against onchocerciasis, also known as river blindness. The working hypothesis is that neutralization of excreted-secreted parasite-derived immuno-modulators will lead to expression of a Th2-driven protective immunity.

To achieve this goal the following investigations were undertaken.
1 Human studies: Gene expression profiling of patients with different clinical and parasitological presentations of onchocerciasis and other filarial infections has been used to define pathways associated with protective immunity. This information will help determine appropriate formulation of experimental vaccines to promote protection while avoiding unwanted induction of pathology.

2 Animal studies: Parallel studies in the Litomosoides sigmodontis-mouse model to defined protective immune responses evoked by vaccination with irradiated L3 larvae.

3 Parasite studies: Detailed genome and proteome mapping of the developmental (life cycle) stages of Onchocerca spp and other filarial species to identify and characterize the excreted/secreted products that modulate [suppress] potential lethal host [Th2] response. E PIAF has completed the genomes of Onchocerca ochengi, O gutterosa, Litomosdoes sigmodontis, Acanthocheilonema viteae, Dirofilaria immitis and Setaria labiatopapillosa (http://badger.bio.ed.ac.uk/filarial/) and with the completion of the genomes of O volvulus, Wuchereria bancrofti, and Brugia spp by the Sanger Centre and The Broad Institute of MIT and Harvard, this means that the genomes of all the major filariae species have now been determined.

4 Vaccine testing: Use of the L sigmodontis-mouse model to test various formulations of vaccines incorporating selected excreted/secreted parasite antigens and aimed at driving the immune response down protective pathways identified by the microarray analyses. Efficacy was assessed by reduction of blood microfilariae and adult worms. Three vaccine candidate have been identified on the basis of their ability to reduce microfilarial loads by a >90%. These vaccine candidates are now ready to take to Phase I safety trials with the prospect of starting Phase 2 trials by 2020 (http://riverblindnessvaccinetova.org)

5 Preliminary modelling analyses, based on an initial vaccine efficacy of 50% against incoming worms, a 90% reduction of microfilarial load, and an 80% coverage of 1-5 yr olds initially with subsequent annual vaccination of 1 yr olds, suggest that after 15 years of vaccination in areas not previously treated with ivermectin, a vaccine would have a substantial impact, markedly reducing microfilarial load in the young (under 20 years of age) in a range of endemicity scenarios. This highlighted the risk of acquiring heavy infections early in life with the prospect of developing onchocerciasis-related morbidity. This suggests that a vaccine would have a beneficial impact in terms of reducing Onchocerca disease burden in these populations. Moreover, a vaccine could markedly decrease the chance of onchocerciasis infection re-spreading to areas where it is deemed that mass drug administration with ivermectin can be stopped. Therefore, a vaccine would protect the substantial investments made by present and past onchocerciasis control programmes (together, the Onchocerciasis Control Programme in West Africa (OCP) and APOC have cost over US$1 billion–excluding the value of ivermectin), decreasing the chance of disease recrudescence and the potential spread of ivermectin resistance.

It is envisaged that vaccination would be used together with ivermectin in any control or elimination programme but it would also have the benefit of protecting pre-school children from severe disease. Furthermore, the therapeutic application of any vaccine is also a real possibility.

Project Results:
Enhanced Protective Immunity Against Filariasis (E PIAF)
HEALTH-2009-4.3.1-1 Contract 242131

E PIAF Summary achievements
1 Cohorts of endemic normals (putative immune) and patients infected with infected only with Onchocerca volvulus, Wuchereia bancrofti, Loa loa or Mansonella perstans; and, individuals with co-infection of two (eg O volvulus + L loa) or more (O volvulus + L loa + M perstans) identified, and sera and cell samples collected.

2 Data bases of clinical and immunological presentations of immune patients and different categories of onchocerciasis, lymphatic filariasis, Loa loa and Mansonella perstans patients established in a central repository.

3 mRNA from all individuals comprising these cohorts have been isolated and processed through the Illumina HT12v4 microarray platform.

4 mRNA has also been collected from two cohorts of mice vaccinated and protected from challenge infections.

5 Gene expression profiles of patients infected with:
a, Onchocerca volvulus.
b, Loa loa.
c, Wuchereria bancrofti.
d, Mansonella perstans.
e, O volvulus and L loa.
f, O volvulus, L loa and Mansonella perstans.
g, O volvulus and W bancrofti

6 Gene expression profiles of individuals who have no clinical or parasitological signs of filarial infections despite having lived entire lives or many years in areas endemic for lymphatic filariasis; onchocerciasis; loiasis; or co-endemic for onchocercaisis-loiasis. These individuals are considered immune to infection and area also known as endemic normals

7 A programme GEVisE, http://gevise.gti.ed.ac.uk/) has been developed to visualise the gene expression profiles from every probe-set in the two mouse and four human and two mouse datasets; each Illumina-based dataset is composed of approximately 47,000 probe-sets.

8 Preliminary anlaysis of the microarray data identified Th2 pathways associated with expression of protective immunity. These observations are supported by classical T cell and cytokine assays.

9 Genomes of Onchocerca ochengi, O gutterosa, Litomosdoes sigmodontis, Acanthocheilonema viteae, Dirofilaria immitis and Setaria labiatopapillosa completed and published. With the completion of the genomes of O volvulus, Wuchereria bancrofti, and Brugia spp by the Sanger Centre and The Broad Institute of MIT and Harvard, this means that the genomes of all the major filariae species have now been determined.

10 Complete genome of Wolbachia determined.

11 Proteomes of infective L3, adults and microfilariae of L sigmodontis determined.

12 Proteomes of adults and microfilariae of Onchocerca ochengi determined.

13 Excreted and secreted antigens of L sigmodontis L3, adult male, adult female and microfilariae determined

14 Identification of vaccine candidates through their association with MHC class II molecules.

15 Successful vaccination of mice against L sigmodontis L3 challenge with recombinant DNA plasmids.

16 Successful vaccination of mice against L sigmodontis microfilariae challenge with synthetic peptides.

12 Three onchocerciasis vaccine candidates identified for first-in-human safety trial. http://www.riverblindnessvaccinetova.org/

This work is aimed at development of a vaccine for children living in all areas endemic for onchocerciasis but particularly forest areas of high prevalence where ivermectin is failing to control the disease. It is also vital for protecting people living in areas where there is a high prevalence of O volvulus and Loa loa co-infections where mass treatment with ivermectin is contra-indicated because of the risk of severe adverse reactions associated with death of L loa microfilariae. It is estimated that at least 7 million people are living in such situations.


Project public website addresses:
http://filaria.eu/
http://riverblindnessvaccineTOVA.org

David W Taylor, Edinburgh, August 2014

Potential Impact:
Enhanced Protective Immunity Against Filariasis (E PIAF)
HEALTH-2009-4.3.1-1 Contract 242131
Expected final results and potential impacts
Three Onchocerca volvulus antigens have been identified as potential vaccine candidates.

The next step is to take one or more to Phase I human safety trials. This will require producing quantities of the antigen to Good Manufacturing Practice and taking these formulations through mandatory/regulatory toxicity tests in animals.

Successful completion of animal test should enable the antigens to be taken through phase I in human volunteers. A two-stage process is envisage with the primary tests being performed in Europe with Europeans of West African origin but who have never travelled to Africa. The second phase would be carried out in Ghana.

Successful completion of the safety trials will permit efficacy trails to be initiated in a phased manner in communities where only Onchocerca volvulus is endemic and second in Cameroon in areas where O volvulus and Loa loa are co-endemic ie areas where ivermectin is contraindicated for mass treatment programmes.

The target population for vaccination is pre-school children who are currently excluded from treatment with ivermectin. Mathematical modelling based on an initial vaccine efficacy of 50% against incoming worms, a 90% reduction of microfilarial load, and an 80% coverage of 1-5 yr olds initially with subsequent annual vaccination of 1 yr olds, suggest that after 15 years of vaccination in areas not previously treated with ivermectin, a vaccine would have a substantial impact, markedly reducing microfilarial load in the young (under 20 years of age) in a range of endemicity scenarios. This has important implications as studies have highlighted the crucial role of acquiring heavy infections earlier in life regarding the risk of developing onchocerciasis-related morbidity and mortality. This suggests that a vaccine would have a beneficial impact in terms of reducing onchocercal disease burden in these populations. Moreover, a vaccine could markedly decrease the chance of onchocerciasis infection re-spreading to areas where it is deemed that mass drug administration with ivermectin can be stopped. Therefore, a vaccine would protect the substantial investments made by present and past onchocerciasis control programmes (together, the Onchocerciasis Control Programme in West Africa (OCP) and APOC have cost over US$1 billion–excluding the value of ivermectin), decreasing the chance of disease recrudescence and the potential spread of ivermectin resistance.

The gene expression profiles of filarial infected individuals and the genomes and proteomes of the parasites can also provide a starting point for data mining for new drugs for both human and veterinary (Dirofilaria immitis, the dog heart worm) application

A spin-off: the onchocerciasis vaccine candidates include potent Th2 immuno-modulators. These may have therapeutic application for treatment of Th2 driven autoimmune diseases such as multiple sclerosis and psoriasis, and allergies.

David W Taylor, Edinburgh, August 2014

Related information

Documents and Publications

Contact

Noble, Angela (Senior European Funding Advisor)
Tel.: +44 131 650 9024
Fax: +44 131 651 9023
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Record Number: 165500 / Last updated on: 2015-06-19
Information source: SESAM