MICA: Development and GMP manufacture of a PfRH5 protein vaccine to induce strain-transcending immunity against blood-stage Plasmodium falciparum.

Lead Research Organisation: University of Oxford
Department Name: The Jenner Institute

Abstract

Plasmodium falciparum is the parasite that causes the most deadly form of human malaria. Current estimates suggest P. falciparum malaria affects 200-300 million people annually, resulting in the death of about 0.8 million individuals. Thus, despite increasing implementation of control measures, the burden of this devastating disease remains far too high. It remains unlikely that vaccines based on the whole parasite organism will be deployable, and therefore most efforts focus on vaccines encoding malaria proteins - so called 'subunit vaccines'. The most advanced malaria subunit vaccine, called RTS,S/AS01 and encoding a protein from the parasite called CSP, is currently in Phase III clinical trials across Africa, with early indications suggesting only 35% efficacy against severe disease in young children. Calls have been made for a second generation vaccine to exert 80% efficacy over four years. If this ambitious rhetoric is to be realised, new approaches to malaria subunit vaccine design are required.

Vaccines that elicit functional antibodies formed the foundation of success for 20th century vaccinology - with almost all licensed human products to date protecting individuals through the induction of antibodies. The malaria parasite has a number of complex life-cycle stages, and it is known that numerous stages of this cycle are susceptible to antibodies. These include the infectious sporozoite-stage which infects the liver (targeted by RTS,S), as well as the subsequent blood-stage infection which causes disease as well as the sexual cells that are taken up by mosquitoes in the infected bloodmeal thus leading to further transmission. However, with the exception of RTS,S, antibody-inducing subunit vaccine development for malaria has faced over a decade of disappointment in the clinic. One central reason for this is likely to have been a narrow focus upon malaria proteins which are highly recognised by the immune system in natural infection. As a consequence they have evolved to cope with immune pressure and are highly variable. Similarly, extremely large amounts of antibody are required to neutralise the parasite, and these levels have been difficult to achieve following human vaccination.

We have recently identified a potential solution to this problem. A protein called PfRH5 appears to perform a function that is essential in order for a parasite to invade red blood cells. It binds a protein called Basigin on the red blood cell's surface and this interaction is critical. Importantly, this interaction can be blocked by low levels of antibody, and even more remarkably, the protein is highly conserved, showing limited variation across lots of different parasite strains. This means antibodies induced by a vaccine can function against all the different types of P. falciparum parasite found in endemic areas. The PfRH5-basigin interaction appears to be the first Achilles' heel identified in the blood-stage parasite.

This three year programme of work will aim to produce a clinical grade vaccine targeting the PfRH5 protein. We have shown this protein can be made in a system that uses insect cells to make the malaria protein. We will optimise this system, and then develop a production process that is suitable for clinical grade vaccine manufacture. This process will be developed in collaboration with an industrial partner called ExpreS2ion Biotechnologies from Denmark who are world experts in the use of insect cells as a vaccine production system. Once the process has been developed, we will transfer it to a vaccine manufacturing facility at the University of Oxford where the clinical grade material will be produced, put into vials and extensively tested according to stringent quality controls processes. The final output of this research will be a batch of clinical grade PfRH5 protein vaccine. We will subsequently aim to take this new vaccine into early phase clinical trials in healthy adult volunteers in Oxford.

Technical Summary

The Need: Current estimates suggest Plasmodium falciparum malaria affects 200-300 million people annually, resulting in the death of about 1 million individuals. The most advanced malaria subunit vaccine, RTS,S/AS01, is currently in Phase III clinical trials, with early indications suggesting only 35-50% efficacy against severe disease in young children. Calls have been made for a second generation vaccine to achieve 80% efficacy over four years. New approaches are thus urgently needed.

Rationale: No vaccine has yet proven effective against the blood-stage of P. falciparum, which causes the severe manifestations of malaria. Critical road blocks have included the need for exceptionally high antibody titres against known targets to confer protection coupled with problematic levels of antigen polymorphism. However, recent data from the Jenner Institute have identified the full-length P. falciparum Reticulocyte Binding Protein Homologue 5 (PfRH5) antigen as the highest priority vaccine target identified in the field for over a decade. We have shown in preclinical animal studies that antibodies induced by PfRH5 vaccination can block erythrocyte invasion to high efficiency and, critically, cross-inhibit all P. falciparum lines tested to date. Importantly we have also now demonstrated, for the first time, high-level efficacy induced by PfRH5 vaccination against heterologous strain challenge in an in vivo Aotus monkey-P. falciparum challenge model.

Solution & Development Plan: We have now identified an S2 Drosophila insect cell expression system as a viable GMP-compatible platform for production of this recombinant malaria antigen. This proposal aims to optimise and process develop this system for full-length PfRH5 protein production, prior to progression to GMP manufacture. The product produced by this work will enable subsequent Phase I/IIa clinical trials to assess the impact of high-titre antibodies against PfRH5 on blood-stage malaria infection in humans.

Planned Impact

Aside from immediate academic beneficiaries / collaborators, results will also be shared with existing malaria vaccine development consortia and funders, such as the Initiative for Vaccine Research at the World Health Organisation and the PATH MVI funded by the Gates Foundation.

We have also found that there is substantial public interest in the malaria vaccine work undertaken at the Jenner Institute, and as such key results will also be presented to the public whenever possible in an appropriate manner. In December 2011, reports relating to the potential of the PfRH5 antigen as a vaccine candidate were covered by the UK national press and international radio. Dr Draper also regularly supports public engagement - through open seminars to other members of the wider University and the public, through departmental podcasts, and through visiting schools to encourage GCSE and A-level students to consider studying science and future science-related careers.

Ultimately, Plasmodium falciparum malaria continues to exert an unacceptable level of morbidity and mortality in the developing world, which is coupled with a devastating burden on resource-poor healthcare systems. In light of the low-level efficacy afforded by the world's leading pre-erythrocytic malaria vaccine candidate (RTS,S) in the field, continued calls for a vaccine that is 80% effective over 4 years, especially in areas of moderate to high transmission intensity, mean that a blood-stage component is almost certainly required. The long-term output of this research, if successful, could contribute an effective component(s) to such a vaccine formulation. If the PfRH5 product developed from this programme showed significant efficacy we are well placed to develop it further. The Jenner Institute is fortunate in having strong links with excellent malaria research groups in Africa and Asia where further assessment of the vaccine could take place. The ultimate end users of such a product would be the target population - infants in endemic areas who would be vaccinated against malaria in the first year of life, and potentially adults, travellers and military.

Publications

10 25 50

 
Description EVI European Vaccine Workshop
Geographic Reach Europe 
Policy Influence Type Citation in other policy documents
URL http://www.ncbi.nlm.nih.gov/pubmed/26431986
 
Description LSTM MRC CiC
Amount £46,750 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Confidence in Concept Scheme
Sector Charity/Non Profit
Country United Kingdom
Start 08/2014 
End 07/2015
 
Description MRC iCASE PhD Studentship
Amount £109,400 (GBP)
Funding ID MR/K017632/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2013 
End 09/2017
 
Description Multi-Stage Malaria Vaccine Consortium
Amount € 15,000,000 (EUR)
Funding ID RIA2016V-1649 
Organisation European Union 
Sector Public
Country European Union (EU)
Start 04/2018 
End 03/2023
 
Description OptiMalVax
Amount € 20,000,000 (EUR)
Funding ID 733273 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2017 
End 12/2021
 
Description Senior Research Fellowship
Amount £1,901,424 (GBP)
Funding ID 106917/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2015 
End 07/2020
 
Description Translation Award
Amount £5,000,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 02/2021
 
Description VAC063 Phase I/IIa Clinical Trial of RH5.1/AS01 vaccine
Amount $1,500,000 (USD)
Organisation United States Agency for International Development 
Sector Public
Country United States
Start 01/2016 
End 12/2018
 
Title Human RH5 malaria mAbs 
Description Human mAbs to P. falciparum RH5 
Type Of Material Antibody 
Year Produced 2019 
Provided To Others? Yes  
Impact First human antibody clones against PfRH5 - now guiding structural vaccine design, therapeutic mAb design and used as reagents by many labs 
URL https://www.ncbi.nlm.nih.gov/pubmed/31204103
 
Title RH5 structure 
Description Structure of RH5 malaria protein for design of new vaccines and small molecule inhibitors 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2014 
Provided To Others? Yes  
Impact Published 
URL http://www.ncbi.nlm.nih.gov/pubmed/25132548
 
Description BAC/Thermo Fisher 
Organisation Thermo Fisher Scientific
Country United States 
Sector Private 
PI Contribution New scientific collaboration/reagents
Collaborator Contribution New scientific collaboration/reagents
Impact New scientific collaboration/reagents
Start Year 2014
 
Description ExpreS2ion Bio 
Organisation ExpreS2ion Biotechnologies
Country Denmark 
Sector Private 
PI Contribution Sharing of research reagents.
Collaborator Contribution Access to research reagents. Grant collaborator.
Impact MRC DPFS grant awarded. European Vaccine Initiative grant awarded. PATH Malaria Vaccine Initiative grant awarded
Start Year 2012
 
Description Okairos/GSK 
Organisation Okairos
Country Greece 
Sector Private 
PI Contribution Sharing of research reagents.
Collaborator Contribution Access to expertise and reagents. Vaccine manufacture.
Impact Grants secured - EU FP7 MultiMalVax. Publications. PMID: 22363582 PMID: 21862998 PMID: 21098232 PMID: 20713623 PMID: 23089736 PMID: 21698193 PMID: 23293353
Start Year 2010
 
Description Sanger Institute 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Sharing of research reagents.
Collaborator Contribution Sharing of research reagents. Grant application collaborators.
Impact Publications. PMID: 22186897 PMID: 23144611
Start Year 2010
 
Title RH5 discontinuous fragments 
Description Vaccines based on RH5 structure 
IP Reference GB1413530.5 
Protection Patent application published
Year Protection Granted 2014
Licensed No
Impact New vaccines in development
 
Title RH5 patent 
Description Vaccines based on the malaria antigen RH5 
IP Reference GB1103293.5 
Protection Patent granted
Year Protection Granted 2011
Licensed No
Impact Publications PMID: 23144611 PMID: 22186897
 
Title RH5 thermostabilised 
Description New RH5 vaccine immunogen that is thermostable 
IP Reference GB1615298.5 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Publication and consideration for clinical vaccine development
 
Title P. falciparum protein RH5 vaccine 
Description RH5 malaria protein vaccine has completed GMP manufacture. Secured DPFS grant from UK MRC for GMP production. USAID funding secured for Phase I/II clinical trial. EDCTP funding secured for a Phase Ib clinical trial. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Publications and grant funding secured. 
URL https://clinicaltrials.gov/ct2/show/NCT02927145
 
Description Departmental Podcast 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Podcast about my reserach for Public access on the NDM website.

Public access on website.
Year(s) Of Engagement Activity 2012
URL http://www.ndm.ox.ac.uk/simon-draper-progress-in-malaria-vaccine-research
 
Description Online Interview 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Online interview/podcast for the European Vaccine Initiative website

Online public engagement.
Year(s) Of Engagement Activity 2013
 
Description Royal Society Summer Science Exhibition 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Summer Science Exhibition 2018 at the Royal Society - 1000+ people per day from the general public for 7 days. Exhibit on "designer malaria vaccines"
Year(s) Of Engagement Activity 2018
URL https://royalsociety.org/science-events-and-lectures/2018/summer-science-exhibition/exhibits/designe...
 
Description School Visit. Nottingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Schools
Results and Impact 50 pupils attended a careers talk, which sparked questions and discussion afterwards

School asked for lab / university visit for sixth form pupils and university application guidance
Year(s) Of Engagement Activity 2011,2012,2013