Clinical and Immunological Evaluation of T cell- and Antibody-Inducing Viral Vector Vaccines against Blood-Stage Malar

Lead Research Organisation: University of Oxford
Department Name: Medical Sciences Division

Abstract

Malaria remains a huge public health problem in the developing world. The development of an effective vaccine remains an important but elusive goal. Malaria is caused by a parasite that first infects the liver before moving into the blood where it causes disease. A few vaccines have been developed recently that can kill some parasites in the liver, however, there is still no vaccine that can kill parasites in the blood.

This research will test a new vaccine technology against the parasites in the blood. These vaccines, developed by scientists at the Jenner Institute, Oxford University, use viruses that are genetically engineered to look like malaria parasites. The work will test the safety and effectiveness of these vaccines in volunteers in clinical trials in Oxford, and importantly also study the immune responses produced by them. Scientists can then attempt to figure out which immune responses are killing the parasites. This research will also assess how malaria infection can interfere with immune responses in humans in both the UK and Africa. It is extremely important to understand these interactions between malaria parasites and the human immune system, because we can use this information to help design better vaccines in the future.

Technical Summary

The development of a highly effective malaria vaccine remains an important but elusive goal. To date, blood-stage malaria candidate vaccines, based primarily on protein-in-adjuvant formulations, have almost all been selected for clinical trials based on their ability to induce growth inhibitory antibodies - assessed using an in vitro assay that lacks T cells or monocytes. Despite these extensive efforts, these technologies have sadly shown limited or no success in clinical settings. A key contributing factor to these difficulties is our limited understanding of protective immune responses in vivo in humans against blood-stage parasites. However, there is growing evidence for the role of T cells and antibody Fc-mediated effector functions in immunity to blood-stage malaria and yet, to date, no vaccine has sought to induce such responses. This research seeks to address the merits of using viral vectored vaccines encoding blood-stage malaria antigens in humans in Phase I/IIa clinical trials. These vaccines induce strong and protective T cell and Th1-type antibody responses against encoded antigens in animal models, and now provide the first opportunity to address fundamental questions in humans regarding the contribution of cellular and antibody Fc-mediated immune responses to protective efficacy against blood-stage malaria.



This research will aim to assess the safety, immunogenicity and efficacy of viral vector blood-stage malaria vaccines; develop a new in vivo assay of antibody Fc effector function; and address fundamental questions about the immuno-modulatory effects of blood-stage parasite exposure on cellular immune responses in both malaria-na?ve and naturally-exposed individuals.



Summary of key goals:



1. Characterise the immunogenicity of viral vector blood-stage malaria vaccines in human volunteers using multi-functional flow cytometry and ELIspot assays for T cell responses as well as ELISAs, GIA assays and memory B cell ELIspot assays for humoral responses.



2. Assess IgG Fc effector functions in vivo by adoptive transfer of IgG from immunised volunteers into mice transgenic for different human Fc?Rs infected with a mouse malaria parasite chimeric for P. falciparum MSP119.



3. Attempt to correlate immunological readouts with efficacy in Phase IIa challenge studies.



4. Assess second generation vaccine strategies in humans using combinations of viral vector and protein-in-adjuvant vaccines.



5. Assess the effects of blood-stage malaria parasite exposure in UK volunteers on cellular and humoral immune responses.



6. Undertake baseline studies in African adults and children to measure i) cellular immune responses to blood-stage antigens, and ii) assess antibody Fc effector functions against MSP119 using the transgenic mouse model.

Publications

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publication icon
Bregu M (2011) Accelerating vaccine development and deployment: report of a Royal Society satellite meeting. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

 
Description AIDS Vaccine Research Subcommittee HIV Vaccine Advisory Meeting
Geographic Reach North America 
Policy Influence Type Participation in advisory committee
 
Description African Training Symposium for Researchers - South Africa
Geographic Reach Africa 
Policy Influence Type Influenced training of practitioners or researchers
 
Description African Training Symposium for Researchers - Uganda
Geographic Reach Africa 
Policy Influence Type Influenced training of practitioners or researchers
 
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 Jenner African Vaccinology Course
Geographic Reach Australia 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Jenner Oxford Vaccinology Course
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Sanofi Pasteur Malaria Advisory Board Meeting
Geographic Reach North America 
Policy Influence Type Participation in advisory committee
 
Description WHO Prime-Boost Vaccine Meeting
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description Clinical Trial for VAC054
Amount $1,102,333 (USD)
Organisation PATH 
Department PATH Malaria Vaccine Initiative
Sector Charity/Non Profit
Country Global
Start 01/2014 
End 12/2014
 
Description DPhil Fellowship
Amount £77,000 (GBP)
Funding ID 092873/Z/10/A 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description EVIMalaR (FP7 Network of Excellence)
Amount € 36,000 (EUR)
Funding ID 242095 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 09/2011 
End 08/2013
 
Description FP7 - MultiMalVax
Amount € 1,000,000 (EUR)
Funding ID 305282 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 11/2012 
End 10/2016
 
Description Grand Challenge Explorations
Amount $100,000 (USD)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 04/2012 
End 10/2013
 
Description LSTM MRC CiC
Amount £46,750 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Confidence in Concept Scheme
Sector Academic/University
Country United Kingdom
Start 08/2014 
End 07/2015
 
Description Lister Institute Research Prize 2013
Amount £200,000 (GBP)
Organisation Lister Institute of Preventive Medicine 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2018
 
Description MRC DCS
Amount £895,435 (GBP)
Funding ID G1100086 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2011 
End 06/2014
 
Description MRC DPFS
Amount £1,274,897 (GBP)
Funding ID MR/K025554/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2013 
End 04/2016
 
Description MRC iCASE PhD Studentship
Amount £109,400 (GBP)
Funding ID MR/K017632/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 09/2017
 
Description Newton Phd Partnership Fund
Amount £8,800 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2015 
End 12/2018
 
Description R&D Innovation Fund 2014
Amount £398,884 (GBP)
Organisation GlaxoSmithKline (GSK) 
Department GSK Biologicals SA
Sector Private
Country Belgium
Start 01/2015 
End 01/2017
 
Description Rare Diseases
Amount $483,381 (USD)
Organisation Pfizer Inc 
Sector Private
Country United States
Start 12/2014 
End 12/2017
 
Description Research Council of Norway
Amount kr 2,964,000 (NOK)
Funding ID 234431/H10 
Organisation Research Council of Norway 
Sector Public
Country Norway
Start 10/2014 
End 09/2017
 
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 University Challenge Seed Fund
Amount £40,000 (GBP)
Organisation Science and Technologies Facilities Council (STFC) 
Department ISIS Neutron and Muon Source
Sector Public
Country United Kingdom
Start 01/2015 
 
Description University Oxford Challenge Seed Fund
Amount £79,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start  
 
Description University of Oxford MRC CiC
Amount £50,000 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Confidence in Concept Scheme
Sector Academic/University
Country United Kingdom
Start 06/2014 
End 05/2015
 
Description iCASE Studentship
Amount £96,565 (GBP)
Funding ID MR/N01796X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2020
 
Title RH5 mouse mAbs 
Description Mouse mAbs against the malaria antigen RH5 
Type Of Material Antibody 
Year Produced 2011 
Provided To Others? Yes  
Impact Published 
URL http://www.ncbi.nlm.nih.gov/pubmed/24293631
 
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 Antibody Fc Receptors 
Organisation Liverpool School of Tropical Medicine
Department Parasite Immunology Liverpool
Country United Kingdom 
Sector Public 
PI Contribution Sharing of materials. Contributions to publications.
Collaborator Contribution Sharing of research materials
Impact Publications. PMID: 22984589 PMID: 21781305 PMID: 24163420 PMID: 23609325
Start Year 2010
 
Description Burnett Institute Australia 
Organisation Burnet Institute
Country Australia 
Sector Learned Society 
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 GIA Reference Centre, NIH 
Organisation Malaria GIA Reference Center - PATH MVI
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Sharing of research reagents.
Collaborator Contribution Significant experimental input.
Impact Publications. PMID: 20713623 PMID: 21698193 PMID: 21799809 PMID: 21862998 PMID: 22186897 PMID: 22363582 PMID: 22984589 PMID: 23089736 PMID: 23144611 PMID: 23872520 Joint PhD student.
Start Year 2010
 
Description GSK Biopharm 
Organisation GlaxoSmithKline (GSK)
Department GSK Biologicals SA
Country Belgium 
Sector Private 
PI Contribution Vaccine testing collaboration
Collaborator Contribution Industrial partnership
Impact No outcomes as yet
Start Year 2014
 
Description ICGEB 
Organisation International Centre for Genetic Engineering and Biotechnology
Country Italy 
Sector Charity/Non Profit 
PI Contribution Sharing of research materials and grant collaboration.
Collaborator Contribution Sharing of research materials. MRC DCS grant collaborator.
Impact Secured grant funding. Publication. PMID: 21813775
Start Year 2008
 
Description KEMRI Kilifi 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Multiple 
PI Contribution Sharing of materials. Contributions to publications. Joint PhD student.
Collaborator Contribution Sharing of research materials.
Impact Publications. PMID: 22186897 PMID: 23144611
Start Year 2010
 
Description NIMR 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Sharing of research reagents.
Collaborator Contribution Sharing of research reagents.
Impact Publications. PMID: 20713623 PMID: 22504652 PMID: 21781305 PMID: 21698193
Start Year 2010
 
Description Okairos/GSK 
Organisation Okairos
Country Italy 
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 PATH 
Organisation PATH
Department PATH Malaria Vaccine Initiative
Country Global 
Sector Charity/Non Profit 
PI Contribution Malaria vaccine development partnership
Collaborator Contribution Malaria vaccine development partnership
Impact Publications and funding
Start Year 2014
 
Description Pfizer Rare Diseases 
Organisation Pfizer Inc
Country United States 
Sector Private 
PI Contribution mAb and protein production
Collaborator Contribution Industrial partnership
Impact Grant funding
Start Year 2014
 
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
 
Description UCC 
Organisation University College Cork
Department Immunology
Country Ireland 
Sector Academic/University 
PI Contribution Sharing of research reagents. Training staff. Grant collaborator.
Collaborator Contribution Sharing of research reagents. Grant collaborator.
Impact Grant secured. Publication. PMID: 22245683
Start Year 2010
 
Description US Navy NAMRU6 
Organisation Naval Medical Research Center Unit-6
Department Parasitology Department
Country Peru 
Sector Public 
PI Contribution Sharing of reagents. Training of staff in Peru.
Collaborator Contribution Access to equipment and facilities.
Impact Publication submitted.
Start Year 2011
 
Description University of Bordeaux 
Organisation University of Bordeaux
Country France 
Sector Academic/University 
PI Contribution New scientific collaboration/reagents
Collaborator Contribution New scientific collaboration/reagents
Impact New scientific collaboration/reagents
Start Year 2014
 
Description University of Oslo, Norway 
Organisation University of Oslo
Department Faculty of Medicine
Country Norway 
Sector Academic/University 
PI Contribution Vaccine development collaboration for malaria
Collaborator Contribution Academic collaboration
Impact Funding secured from GlobVac
Start Year 2014
 
Description WRAIR 
Organisation Government of the United States of America
Department United States Armed Forces
Country United States 
Sector Public 
PI Contribution New scientific collaboration/reagents
Collaborator Contribution New scientific collaboration/reagents
Impact New scientific collaboration/reagents
Start Year 2014
 
Title Adjuvant Mixing 
Description Immunogenic compositions of viral vaccines and adjuvants 
IP Reference GB1016471.3 
Protection Patent application published
Year Protection Granted 2010
Licensed No
Impact Publication. PMID: 20937436
 
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 P. falciparum viral vectored RH5 vaccine 
Description Viral vectored vaccine against blood-stage Plasmodium falciparum - entered Phase Ia clinical trial in August 2014 and Phase Ib trial in Tanzania in 2018. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Publications and clinical trial funding 
URL https://clinicaltrials.gov/ct2/show/NCT02181088?term=vac057&rank=1
 
Description 80,000 hours public talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Lively discussion with public audience about vaccines and malaria

Increased public awareness about malaria and vaccines
Year(s) Of Engagement Activity 2014
 
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 Radio Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Radio interviews in the UK and Internation due to Press Release surrounding RH5 vaccine data publication in Nature Communications journal.

Increased public profile for this vaccine project.
Year(s) Of Engagement Activity 2011
 
Description School Visit, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk on Malaria, Ebola and Vaccines to 130 Year 6 pupils followed by questions afterwards.
Year(s) Of Engagement Activity 2015
 
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
 
Description School visit Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Lively discussion with junior school children about vaccines, malaria and infectious diseases.

Positive feedback from teachers at the school
Year(s) Of Engagement Activity 2014
 
Description Science Oxford Public Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk to about 50 members of the public at "Science Oxford" - a local organisation seeking to engage the public about science

Public engagement about malaria and vaccines.
Year(s) Of Engagement Activity 2013
 
Description Trinity College Science Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Talk on malaria and ebola vaccines to Trinity College Scientific Society
Year(s) Of Engagement Activity 2015
 
Description Website Interview 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interview of the University of Oxford, Nuffield Department of Medicine website for WHO World Immunization Day
Year(s) Of Engagement Activity 2015
URL http://www.ndm.ox.ac.uk/making-vaccines-more-effective