A. Olotu, Ifakara Health Institute - Immune responses in malaria-exposed children immunised with a new generation blood-stage malaria vaccine.

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

Abstract

Scientists have discovered a protein called Pf reticulocyte-binding protein homolog 5 (PfRH5) which has shown promising results as a candidate malaria vaccine in studies conducted in monkeys and humans living in areas where there is no malaria. The safety and the ability of this vaccine to produce protective antibody responses in adults, young children and infants residing in areas with malaria is unknown.

The ARL candidate will conduct a clinical trial and use standard laboratory techniques to determine if this vaccine is safe and well-tolerated in adults, young children and infants and to find out if it can produce antibodies capable of killing parasites growing in red blood cells in laboratory tests. The study will recruit volunteers residing in a low malaria transmission area in Bagamoyo, Tanzania.

The study will provide new knowledge with regard to the potential for PfRH5 protein to be included in a malaria vaccine and inform decisions to conduct larger field trials to evaluate efficacy. The results will also identify whether there is scope to further improve this vaccine before conducting bigger trials in the field.

Technical Summary

Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is a new generation and highly promising blood-stage malaria vaccine antigen. Preclinical and early clinical data show the antigen elicits functional antibodies against merozoites in non-human primates and malaria-naïve UK adults in contrast to those elicited by natural malaria exposure. The safety and capability of PfRH5 immunisation to induce functional immune responses in adults, young children and infants residing in malaria endemic countries is unknown.

Using an age de-escalation dose-escalation randomised double-blind controlled trial, and established immunological techniques, the ARL candidate will establish the safe and well-tolerated dose of PfRH5 in adults, young children and infants and characterise the magnitude, quality and longevity of immune responses following immunization by a heterologous prime-boost approach with chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) expressing PfRH5. The study will recruit volunteers from low malaria transmission areas in Bagamoyo, Tanzania.

The study will provide new knowledge with regard to the potential for PfRH5 as a malaria vaccine and inform decisions to conduct larger field trials to evaluate efficacy. The immunological outcomes will provide data on the human antibody response, to determine if there is scope to further improve the PfRH5 immunogen in future iterations of the vaccine.

Planned Impact

This research will benefit academics in three main areas:

a) Vaccine Developers

The proposed research will benefit scientists working in the field of malaria vaccine research. Information about the safety and quantity and quality of the immune responses induced by PfRH5 in malaria exposed infants and young children will guide further optimisation of the antigen and inform decisions to conduct larger field trials to evaluate efficacy against clinical malaria.

Data from the proposed research will be shared with the scientific community as soon as possible through presentation in scientific conferences, publication in open-access peer reviewed journals and open public domain platforms held by both the Jenner Institute and Ifakara Health Institute.

The University of Oxford has a long-standing collaboration with GSK, and together they are developing next-generation malaria vaccines including those targeting the blood-stage parasite using the PfRH5 antigen. They have recently completed the VAC057 Phase Ia clinical trial in Oxford using the ChAd63 RH5 vector funded by the European Commission MultiMalVax programme. The result of this proposed research will provide more data on the potential utility of the PfRH5 antigen as a candidate blood-stage vaccine and guide further research and development.

b) African Research Institution

The proposed research will increase the skill and knowledge base at Ifakara Health Institute which will increase the capability of the Institute to conduct more malaria vaccine research. Technology transfer that will happen during the research period will not only benefit malaria research but other research fields such as tuberculosis and HIV vaccine development. IHI has a Clinical Trial Facility (CTF) which conducts all phases of vaccine trials. The research team at IHI CTF plan to use the Controlled Human Malaria Infection model to investigate new drugs and vaccines against malaria including characterising vaccine-induced immune responses following immunisation. The knowledge and skills gained by the ARL candidate will enrich the team's knowledge base and facilitate clinical and immunological assessment of candidate malaria vaccines.

The ARL candidate will establish collaboration with the UK PI and other partners and this will facilitate more transfer of skills and technology and sharing platforms to conduct malaria vaccine research.

c) Global Health

Recently experts (SAGE committee) have advised the World Health Organisation to conduct a large pilot implementation program for the RTS,S candidate malaria vaccine in children aged 5-17 months in areas of moderate and high malaria transmission. This follows results of a large Phase III trial indicating potential benefit of a 4-dose vaccination regimen. Although RTS,S represents an important milestone in malaria vaccine development, inclusion of an effective blood-stage component is essential to improve efficacy and prolong protective efficacy.

PfRH5 is a new generation blood-stage candidate malaria vaccine antigen which, unlike other merozoite antigens, is highly conserved across parasite lines resulting to strain-transcending neutralising antibodies following immunisation. Although the current proposed research may not lead directly to the vaccine which can be used by the population, it will generate important data to inform further development of the this candidate antigen and allow decisions on whether to progress to larger (Phase IIb and III) field trials. An effective blood-stage malaria vaccine will be an important component in a multi-stage malaria vaccine to prevent malaria infection, disease and transmission. Therefore the ultimate impact of this research is to contribute towards efforts to improve the health and quality of life worldwide and especially in sub-Saharan Africa where more than 90% of the malaria deaths occur.

Publications

10 25 50
 
Description World Health Organisation MALVAC Meeting "Next Generation Malaria Vaccines and Biologicals Research and Development: Landscape Review
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description EDCTP Senior Fellowship
Amount € 494,713 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2020 
End 12/2024
 
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 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 Ifakara Health Institute 
Organisation Ifakara Health Institute
Country Tanzania, United Republic of 
Sector Charity/Non Profit 
PI Contribution Joint clinical trial sponsored by Oxford
Collaborator Contribution Leading Phase Ib clinical trial
Impact Joint grant from UK MRC
Start Year 2017
 
Description KEMRI Kilifi 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Academic/University 
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 Novavax Matrix-M adjuvant 
Organisation Novavax AB
Country Sweden 
Sector Private 
PI Contribution Vaccine development
Collaborator Contribution Matrix-M adjuvant provision
Impact Collaborative clinical vaccine development. Joint grant applications.
Start Year 2017
 
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
 
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 initiated early 2021. 
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
 
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