Malaria Programme: Pre-erythrocytic Vaccines

The malaria vaccine programme at Oxford is a linked pre-clinical and clinical vaccine development programme, facilitating rapid translation of new vaccine candidates and technologies from the bench to the clinic.

Pre-clinical research

Our pre-clinical research aims to develop new and improved vaccines/vaccination regimes against malaria from the point of injection of parasites from an infected mosquito to the emergence of blood-stage parasites from the liver. In addition we aim to better understand the natural and vaccine-induced immune response during this stage of malaria.

Our key areas of research include:

1. Improving and optimising T cell inducing vaccines against the liver-stage of malaria.

2. Improving and understanding antibody-based vaccines against the sporozoite stage of malaria.

3. Screening of new liver-stage malaria antigens for the ability of T cells to kill malaria infected hepatocytes.

4. Improving our understanding of the immune response to the pre-erythrocytic stage of malaria.

Clinical trials

The early period of our clinical program primarily focussed on the induction of high level T cell responses against pre-erythrocytic antigens. We undertook the first prophylactic DNA vaccine trials in Europe and showed that DNA administered by needle or by gene gun generated only moderate immunogenicity and was not protective. Since these first clinical trials we have consistently translated our pre-clinical testing and demonstrated an increase in immunogenicity with development of new vectored vaccine platforms. Our most promising vaccine regime to date is the use of a simian Adenoviral vaccine expressing METRAP in combination with a modified Ankara virus (MVA) boost which induces some of the strong T cells responses observed to date.

Our current clinical trials are aimed at assessing novel antigens or vaccination regimes to maximise the breadth, quality and quantity of the immune response to pre-erythrocytic malaria. In addition we have undertaken a number of Phase IIb trials occurring in both West and East Africa to investigate the immunogenicity and efficacy of our leading clinical candidate vaccine combination. All of these clinical trials present the unique opportunity to understand vaccine induced immune responses and type of immune response required for protection against malaria.

More recently, we have developed a highly immunogenic virus-like particle vaccine to target the sporozoite stage of the malaria life-cycle. This new vaccine, known as R21, induces anti-sporozoite antibodies and has shown a high level of protective efficacy in a mouse model. R21 is now under evaluation in a number of Phase 1/2a clinical trials.  

Additionally, we have an active immunology research program looking at mechanisms determining sub-optimal immunogenicity of vaccines in different regimes and populations.

Group Members

Adrian Hill, Programme Leader

Paulo Bettencourt, Post-doctoral scientist (pre-clinical)

Duncan Bellamy, Research Assistant

Thomas Broadhead, Insectary Technician

Georgina Bowyer, Research Assistant & DPhil Student

Mehreen Datoo, Clinical Research Fellow

Nick Edwards, Senior Research Assistant

Katie Ewer, Senior Immunologist (clinical trials)

Amy Flaxman, post-doctoral scientist (clinical trials)

Daniel Jenkins, Clinical Research Fellow

Alison Lawrie, Senior Vaccine Development Co-ordinator & Clinical Project Manager

Catherine Mair, Research Assistant

Richard Morter, IITM DPhil Student

Ian Poulton, Study Coordinator

Rachel Roberts, Malaria & Flu Vaccine Programme Coordinator

Ahmed Salman, Post-doctoral scientist (pre-clinical)

Alex Spencer, Senior Immunologist (pre-clinical)

Marta Ulaszewska, Research Technician

Publications

CXCR3+ T Follicular Helper Cells Induced by Co-Administration of RTS,S/AS01B and Viral-Vectored Vaccines Are Associated With Reduced Immunogenicity and Efficacy Against Malaria. Bowyer, G., et al. 2018. Front. Immunol. 9:1660. doi: 10.3389/fimmu.2018.01660

Assessment of novel vaccination regimens using viral vectored liver stage malaria vaccines encoding ME-TRAP. Bliss, C.M., et al. Sci Rep. 2018 Feb 21;8(1):3390. doi: 10.1038/s41598-018-21630-4.

Safety and Immunogenicity of Malaria Vectored Vaccines Given with Routine Expanded Program on Immunization Vaccines in Gambian Infants and Neonates: A Randomized Controlled Trial. Mensah, V.A., et al. Front Immunol. 2017 Nov 20;8:1551. doi: 10.3389/fimmu.2017.01551. eCollection 2017.

Enhancing protective immunity to malaria with a highly immunogenic virus-like particle vaccine. Collins, K., et al. Sci Rep. 2017 Apr 19;7:46621. doi: 10.1038/srep46621.

An in vitro assay to measure antibody-mediated inhibition of P. berghei sporozoite invasion against P. falciparum antigens. Rodríguez-Galán A, et al., Sci Rep. 2017 Dec 5;7(1):17011. doi: 10.1038/s41598-017-17274-5. PMID:29209029

Viral Vector Malaria Vaccines Induce High-Level T Cell and Antibody Responses in West African Children and Infants. Bliss, C.M., et al. Mol Ther. 2017 Feb 1;25(2):547-559. doi:10.1016/j.ymthe.2016.11.003.

The Threshold of Protection from Liver-Stage Malaria Relies on a Fine Balance between the Number of Infected Hepatocytes and Effector CD8+ T Cells Present in the Liver. Spencer AJ, Longley RJ, Gola A, Ulaszewska M, Lambe T, Hill AV. J Immunol. 2017 Mar 1;198(5):2006-2016. doi: 10.4049/jimmunol.1601209. PMID:28087668

Adjuvanting a viral vectored vaccine against pre-erythrocytic malaria. Milicic A, S Rollier C, Tang CK, Longley R, Hill AVS, Reyes-Sandoval A. Sci Rep. 2017 Aug 4;7(1):7284. doi: 10.1038/s41598-017-07246-0. PMID:28779101.

Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP. Rampling, T., et al. J Infect Dis. 2016 Sep 1;214(5):772-81. 

Comparative assessment of vaccine vectors encoding ten malaria antigens identifies two protective liver-stage candidates. Longley, RJ., et al. Sci Rep. 2015 Jul 3;5:11820.

Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults. Ogwang, C., et al. Sci Transl Med. 2015 May 6;7(286):286re5.  

Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation. Ewer, KJ., et al., Nat Commun. 2013;4:2836. doi: 10.1038/ncomms3836.