Malaria Programme: Blood-Stage Vaccines
The research undertaken in the Draper group focuses on the development of novel and improved approaches to blood-stage malaria vaccine design, as well as aiming to better understand mechanisms of vaccine-induced immunity to blood-stage malaria infection. More recently, the group is also working on the isolation of human monoclonal antibodies (mAbs) from vaccinated volunteers in clinical trials for both malaria and Ebola, seeking to understand the human antibody response to key antigens and to further develop these for prophylactic or therapeutic human delivery. In parallel, we have a number of projects funded by industrial partners, working towards the development of new vaccine adjuvants, as well therapeutic mAbs and proteins for other disease conditions.
This work has a number of important goals:
1. Improving antibody induction by human-compatible subunit vaccine platforms – including viral vectored, protein-in-adjuvant and virus-like particle (VLP) vaccine delivery systems.
2. Improving our understanding of antibody and B cell induction by subunit vaccine delivery platforms.
3. Antigen-screening to define optimal target combinations that neutralise blood-stage malaria parasites, and the development of new candidate vaccines capable of delivering these targets.
4. Improving our understanding of how vaccine-induced immune effector mechanisms can control or eliminate blood-stage malaria parasites.
5. Development of new mAbs against candidate antigens which are progressed to functional studies, as well as structural characterisation in collaboration with Prof Matt Higgins at the Department of Biochemistry, University of Oxford.
Alongside basic research, there is a strong translational emphasis, with the most promising new approaches and/or candidate vaccines feeding into the Blood-Stage Clinical Trials Programme. Candidate vaccines are manufactured to current Good Manufacturing Practice (cGMP) at the Clinical BioManufacturing Facility, with clinical trials subsequently being led from the Centre for Clinical Vaccinology and Tropical Medicine. These include Phase Ia trials to assess vaccine safety and immunogenicity, as well as Phase IIa controlled human malaria infection (CHMI) trials to assess efficacy.
The latest Draper group trials are recruiting here: VAC069.
The Draper group has so far undertaken eight Phase I/IIa clinical trials in Oxford. Originally, we developed simian adenovirus (ChAd63) and MVA viral vectored vaccines targeting two major candidate antigens from the human malaria parasite P. falciparum (PfMSP1 and PfAMA1), having demonstrated strong T cell and antibody immunogenicity in preclinical models. We translated these findings into Phase I/IIa clinical vaccine trials funded by the UK MRC and EMVDA. The aims of this work were to assess the safety, immunogenicity and protective efficacy of these new vaccines in human volunteers.
We subsequently sought to assess whether improved antibody responses could be achieved in healthy adult volunteers immunised with the ChAd63 and MVA vectors encoding PfAMA1, when these were further combined with a protein AMA1 vaccine formulated with Alhydrogel ± CpG adjuvant.
We subsequently tested the safety and immunogenicity of new ChAd63 and MVA candidate vaccines encoding the PvDBP_RII antigen from P. vivax malaria and the PfRH5 antigen from P. falciparum. These trials were supported by funding from the UK MRC and the European Commission FP7 MultiMalVax programme, respectively. Both of these trials saw these antigens enter human testing for the first time.
In parallel, we sought to establish a blood-stage controlled human malaria infection (CHMI) model to allow for proof-of-concept early-phase efficacy testing of new vaccines whereby impact of the vaccine on parasite multiplication rate (PMR) is the primary endpoint.
Currently a PfRH5 protein vaccine called RH5.1 has undergone cGMP manufacture and entered a Phase I/IIa trial called VAC063. This was initiated in 2016 delivering the RH5.1 protein in AS01B adjuvant. This vaccine will be assessed for efficacy in late 2017 using the blood-stage CHMI model.
We are also currently establishing CHMI with P. vivax malaria, with funding support from the European Commission H2020 MultiViVax programme. These studies will initiate in early 2018.
The CHMI studies provide a valuable opportunity to better understand how vaccine-induced responses can protect against malaria infection in humans, and also how exposure to the parasite can modulate immunity. We have a particular interest in B cells and assessment of the human antibody repertoire induced through vaccination and following malaria exposure.
The blood-stage malaria clinical trials undertaken to-date include:
- VAC079 Phase I/IIa safety, immunogenicity & efficacy of PvDBPII/Matrix-M [NCT04201431]
- VAC071 Phase I/IIa safety, immunogenicity & efficacy of ChAd63-MVA PvDBP_RII [NCT04009096]
- VAC070 Phase Ib safety & immunogenicity of ChAd63-MVA RH5 in Tanzania [NCT03435874]
- VAC069 Study of repeat controlled human Plasmodium vivax blood-stage infection [NCT03797989]
- VAC068 Study of controlled human Plasmodium vivax sporozoite infection [NCT03377296]
- VAC063C Study of repeat blood-stage controlled human Plasmodium falciparum infection [NCT03906474]
- VAC063 Phase I/IIa safety, immunogenicity & efficacy of RH5.1/AS01B [NCT02927145]
- VAC057 Phase Ia safety & immunogenicity of ChAd63-MVA RH5 [NCT02181088]
- VAC054 Phase I/IIa safety, immunogenicity & efficacy of FMP2.1/AS01B [NCT02044198]
- VAC051 Phase Ia safety & immunogenicity of ChAd63-MVA PvDBP_RII [NCT01816113]
- VAC044 Phase Ia safety & immunogenicity of ChAd63-MVA AMA1 combined with AMA1-C1 protein vaccine formulated with Alhydrogel ± CpG adjuvant [NCT01351948]
- VAC039 Phase I/IIa safety, immunogenicity & efficacy of ChAd63-MVA AMA1 ± MSP1 [NCT01142765]
- VAC037 Phase I/IIa safety, immunogenicity & efficacy of ChAd63-MVA MSP1 [NCT01003314]
- VAC036 Phase Ia safety & immunogenicity of ChAd63-MVA AMA1 [NCT01095055]