InnoMalVac (project completed)

Optimising Antigen Production and Selection for a Vaccine against Blood-Stage Plasmodium falciparum Malaria bas ed on the P. falciparum Reticulocyte Binding Protein Homologue 5 (PfRH5)

Background

There is a clear need for innovative approaches in the malaria vaccine field, in order to identify and select antigens that are susceptible to vaccine-inducible levels of antibody, and to optimise protein expressions systems that can produce these recombinant antigens.  Development of Good Manufacturing Practise (GMP)-compliant protein vaccine production platforms is a clear strategic priority.

In addition Simon Draper’s group, University of Oxford (UOXF), proposes that there remain, as yet undefined, antigens encoded within the malaria genome that are highly susceptible to vaccine-induced antibodies and which could be exploited as vaccine targets.  The group aims to define single antigen targets and/or combinations that elicit the highest levels of broadly-neutralising activity for the lowest given level of vaccine-induced antibodies – the scenario most likely to be successful when faced with developing a human vaccine against antibody-susceptible stages of the malaria parasite life-cycle.  The current project will make a major contribution towards both of these essential facets of malaria vaccine development.

In support of the above assertions, Simon Draper’s group has recently compared human-compatible viral vectored vaccines in animal models targeting ten different blood-stage antigens.  Such a vaccine delivery platform essentially constitutes “in vivomammalian expression of malaria antigens”.  This work showed that, unlike the leading blood-stage candidate antigen P. falciparum Apical membrane antigen 1 (PfAMA1), the full-length P. falciparum Reticulocyte Binding Protein Homologue 5 (PfRH5) antigen is highly susceptible to cross-strain neutralising vaccine-induced antibodies, out-performing all other antigens tested.  These data, generated from a screen of ten antigens, exemplify the benefits of searching the malaria genome for new and promising antigen targets.  Moreover, there has also been no report to-date that recombinant full-length PfRH5 antigen can be produced in bacterial- or yeast-based expression platforms, despite extensive efforts from a number of excellent groups.  These data highlight the need to explore other GMP-compliant protein expression platforms not only in the context of PfRH5-based clinical vaccine development, but also as a means to feed-back into accelerated preclinical antigen discovery programmes.

Objectives

This project aims to address the critical need for innovation in the context of antigen production and selection.  The objective of this project is to enable the production of a recombinant full-length PfRH5 protein antigen that is suitable for clinical development.

Simon Draper’s group has recently identified the Schneider 2 (S2) Drosophila insect cell expression system as the only known GMP-compatible platform for production of recombinant full-length PfRH5 antigen.  The primary deliverable from this work will be a fully characterised full-length PfRH5 protein product that can be purified at an acceptable yield.  This will enable subsequent technology transfer, process development and GMP manufacture of the product prior to proof-of-concept phase I/IIa clinical trials.

Major Milestones

  • Generation of stable S2 cell lines and confirmation of PfRH5 expression (full-length PfRH5 recombinant protein expressed in Drosophila S2 cells)
  • Protocols for preclinical culture and purification conditions 
  • Confirm functional antibody induction by protein PfRH5 vaccine candidates 
  • Secure funding for GMP manufacture of defined PfRH5 vaccine candidate

Achievements

The malaria vaccine group at the Jenner Institute, UOXF, has recently secured European Commission (EC) Seventh Framework Programme (FP7) funding through the MultiMalVax project to progress adenovirus-poxvirus viral vectored vaccines encoding PfRH5 to phase I/IIa clinical trial.  Furthermore, onward funding for the GMP manufacture of the PfRH5 protein vaccine from the UK Medical Research Council has been secured. This project is underway, with manufacture scheduled for 2015 at the Clinical Biomanufacturing Facility in Oxford.

The project started in June 2013 and since then the project has progressed according to plan with some polyclonal S2 cell lines expressing different variants of  the PfRH5 being established.

Publications

Nature scientific reports 6:30357 DOI: 10.1038/srep30357, July 2016
Nature doi: 10.1038/Nature 13715