P27A

Fragment P27A of the novel malaria protein PFF0165c

Background

Preclinical validation of the vaccine potential of P27A, an intrinsically unstructured, 104-amino acid long hydrophilic fragment of the Plasmodium falciparum malaria protein PFF0165c, submitted in 2007 by Professor Giampietro Corradin of the University of Lausanne (UNIL), was not originally recommended for funding by the Scientific Advisory Committee (SAC).  However, in accordance with a Board decision to help improve certain proposals, a six month contract was signed with UNIL in September 2008 for the evaluation of the malaria vaccine potential of P27A with various adjuvants, and a successful proposal was submitted in response to the call in 2008.

In the search for novel vaccine candidates through genome mining, both inhibition of merozoite invasion and monocyte triggering by antibodies in an Antibody-Dependent Cellular Inhibition (ADCI) assay were investigated, using first, naturally occurring antibodies in individuals with acquired protection through exposure to the malaria parasite, and later on, antibodies induced by immunisation with the various constructs studied.  From a series of 95 polypeptides corresponding to 95 novel unexploredPlasmodium falciparum alpha helical coiled coil segments of malaria blood stage proteins, the screening process focused on 18 such novel antigenic genes, i.e. recognised by antibodies in exposed populations.  Affinity purified antibodies studied in both Growth Inhibition Assay (GIA) and ADCI assays revealed that antibodies specific to 11 peptides totally or partially interrupted the intra-erythrocytic development of Plasmodium falciparum solely in cooperation with blood monocytes.  No direct effect was observed (Villard et al., 2007).

These results are in agreement with passive transfer experiments that showed that total immunoglobulin from protected individuals passively transferred in naïve recipients were effective mainly through a monocyte-dependent, antibody-mediated effect.  Selection of the vaccine candidate proposed here resulted from a series of successive screens that highlighted P27A as target of an immune response with satisfactory characteristics for vaccine development (Olugbile et al., 2009).

Objectives

A major objective of the project supported by EVI is to assess the clinical safety and immunogenicity of the P27A molecule as a malaria blood stage vaccine candidate.  Other objectives are successful process development, Good Manufacturing Practice (GMP) manufacturing, toxicology studies and a phase I clinical trial.

Major Milestones

  • Pre-GMP batch availability for immunogenicity check at UNIL: Q3 2010
  • Immunogenicity results at UNIL: Q4 2012
  • Drug Substance GMP batch: Q3 2011
  • Drug Product GMP batch: Q3 2012
  • Toxicity studies final report: Q4 2012
  • Selection of investigational site and sponsor: Q3 2012
  • Submission of Clinical Trial Application: Q2 2013
  • Start of phase I clinical trial: Q1 2014
  • Expected end of phase I clinical trial: Q4 2015

Achievements

  • The P27A Drug Product GMP batch was certified for use in clinical trial in January 2014.
  • In January 2014, the two-centre phase I clinical trial of the P27A vaccine candidate started in Switzerland at the Centre Hospitalier Universitaire Vaudois, targeting adults from non-endemic areas.  In August 2014, the trial proceeded to the target population in Tanzania at the Ifakara Health Institute.

References

  1. Villard V, Agak GW, Frank G, Jafarshad A, Servis C, et al (2007) Rapid Identification of Malaria Vaccine Candidates Based on a-Helical Coiled Coil Protein Motif. PLoS ONE 2(7): e645. doi:10.1371/journal.pone.0000645
  2. Olugbile S, Kulangara C, Bang G, Bertholet S, Suzarte E, Villard V, Frank G, Audran R, Razaname A, Nebie I, Awobusuyi O, Spertini F, Kajava AV, Felger I, Druilhe P, Corradin G. Vaccine potentials of an intrinsically unstructured fragment derived from the blood stage-associated Plasmodium falciparum protein PFF0165c. Infect Immun. 2009 Dec;77(12):5701-9.

Publications

PLOS One, vol 7, issue 10, e46112