Low immunogenicity of malaria pre‐erythrocytic stages can be overcome by vaccination

Müller, K., Gibbins, M. P. , Roberts, M., Reyes-Sandoval, A., Hill, A. V.S., Draper, S. J., Matuschewski, K., Silvie, O. and Hafalla, J. C. R. (2021) Low immunogenicity of malaria pre‐erythrocytic stages can be overcome by vaccination. EMBO Molecular Medicine, 13(4), e13390. (doi: 10.15252/emmm.202013390) (PMID:33709544) (PMCID:PMC8033512)

Abstract

Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria pre‐erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well‐characterised epitope for stimulation of CD8+ T cells, either as an antigen in the sporozoite surface‐expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregulated in sporozoites 4 (UIS4) expressed in exo‐erythrocytic forms (EEFs). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust, superior antigen‐specific CD8+ T‐cell responses, whilst an EEF antigen evokes poor responses. Despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine‐induced effector CD8+ T cells results in high levels of protection when targeting either antigen. Our study is the first demonstration that poorly immunogenic EEF antigens do not preclude their susceptibility to antigen‐specific CD8+ T‐cell killing, which has wide‐ranging implications on antigen prioritisation for next‐generation pre‐erythrocytic malaria vaccines.

• Item Type: Articles
• Additional Information: S.J.D is a Jenner Investigator, Lister Institute Research Prize Fellow and Wellcome Trust Senior Fellow (106917/Z/15/Z). K. Matuschewski was supported by the Max Planck Society and grants from the European Commission (EviMalaR Network of Excellence #34) and the Chica and Heinz Schaller Foundation. O.S. was funded in part by the Laboratoire d’Excellence ParaFrap (ANR-11-LABX0024). J.C.R.H. was funded by grants from The Royal Society (University Research Fellowship UF0762736/UF120026 and Project Grant RG130034) and the National Centre for the Replacement, Refinement & Reduction of Animals in Research (Project Grant NC/L000601/1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gibbins, Dr Matt
• Authors: Müller, K., Gibbins, M. P., Roberts, M., Reyes-Sandoval, A., Hill, A. V.S., Draper, S. J., Matuschewski, K., Silvie, O., and Hafalla, J. C. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: EMBO Molecular Medicine
• Publisher: EMBO Press
• ISSN: 1757-4676
• ISSN (Online): 1757-4684
• Published Online: 11 March 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in EMBO Molecular Medicine 13(4): e13390
• Publisher Policy: Reproduced under a Creative Commons License