RT Journal Article
SR Electronic
T1 Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 613653
DO 10.1101/613653
A1 Chafen Lu
A1 Gaojie Song
A1 Kristin Beale
A1 Jiabin Yan
A1 Emma Garst
A1 Emily Lund
A1 Flaminia Catteruccia
A1 Timothy A. Springer
YR 2019
UL http://biorxiv.org/content/early/2019/05/08/613653.abstract
AB The circumsporozoite protein (CSP) and thrombospondin-related adhesion protein (TRAP) are major targets for pre-erythrocytic malaria vaccine development. However, the most advanced CSP-based vaccine RTS,S provides only partial protection, highlighting the need for innovative approaches for vaccine design and development. Here we design and characterize TRAP-CSP fusion antigens, and evaluate their immunogenicity and protection against malaria infection. TRAP N-terminal folded domains were fused to CSP C-terminal fragments consisting of the C-terminal αTSR domain with or without the intervening repeat region. Homogenous, monomeric and properly folded fusion proteins were purified from mammalian transfectants. Notably, fusion improved expression of chimeras relative to the TRAP or CSP components alone. Immunization of BALB/c mice with the P. berghei TRAP-CSP fusion antigens formulated in AddaVax adjuvant elicited antigen-specific antibody responses. Remarkably, fusion antigens containing the CSP repeat region conferred complete sterile protection against P. berghei sporozoite challenge, and furthermore, mice that survived the challenge were completely protected from re-challenge 16 weeks after the first challenge. In contrast, fusion antigens lacking the CSP repeat region were less effective, indicating that the CSP repeat region provided enhanced protection, which correlated with higher antibody titers elicited by fusion antigens containing the CSP repeat region. In addition, we demonstrated that N-linked glycans had no significant effect on antibody elicitation or protection. Our results show that TRAP-CSP fusion antigens could be highly effective vaccine candidates. Our approach provides a platform for designing multi-antigen/multi-stage fusion antigens as next generation more effective malaria vaccines.