Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines.
The circumsporozoite protein (CSP) and thrombospondin-related adhesion protein (TRAP) are major targets for pre-erythrocytic malaria vaccine development. However, the CSP-based vaccine RTS,S provides only marginal protection, highlighting the need for innovative vaccine design and development. Here...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0216260 |
| _version_ | 1818924861739761664 |
|---|---|
| author | Chafen Lu Gaojie Song Kristin Beale Jiabin Yan Emma Garst Juan Feng Emily Lund Flaminia Catteruccia Timothy A Springer |
| author_facet | Chafen Lu Gaojie Song Kristin Beale Jiabin Yan Emma Garst Juan Feng Emily Lund Flaminia Catteruccia Timothy A Springer |
| author_sort | Chafen Lu |
| collection | DOAJ |
| description | The circumsporozoite protein (CSP) and thrombospondin-related adhesion protein (TRAP) are major targets for pre-erythrocytic malaria vaccine development. However, the CSP-based vaccine RTS,S provides only marginal protection, highlighting the need for innovative vaccine design and development. Here we design and characterize expression and folding of P. berghei (Pb) and P. falciparum (Pf) TRAP-CSP fusion proteins, and evaluate immunogenicity and sterilizing immunity in mice. TRAP N-terminal domains were fused to the CSP C-terminal αTSR domain with or without the CSP repeat region, expressed in mammalian cells, and evaluated with or without N-glycan shaving. Pb and Pf fusions were each expressed substantially better than the TRAP or CSP components alone; furthermore, the fusions but not the CSP component could be purified to homogeneity and were well folded and monomeric. As yields of TRAP and CSP fragments were insufficient, we immunized BALB/c mice with Pb TRAP-CSP fusions in AddaVax adjuvant and tested the effects of absence or presence of the CSP repeats and absence or presence of high mannose N-glycans on total antibody titer and protection from infection by mosquito bite both 2.5 months and 6 months after the last immunization. Fusions containing the repeats were completely protective against challenge and re-challenge, while those lacking repeats were significantly less effective. These results correlated with higher total antibody titers when repeats were present. Our results show that TRAP-CSP fusions increase protein antigen production, have the potential to yield effective vaccines, and also guide design of effective proteins that can be encoded by nucleic acid-based and virally vectored vaccines. |
| first_indexed | 2024-12-20T02:32:04Z |
| format | Article |
| id | doaj.art-15233e9e0cbe4671a458358c4eed0861 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T02:32:04Z |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-15233e9e0cbe4671a458358c4eed08612022-12-21T19:56:32ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01151e021626010.1371/journal.pone.0216260Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines.Chafen LuGaojie SongKristin BealeJiabin YanEmma GarstJuan FengEmily LundFlaminia CatterucciaTimothy A SpringerThe circumsporozoite protein (CSP) and thrombospondin-related adhesion protein (TRAP) are major targets for pre-erythrocytic malaria vaccine development. However, the CSP-based vaccine RTS,S provides only marginal protection, highlighting the need for innovative vaccine design and development. Here we design and characterize expression and folding of P. berghei (Pb) and P. falciparum (Pf) TRAP-CSP fusion proteins, and evaluate immunogenicity and sterilizing immunity in mice. TRAP N-terminal domains were fused to the CSP C-terminal αTSR domain with or without the CSP repeat region, expressed in mammalian cells, and evaluated with or without N-glycan shaving. Pb and Pf fusions were each expressed substantially better than the TRAP or CSP components alone; furthermore, the fusions but not the CSP component could be purified to homogeneity and were well folded and monomeric. As yields of TRAP and CSP fragments were insufficient, we immunized BALB/c mice with Pb TRAP-CSP fusions in AddaVax adjuvant and tested the effects of absence or presence of the CSP repeats and absence or presence of high mannose N-glycans on total antibody titer and protection from infection by mosquito bite both 2.5 months and 6 months after the last immunization. Fusions containing the repeats were completely protective against challenge and re-challenge, while those lacking repeats were significantly less effective. These results correlated with higher total antibody titers when repeats were present. Our results show that TRAP-CSP fusions increase protein antigen production, have the potential to yield effective vaccines, and also guide design of effective proteins that can be encoded by nucleic acid-based and virally vectored vaccines.https://doi.org/10.1371/journal.pone.0216260 |
| spellingShingle | Chafen Lu Gaojie Song Kristin Beale Jiabin Yan Emma Garst Juan Feng Emily Lund Flaminia Catteruccia Timothy A Springer Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines. PLoS ONE |
| title | Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines. |
| title_full | Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines. |
| title_fullStr | Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines. |
| title_full_unstemmed | Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines. |
| title_short | Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines. |
| title_sort | design and assessment of trap csp fusion antigens as effective malaria vaccines |
| url | https://doi.org/10.1371/journal.pone.0216260 |
| work_keys_str_mv | AT chafenlu designandassessmentoftrapcspfusionantigensaseffectivemalariavaccines AT gaojiesong designandassessmentoftrapcspfusionantigensaseffectivemalariavaccines AT kristinbeale designandassessmentoftrapcspfusionantigensaseffectivemalariavaccines AT jiabinyan designandassessmentoftrapcspfusionantigensaseffectivemalariavaccines AT emmagarst designandassessmentoftrapcspfusionantigensaseffectivemalariavaccines AT juanfeng designandassessmentoftrapcspfusionantigensaseffectivemalariavaccines AT emilylund designandassessmentoftrapcspfusionantigensaseffectivemalariavaccines AT flaminiacatteruccia designandassessmentoftrapcspfusionantigensaseffectivemalariavaccines AT timothyaspringer designandassessmentoftrapcspfusionantigensaseffectivemalariavaccines |