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Optimization of a Plasmodium falciparum circumsporozoite protein repeat vaccine using the tobacco mosaic virus platform
- Source :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2020
- Publisher :
- Proceedings of the National Academy of Sciences, 2020.
-
Abstract
- Significance RTS,S/AS01 is a circumsporozoite protein (CSP)-based malaria vaccine that confers partial protection against malaria in endemic areas. Recent reports have elucidated structures of monoclonal antibodies that bind to the central (NPNA) repeat region of CSP and that inhibit parasite invasion. Antigen configuration and copy number of CSP repeats displayed on a tobacco mosaic virus (TMV) particle platform were studied. A TMV vaccine containing CSP repeats displayed as a loop induced 10× better antibody titer than a nearly full-length CSP in mice. In rhesus model, this translated to a 5× improvement in titer. Rhesus antibodies potently inhibited parasite invasion up to 11 mo after vaccination. An optimized epitope-focused, repeat-only CSP vaccine may be sufficient or better than the existing CSP vaccines.<br />Plasmodium falciparum vaccine RTS,S/AS01 is based on the major NPNA repeat and the C-terminal region of the circumsporozoite protein (CSP). RTS,S-induced NPNA-specific antibody titer and avidity have been associated with high-level protection in naïve subjects, but efficacy and longevity in target populations is relatively low. In an effort to improve upon RTS,S, a minimal repeat-only, epitope-focused, protective, malaria vaccine was designed. Repeat antigen copy number and flexibility was optimized using the tobacco mosaic virus (TMV) display platform. Comparing antigenicity of TMV displaying 3 to 20 copies of NPNA revealed that low copy number can reduce the abundance of low-affinity monoclonal antibody (mAb) epitopes while retaining high-affinity mAb epitopes. TMV presentation improved titer and avidity of repeat-specific Abs compared to a nearly full-length protein vaccine (FL-CSP). NPNAx5 antigen displayed as a loop on the TMV particle was found to be most optimal and its efficacy could be further augmented by combination with a human-use adjuvant ALFQ that contains immune-stimulators. These data were confirmed in rhesus macaques where a low dose of TMV-NPNAx5 elicited Abs that persisted at functional levels for up to 11 mo. We show here a complex association between NPNA copy number, flexibility, antigenicity, immunogenicity, and efficacy of CSP-based vaccines. We hypothesize that designing minimal epitope CSP vaccines could confer better and more durable protection against malaria. Preclinical data presented here supports the evaluation of TMV-NPNAx5/ALFQ in human trials.
- Subjects :
- Models, Molecular
Antigenicity
animal structures
Recombinant Fusion Proteins
Plasmodium falciparum
malaria
Protozoan Proteins
Antibodies, Protozoan
immunogenicity
Protein Engineering
complex mixtures
Epitope
Mice
Immunology and Inflammation
Immunogenicity, Vaccine
CSP
Malaria Vaccines
parasitic diseases
Animals
Humans
Avidity
Malaria, Falciparum
Multidisciplinary
biology
Malaria vaccine
Immunogenicity
fungi
Antibody titer
Biological Sciences
vaccines
biology.organism_classification
Macaca mulatta
Virology
Mice, Inbred C57BL
Tobacco Mosaic Virus
Circumsporozoite protein
HEK293 Cells
antigenicity
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 117
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....c2bb3acc32779233b375122d7a372750