Optimization of aPlasmodium falciparumcircumsporozoite protein repeat vaccine using the tobacco mosaic virus platform
Abstract
Plasmodium falciparumvaccine 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 27, 2020
- Source ID
- 10.1073/pnas.1911792117
Entities
People
- Adrian H. Batchelor
- Alexis A. Bitzer
- Andrew J. Schrader
- Christopher J. Genito
- Farhat A. Khan
- Gary R Matyas
- Kimberly Soto
- Mark D. Langowski
- Merricka C. Livingstone
- Monica L. Martin
- Sheetij Dutta
- Sri Hadiwidjojo
- Xiaoyan Zou
- Zoltan Beck
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine
- Naval Medical Research Center
- United States Agency for International Development
- United States Army
- Walter Reed Army Institute of Research