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Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):3114-3122. doi: 10.1073/pnas.1911792117. Epub 2020 Jan 27.

Optimization of a Plasmodium falciparum circumsporozoite protein repeat vaccine using the tobacco mosaic virus platform.

Author information

1
Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910.
2
Division of Veterinary Medicine, Walter Reed Army Institute of Research, Silver Spring, MD 20910.
3
Malaria Department, Naval Medical Research Center, Silver Spring, MD 20910.
4
Henry M Jackson Foundation for the Advancement of Military Medicine, Rockville, MD 20817.
5
Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910.
6
Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910; sheetij.dutta.civ@mail.mil.

Abstract

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.

KEYWORDS:

CSP; antigenicity; immunogenicity; malaria; vaccines

Conflict of interest statement

Competing interest statement: M.D.L., F.A.K., A.H.B., and S.D. have filed a patent on the tobacco mosaic virus (TMV)-based malaria vaccine described herein.

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