Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria

The most advanced malaria vaccine, RTS,S, includes the central repeat and C-terminal domains of the <i>Plasmodium falciparum</i> circumsporozoite protein (PfCSP). We have recently isolated human antibodies that target the junctional region between the N-terminal and repeat domains that a...

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Main Authors: Joseph R. Francica, Wei Shi, Gwo-Yu Chuang, Steven J. Chen, Lais Da Silva Pereira, S. Katie Farney, Barbara J. Flynn, Li Ou, Tyler Stephens, Yaroslav Tsybovsky, Lawrence T. Wang, Alexander Anderson, Zoltan Beck, Marlon Dillon, Azza H. Idris, Nicholas Hurlburt, Tracy Liu, Baoshan Zhang, Carl R. Alving, Gary R. Matyas, Marie Pancera, John R. Mascola, Peter D. Kwong, Robert A. Seder
Format: Article
Language:English
Published: MDPI AG 2021-03-01
Series:Vaccines
Subjects:
Online Access:https://www.mdpi.com/2076-393X/9/3/272
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author Joseph R. Francica
Wei Shi
Gwo-Yu Chuang
Steven J. Chen
Lais Da Silva Pereira
S. Katie Farney
Barbara J. Flynn
Li Ou
Tyler Stephens
Yaroslav Tsybovsky
Lawrence T. Wang
Alexander Anderson
Zoltan Beck
Marlon Dillon
Azza H. Idris
Nicholas Hurlburt
Tracy Liu
Baoshan Zhang
Carl R. Alving
Gary R. Matyas
Marie Pancera
John R. Mascola
Peter D. Kwong
Robert A. Seder
author_facet Joseph R. Francica
Wei Shi
Gwo-Yu Chuang
Steven J. Chen
Lais Da Silva Pereira
S. Katie Farney
Barbara J. Flynn
Li Ou
Tyler Stephens
Yaroslav Tsybovsky
Lawrence T. Wang
Alexander Anderson
Zoltan Beck
Marlon Dillon
Azza H. Idris
Nicholas Hurlburt
Tracy Liu
Baoshan Zhang
Carl R. Alving
Gary R. Matyas
Marie Pancera
John R. Mascola
Peter D. Kwong
Robert A. Seder
author_sort Joseph R. Francica
collection DOAJ
description The most advanced malaria vaccine, RTS,S, includes the central repeat and C-terminal domains of the <i>Plasmodium falciparum</i> circumsporozoite protein (PfCSP). We have recently isolated human antibodies that target the junctional region between the N-terminal and repeat domains that are not included in RTS,S. Due to the fact that these antibodies protect against malaria challenge in mice, their epitopes could be effective vaccine targets. Here, we developed immunogens displaying PfCSP junctional epitopes by genetic fusion to either the N-terminus or B domain loop of the E2 protein from chikungunya (CHIK) alphavirus and produced CHIK virus-like particles (CHIK-VLPs). The structural integrity of these junctional-epitope–CHIK-VLP immunogens was confirmed by negative-stain electron microscopy. Immunization of these CHIK-VLP immunogens reduced parasite liver load by up to 95% in a mouse model of malaria infection and elicited better protection than when displayed on keyhole limpet hemocyanin, a commonly used immunogenic carrier. Protection correlated with PfCSP serum titer. Of note, different junctional sequences elicited qualitatively different reactivities to overlapping PfCSP peptides. Overall, these results show that the junctional epitopes of PfCSP can induce protective responses when displayed on CHIK-VLP immunogens and provide a basis for the development of a next generation malaria vaccine to expand the breadth of anti-PfCSP immunity.
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spelling doaj.art-277cfc8acf7447ca984b6d9fdb635f462023-11-21T10:59:23ZengMDPI AGVaccines2076-393X2021-03-019327210.3390/vaccines9030272Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against MalariaJoseph R. Francica0Wei Shi1Gwo-Yu Chuang2Steven J. Chen3Lais Da Silva Pereira4S. Katie Farney5Barbara J. Flynn6Li Ou7Tyler Stephens8Yaroslav Tsybovsky9Lawrence T. Wang10Alexander Anderson11Zoltan Beck12Marlon Dillon13Azza H. Idris14Nicholas Hurlburt15Tracy Liu16Baoshan Zhang17Carl R. Alving18Gary R. Matyas19Marie Pancera20John R. Mascola21Peter D. Kwong22Robert A. Seder23Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAElectron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD 21701, USAElectron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD 21701, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Adjuvant & Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USALaboratory of Adjuvant & Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Adjuvant & Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USALaboratory of Adjuvant & Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USAThe most advanced malaria vaccine, RTS,S, includes the central repeat and C-terminal domains of the <i>Plasmodium falciparum</i> circumsporozoite protein (PfCSP). We have recently isolated human antibodies that target the junctional region between the N-terminal and repeat domains that are not included in RTS,S. Due to the fact that these antibodies protect against malaria challenge in mice, their epitopes could be effective vaccine targets. Here, we developed immunogens displaying PfCSP junctional epitopes by genetic fusion to either the N-terminus or B domain loop of the E2 protein from chikungunya (CHIK) alphavirus and produced CHIK virus-like particles (CHIK-VLPs). The structural integrity of these junctional-epitope–CHIK-VLP immunogens was confirmed by negative-stain electron microscopy. Immunization of these CHIK-VLP immunogens reduced parasite liver load by up to 95% in a mouse model of malaria infection and elicited better protection than when displayed on keyhole limpet hemocyanin, a commonly used immunogenic carrier. Protection correlated with PfCSP serum titer. Of note, different junctional sequences elicited qualitatively different reactivities to overlapping PfCSP peptides. Overall, these results show that the junctional epitopes of PfCSP can induce protective responses when displayed on CHIK-VLP immunogens and provide a basis for the development of a next generation malaria vaccine to expand the breadth of anti-PfCSP immunity.https://www.mdpi.com/2076-393X/9/3/272junctional epitopemalarianeutralizing antibodiesparasite<i>Plasmodium falciparum</i>vaccines
spellingShingle Joseph R. Francica
Wei Shi
Gwo-Yu Chuang
Steven J. Chen
Lais Da Silva Pereira
S. Katie Farney
Barbara J. Flynn
Li Ou
Tyler Stephens
Yaroslav Tsybovsky
Lawrence T. Wang
Alexander Anderson
Zoltan Beck
Marlon Dillon
Azza H. Idris
Nicholas Hurlburt
Tracy Liu
Baoshan Zhang
Carl R. Alving
Gary R. Matyas
Marie Pancera
John R. Mascola
Peter D. Kwong
Robert A. Seder
Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria
Vaccines
junctional epitope
malaria
neutralizing antibodies
parasite
<i>Plasmodium falciparum</i>
vaccines
title Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria
title_full Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria
title_fullStr Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria
title_full_unstemmed Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria
title_short Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria
title_sort design of alphavirus virus like particles presenting circumsporozoite junctional epitopes that elicit protection against malaria
topic junctional epitope
malaria
neutralizing antibodies
parasite
<i>Plasmodium falciparum</i>
vaccines
url https://www.mdpi.com/2076-393X/9/3/272
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