Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria
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
Affiliations
Joseph R. Francica
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Wei Shi
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Gwo-Yu Chuang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Steven J. Chen
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Lais Da Silva Pereira
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
S. Katie Farney
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Barbara J. Flynn
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Li Ou
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Tyler Stephens
Electron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD 21701, USA
Yaroslav Tsybovsky
Electron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD 21701, USA
Lawrence T. Wang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Alexander Anderson
Laboratory of Adjuvant & Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Zoltan Beck
Laboratory of Adjuvant & Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Marlon Dillon
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Azza H. Idris
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Nicholas Hurlburt
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Tracy Liu
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Baoshan Zhang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Carl R. Alving
Laboratory of Adjuvant & Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Gary R. Matyas
Laboratory of Adjuvant & Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
Marie Pancera
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
John R. Mascola
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Peter D. Kwong
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Robert A. Seder
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
The most advanced malaria vaccine, RTS,S, includes the central repeat and C-terminal domains of the Plasmodium falciparum 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.
