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

  1. Author:
    Francica, Joseph R.
    Shi, Wei
    Chuang, Gwo-Yu
    Chen, Steven J.
    Da Silva Pereira, Lais
    Farney, S. Katie
    Flynn, Barbara J.
    Ou, Li
    Stephens, Tyler
    Tsybovsky,Yaroslav
    Wang, Lawrence T.
    Anderson, Alexander
    Beck, Zoltan
    Dillon, Marlon
    Idris, Azza H.
    Hurlburt, Nicholas
    Liu, Tracy
    Zhang, Baoshan
    Alving, Carl R.
    Matyas, Gary R.
    Pancera, Marie
    Mascola, John R.
    Kwong, Peter D.
    Seder, Robert A.

  2. Author Address

    NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.NCI, Electron Microscopy Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA.US Mil HIV Res Program, Lab Adjuvant & Antigen Res, Walter Reed Army Inst Res, Silver Spring, MD 20910 USA.Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA.Pfizer, 401 N Middletown Rd, Pearl River, NY 10965 USA.
    1. Year: 2021
    2. Date: Mar 18
  2. Journal: Vaccines
  3. MDPI,
    1. 9
    2. 3
  5. Type of Article: Article
  6. Article Number: ARTN 272
  7. ISSN: 2076-393X
  1. Abstract:

    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.

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External Sources

  1. View Full Text
  2. DOI: 10.3390/vaccines9030272
  3. PMID: 33803622
  4. PMCID: PMC8003078
  5. View record in Web of Science®
  6. WOS: 000634223300001

Library Notes

  1. Open Access Publication
  2. Fiscal Year: FY2020-2021
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