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Structure-based design of a strain transcending AMA1-RON2L malaria vaccine

Author

Listed:
  • Palak N. Patel

    (National Institutes of Health)

  • Thayne H. Dickey

    (National Institutes of Health)

  • Ababacar Diouf

    (National Institutes of Health)

  • Nichole D. Salinas

    (National Institutes of Health)

  • Holly McAleese

    (National Institutes of Health)

  • Tarik Ouahes

    (National Institutes of Health)

  • Carole A. Long

    (National Institutes of Health)

  • Kazutoyo Miura

    (National Institutes of Health)

  • Lynn E. Lambert

    (National Institutes of Health)

  • Niraj H. Tolia

    (National Institutes of Health)

Abstract

Apical membrane antigen 1 (AMA1) is a key malaria vaccine candidate and target of neutralizing antibodies. AMA1 binds to a loop in rhoptry neck protein 2 (RON2L) to form the moving junction during parasite invasion of host cells, and this complex is conserved among apicomplexan parasites. AMA1-RON2L complex immunization achieves higher growth inhibitory activity than AMA1 alone and protects mice against Plasmodium yoelii challenge. Here, three single-component AMA1-RON2L immunogens were designed that retain the structure of the two-component AMA1-RON2L complex: one structure-based design (SBD1) and two insertion fusions. All immunogens elicited high antibody titers with potent growth inhibitory activity, yet these antibodies did not block RON2L binding to AMA1. The SBD1 immunogen induced significantly more potent strain-transcending neutralizing antibody responses against diverse strains of Plasmodium falciparum than AMA1 or AMA1-RON2L complex vaccination. This indicates that SBD1 directs neutralizing antibody responses to strain-transcending epitopes in AMA1 that are independent of RON2L binding. This work underscores the importance of neutralization mechanisms that are distinct from RON2 blockade. The stable single-component SBD1 immunogen elicits potent strain-transcending protection that may drive the development of next-generation vaccines for improved malaria and apicomplexan parasite control.

Suggested Citation

  • Palak N. Patel & Thayne H. Dickey & Ababacar Diouf & Nichole D. Salinas & Holly McAleese & Tarik Ouahes & Carole A. Long & Kazutoyo Miura & Lynn E. Lambert & Niraj H. Tolia, 2023. "Structure-based design of a strain transcending AMA1-RON2L malaria vaccine," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40878-7
    DOI: 10.1038/s41467-023-40878-7
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    References listed on IDEAS

    as
    1. Palak N. Patel & Thayne H. Dickey & Christine S. Hopp & Ababacar Diouf & Wai Kwan Tang & Carole A. Long & Kazutoyo Miura & Peter D. Crompton & Niraj H. Tolia, 2022. "Neutralizing and interfering human antibodies define the structural and mechanistic basis for antigenic diversion," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Mauld H. Lamarque & Magali Roques & Marie Kong-Hap & Michelle L. Tonkin & George Rugarabamu & Jean-Baptiste Marq & Diana M. Penarete-Vargas & Martin J. Boulanger & Dominique Soldati-Favre & Maryse Leb, 2014. "Plasticity and redundancy among AMA–RON pairs ensure host cell entry of Toxoplasma parasites," Nature Communications, Nature, vol. 5(1), pages 1-13, September.
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