Mechanistic insights into the structure-based design of a CspZ-targeting Lyme disease vaccine

Kalvis Brangulis (), Jill Malfetano, Ashley L. Marcinkiewicz, Alan Wang, Yi-Lin Chen, Jungsoon Lee, Zhuyun Liu, Xiuli Yang, Ulrich Strych, Dagnija Tupina, Inara Akopjana, Maria-Elena Bottazzi, Utpal Pal, Ching-Lin Hsieh (), Wen-Hsiang Chen () and Yi-Pin Lin ()
Additional contact information
Kalvis Brangulis: Latvian Biomedical Research and Study Centre
Jill Malfetano: NYSDOH
Ashley L. Marcinkiewicz: NYSDOH
Alan Wang: NYSDOH
Yi-Lin Chen: Baylor College of Medicine
Jungsoon Lee: Baylor College of Medicine
Zhuyun Liu: Baylor College of Medicine
Xiuli Yang: University of Maryland
Ulrich Strych: Baylor College of Medicine
Dagnija Tupina: Latvian Biomedical Research and Study Centre
Inara Akopjana: Latvian Biomedical Research and Study Centre
Maria-Elena Bottazzi: Baylor College of Medicine
Utpal Pal: University of Maryland
Ching-Lin Hsieh: The University of Texas at Austin
Wen-Hsiang Chen: Baylor College of Medicine
Yi-Pin Lin: NYSDOH

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Borrelia burgdorferi (Bb) causes Lyme disease (LD), one of the most common vector-borne diseases in the Northern Hemisphere. Here, we solve the crystal structure of a mutated Bb vaccine antigen, CspZ-YA that lacks the ability to bind to host complement factor H (FH). We generate point mutants of CspZ-YA and identify CspZ-YAI183Y and CspZ-YAC187S to trigger more robust bactericidal responses. Compared to CspZ-YA, these CspZ-YA mutants require a lower immunization frequency to protect mice from LD-associated inflammation and bacterial colonization. Antigenicity of wild-type and mutant CspZ-YA proteins are similar, as measured using sera from infected people or immunized female mice. Structural comparison of CspZ-YA with CspZ-YAI183Y and CspZ-YAC187S shows enhanced interactions of two helices adjacent to the FH-binding sites in the mutants, consistent with their elevated thermostability. In line with these findings, protective CspZ-YA monoclonal antibodies show increased binding to CspZ-YA at a physiological temperature (37 °C). In summary, this proof-of-concept study applies structural vaccinology to enhance intramolecular interactions for the long-term stability of a Bb antigen while maintaining its protective epitopes, thus promoting LD vaccine development.

Date: 2025
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DOI: 10.1038/s41467-025-58182-x

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