Heritable transgenic schistosomes as a living platform for SARS-CoV-2 neutralizing antibody secretion

We report the generation and propagation of not only the first heritable transgenic schistosome line but also a line that secretes a functional therapeutic protein in vivo. Using multiplexed CRISPR/Cas-mediated homology-directed knock-in targeted to a predicted genomic safe-harbor, we inserted a VHH-IgG1 Fc (termed C5-Fc) transgene into Schistosoma mansoni eggs. Single-miracidium infections of Biomphalaria glabrata yielded parental P0 lines; serial passage through snail and mouse hosts produced an F2 cohort in which all parasites carried the C5-Fc transgene and secreted C5-Fc into the murine venous circulation. Molecular assays confirmed chromosomal insertion, germline transmission and systemic secretion. Sera from mice harboring C5-Fc transgenic worms neutralized SARS-CoV-2 in vitro with potent activity consistent with the expected ACE2-binding blockade by the C5 variable domain of heavy-chain-only antibody (VHH). These results demonstrate (i) stable, heritable transgenesis of a platyhelminth, (ii) delivery of a biologically active antibody fragment by a live helminth in a mammalian host, and (iii) feasibility of using transgenic schistosomes as sustained, single-dose protein delivery platforms. This technology and delivery system enable new experimental approaches for schistosome biology and motivate exploration of living-foundry therapeutics.

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Journal
Nature Communications
Published
2026-08-26
DOI
https://doi.org/10.1038/s41467-026-76465-9
Primary Topic
Parasites and Host Interactions
Type
article
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article

Heritable transgenic schistosomes as a living platform for SARS-CoV-2 neutralizing antibody secretion

Sergej Djuranović, Margaret Mentink‐Kane, Paul J. Brindley, Michael J. Smout et al.
Nature Communications
Parasites and Host Interactions
article

Heritable transgenic schistosomes as a living platform for SARS-CoV-2 neutralizing antibody secretion

Sergej Djuranović, Margaret Mentink‐Kane, Paul J. Brindley, Michael J. Smout, Darren Pickering, Sean Kinahan, Danielle N. Rivera, Daniel Watterson, María Elena Bottazzi, Bruce A. Rosa, Christoph G. Grevelding, Joshua L. Santarpia, Victoria H. Mann, Cornelis H. Hokke, Daniel N. Ackerman, Meta Roestenberg, Loukas Alex, Bethany K. Bracken, Paul Giacomin, Naphak Modhiran, Makedonka Mitreva, Max F. Moescheid, Wannaporn Ittiprasert, Matthew Moyle, Eric C. Carnes, Marina Reis Costa
article en

Abstract

We report the generation and propagation of not only the first heritable transgenic schistosome line but also a line that secretes a functional therapeutic protein in vivo. Using multiplexed CRISPR/Cas-mediated homology-directed knock-in targeted to a predicted genomic safe-harbor, we inserted a VHH-IgG1 Fc (termed C5-Fc) transgene into Schistosoma mansoni eggs. Single-miracidium infections of Biomphalaria glabrata yielded parental P0 lines; serial passage through snail and mouse hosts produced an F2 cohort in which all parasites carried the C5-Fc transgene and secreted C5-Fc into the murine venous circulation. Molecular assays confirmed chromosomal insertion, germline transmission and systemic secretion. Sera from mice harboring C5-Fc transgenic worms neutralized SARS-CoV-2 in vitro with potent activity consistent with the expected ACE2-binding blockade by the C5 variable domain of heavy-chain-only antibody (VHH). These results demonstrate (i) stable, heritable transgenesis of a platyhelminth, (ii) delivery of a biologically active antibody fragment by a live helminth in a mammalian host, and (iii) feasibility of using transgenic schistosomes as sustained, single-dose protein delivery platforms. This technology and delivery system enable new experimental approaches for schistosome biology and motivate exploration of living-foundry therapeutics.

Nature CommunicationsVol. 17(1)
James S. McDonnell Foundation (US), Nebraska Medical Center (US), The University of Queensland (AU), George Washington University (US), Justus-Liebig-Universität Gießen (DE), Washington University in St. Louis (US), Brown University (US), Leiden University Medical Center (NL), Australian Institute of Tropical Health and Medicine (AU), Centro Nacional de Medicina Tropical (ES), Biomedical Research Institute (US), Australian e-Health Research Centre (AU), Texas Children's Hospital (US), Charles River Analytics (United States) (US), University of Nebraska Medical Center (US), University of Montenegro (ME), James Cook University (AU)
U.S. Department of Defense, Wellcome Trust, Deutsche Forschungsgemeinschaft, National Institutes of Health, Centers for Disease Control and Prevention, Defense Advanced Research Projects Agency, Advanced Research Projects Agency, Medical Research Council, National Health and Medical Research Council, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Naval Information Warfare Center Pacific
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Parasites and Host Interactions
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