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The combined vaccine is expected to simplify the immunization program and increase coverage. However, due to antigen compatibility, immunogenicity balance, and formulation complexity, it remains technically challenging. Here, we report a modular strategy that uses a single-component nanobody binder to non-covalently attach multiple antigens to the intact particles of the licensed hepatitis E vaccine. To determine the appropriate binder, sheep goats were immunized with the vaccine, and nanobodies were screened through phage display. A nanobody P1-5B selectively binds to the concave non-immunogenic sites on the particle surface and achieves stable antigen display without disrupting the natural immunogenicity. Using this binder, we generated three vaccine formulations, displaying 5 to 11 antigens, including variants of the SARS-2 coronavirus, influenza virus, and respiratory syncytial virus. These multivalent particles exhibit high affinity assembly, maintain solubility, and induce neutralizing titers three orders of magnitude higher than soluble antigens. In mice, hamsters, and non-human primates, the candidate vaccines have strong protective effects and show good safety. This method introduces an expandable plug-and-play system for the rapid development of customizable combined vaccines. This study was published in Nature Biomedical Engineering under the title "Nanobody-based combination vaccine using licensed protein nanoparticles protects animals against respiratory and viral infections".
References:
DOI: 10.1038/s41551-025-01529-y
