Qiong Zhang, etc.,al. [preprint]Preclinical Evaluation of an mRNA Vaccine Developed from the First Human Isolate of Bovine H5N1. https://doi.org/10.21203/rs.3.rs-6758243/v1
Given the ongoing global health threat posed by the zoonotic emergence of H5N1 clade 2.3.4.4b highly pathogenic avian influenza (HPAI), there is an urgent need for the rapid development of effective vaccines. The demonstrated success of mRNA vaccine technology, with its rapid development and scalability, highlights its potential to address emerging infectious diseases. Leveraging our well-established COVID-19 mRNA vaccine platform, we developed an mRNA vaccine candidate targeting the first known bovine-to-human transmission strain (A/Texas/37/2024). Comprehensive evaluations in murine models showed that both wild-type (WT) and cleavage-defective mutant (Mut) hemagglutinin (HA)-encoding mRNA vaccines elicited robust humoral immune responses. Notably, our H5N1 vaccine candidate induced long-lasting and cross-clade antibodies and initiated a well-balanced Th1/Th2 cellular immune response, providing complete protection against lethal homologous virus challenges in mice. Additionally, in avian models, the vaccine candidate conferred full protection against lethal challenges from cross-clade viruses, including 2.3.4.4b and 2.3.4.4h, demonstrating broad-spectrum efficacy. Specifically, the vaccine induced broader and potent antibody response, which significantly outperforming the WHO-recommended vaccine candidate (A/Astrakhan/3212/2020). Remarkably, pre-existing immunity to seasonal H1 influenza did not compromise H5-specific responses. We also formulated the vaccine using a novel ionizable lipid, which elicited humoral and T-cell responses comparable to the benchmark SM102 LNP. Safety assessments in rats further confirmed the favorable tolerability profile of our vaccine candidates, supporting the translational potential of both formulations. This work establishes a rapidly adaptable mRNA-LNP vaccine prototype with dual advantages of broad H5 coverage and resilience to pre-existing influenza immunity, offering a critical tool for pandemic preparedness against evolving avian influenza threats.
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