Neuraminidase-specific antibodies drive differential cross-protection between contemporary FLUBV lineagesPage, Shepard, Ray
et alSci Adv (2025) 11 (13), eadu3344
Abstract: The two influenza B virus (FLUBV) lineages have continuously diverged from each other since the 1980s, with recent (post-2015) viruses exhibiting accelerated evolutionary rates. Emerging data from human studies and epidemiological models suggest that increased divergence in contemporary viruses may drive differential cross-protection, where infection with Yamagata lineage viruses provides limited immunity against Victoria lineage viruses. Here, we developed animal models to investigate the mechanisms behind asymmetric cross-protection between contemporary FLUBV lineages. Our results show that contemporary Victoria immunity provides robust cross-protection against the Yamagata lineage, whereas Yamagata immunity offers limited protection against the Victoria lineage. This differential cross-protection is driven by Victoria-elicited neuraminidase (NA)-specific antibodies, which show cross-lineage reactivity, unlike those from Yamagata infections. These findings identify a phenomenon in contemporary FLUBV that may help explain the recent disappearance of the Yamagata lineage from circulation, highlighting the crucial role of targeting NA in vaccination strategies to enhance cross-lineage FLUBV protection.
Identification of Novel Neuraminidase Inhibitors as Potential Anti-Influenza Agents: Virtual Screening, Molecular Docking, in vitro Validation and Molecular Dynamic Simulation StudiesLiu, Niu, Xu
et alCell Biochem Biophys (2025)
Abstract: The influenza virus causes approximately hundreds of thousands of deaths annually. Coupled with the emergence of drug resistance, there is an urgent need to develop new drugs for the treatment of influenza. Neuraminidase (NA) has long been recognized as a valid drug target for anti-influenza therapy. Herein, in order to identify potential NA inhibitors with novel structures, we employed a structure-based virtual screening strategy to screen a library containing 1.6 million compounds. Based on XP docking score and free energy calculation results, the three compounds E570-1769, K788-4718, and C071-0424 were selected that may have better binding affinity for the NA protein compared to oseltamivir. Amongst, E570-1769 was identified to be the most potential hit. Docking study showed that E570-1769 bound to NA with a binding energy of -10.3 kcal/mol. Moreover, in silico ADME/T studies demonstrated the druggability of E570-1769 was quite well. Furthermore, in vitro assay demonstrated that E570-1769 inhibited the wild-type and H274Y-muatated NAs with IC50 values of 72.6 μM and 229 μM, respectively. Additionally, molecular dynamic (MD) simulation studies were performed to gain a deep insight into the binding modes of E570-1769 in complex with NA. While less potent than oseltamivir, the novel structure of E570-1769 and promising ADME/T properties indicates it as a promising lead for future research.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Broad Mucosal and Systemic Immunity in Mice Induced by Intranasal Booster With a Novel Recombinant Adenoviral Based Vaccine Protects Against Divergent Influenza A VirusLi, Wang, Guo
et alJ Med Virol (2025) 97 (4), e70326
Abstract: The development of broad-spectrum universal influenza vaccines and optimization of vaccination strategies to address the threats posed by pandemics and emerging influenza viruses are critical for public health. In this study, an adenovirus type 5 vector-based influenza vaccine carrying the hemagglutinin (HA) stem of H1, HA stem of H3, and neuraminidase (NA) of N1 from the influenza virus was constructed. Immune responses were evaluated in mice using various vaccination strategies: prime-only (intramuscular [IM] or intranasal [IN]) and prime-boost (IM + IN). Compared with the prime-only strategy, the prime-boost strategy significantly enhanced the systemic immune response, inducing higher levels of antigen-specific IgG, mucosal IgA, and T cell immunity in the spleen and lungs. Furthermore, the IN boosting strategy provided complete protection in mice challenged with the H1N1-PR8, rgH3N2-X31, and rgH5N1-Vietnam viruses, significantly reducing viral loads in the lungs and alleviating lung tissue pathologies. In conclusion, this study elucidates potential avenues for the development and application of universal influenza vaccines using customized mucosal boosting strategies.© 2025 Wiley Periodicals LLC.
A strategy of enhancing the protective efficacy of seasonal influenza vaccines by providing additional immunity to neuraminidase and M2eRaha, Kim, Tien Le
et alVirology (2025) 606, 110510
Abstract: It is a high priority to enhance the efficacy of seasonal influenza vaccines based on hemagglutinin (HA) strain-specific neutralizing immunity. Here, we investigated a vaccination strategy of supplementing inactivated split seasonal vaccines with a virus-like particle vaccine containing multi-subtype neuraminidase (NA) and M2 ectodomain (M2e) repeat (NA-M2e) in mice. NA-M2e and split combined vaccine (S + NA-M2e) stimulated a unique pattern of innate immune responses within a day after intramuscular injection of mice. The combined S + NA-M2e vaccination induced enhanced levels of IgG antibodies to viral antigens, hemagglutination inhibiting activities, and humoral and cellular immune responses to NA and M2e. The addition of NA-M2e to split vaccination provided higher efficacy of protection against homologous and heterologous viruses compared to split alone, where NA-M2e significantly contributed to enhancing protection under naïve and primed mouse models. This study supports a vaccination strategy to improve the efficacy of seasonal vaccines by providing additional immunity to NA and M2e.Copyright © 2025. Published by Elsevier Inc.
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