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Molecular divergence and #convergence of mammalian #antibody responses to the #influenza virus #hemagglutinin stem

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By G.M.

 


Significance

Since pigs serve as intermediate hosts between humans and the natural reservoir of influenza viruses in wild birds, they play a key role in the emergence of influenza strains with pandemic potential, as demonstrated by the 2009 pandemic. Therefore, influenza pandemic preparedness will benefit from the development of vaccines that broadly protect pigs against diverse influenza A strains. However, progress is limited by our poor molecular understanding of porcine antibody responses to influenza virus. This study isolates and characterizes a panel of broadly neutralizing influenza antibodies from pigs. Our findings not only have significant implications for the development of broadly protective influenza vaccines for pigs, but also reveal the molecular differences in the antibody responses between pigs and humans.


Abstract

Antibody responses to the influenza virus hemagglutinin (HA) stem, a major target for broadly protective vaccine development, have been extensively characterized in humans. However, they remain largely elusive in other natural influenza hosts, including pigs, which are considered intermediate hosts for the emergence of pandemic strains. By leveraging single-cell variable, diversity, and joining (VDJ) sequencing, this study identified 25 porcine antibodies to the HA stem, including two cross-group bnAbs, 14-8 and 15-1, from vaccinated specific-pathogen-free pigs and unvaccinated domestic pigs. Cryogenic electron microscopy analysis showed that 14-8 targeted the well-characterized central stem epitope, whereas 15-1 bound to a linear epitope spanning the HA1/HA2 junction. Additionally, while some porcine and human bnAbs targeted the central stem epitope via convergent molecular signatures, our results revealed a pig-specific recurring binding motif. Overall, our findings provide important insights into the commonalities and uniqueness of antibody responses between different species, which have significant implications for vaccine development for nonhuman animals.

Source: Proceedings of the National Academy of Sciences of the United States of America, https://www.pnas.org/doi/abs/10.1073/pnas.2510927122?af=R

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