Uncovering the features of Measles-targeting human antibodies elicited by the MMR vaccine

Acciani, M. D.; Zyla, D. S.; Niemeyer, G.; Harkins, S. S.; Parekh, D.; Pawlack, E.; Lacarbonara, D.; Niewiesk, S.; POROTTO, M.; Hastie, K.; Saphire, E. O.

doi:10.1101/2025.09.09.675230

bioRxiv · 10.1101/2025.09.09.675230

Uncovering the features of Measles-targeting human antibodies elicited by the MMR vaccine

Acciani, M. D.·Zyla, D. S.·Niemeyer, G.·Harkins, S. S.·Parekh, D.·Pawlack, E.·Lacarbonara, D.·Niewiesk, S.·POROTTO, M.·Hastie, K.·Saphire, E. O.

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Abstract

Measles virus (MeV), a highly transmissible paramyxovirus, causes disease that can lead to severe complications and death, particularly in babies and young children. Deployment of the durable, highly effective, live-attenuated measles vaccine has saved an estimated 94 million lives in the past 50 years,1 yet the immunological explanation for this vaccines unique success and its landscape of antibody recognition remains unclear. Here we report the first panel of human monoclonal antibodies (mAbs) specific for the MeV hemagglutinin (H) and fusion (F) surface proteins, derived from the memory B cells of an MMR vaccinee. From over 100 cloned human mAbs, we mapped four major epitope clusters on H and another five major clusters on F, and structurally characterized 17 representative mAbs including one or more examples of each of the nine epitope clusters on the two surface antigens. We find that antibodies against both H and F can lead to potent virus neutralization and reduction of viral loads in vivo, including one mAb against F that reduces viral loads to below the limit of detection for all animals. High-resolution cryo-EM reveals contact sites of the most protective antibodies against both surface antigens. Discovery, characterization, and in vitro and in vivo success of these fully human mAbs now provide new avenues for prophylactic or therapeutic intervention against this re-emerging virus. HighlightsO_LIA large panel of Measles-specific monoclonal antibodies was isolated from a human MMR vaccinee, years after vaccination. C_LIO_LIStructural and biochemical mapping paints a landscape of antibody recognition with nine major competition groups, including four major sites on Hemagglutinin (H) and five on the fusion protein (F). C_LIO_LIAntibodies against both H and F confer in vitro neutralization and in vivo protection, including, in one case, undetectable viral load after antibody treatment. C_LIO_LIThe most protective H-specific mAbs, 4D08 and 1C08, target the receptor-binding site and the F-proximal outside of the H dimer, and likely function by interfering with receptor binding and H-F interactions, respectively. C_LIO_LIThe most protective F-specific mAbs, 3A12 and 4F09, target the sides and apex of the prefusion F trimer, and likely function by locking F into its pre-fusion state C_LI

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Acciani, M. D., Zyla, D. S., Niemeyer, G., Harkins, S. S., Parekh, D., Pawlack, E., Lacarbonara, D., Niewiesk, S., POROTTO, M., Hastie, K., Saphire, E. O.. 2025-09-15. Uncovering the features of Measles-targeting human antibodies elicited by the MMR vaccine. https://doi.org/10.1101/2025.09.09.675230

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