Multivalent Influenza Hemagglutinin Promotes The Immundominance Of Non-neutralizing Antibody Responses Through Repetitively Constrained Orientation | 51627
Journal of Infectious Diseases & Therapy
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Much of the influenza virion surface is occupied by a dense array of trimeric hemagglutinin (HA) that functions to engage sialyloligosaccharide
on a target cell. This dense packing of spike protein is also thought to restrict antibody access to the conserved
HA stem epitope, a weak immunogenic target for broadly neutralizing antibody (bnAb) responses against this virus. However,
recent cryo-EM studies, have suggested that stem-directed bnAbs do not have restricted access to this site. To functionally define
the source of weakened immunogenicity to the stem epitope, we compared stem specific antibody responses to three structurallydefined
presentations of HA: Soluble trimer and ferritin nanoparticle 8mers displaying either the full-length trimer or stem/stalk
region alone. Surprisingly, we found that while the nanoparticles were more immunogenic, only the soluble trimeric format elicited
detectable stem-epitope directed antibodies upon initial exposure to antigen. We propose that antigen multivalency, a cornerstone of
both vaccine design and viral architecture, imposes not only repetitive array to increase immunogenicity but also restricted antigen
orientation, which can limit exploration of antigenic space, insuring that immunodominant non-neutralizing responses are nonlinearly
amplified during this process. Repetitive exposure to the soluble HA trimer eliminates reactivity to stem due to amplification
of immunodominant non-stem responses; our work shows that multivalent HA display can achieves the same result within a single
encounter. These data highlight a previously unrecognized mode of immune distraction and delineate the relationship between
antigen valency and the target-specificity of the humoral response.
Daniel Lingwood is an Assistant Professor at The Ragon Institute of MGH, MIT and Harvard and is a Faculty Member in the Virology Program at Harvard Medical School. He has received his PhD from the Max Planck Institute for Molecular Biology and Genetics and conducted Postdoctoral work at the Vaccine Research Center at NIH. He has garnered international recognition for his discovery that humans possess genetically-encoded antibody sequences that when properly oriented as germline B cell receptors, naturally engage conserved sites of viral vulnerability and serve as substrates upon which broadly neutralizing antibodies can be developed.