8d21
Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited, human antibody 1B06 in complex with a stabilized NC99 HA trimer
Structural highlights
FunctionQ6WG00_9INFA Binds to sialic acid-containing receptors on the cell surface, bringing about the attachment of the virus particle to the cell. This attachment induces virion internalization of about two third of the virus particles through clathrin-dependent endocytosis and about one third through a clathrin- and caveolin-independent pathway. Plays a major role in the determination of host range restriction and virulence. Class I viral fusion protein. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in HA2, releasing the fusion hydrophobic peptide. Several trimers are required to form a competent fusion pore (By similarity).[SAAS:SAAS00204388] Publication Abstract from PubMedCurrent yearly seasonal influenza vaccines primarily induce an antibody response directed against the immunodominant but continually diversifying hemagglutinin (HA) head region. These antibody responses provide protection against the vaccinating strain but little cross-protection against other influenza strains or subtypes. To focus the immune response on subdominant but more conserved epitopes on the HA stem that might protect against a broad range of influenza strains, we developed a stabilized H1 stem immunogen lacking the immunodominant head displayed on a ferritin nanoparticle (H1ssF). Here, we evaluated the B cell response to H1ssF in healthy adults ages 18 to 70 in a phase 1 clinical trial (NCT03814720). We observed both a strong plasmablast response and sustained elicitation of cross-reactive HA stem-specific memory B cells after vaccination with H1ssF in individuals of all ages. The B cell response was focused on two conserved epitopes on the H1 stem, with a highly restricted immunoglobulin repertoire unique to each epitope. On average, two-thirds of the B cell and serological antibody response recognized a central epitope on the H1 stem and exhibited broad neutralization across group 1 influenza virus subtypes. The remaining third recognized an epitope near the viral membrane anchor and was largely limited to H1 strains. Together, we demonstrate that an H1 HA immunogen lacking the immunodominant HA head produces a robust and broadly neutralizing HA stem-directed B cell response. An influenza H1 hemagglutinin stem-only immunogen elicits a broadly cross-reactive B cell response in humans.,Andrews SF, Cominsky LY, Shimberg GD, Gillespie RA, Gorman J, Raab JE, Brand J, Creanga A, Gajjala SR, Narpala S, Cheung CSF, Harris DR, Zhou T, Gordon I, Holman L, Mendoza F, Houser KV, Chen GL, Mascola JR, Graham BS, Kwong PD, Widge A, Dropulic LK, Ledgerwood JE, Kanekiyo M, McDermott AB Sci Transl Med. 2023 Apr 19;15(692):eade4976. doi: 10.1126/scitranslmed.ade4976. , Epub 2023 Apr 19. PMID:37075126[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
