8D21

Cryo-EM structure of the VRC321 clinical trial, vaccine-elicited, human antibody 1B06 in complex with a stabilized NC99 HA trimer

Summary for 8D21

• Entry DOI: 10.2210/pdb8d21/pdb
• EMDB information: 27139
• Descriptor: Hemagglutinin HA2 chain, Hemagglutinin HA1 chain, 1B06 Heavy Chain, ... (6 entities in total)
• Functional Keywords: vrc, immune system, vrc321, fab, stem, immune system-viral protein complex, immune system/viral protein
• Biological source: Influenza A virus; More
• Total number of polymer chains: 12
• Total formula weight: 267249.50

Authors

Gorman, J.,Kwong, P.D. (deposition date: 2022-05-27, release date: 2023-04-12, Last modification date: 2024-11-06)

Primary citation

Andrews, S.F.,Cominsky, L.Y.,Shimberg, G.D.,Gillespie, R.A.,Gorman, J.,Raab, J.E.,Brand, J.,Creanga, A.,Gajjala, S.R.,Narpala, S.,Cheung, C.S.F.,Harris, D.R.,Zhou, T.,Gordon, I.,Holman, L.,Mendoza, F.,Houser, K.V.,Chen, G.L.,Mascola, J.R.,Graham, B.S.,Kwong, P.D.,Widge, A.,Dropulic, L.K.,Ledgerwood, J.E.,Kanekiyo, M.,McDermott, A.B.
An influenza H1 hemagglutinin stem-only immunogen elicits a broadly cross-reactive B cell response in humans.
Sci Transl Med, 15:eade4976-eade4976, 2023

PubMed Abstract: Current 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.

PubMed: 37075126
DOI: 10.1126/scitranslmed.ade4976

Experimental method

ELECTRON MICROSCOPY (3.96 Å)