7LKB

Crystal structure of PfCSP peptide 21 with vaccine-elicited human anti-malaria antibody m42.127

Summary for 7LKB

• Entry DOI: 10.2210/pdb7lkb/pdb
• Descriptor: m42.127 Fab heavy Chain, m42.127 Fab light chain, Circumsporozoite protein, ... (5 entities in total)
• Functional Keywords: malaria, csp, junction region, antibody, m42.127, immune system, immune system-antigen complex, immune system/antigen
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 102239.75

Authors

Xu, K.,Kwong, P.D. (deposition date: 2021-02-02, release date: 2021-12-15, Last modification date: 2023-10-18)

Primary citation

Kratochvil, S.,Shen, C.H.,Lin, Y.C.,Xu, K.,Nair, U.,Da Silva Pereira, L.,Tripathi, P.,Arnold, J.,Chuang, G.Y.,Melzi, E.,Schon, A.,Zhang, B.,Dillon, M.,Bonilla, B.,Flynn, B.J.,Kirsch, K.H.,Kisalu, N.K.,Kiyuka, P.K.,Liu, T.,Ou, L.,Pancera, M.,Rawi, R.,Reveiz, M.,Seignon, K.,Wang, L.T.,Waring, M.T.,Warner, J.,Yang, Y.,Francica, J.R.,Idris, A.H.,Seder, R.A.,Kwong, P.D.,Batista, F.D.
Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies.
Immunity, 54:2859-2876.e7, 2021

PubMed Abstract: Repeat antigens, such as the Plasmodium falciparum circumsporozoite protein (PfCSP), use both sequence degeneracy and structural diversity to evade the immune response. A few PfCSP-directed antibodies have been identified that are effective at preventing malaria infection, including CIS43, but how these repeat-targeting antibodies might be improved has been unclear. Here, we engineered a humanized mouse model in which B cells expressed inferred human germline CIS43 (iGL-CIS43) B cell receptors and used both vaccination and bioinformatic analysis to obtain variant CIS43 antibodies with improved protective capacity. One such antibody, iGL-CIS43.D3, was significantly more potent than the current best-in-class PfCSP-directed antibody. We found that vaccination with a junctional epitope peptide was more effective than full-length PfCSP at recruiting iGL-CIS43 B cells to germinal centers. Structure-function analysis revealed multiple somatic hypermutations that combinatorically improved protection. This mouse model can thus be used to understand vaccine immunogens and to develop highly potent anti-malarial antibodies.

PubMed: 34788599
DOI: 10.1016/j.immuni.2021.10.017

Experimental method

X-RAY DIFFRACTION (1.8 Å)