7UNB

Crystal structure of malaria transmission-blocking antigen Pfs48/45-6C variant in complex with human antibodies RUPA-117 and RUPA-47

Summary for 7UNB

• Entry DOI: 10.2210/pdb7unb/pdb
• Descriptor: RUPA-47 Fab kappa chain, Gametocyte surface protein P45/48, RUPA-117 Fab kappa chain, ... (7 entities in total)
• Functional Keywords: pfs48/45, human transmission-blocking antibodies, plasmodium falciparum, malaria, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 111728.93

Authors

Hailemariam, S.,McLeod, B.,Julien, J.-P. (deposition date: 2022-04-10, release date: 2022-08-10, Last modification date: 2024-11-20)

Primary citation

McLeod, B.,Mabrouk, M.T.,Miura, K.,Ravichandran, R.,Kephart, S.,Hailemariam, S.,Pham, T.P.,Semesi, A.,Kucharska, I.,Kundu, P.,Huang, W.C.,Johnson, M.,Blackstone, A.,Pettie, D.,Murphy, M.,Kraft, J.C.,Leaf, E.M.,Jiao, Y.,van de Vegte-Bolmer, M.,van Gemert, G.J.,Ramjith, J.,King, C.R.,MacGill, R.S.,Wu, Y.,Lee, K.K.,Jore, M.M.,King, N.P.,Lovell, J.F.,Julien, J.P.
Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses.
Immunity, 55:1680-1692.e8, 2022

PubMed Abstract: Malaria transmission-blocking vaccines (TBVs) aim to elicit human antibodies that inhibit sporogonic development of Plasmodium falciparum in mosquitoes, thereby preventing onward transmission. Pfs48/45 is a leading clinical TBV candidate antigen and is recognized by the most potent transmission-blocking monoclonal antibody (mAb) yet described; still, clinical development of Pfs48/45 antigens has been hindered, largely by its poor biochemical characteristics. Here, we used structure-based computational approaches to design Pfs48/45 antigens stabilized in the conformation recognized by the most potently inhibitory mAb, achieving >25°C higher thermostability compared with the wild-type protein. Antibodies elicited in mice immunized with these engineered antigens displayed on liposome-based or protein nanoparticle-based vaccine platforms exhibited 1-2 orders of magnitude superior transmission-reducing activity, compared with immunogens bearing the wild-type antigen, driven by improved antibody quality. Our data provide the founding principles for using molecular stabilization solely from antibody structure-function information to drive improved immune responses against a parasitic vaccine target.

PubMed: 35977542
DOI: 10.1016/j.immuni.2022.07.015

Experimental method

X-RAY DIFFRACTION (2.18 Å)