Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses

• Published in: Immunity (Cambridge, Mass.) Vol. 55; no. 9; pp. 1680 - 1692.e8
• Main Authors: McLeod, Brandon, Mabrouk, Moustafa T, Miura, Kazutoyo, Ravichandran, Rashmi, Kephart, Sally, Hailemariam, Sophia, Pham, Thao P, Semesi, Anthony, Kucharska, Iga, Kundu, Prasun, Huang, Wei-Chiao, Johnson, Max, Blackstone, Alyssa, Pettie, Deleah, Murphy, Michael, Kraft, John C, Leaf, Elizabeth M, Jiao, Yang, van de Vegte-Bolmer, Marga, van Gemert, Geert-Jan, Ramjith, Jordache, King, C Richter, MacGill, Randall S, Wu, Yimin, Lee, Kelly K, Jore, Matthijs M, King, Neil P, Lovell, Jonathan F, Julien, Jean-Philippe
• Format: Journal Article
• Language: English
• Published: United States Cell Press 13.09.2022
• Subjects: Animals; Antibodies, Blocking; Antibodies, Monoclonal; Antibodies, Protozoan; Antibody Formation; Antigens, Protozoan; Humans; Malaria Vaccines; Malaria, Falciparum - prevention & control; Membrane Glycoproteins; Mice; Plasmodium falciparum; Protozoan Proteins; Vaccination; malaria; structure-based immunogen design; antibodies
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2022.07.015

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.