Abstract

Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans

Willis JR Prabhakaran M Muthui M Naidoo A Sincomb T Wu W Cottrell CA Landais E deCamp AC Keshavarzi NR Kalyuzhniy O Lee JH Murungi LM Ogonda WA Yates NL Corcoran MM Phulera S Musando J Tsai A Lemire G Sein Y Muteti M Alamuri P Bohl JA Holman D Himansu S Leav B Reuter C Lin LA Ding B He C Straus WL MacPhee KJ Regadas I Nyabundi DV Chirchir R Anzala O Kimotho JN Kibet C Greene K Gao H Beatman E Benson K Laddy D Brown DM Bronson R Jean-Baptiste J Gajjala S Rikhtegaran-Tehrani Z Benner A Ramaswami M Lu D Alavi N Amirzehni S Kubitz M Tingle R Georgeson E Phelps N Adachi Y Liguori A Flynn C McKenney K Zhou X Owuor DC Owuor SA Kim SY Duff M Kim JY Gibson G Baboo S Diedrich J Schiffner T Shields M Matsoso M Santos J Syvertsen K Kennedy A Schroeter M Vekemans J Yates JR, 3rd Paulson JC Hyrien O McDermott AB Maenetje P Nyombayire J Karita E Ingabire R Edward V Muturi-Kioi V Maenza J Shapiro AE McElrath MJ Edupuganti S Taylor BS Diemert D Ozorowski G Koup RA Montefiori D Ward AB Karlsson Hedestam GB Tomaras G Hunt DJ Muema D Sok D Laufer DS Andrews SF Nduati EW Schief WR
Science. 2025;389eadr8382

Permenent descriptor

A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI G002 in the United States and IAVI G003 in Rwanda and South Africa (IAVI, International Aids Vaccine Initiative), we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI G002). The vaccines were generally safe and well tolerated, except that 18% of IAVI G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM; heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development; and elicited antibodies exhibited precise bnAb structural mimicry. The results establish clinical proof of concept that heterologous boosting can advance bnAb precursor maturation and demonstrate bnAb priming in Africa, where the HIV burden is highest.