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 L-A., 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 S-Y., 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., 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.
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.