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Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates.

Jon M SteichenIvy PhungEugenia SalcedoGabriel OzorowskiJordan R WillisSabyasachi BabooAlessia LiguoriChristopher A CottrellJonathan L TorrePatrick J MaddenKrystal M MaHenry J SuttonJeong Hyun LeeOleksandr KalyuzhniyJoel D AllenOscar L RodriguezYumiko AdachiTina-Marie MullenErik GeorgesonMichael KubitzAlison BurnsShawn BarmanRohini MopuriAmanda MetzTasha K AltheideJolene K DiedrichSwati SahaKaitlyn ShieldsSteven E SchultzeMelissa Laird SmithTorben SchiffnerDennis R BurtonCorey T WatsonSteven E BosingerMax CrispinJohn Yates IiiJames C PaulsonAndrew B WardDevin SokShane CrottyWilliam R Schief
Published in: Science (New York, N.Y.) (2024)
Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in eight of eight rhesus macaques to substantial frequencies and with diverse lineages in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. Our results demonstrate proof of principle for HCDR3-dominant bnAb-precursor priming in outbred animals and suggest that N332-GT5 holds promise for the induction of similar responses in humans.
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