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<p>The high antigenic diversity of HIV has been a major obstacle to development of a broadly protective vaccine. Nevertheless, protective HIV broadly neutralizing antibodies (bnAbs) exist and have been proposed as templates for vaccine development<sup>1-6</sup>. Germline-targeting is a conceptually radical vaccine design approach to elicit bnAbs, aiming to prime rare bnAb-precursor B cells possessing pre-determined human genetic and structural features shared with template bnAbs, and then guide B cell affinity maturation to potent bnAb evolution with heterologous boosters<sup>7-11</sup>. Although the approach has shown promise in clinical<sup>12-17</sup> and pre-clinical<sup>18-34</sup> studies, it faces many immunological challenges and, to date, has not succeeded in generating bnAbs in humans or nontransgenic animals. Here, we report an adjuvanted protein germline-targeting vaccine tested in outbred nonhuman primates that generated bnAb-class memory B cells and sera capable of neutralizing diverse HIV clinical isolates. bnAb lineages were generated in ≥50% of animals, achieving up to 67% neutralization breadth compared to the reference bnAb. Vaccine-induced bnAbs exhibited precise structural mimicry of human bnAb interactions with HIV envelope (Env), matching the germline-targeting predictions. Furthermore, serum bnAb activity developed in 44% of animals and in the most striking instance reached titers expected to confer protection against diverse HIV isolates. These results demonstrate proof of principle that germline-targeting vaccines can reproducibly elicit prespecified classes of bnAbs to prespecified epitopes under endogenous conditions, supporting further optimization of this approach for HIV vaccine development.</p>

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Vaccination elicits HIV broadly neutralizing antibodies in primates

  • 期刊论文

  • 发表日期：

    2026年6月30日

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  • Jon M. Steichen,
  • Patrick J. Madden,
  • Claudia T. Flynn,
  • Swastik Phulera,
  • Monolina Shil,
  • Oleksandr Kalyuzhniy,
  • Alessia Liguori,
  • Carolyne Kifude,
  • Leigh M. Sewall,
  • Christopher A. Cottrell,
  • Krystal M. Ma,
  • Sabyasachi Baboo,
  • Jolene K. Diedrich,
  • Katherine McKenney,
  • Allan C. deCamp,
  • Diane G. Carnathan,
  • Ivy Phung,
  • Parham Ramezani-Rad,
  • Ester Marina-Zárate,
  • Brian Freeman,
  • Zhenfei Xie,
  • Jeong Hyun Lee,
  • Troy Sincomb,
  • Nicole Phelps,
  • Danny Lu,
  • Diana Goodwin,
  • Ryan Tingle,
  • Yumiko Adachi,
  • Nushin Alavi,
  • Jenny Tran,
  • Andy S. Tran,
  • Alyne Nascimento,
  • Catherine Sovie,
  • Daniel L. V. Bader,
  • Hannah Voic,
  • Xiaoya Zhou,
  • Grace Pixton,
  • Agnes Walsh,
  • Mariane B. Melo,
  • Torben Schiffner,
  • Facundo D. Batista,
  • Dennis R. Burton,
  • Darrell J. Irvine,
  • James C. Paulson,
  • John R. Yates III,
  • Gabriel Ozorowski,
  • Andrew B. Ward,
  • Guido Silvestri,
  • Shane Crotty,
  • William R. Schief

摘要

The high antigenic diversity of HIV has been a major obstacle to development of a broadly protective vaccine. Nevertheless, protective HIV broadly neutralizing antibodies (bnAbs) exist and have been proposed as templates for vaccine development1-6. Germline-targeting is a conceptually radical vaccine design approach to elicit bnAbs, aiming to prime rare bnAb-precursor B cells possessing pre-determined human genetic and structural features shared with template bnAbs, and then guide B cell affinity maturation to potent bnAb evolution with heterologous boosters7-11. Although the approach has shown promise in clinical12-17 and pre-clinical18-34 studies, it faces many immunological challenges and, to date, has not succeeded in generating bnAbs in humans or nontransgenic animals. Here, we report an adjuvanted protein germline-targeting vaccine tested in outbred nonhuman primates that generated bnAb-class memory B cells and sera capable of neutralizing diverse HIV clinical isolates. bnAb lineages were generated in ≥50% of animals, achieving up to 67% neutralization breadth compared to the reference bnAb. Vaccine-induced bnAbs exhibited precise structural mimicry of human bnAb interactions with HIV envelope (Env), matching the germline-targeting predictions. Furthermore, serum bnAb activity developed in 44% of animals and in the most striking instance reached titers expected to confer protection against diverse HIV isolates. These results demonstrate proof of principle that germline-targeting vaccines can reproducibly elicit prespecified classes of bnAbs to prespecified epitopes under endogenous conditions, supporting further optimization of this approach for HIV vaccine development.