Nature Communications (Oct 2024)

Loss of HIV candidate vaccine efficacy in male macaques by mucosal nanoparticle immunization rescued by V2-specific response

  • Mohammad Arif Rahman,
  • Massimiliano Bissa,
  • Hanna Scinto,
  • Savannah E. Howe,
  • Sarkis Sarkis,
  • Zhong-Min Ma,
  • Anna Gutowska,
  • Xunqing Jiang,
  • Christina C. Luo,
  • Luca Schifanella,
  • Ramona Moles,
  • Isabela Silva de Castro,
  • Shraddha Basu,
  • Kombo F. N’guessan,
  • LaTonya D. Williams,
  • Manuel Becerra-Flores,
  • Melvin N. Doster,
  • Tanya Hoang,
  • Hyoyoung Choo-Wosoba,
  • Emmanuel Woode,
  • Yongjun Sui,
  • Georgia D. Tomaras,
  • Dominic Paquin-Proulx,
  • Mangala Rao,
  • James D. Talton,
  • Xiang-Peng Kong,
  • Susan Zolla-Pazner,
  • Timothy Cardozo,
  • Genoveffa Franchini,
  • Jay A. Berzofsky

DOI
https://doi.org/10.1038/s41467-024-53359-2
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 19

Abstract

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Abstract Systemic vaccination of macaques with V1-deleted (ΔV1) envelope immunogens reduce the risk of SIVmac251 acquisition by approximately 60%, with protective roles played by V2-specific ADCC and envelope-specific mucosal IL-17+NKp44+ innate lymphoid cells (ILCs). We investigated whether increased mucosal responses to V2 benefit vaccine efficacy by delivering oral nanoparticles (NPs) that release V2-scaffolded on Typhoid Toxin B (TTB) to the large intestine. Strikingly, mucosal immunization of male macaques abrogated vaccine efficacy with control TTB or empty NPs, but vaccine efficacy of up to 47.6% was preserved with V2-TTB NPs. The deleterious effects of NPs were linked to preferential recruitment of mucosal plasmacytoid dendritic cells (pDCs), reduction of protective mucosal NKp44+ ILCs, increased non-protective mucosal PMA/Ionomycin-induced IFN-γ+NKG2A-NKp44-ILCs, and increased levels of mucosal activated Ki67+CD4+ T cells, a potential target for virus infection. V2-TTB NP mucosal boosting rescued vaccine efficacy, likely via high avidity V2-specific antibodies mediating ADCC, and higher frequencies of mucosal NKp44+ ILCs and of ∆V1gp120 binding antibody-secreting B cells in the rectal mucosa. These findings emphasize the central role of systemic immunization and mucosal V2-specific antibodies in the protection afforded by ΔV1 envelope immunogens and encourage careful evaluation of vaccine delivery platforms to avoid inducing immune responses favorable to HIV transmission.