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

Systemic vaccination of macaques with V1-deleted (ΔV1) envelope immunogens reduce the risk of SIV<sub>mac251</sub> acquisition by approximately 60%, with protective roles played by V2-specific ADCC and envelope-specific mucosal IL-17<sup>+</sup>NKp44<sup>+</sup> 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<sup>+</sup> ILCs, increased non-protective mucosal PMA/Ionomycin-induced IFN-γ<sup>+</sup>NKG2A<sup>-</sup>NKp44<sup>-</sup>ILCs, and increased levels of mucosal activated Ki67<sup>+</sup>CD4<sup>+</sup> 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<sup>+</sup> 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.

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Journal
Nature Communications
Published
2024-10-22
DOI
https://doi.org/10.1038/s41467-024-53359-2
Citations
2
Primary Topic
HIV Research and Treatment
Type
article
Field-Weighted Citation Impact
0.59

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article

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

Luca Schifanella, Savannah E. Howe, Yongjun Sui, Dominic Paquin‐Proulx et al.
2 citations
Nature Communications
HIV Research and Treatment
0.59
article

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

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

Abstract

Systemic vaccination of macaques with V1-deleted (ΔV1) envelope immunogens reduce the risk of SIV<sub>mac251</sub> acquisition by approximately 60%, with protective roles played by V2-specific ADCC and envelope-specific mucosal IL-17<sup>+</sup>NKp44<sup>+</sup> 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<sup>+</sup> ILCs, increased non-protective mucosal PMA/Ionomycin-induced IFN-γ<sup>+</sup>NKG2A<sup>-</sup>NKp44<sup>-</sup>ILCs, and increased levels of mucosal activated Ki67<sup>+</sup>CD4<sup>+</sup> 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<sup>+</sup> 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.

Nature CommunicationsVol. 15(1)
Henry M. Jackson Foundation (US), National Institutes of Health (US), Duke University (US), National Cancer Institute (US), Alchem Laboratories (United States) (US), Center for Cancer Research (US), New York University (US), University of California, Davis (US), Walter Reed Army Institute of Research (US), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Defense, Henry M. Jackson Foundation, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 32%
HIV Research and Treatment
0.59
DOIOpen Access PDFOpenAlex
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