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 () and Jay A. Berzofsky ()
Additional contact information
Mohammad Arif Rahman: National Institutes of Health
Massimiliano Bissa: National Institutes of Health
Hanna Scinto: National Institutes of Health
Savannah E. Howe: National Institutes of Health
Sarkis Sarkis: National Institutes of Health
Zhong-Min Ma: University of California
Anna Gutowska: National Institutes of Health
Xunqing Jiang: NYU Grossman School of Medicine
Christina C. Luo: NYU Grossman School of Medicine
Luca Schifanella: National Institutes of Health
Ramona Moles: National Institutes of Health
Isabela Silva de Castro: National Institutes of Health
Shraddha Basu: Walter Reed Army Institute of Research
Kombo F. N’guessan: Walter Reed Army Institute of Research
LaTonya D. Williams: Duke University School of Medicine
Manuel Becerra-Flores: NYU Langone Health
Melvin N. Doster: National Institutes of Health
Tanya Hoang: National Institutes of Health
Hyoyoung Choo-Wosoba: National Cancer Institute
Emmanuel Woode: National Institutes of Health
Yongjun Sui: National Institutes of Health
Georgia D. Tomaras: Duke University School of Medicine
Dominic Paquin-Proulx: Walter Reed Army Institute of Research
Mangala Rao: Walter Reed Army Institute of Research
James D. Talton: Alchem Laboratories Corporation
Xiang-Peng Kong: NYU Grossman School of Medicine
Susan Zolla-Pazner: Icahn School of Medicine at Mount Sinai
Timothy Cardozo: NYU Langone Health
Genoveffa Franchini: National Institutes of Health
Jay A. Berzofsky: National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53359-2

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