@article{056cd53650354444abcaf34241084b6b,
title = "Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses",
abstract = "The V1V2 region of the HIV-1 envelope is the target of several broadly neutralizing antibodies (bNAbs). Antibodies to V1V2 elicited in the RV144 clinical trial correlated with a reduced risk of HIV infection, but these antibodies were without broad neutralizing activity. Antibodies targeting V1V2 also correlated with a reduced viral load in immunized macaques challenged with simian immunodeficiency virus (SIV) or simian/human immunodeficiency virus (SHIV). To focus immune responses on V1V2, we engrafted the native, glycosylated V1V2 domain onto five different multimeric scaffold proteins and conducted comparative immunogenicity studies in macaques. Vaccinated macaques developed high titers of plasma and mucosal antibodies that targeted structurally distinct V1V2 epitopes. Plasma antibodies displayed limited neutralizing activity but were functionally active for ADCC and phagocytosis, which was detectable 1–2 years after immunizations ended. This study demonstrates that multivalent, glycosylated V1V2-scaffold protein immunogens focus the antibody response on V1V2 and are differentially effective at inducing polyfunctional antibodies with characteristics associated with protection.",
keywords = "Fc receptors, HIV envelope vaccines, V1V2 domain, antibodies, binding antibody, co-immunization, gp120 envelope glycoprotein, humoral responses, neutralizing antibody, nonhuman primate",
author = "Hessell, {Ann J.} and Rebecca Powell and Xunqing Jiang and Christina Luo and Svenja Weiss and Vincent Dussupt and Vincenza Itri and Alisa Fox and Shapiro, {Mariya B.} and Shilpi Pandey and Tracy Cheever and Fuller, {Deborah H.} and Byung Park and Krebs, {Shelly J.} and Maxim Totrov and Haigwood, {Nancy L.} and Kong, {Xiang Peng} and Susan Zolla-Pazner",
note = "Funding Information: We wish to thank William F. Sutton, Letzibeth Mendez-Riveria, Philip Barnette, Heidi Henderson, and Rebecca Lewinsohn for excellent technical assistance. We thank ONPRC veterinarians and animal technicians for animal procedures and sample collection. We thank Catarina Hioe and Mirek Gorny for valuable discussions throughout the study. This work was supported by P01 AI100151 and P51 OD011092. The Icahn School of Medicine at Mount Sinai provided partial support for S.Z.-P. This work was also supported by cooperative agreements W81XWH-07-2-0067 and W81XWH-11-2-0174 between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. , and the U.S. Department of Defense (DOD). The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or Department of Defense. Funding Information: We wish to thank William F. Sutton, Letzibeth Mendez-Riveria, Philip Barnette, Heidi Henderson, and Rebecca Lewinsohn for excellent technical assistance. We thank ONPRC veterinarians and animal technicians for animal procedures and sample collection. We thank Catarina Hioe and Mirek Gorny for valuable discussions throughout the study. This work was supported by P01 AI100151 and P51 OD011092. The Icahn School of Medicine at Mount Sinai provided partial support for S.Z.-P. This work was also supported by cooperative agreements W81XWH-07-2-0067 and W81XWH-11-2-0174 between The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD). The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or Department of Defense. A.J.H. S.Z.-P. X.-P.K. and N.L.H. wrote the manuscript and analyzed the data. X.-P.K. and M.T. conceptualized, designed, and developed the V1V2 and V3 scaffold immunogens. A.J.H. and N.L.H. designed the macaque immunogenicity studies, oversaw NHP immunizations, directed in vitro evaluations of immune responses performed at ONPRC, and analyzed the data. M.S. propagated virus for ADCC and optimized assay protocols. S.P. managed animal assignments and placement and supervised sample collection, processing, storage, and distribution. R.P. and A.F. performed and analyzed the ADCP experiments. X.J. and C.L. produced and quality-checked the protein immunogens and antigens. S.W. and V.I. performed and analyzed the Luminex binding experiments. V.D. performed and analyzed the BLI experiments. M.B.S. and H.H. performed and analyzed the ADCC experiments. T.C. prepared DNA gene gun bullets for macaque immunizations and performed and analyzed the plasma ELISA and neutralization assays. D.H.F. provided the particle-mediated epidermal delivery (PMED) gene gun and advice for immunizations. B.P. analyzed the datasets and provided statistical analysis. S.W. V.D. M.T. R.P. and S.J.K. contributed edits to the manuscript. M.T. X.J. S.Z.-P. and X.-P.K. have filed for a patent (USPTO_29527.1901) covering the design of the V1V2-scaffold protein immunogens Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jul,
day = "23",
doi = "10.1016/j.celrep.2019.06.074",
language = "English (US)",
volume = "28",
pages = "877--895.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}