학술논문
Polytopic fractional delivery of an HIV vaccine alters cellular responses and results in increased epitope breadth in a phase 1 randomized trial
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article
Author
Miner, Maurine D; deCamp, Allan; Grunenberg, Nicole; De Rosa, Stephen C; Fiore-Gartland, Andrew; Bar, Katherine; Spearman, Paul; Allen, Mary; Yu, Pei-Chun; Manso, Bryce; Frahm, Nicole; Kalams, Spyros; Baden, Lindsey; Keefer, Michael C; Scott, Hyman M; Novak, Richard; Van Tieu, Hong; Tomaras, Georgia D; Kublin, James G; McElrath, M Juliana; Corey, Lawrence; Frank, Ian; Team, HVTN 085 Study; Kalichman, Artur; Edlefsen, Paul; Enama, Mary; Hural, John; Holt, Renee; Dunbar, Debora; Crawford, Dave; Maki, Ian; Johannessen, Jan; Estep, Scharla; Grigoriev, Yevgeny; Madenwald, Tamra; Hansen, Marianne; Holman, Drienna; Fair, Ramey; Meyer, Genevieve; Luke-Kilolam, Anya
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Abstract
BackgroundElicitation of broad immune responses is understood to be required for an efficacious preventative HIV vaccine. This Phase 1 randomized controlled trial evaluated whether administration of vaccine antigens separated at multiple injection sites vs combined, fractional delivery at multiple sites affected T-cell breadth compared to standard, single site vaccination.MethodsWe randomized 90 participants to receive recombinant adenovirus 5 (rAd5) vector with HIV inserts gag, pol and env via three different strategies. The Standard group received vaccine at a single anatomic site (n = 30) compared to two polytopic (multisite) vaccination groups: Separated (n = 30), where antigens were separately administered to four anatomical sites, and Fractioned (n = 30), where fractions of each vaccine component were combined and administered at four sites. All groups received the same total dose of vaccine.FindingsCD8 T-cell response rates and magnitudes were significantly higher in the Fractioned group than Standard for several antigen pools tested. CD4 T-cell response magnitudes to Pol were higher in the Separated than Standard group. T-cell epitope mapping demonstrated greatest breadth in the Fractioned group (median 8.0 vs 2.5 for Standard, Wilcoxon p = 0.03; not significant after multiplicity adjustment for co-primary endpoints). IgG binding antibody response rates to Env were higher in the Standard and Fractioned groups vs Separated group.InterpretationThis study shows that the number of anatomic sites for which a vaccine is delivered and distribution of its antigenic components influences immune responses in humans.FundingNational Institute of Allergy and Infectious Diseases, NIH.