Polytopic fractional delivery of an HIV vaccine alters cellular responses and results in increased epitope breadth in a phase 1 randomized trialResearch in context
Maurine D. Miner,
Allan deCamp,
Nicole Grunenberg,
Stephen C. De Rosa,
Andrew Fiore-Gartland,
Katherine Bar,
Paul Spearman,
Mary Allen,
Pei-Chun Yu,
Bryce Manso,
Nicole Frahm,
Spyros Kalams,
Lindsey Baden,
Michael C. Keefer,
Hyman M. Scott,
Richard Novak,
Hong Van Tieu,
Georgia D. Tomaras,
James G. Kublin,
M. Juliana McElrath,
Lawrence Corey,
Ian Frank,
Artur Kalichman,
Paul Edlefsen,
Mary Enama,
John Hural,
Renee Holt,
Debora Dunbar,
Dave Crawford,
Ian Maki,
Jan Johannessen,
Scharla Estep,
Yevgeny Grigoriev,
Tamra Madenwald,
Marianne Hansen,
Drienna Holman,
Ramey Fair,
Genevieve Meyer,
Anya Luke-Kilolam
Affiliations
Maurine D. Miner
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA; Corresponding author. 1100 Fairview Ave N, Mail Stop E3-300, Seattle, WA, 98109, USA.
Allan deCamp
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
Nicole Grunenberg
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
Stephen C. De Rosa
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA; Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA, USA
Andrew Fiore-Gartland
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
Katherine Bar
University of Pennsylvania, Philadelphia, PA, USA
Paul Spearman
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Mary Allen
Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Pei-Chun Yu
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
Bryce Manso
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
Nicole Frahm
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
Spyros Kalams
Vanderbilt University Medical Center, Nashville, TN, USA
Lindsey Baden
Brigham and Women's Hospital, Boston, MA, USA
Michael C. Keefer
Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA
Hyman M. Scott
San Francisco Department of Public Health, San Francisco, CA, USA
Richard Novak
University of Illinois, Chicago, IL, USA
Hong Van Tieu
Laboratory of Infectious Disease Prevention, Lindsley F. Kimball Research Institute, New York Blood Center, New York City, NY, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York City, NY, USA
Georgia D. Tomaras
Department of Surgery, Duke University, Durham, NC, USA
James G. Kublin
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
M. Juliana McElrath
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
Lawrence Corey
Vaccine and Infectious Disease Division, Fred Hutch Cancer Center, Seattle, WA, USA
Summary: Background: Elicitation 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. Methods: We 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. Findings: CD8 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. Interpretation: This 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. Funding: National Institute of Allergy and Infectious Diseases, NIH.
