Sequence and vector shapes vaccine induced antibody effector functions in HIV vaccine trials

• Type of Material: Article
• Authors: Stephanie Fischinger, Ragon Institute of MGH, Harvard and MGH; Deniz Cizmeci, Ragon Institute of MGH, Harvard and MGH; Davy Deng, University of California Berkeley; Shannon P Grant, Fred Hutchinson Cancer Research Center; Nicole Frahm, Fred Hutchinson Cancer Research Center; Julie McElrath, Fred Hutchinson Cancer Research Center; Jonathan Fuchs, San Francisco Department of Public Health; Pierre-Alexandre Bart, University of Lausanne; Giuseppe Pantaleo, University of Lausanne; Michael Keefer, University of Rochester; William O Hahn, University of Washington; Nadine Rouphael, Emory University; Gavin Churchyard, Aurum Institute, Parktown; Zoe Moodie, Fred Hutchinson Cancer Research Center; Yeycy Donastorg, Inst Dermatol & Cirugia Piel IDCP; Hendrik Streeck, University of Duisburg Essen; Galit Alter, Ragon Institute of MGH, Harvard and MGH
• Language: English
• Date: 2021-11-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Fischinger et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1010016
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 17
• Issue: 11
• Start Page: e1010016
• End Page: e1010016
• Keywords: Science & Technology; VIRUS; EFFICACY; Virology; RHESUS-MONKEYS; STRATEGIES; ALVAC; ADENOVIRUS; Microbiology; HIGH-THROUGHPUT; RESPONSES; IMMUNIZATION; NEUTRALIZING ANTIBODIES; Life Sciences & Biomedicine; Parasitology
• Research Categories: Health Sciences, Public Health; Health Sciences, Immunology

Abstract

Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA/vector, vector/vector and DNA/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA/rAd5 and rAd35/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies.