Diversion of HIV-1 vaccine–induced immunity by gp41-microbiota cross-reactive antibodies

Wilton B. Williams1,?, Hua-Xin Liao1, M. Anthony Moody1, Thomas B. Kepler2, S. Munir Alam1, Feng Gao1, Kevin Wiehe1, Ashley M. Trama1, Kathryn Jones1, Ruijun Zhang1, Hongshuo Song1, Dawn J. Marshall1, John F. Whitesides1, Kaitlin Sawatzki2, Axin Hua2, Pinghuang Liu1, Matthew Z. Tay1, Kelly Seaton1, Xiaoying Shen1, Andrew Foulger1, Krissey E. Lloyd1, Robert Parks1, Justin Pollara1, Guido Ferrari1, Jae-Sung Yu1, Nathan Vandergrift1, David C. Montefiori1, Magdalena E. Sobieszczyk3, Scott Hammer3, Shelly Karuna4, Peter Gilbert5, Doug Grove5, Nicole Grunenberg4, Julie McElrath4, John R. Mascola6, Richard A. Koup6, Lawrence Corey4, Gary J. Nabel6,*, Cecilia Morgan5, Gavin Churchyard7, Janine Maenza4, Michael Keefer8, Barney S. Graham6, Lindsey R. Baden9, Georgia D. Tomaras1, Barton F. Haynes1,?

A HIV-1 DNA prime-recombinant Adenovirus Type 5 (rAd5) boost vaccine failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive plasma Ab titers were higher to Env gp41 than gp120, and repertoire analysis demonstrated that 93% of HIV-1-reactive Abs from memory B cells was to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies (mAbs) were non-neutralizing, and frequently polyreactive with host and environmental antigens including intestinal microbiota (IM). Next generation sequencing of an IGHV repertoire prior to vaccination revealed an Env-IM cross-reactive Ab that was clonally-related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.