Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance

Kimberly M Cirelli; Diane G Carnathan; Bartek Nogal; Jacob T Martin; Oscar L Rodriguez; Amit A Upadhyay; Chiamaka A Enemuo; Etse H Gebru; Yury Choe; Federico Viviano; Catherine Nakao; Matthias G Pauthner; Samantha Reiss; Christopher A Cottrell; Melissa L Smith; Raiza Bastidas; William Gibson; Amber N Wolabaugh; Mariane B Melo; Benjamin Cossette; Venkatesh Kumar; Nirav B Patel; Talar Tokatlian; Sergey Menis; Daniel W Kulp; Dennis R Burton; Ben Murrell; William R Schief; Steven E Bosinger; Andrew B Ward; Corey T Watson; Guido Silvestri; Darrell J Irvine; Shane Crotty

doi:10.1016/j.cell.2019.04.012

Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance

Cell. 2019 May 16;177(5):1153-1171.e28. doi: 10.1016/j.cell.2019.04.012. Epub 2019 May 9.

Authors

Kimberly M Cirelli¹, Diane G Carnathan², Bartek Nogal³, Jacob T Martin⁴, Oscar L Rodriguez⁵, Amit A Upadhyay⁶, Chiamaka A Enemuo⁷, Etse H Gebru⁷, Yury Choe⁷, Federico Viviano⁷, Catherine Nakao⁸, Matthias G Pauthner⁹, Samantha Reiss¹, Christopher A Cottrell³, Melissa L Smith⁵, Raiza Bastidas⁹, William Gibson¹⁰, Amber N Wolabaugh⁶, Mariane B Melo⁴, Benjamin Cossette¹¹, Venkatesh Kumar¹², Nirav B Patel¹³, Talar Tokatlian⁴, Sergey Menis⁹, Daniel W Kulp¹⁴, Dennis R Burton¹⁵, Ben Murrell¹⁶, William R Schief¹⁵, Steven E Bosinger¹⁷, Andrew B Ward³, Corey T Watson¹⁰, Guido Silvestri², Darrell J Irvine¹⁸, Shane Crotty¹⁹

Affiliations

¹ Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA.
² Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
³ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
⁷ Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁸ Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.
⁹ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁰ Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
¹¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹² Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
¹³ Yerkes NHP Genomics Core Laboratory, Yerkes National Primate Research Center, Atlanta, GA 30329, USA.
¹⁴ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Vaccine and Immunotherapy Center, Wistar Institute, Philadelphia, PA 19104, USA.
¹⁵ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA.
¹⁶ Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
¹⁷ Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA; Yerkes NHP Genomics Core Laboratory, Yerkes National Primate Research Center, Atlanta, GA 30329, USA.
¹⁸ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA; Departments of Biological Engineering and Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁹ Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address: shane@lji.org.

Abstract

Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (T_FH) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.

Keywords: FNA; GC- T(FH); HIV vaccine; affinity maturation; immune complexes; memory B cells; non-human primates; rhesus macaque genome; somatic hypermutation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / immunology*
B-Lymphocytes / immunology*
B-Lymphocytes / pathology
Female
Germinal Center / immunology*
Germinal Center / pathology
Germinal Center / virology
HIV Antibodies / immunology*
HIV-1 / immunology*
Immunization, Passive*
Macaca mulatta
Male
T-Lymphocytes, Helper-Inducer / immunology*
T-Lymphocytes, Helper-Inducer / pathology
env Gene Products, Human Immunodeficiency Virus / immunology

Substances

Antibodies, Neutralizing
HIV Antibodies
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding