Targeting HIV Env immunogens to B cell follicles in nonhuman primates through immune complex or protein nanoparticle formulations

Jacob T Martin; Christopher A Cottrell; Aleksandar Antanasijevic; Diane G Carnathan; Benjamin J Cossette; Chiamaka A Enemuo; Etse H Gebru; Yury Choe; Federico Viviano; Stephanie Fischinger; Talar Tokatlian; Kimberly M Cirelli; George Ueda; Jeffrey Copps; Torben Schiffner; Sergey Menis; Galit Alter; William R Schief; Shane Crotty; Neil P King; David Baker; Guido Silvestri; Andrew B Ward; Darrell J Irvine

doi:10.1038/s41541-020-00223-1

Targeting HIV Env immunogens to B cell follicles in nonhuman primates through immune complex or protein nanoparticle formulations

NPJ Vaccines. 2020 Aug 5;5(1):72. doi: 10.1038/s41541-020-00223-1. eCollection 2020.

Authors

Jacob T Martin^#^{1

2}, Christopher A Cottrell^#^{2

3}, Aleksandar Antanasijevic^#^{2

3}, Diane G Carnathan^{2

4

5}, Benjamin J Cossette^{1

2}, Chiamaka A Enemuo^{4

5}, Etse H Gebru^{4

5}, Yury Choe^{4

5}, Federico Viviano^{4

5}, Stephanie Fischinger^{6

7}, Talar Tokatlian^{1

2}, Kimberly M Cirelli^{2

8}, George Ueda^{9

10}, Jeffrey Copps³, Torben Schiffner^{2

11}, Sergey Menis^{2

11}, Galit Alter⁶, William R Schief^{2

6

11}, Shane Crotty^{2

8

12}, Neil P King^{9

10}, David Baker^{9

10

13}, Guido Silvestri^{2

4

5}, Andrew B Ward^{2

3

11}, Darrell J Irvine^{1

2

6

13

14

15}

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 USA.
² Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037 USA.
³ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037 USA.
⁴ Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322 USA.
⁵ Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322 USA.
⁶ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139 USA.
⁷ University of Duisburg-Essen, 47057 Essen, Germany.
⁸ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037 USA.
⁹ Department of Biochemistry, University of Washington, Seattle, WA 98195 USA.
¹⁰ Institute for Protein Design, University of Washington, Seattle, WA 98195 USA.
¹¹ International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037 USA.
¹² Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA 92037 USA.
¹³ Howard Hughes Medical Institute, Chevy Chase, MD 20815 USA.
¹⁴ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 USA.
¹⁵ Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 USA.

^# Contributed equally.

Abstract

Following immunization, high-affinity antibody responses develop within germinal centers (GCs), specialized sites within follicles of the lymph node (LN) where B cells proliferate and undergo somatic hypermutation. Antigen availability within GCs is important, as B cells must acquire and present antigen to follicular helper T cells to drive this process. However, recombinant protein immunogens such as soluble human immunodeficiency virus (HIV) envelope (Env) trimers do not efficiently accumulate in follicles following traditional immunization. Here, we demonstrate two strategies to concentrate HIV Env immunogens in follicles, via the formation of immune complexes (ICs) or by employing self-assembling protein nanoparticles for multivalent display of Env antigens. Using rhesus macaques, we show that within a few days following immunization, free trimers were present in a diffuse pattern in draining LNs, while trimer ICs and Env nanoparticles accumulated in B cell follicles. Whole LN imaging strikingly revealed that ICs and trimer nanoparticles concentrated in as many as 500 follicles in a single LN within two days after immunization. Imaging of LNs collected seven days postimmunization showed that Env nanoparticles persisted on follicular dendritic cells in the light zone of nascent GCs. These findings suggest that the form of antigen administered in vaccination can dramatically impact localization in lymphoid tissues and provides a new rationale for the enhanced immune responses observed following immunization with ICs or nanoparticles.

Keywords: HIV infections; Innate immunity; Protein vaccines.

Abstract

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