HIV broadly neutralizing antibody precursors to the Apex epitope induced in nonhuman primates

Krystal M Ma; Henry J Sutton; Payal P Pratap; Jon M Steichen; Diane Carnathan; James Quinn; Oleksandr Kalyuzhniy; Alessia Liguori; Sashank Agrawal; Sabyasachi Baboo; Patrick Madden; Christopher A Cottrell; Jordan R Willis; Jeong-Hyun Lee; Elise Landais; Xiaozhen Hu; Parham Ramezani-Rad; Gabriel Ozorowski; Vanessa R Lewis; Jolene K Diedrich; Xiaoya Zhou; Tasha K Altheide; Nicole Phelps; Erik Georgeson; Nushin B Alavi; Danny Lu; Saman Eskandarzadeh; Michael Kubitz; Yumiko Adachi; Tina-Marie Mullen; Murillo Silva; Mariane B Melo; Sunny Himansu; Darrell J Irvine; Dennis R Burton; John R Yates 3rd; James C Paulson; Devin Sok; Ian A Wilson; Guido Silvestri; Andrew B Ward; Shane Crotty; William R Schief

doi:10.1126/sciimmunol.adt6660

HIV broadly neutralizing antibody precursors to the Apex epitope induced in nonhuman primates

Sci Immunol. 2025 Aug 22;10(110):eadt6660. doi: 10.1126/sciimmunol.adt6660. Epub 2025 Aug 22.

Authors

Krystal M Ma^{1

2

3}, Henry J Sutton^{1

4}, Payal P Pratap^{1

2

5}, Jon M Steichen^{1

2

3}, Diane Carnathan^{1

6

7}, James Quinn^{1

4}, Oleksandr Kalyuzhniy^{1

2

3}, Alessia Liguori^{1

2

3}, Sashank Agrawal^{1

2

5}, Sabyasachi Baboo⁸, Patrick Madden^{1

4}, Christopher A Cottrell^{1

2

3}, Jordan R Willis^{1

2

3}, Jeong-Hyun Lee^{1

2

3}, Elise Landais^{1

2

3}, Xiaozhen Hu^{1

2

3}, Parham Ramezani-Rad^{1

4}, Gabriel Ozorowski^{1

2

5}, Vanessa R Lewis^{1

6

7}, Jolene K Diedrich⁸, Xiaoya Zhou^{1

2

3}, Tasha K Altheide^{1

4}, Nicole Phelps^{1

2

3}, Erik Georgeson^{1

2

3}, Nushin B Alavi^{1

2

3}, Danny Lu^{1

2

3}, Saman Eskandarzadeh^{1

2

3}, Michael Kubitz^{1

2

3}, Yumiko Adachi^{1

2

3}, Tina-Marie Mullen^{1

2

3}, Murillo Silva¹, Mariane B Melo^{1

9}, Sunny Himansu¹⁰, Darrell J Irvine^{1

9

11

12

13

14}, Dennis R Burton^{1

2

3}, John R Yates 3rd⁸, James C Paulson^{3

8}, Devin Sok^{1

2}, Ian A Wilson^{1

2

5}, Guido Silvestri^{1

6

7}, Andrew B Ward^{1

2

5}, Shane Crotty^{1

4

15}, William R Schief^{1

2

3

10}

Affiliations

¹ Consortium for HIV/AIDS Vaccine Development (CHAVD), Scripps Research Institute, La Jolla, CA 92037, USA.
² IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92037, USA.
³ Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
⁵ Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
⁶ Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
⁷ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30329, USA.
⁸ Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037, USA.
⁹ Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
¹⁰ Moderna Inc., Cambridge, MA 02139, USA.
¹¹ David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
¹² Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA.
¹³ Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
¹⁴ Ragon Institute of Massachusetts General Hospital, Cambridge, MA 02139, USA.
¹⁵ Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA, 92037 USA.

Abstract

An effective prophylactic HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). bnAbs to the Apex region of the HIV envelope glycoprotein (Env) are promising targets for vaccination because of their relatively low somatic hypermutation compared with other bnAbs. Most Apex bnAbs engage Env using an exceptionally long heavy-chain complementarity-determining region 3 (HCDR3) containing specific binding motifs, which reduces bnAb precursor frequency and makes priming of rare bnAb precursors a likely limiting step in the path to Apex bnAb induction. We found that adjuvanted protein or mRNA lipid nanoparticle (LNP) immunization of rhesus macaques with ApexGT6, an Env trimer engineered to bind Apex bnAb precursors, consistently induced Apex bnAb-related precursors with long HCDR3s bearing bnAb-like sequence motifs. Cryo-electron microscopy revealed that elicited Apex bnAb-related HCDR3s had structures combining elements of several prototype Apex bnAbs. These results achieve a critical HIV vaccine development milestone in outbred primates.

MeSH terms

AIDS Vaccines* / immunology
Animals
Antibodies, Neutralizing* / immunology
Broadly Neutralizing Antibodies* / immunology
Complementarity Determining Regions / immunology
Epitopes* / immunology
HIV Antibodies* / immunology
HIV Infections* / immunology
HIV Infections* / prevention & control
HIV-1* / immunology
Humans
Macaca mulatta
env Gene Products, Human Immunodeficiency Virus* / immunology

Substances

Epitopes
HIV Antibodies
AIDS Vaccines
Antibodies, Neutralizing
env Gene Products, Human Immunodeficiency Virus
Broadly Neutralizing Antibodies
Complementarity Determining Regions

Abstract

MeSH terms

Substances

Grants and funding