Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice.
A major obstacle to a broadly neutralizing antibody (bnAb)-based HIV vaccine is the activation of appropriate B cell precursors. Germline-targeting immunogens must be capable of priming rare bnAb precursors in the physiological setting. We tested the ability of the VRC01-class bnAb germline-targeting immunogen eOD-GT8 60mer (60-subunit self-assembling nanoparticle) to activate appropriate precursors in mice transgenic for human immunoglobulin (Ig) loci. Despite an average frequency of, at most, about one VRC01-class precursor per mouse, we found that at least 29% of singly immunized mice produced a VRC01-class memory response, suggesting that priming generally succeeded when at least one precursor was present. The results demonstrate the feasibility of using germline targeting to prime specific and exceedingly rare bnAb-precursor B cells within a humanlike repertoire.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Devin
D
Sok
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Bryan
B
Briney
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Joseph G
JG
Jardine
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Daniel W
DW
Kulp
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Sergey
S
Menis
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Matthias
M
Pauthner
Kymab Ltd, The Bennet Building (B930), Babraham Research Campus, Cambridge CB22 3AT, UK.
Andrew
A
Wood
Kymab Ltd, The Bennet Building (B930), Babraham Research Campus, Cambridge CB22 3AT, UK.
E-Chiang
EC
Lee
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Khoa M
KM
Le
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Meaghan
M
Jones
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Alejandra
A
Ramos
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Oleksandr
O
Kalyuzhniy
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Yumiko
Y
Adachi
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Michael
M
Kubitz
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Skye
S
MacPherson
Kymab Ltd, The Bennet Building (B930), Babraham Research Campus, Cambridge CB22 3AT, UK. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Allan
A
Bradley
Kymab Ltd, The Bennet Building (B930), Babraham Research Campus, Cambridge CB22 3AT, UK.
Glenn A
GA
Friedrich
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Ragon Institute of Massachusetts General Hospital (MGH), MIT, and Harvard, Cambridge, MA 02129, USA. burton@scripps.edu schief@scripps.edu.
William R
WR
Schief
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Ragon Institute of Massachusetts General Hospital (MGH), MIT, and Harvard, Cambridge, MA 02129, USA. burton@scripps.edu schief@scripps.edu.
Dennis R
DR
Burton
D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000080908:Broadly Neutralizing Antibodies; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics / Q000276:immunology*; D056426:Genetic Loci; D005854:Germ Cells / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory; D051379:Mice; D008822:Mice, Transgenic; D053758:Nanoparticles; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D000072417:Protein Domains / Q000235:genetics / Q000276:immunology
D016915:AIDS Vaccines; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies; C578595:VRC01 monoclonal antibody