Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice.
A vaccine that elicits broadly neutralizing antibodies (bNAbs) against HIV-1 is likely to be protective, but this has not been achieved. To explore immunization regimens that might elicit bNAbs, we produced and immunized mice expressing the predicted germline PGT121, a bNAb specific for the V3-loop and surrounding glycans on the HIV-1 spike. Priming with an epitope-modified immunogen designed to activate germline antibody-expressing B cells, followed by ELISA-guided boosting with a sequence of directional immunogens, native-like trimers with decreasing epitope modification, elicited heterologous tier-2-neutralizing responses. In contrast, repeated immunization with the priming immunogen did not. Antibody cloning confirmed elicitation of high levels of somatic mutation and tier-2-neutralizing antibodies resembling the authentic human bNAb. Our data establish that sequential immunization with specifically designed immunogens can induce high levels of somatic mutation and shepherd antibody maturation to produce bNAbs from their inferred germline precursors.
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Amelia
A
Escolano
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Jon M
JM
Steichen
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Pia
P
Dosenovic
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Daniel W
DW
Kulp
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Jovana
J
Golijanin
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, New York, NY 10004, USA.
Devin
D
Sok
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Natalia T
NT
Freund
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Alexander D
AD
Gitlin
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Thiago
T
Oliveira
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Tatsuya
T
Araki
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Sarina
S
Lowe
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Spencer T
ST
Chen
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Jennifer
J
Heinemann
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Kai-Hui
KH
Yao
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Erik
E
Georgeson
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Karen L
KL
Saye-Francisco
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
Anna
A
Gazumyan
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Yumiko
Y
Adachi
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Michael
M
Kubitz
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, 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.
Dennis R
DR
Burton
Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, 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. Electronic address: schief@scripps.edu.
William R
WR
Schief
Laboratory of Molecular Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: nussen@rockefeller.edu.
Michel C
MC
Nussenzweig
D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000956:Antigens, Viral / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D000939:Epitopes / Q000276:immunology; D055879:Gene Knock-In Techniques; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D007114:Immunization; D007136:Immunoglobulins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D016415:Sequence Alignment
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; D017931:DNA Primers; D000939:Epitopes; D015483:HIV Antibodies; D007136:Immunoglobulins