Sequential Immunization Elicits Broadly Neutralizing anti-HIV-1 Antibodies in Ig Knock-in Mice

• Published in: Cell 2016-09, Vol.166 (6), p.1445-1458.e12
• Main Authors: Escolano, Amelia, Steichen, Jon M., Dosenovic, Pia, Kulp, Daniel W., Golijanin, Jovana, Sok, Devin, Freund, Natalia T., Gitlin, Alexander D., Oliveira, Thiago, Araki, Tatsuya, Lowe, Sarina, Chen, Spencer T., Heinemann, Jennifer, Yao, Kai-Hui, Georgeson, Erik, Saye-Francisco, Karen L., Gazumyan, Anna, Adachi, Yumiko, Kubitz, Michael, Burton, Dennis R., Schief, William R., Nussenzweig, Michel C.
• Format: Article
• Language: English
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.07.030

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 of PGT121, a bNAb specific for the V3-loop and surrounding glycans on the HIV-1 spike. Priming with an epitope modifiied 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 establishes 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. Generation of HIV broadly neutralizing antibodies - a major goal in vaccine research - can be achieved through sequential immunization with HIV envelope glycoproteins designed to engage PGT121 antibody precursors and their intermediates.