Design of immunogens to elicit broadly neutralizing antibodies against HIV targeting the CD4 binding site.

Simone Conti, Kevin J Kaczorowski, Ge Song, Katelyn Porter, Raiees Andrabi, Dennis R Burton, Arup K Chakraborty, Martin Karplus

Journal: Proceedings of the National Academy of Sciences of the United States of America 2021;118(9):e2018338118

PMID: 33637649

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Abstract

A vaccine which is effective against the HIV virus is considered to be the best solution to the ongoing global HIV/AIDS epidemic. In the past thirty years, numerous attempts to develop an effective vaccine have been made with little or no success, due, in large part, to the high mutability of the virus. More recent studies showed that a vaccine able to elicit broadly neutralizing antibodies (bnAbs), that is, antibodies that can neutralize a high fraction of global virus variants, has promise to protect against HIV. Such a vaccine has been proposed to involve at least three separate stages: First, activate the appropriate precursor B cells; second, shepherd affinity maturation along pathways toward bnAbs; and, third, polish the Ab response to bind with high affinity to diverse HIV envelopes (Env). This final stage may require immunization with a mixture of Envs. In this paper, we set up a framework based on theory and modeling to design optimal panels of antigens to use in such a mixture. The designed antigens are characterized experimentally and are shown to be stable and to be recognized by known HIV antibodies.

Address: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138.; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.; Scripps Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037.; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037.; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037.; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139.; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139; [email protected] [email protected].; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; [email protected] [email protected].; Laboratoire de Chimie Biophysique, Institut de Science et d'Ingénierie Supramoléculaires, Université de Strasbourg, 67000 Strasbourg, France.

DOI: 10.1073/pnas.2018338118