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Defining and Manipulating B Cell Immunodominance Hierarchies to Elicit Broadly Neutralizing Antibody Responses Against Influenza Virus

64 Pages Posted: 18 May 2020 Publication Status: Published

See all articles by Assaf Amitai

Assaf Amitai

Massachusetts Institute of Technology (MIT) - Department of Chemical Engineering

Maya Sangesland

Ragon Institute of MGH, MIT and Harvard

Ralston Barnes

Bristol Myers Squibb

Daniel Rohrer

Bristol Myers Squibb

Nils Lonberg

Bristol Myers Squibb

Daniel Lingwood

Ragon Institute of MGH, MIT and Harvard

Arup K. Chakraborty

Massachusetts Institute of Technology (MIT) - Department of Chemical Engineering

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Abstract

The antibody repertoire possesses near limitless diversity, enabling the adaptive immune system to accommodate essentially any antigen. However, this diversity explores the antigenic space unequally, allowing some pathogens like influenza virus to impose complex immunodominance hierarchies that distract antibody responses away from key sites of virus vulnerability. We developed a computational model of affinity maturation to map the patterns of immunodominance that evolve upon immunization with natural and engineered displays of hemagglutinin (HA), the influenza vaccine antigen. Based on this knowledge, we designed immunization protocols that subvert immune distraction and focus serum antibody responses upon a functionally conserved, but normally immunologically recessive, target of human broadly neutralizing antibodies. We tested in silico predictions by vaccinating transgenic mice in which antibody diversity was humanized to mirror clinically relevant humoral output. Collectively, our results demonstrate that complex patterns in antibody immunogenicity can be rationally defined and then manipulated to elicit engineered immunity.

Keywords: Antibody targeting, immunodominance, in silico, in vivo, influenza virus, vaccine, germinal center, affinity maturation

Suggested Citation

Amitai, Assaf and Sangesland, Maya and Barnes, Ralston and Rohrer, Daniel and Lonberg, Nils and Lingwood, Daniel and Chakraborty, Arup K., Defining and Manipulating B Cell Immunodominance Hierarchies to Elicit Broadly Neutralizing Antibody Responses Against Influenza Virus. Available at SSRN: https://ssrn.com/abstract=3586996 or http://dx.doi.org/10.2139/ssrn.3586996
This version of the paper has not been formally peer reviewed.

Assaf Amitai

Massachusetts Institute of Technology (MIT) - Department of Chemical Engineering ( email )

77 Massachusetts Avenue, Room 66-350
Cambridge, MA 02139
United States

Maya Sangesland

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Ralston Barnes

Bristol Myers Squibb

Daniel Rohrer

Bristol Myers Squibb

Nils Lonberg

Bristol Myers Squibb

Daniel Lingwood

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Arup K. Chakraborty (Contact Author)

Massachusetts Institute of Technology (MIT) - Department of Chemical Engineering ( email )

77 Massachusetts Avenue, Room 66-350
Cambridge, MA 02139
United States

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