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MEMP - Thesis Defense - Joy E. Louveau

Tuesday, April 10, 2018 -- 2:30 PM

MIT E25-202

A Statistical Mechanics approach to vaccination against HIV

The key process in antibody development is a stochastic process known as affinity maturation (AM) which generates strain-specific antibodies upon immunization by one antigen. A highly mutable virus like HIV evades recognition by these strain-specific antibodies via the emergence of mutant strains within the patient. In some chronically infected patients, antibodies that protect against many HIV strains arise naturally; they are named broadly-neutralizing antibodies (bnAbs). A vaccine that elicits bnAbs could prevent HIV infections. This vaccine is expected to contain several antigens. However, the complex mechanisms by which bnAbs emerge are not well understood. Theoretical models of AM could help identify promising vaccination strategies and shed light on how AM works with several antigens.

I investigated two pathways for breadth evolution. First, motivated by experimental findings that bnAbs have many mutations that may modify the flexibility of the binding region, I examined how flexibility influences breadth. A flexible binding region is expected to enable different conformations and therefore to allow binding to diverse antigens. Towards that goal, I developed a theoretical model of AM which, combined with Molecular Dynamics simulations, suggests that eliciting flexibility-affecting mutations is not essential for the evolution of bnAbs if proper germline B cells are first activated. This is significant as it simplifies the task of immunogen design.

Secondly, I studied how separating the different antigens in time and mutational distance affects breadth and antibody titers. The main observation is that sequentially introducing one antigen per injection yields the greatest breadth and antibody titers.

Thesis Supervisor:
Arup K. Chakraborty, PhD
Robert T. Haslam Professor of Chemical Engineering, Professor of Chemistry, Biological Engineering, and Physics, Founding Director of (IMES) Institute for Medical Engineering and Science, MIT

Thesis Committee Chair:
Mehran Kardar, PhD
Francis Friedman Professor of Physics, MIT

Thesis Reader:
Darrell Irvine, PhD 
Professor of Materials Science and Engineering and Biological Engineering, MIT

Date and Time: 
Tuesday, April 10, 2018 - 2:30pm to 4:30pm

MIT E25-202