Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

J Scott Shaffer; Penny L Moore; Mehran Kardar; Arup K Chakraborty

doi:10.1073/pnas.1614940113

Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

Proc Natl Acad Sci U S A. 2016 Nov 8;113(45):E7039-E7048. doi: 10.1073/pnas.1614940113. Epub 2016 Oct 24.

Authors

J Scott Shaffer¹, Penny L Moore^{2

3

4}, Mehran Kardar⁵, Arup K Chakraborty^{6

5

7

8

9

10}

Affiliations

¹ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
² Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, 2131, South Africa.
³ Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa.
⁴ Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, 4041, South Africa.
⁵ Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.
⁶ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139; arupc@mit.edu.
⁷ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
⁸ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
⁹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
¹⁰ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02139.

Abstract

Strategies to elicit Abs that can neutralize diverse strains of a highly mutable pathogen are likely to result in a potent vaccine. Broadly neutralizing Abs (bnAbs) against HIV have been isolated from patients, proving that the human immune system can evolve them. Using computer simulations and theory, we study immunization with diverse mixtures of variant antigens (Ags). Our results show that particular choices for the number of variant Ags and the mutational distances separating them maximize the probability of inducing bnAbs. The variant Ags represent potentially conflicting selection forces that can frustrate the Darwinian evolutionary process of affinity maturation. An intermediate level of frustration maximizes the chance of evolving bnAbs. A simple model makes vivid the origin of this principle of optimal frustration. Our results, combined with past studies, suggest that an appropriately chosen permutation of immunization with an optimally designed mixture (using the principles that we describe) and sequential immunization with variant Ags that are separated by relatively large mutational distances may best promote the evolution of bnAbs.

Keywords: HIV; biophysics; broadly neutralizing antibodies; evolutionary biology; statistical mechanics.