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

J. Scott Shaffer, Penny L. Moore, Mehran Kardar, Arup K. Chakraborty

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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.

Original language	English
Pages (from-to)	E7039-E7048
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	45
DOIs	https://doi.org/10.1073/pnas.1614940113
State	Published - 8 Nov 2016
Externally published	Yes

Bibliographical note

Funding Information:
We thank Joy E. Louveau, Jinal N. Bhiman, and Shenshen Wang for helpful discussions. Financial support was provided by the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University. P.L.M. is supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa and the South African Medical Research Council Strategic Health Innovation Partnerships Program.

Funding

We thank Joy E. Louveau, Jinal N. Bhiman, and Shenshen Wang for helpful discussions. Financial support was provided by the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University. P.L.M. is supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa and the South African Medical Research Council Strategic Health Innovation Partnerships Program.

Funders	Funder number
National Research Foundation of South Africa
Ragon Institute of Massachusetts General Hospital
Massachusetts Institute of Technology
Harvard University
South African Medical Research Council
Department of Science and Technology, Government of Kerala

Keywords

Biophysic
Broadly neutralizing antibodies
Evolutionary biology
HIV
Statistical mechanics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.1614940113

Cite this

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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.",

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Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens. / Shaffer, J. Scott; Moore, Penny L.; Kardar, Mehran et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 45, 08.11.2016, p. E7039-E7048.

Research output: Contribution to journal › Article › peer-review

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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