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

Significance The design of vaccination strategies that generate potent Abs directed against diverse strains of highly mutable pathogens, like HIV and malaria, will significantly impact global health. Such Abs are called broadly neutralizing Abs (bnAbs). Abs are produced by a Darwinian evolutionary process called affinity maturation. Induction of bnAbs will likely require vaccination with diverse mutant antigens. How affinity maturation occurs in the presence of multiple diverse antigens is not well-understood, thus hindering rational design of immunization strategies. We study this issue using computer simulations and statistical mechanical theory. Our results provide guides for the rational design of optimal vaccination strategies, and they reveal mechanistic principles at a crossroad of immunology and evolutionary biology. 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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