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

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.HIV | broadly neutralizing antibodies | statistical mechanics | evolutionary biology | biophysics

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers

“…Several studies suggest that sequential delivery of a mix of Env immunogens may be preferable over a repeated cocktail immunization for the elicitation of bNAb responses [141, 142]. This contrasts by GC modeling studies [143] and with findings from studies of elite neutralizers, where a burst of viral diversity typically precedes acquisition of breadth [47, 58, 59]. Furthermore, the association of bNAbs with slower viral escape, and the existence of antibody “dead-ends”, suggests that too much variation between prime and boost Envs may terminate a nascent lineage.…”

Humanized Immunoglobulin Mice

“…Additionally, while the sequential boosting approaches for driving breadth are gaining traction in the field based on the rationale discussed above, it will also be key to comparatively evaluate related but distinct boosting approaches proposed for recapitulating diversity, such as concepts that “incremental” boosting, where Env diversity is gradually increased, or “swarm” boosting, where a cocktail of co-evolved Envs in a bnAb maturation pathway (or even more generally, from multiple donors, representative of the natural viral diversity seen in several similar lineages) are administered simultaneously (Haynes et al, 2016). The assertion that sequential boosting may be superior (relative to additive or swarm boosting approaches) in guiding bnAb maturation towards breadth is supported by recent bioinformatic modeling studies (Shaffer et al, 2016; Wang et al, 2015). However, it could also be theoretically argued that the antigenic diversity swarm/additive approaches confer is beneficial, rooted on notions extrapolated from both the above viral-Ab co-evolution studies and central tenets of B-cell affinity maturation studies, namely that: i) activating B-cells of varying affinities in an oligoclonal family may increase the pool to generate high-affinity memory B-cells, and ii) HIV-1 quasi-species continuously evolve during infection, and as such Env variants may not be generated in a perfectly sequential manner, but as overlapping pools of related Envs.…”

Calculating germinal centre reactions

“…Several GCs in parallel [24,30,35] Several consecutive exposures [24,35] Spatially resolved GC [33,34,42] Shape space sequence [33,34,50] Co-evolving epitopes [49] Binary sequence [35,49] Sequence-free [40,41,48,52,54] Seeding by memory B cells [24,35] Stochastic differential equations [49] ODE-based simulation [41,48,54] Agent-based simulation [24,33,34,35,50,40] Class-switching [54] Molecular detail of T-B interaction [33,34] Full AA alphabet sequence [24,43] Role for plasma B cells [49,54,30] Treatment of Ab CDR and FWR regions [24,52] Rugged fitness landscape [30] Several epitopes simultaneously [30,35,48,50,53] Role for memory B cells [35,24] ...…”

“…Here, the fixation probability of broadly binding lineages has been reported to exceed that of antibodies with higher specificity [49]. The optimal immune cocktail for eliciting broadly binding antibodies has been suggested to contain 6-8 antigen variants separated by 3-10 mutations [50]. However, others have argued that separating conflicting selection forces in time by sequential administration of variant antigens leads to more robust emergence of broadly binding antibodies [28,35].…”