A Minimal Framework for Optimizing Vaccination Protocols Targeting Highly Mutable Pathogens.

A persistent public health challenge is finding immunization schemes that are effective in combating highly mutable pathogens such as HIV and influenza viruses. To address this, we analyze a simplified model of affinity maturation, the Darwinian evolutionary process B cells undergo during immunization. The vaccination protocol dictates selection forces that steer affinity maturation to generate antibodies. We focus on determining the optimal selection forces exerted by a generic time-dependent vaccination protocol to maximize production of broadly neutralizing antibodies (bnAbs) that can protect against a broad spectrum of pathogen strains. The model lends itself to a path integral representation and operator approximations within a mean-field limit, providing guiding principles for optimizing time-dependent vaccine-induced selection forces to enhance bnAb generation. We compare our analytical mean-field results with the outcomes of stochastic simulations and discuss their similarities and differences.

Coordinated head direction representations in mouse anterodorsal thalamic nucleus and retrosplenial cortex.

The sense of direction is critical for survival in changing environments and relies on flexibly integrating self-motion signals with external sensory cues. While the anatomical substrates involved in head direction (HD) coding are well known, the mechanisms by which visual information updates HD representations remain poorly understood. Retrosplenial cortex (RSC) plays a key role in forming coherent representations of space in mammals and it encodes a variety of navigational variables, including HD. Here, we use simultaneous two-area tetrode recording to show that RSC HD representation is nearly synchronous with that of the anterodorsal nucleus of thalamus (ADn), the obligatory thalamic relay of HD to cortex, during rotation of a prominent visual cue. Moreover, coordination of HD representations in the two regions is maintained during darkness. We further show that anatomical and functional connectivity are consistent with a strong feedforward drive of HD information from ADn to RSC, with anatomically restricted corticothalamic feedback. Together, our results indicate a concerted global HD reference update across cortex and thalamus.

Optimizing immunization protocols to elicit broadly neutralizing antibodies.

Natural infections and vaccination with a pathogen typically stimulate the production of potent antibodies specific for the pathogen through a Darwinian evolutionary process known as affinity maturation. Such antibodies provide protection against reinfection by the same strain of a pathogen. A highly mutable virus, like HIV or influenza, evades recognition by these strain-specific antibodies via the emergence of new mutant strains. A vaccine that elicits antibodies that can bind to many diverse strains of the virus-known as broadly neutralizing antibodies (bnAbs)-could protect against highly mutable pathogens. Despite much work, the mechanisms by which bnAbs emerge remain uncertain. Using a computational model of affinity maturation, we studied a wide variety of vaccination strategies. Our results suggest that an effective strategy to maximize bnAb evolution is through a sequential immunization protocol, wherein each new immunization optimally increases the pressure on the immune system to target conserved antigenic sites, thus conferring breadth. We describe the mechanisms underlying why sequentially driving the immune system increasingly further from steady state, in an optimal fashion, is effective. The optimal protocol allows many evolving B cells to become bnAbs via diverse evolutionary paths.