Mechanisms that promote the evolution of cross-reactive antibodies upon vaccination with designed influenza immunogens.

Immunogens that elicit broadly neutralizing antibodies targeting the conserved receptor-binding site (RBS) on influenza hemagglutinin may serve as candidates for a universal influenza vaccine. Here, we develop a computational model to interrogate antibody evolution by affinity maturation after immunization with two types of immunogens: a heterotrimeric "chimera" hemagglutinin that is enriched for the RBS epitope relative to other B cell epitopes and a cocktail composed of three non-epitope-enriched homotrimers of the monomers that comprise the chimera. Experiments in mice find that the chimera outperforms the cocktail for eliciting RBS-directed antibodies. We show that this result follows from an interplay between how B cells engage these antigens and interact with diverse helper T cells and requires T cell-mediated selection of germinal center B cells to be a stringent constraint. Our results shed light on antibody evolution and highlight how immunogen design and T cells modulate vaccination outcomes.

Antigen presentation dynamics shape the antibody response to variants like SARS-CoV-2 Omicron after multiple vaccinations with the original strain.

The Omicron variant of SARS-CoV-2 is not effectively neutralized by most antibodies elicited by two doses of mRNA vaccines, but a third dose increases anti-Omicron neutralizing antibodies. We reveal mechanisms underlying this observation by combining computational modeling with data from vaccinated humans. After the first dose, limited antigen availability in germinal centers (GCs) results in a response dominated by B cells that target immunodominant epitopes that are mutated in an Omicron-like variant. After the second dose, these memory cells expand and differentiate into plasma cells that secrete antibodies that are thus ineffective for such variants. However, these pre-existing antigen-specific antibodies transport antigen efficiently to secondary GCs. They also partially mask immunodominant epitopes. Enhanced antigen availability and epitope masking in secondary GCs together result in generation of memory B cells that target subdominant epitopes that are less mutated in Omicron. The third dose expands these cells and boosts anti-variant neutralizing antibodies.

Two-dose "extended priming" immunization amplifies humoral immune responses by synchronizing vaccine delivery with the germinal center response.

"Extended priming" immunization regimens that prolong exposure of the immune system to vaccines during the primary immune response have shown promise in enhancing humoral immune responses to a variety of subunit vaccines in preclinical models. We previously showed that escalating-dosing immunization (EDI), where a vaccine is dosed every other day in an increasing pattern over 2 weeks dramatically amplifies humoral immune responses. But such a dosing regimen is impractical for prophylactic vaccines. We hypothesized that simpler dosing regimens might replicate key elements of the immune response triggered by EDI. Here we explored "reduced ED" immunization regimens, assessing the impact of varying the number of injections, dose levels, and dosing intervals during EDI. Using a stabilized HIV Env trimer as a model antigen combined with a potent saponin adjuvant, we found that a two-shot extended-prime regimen consisting of immunization with 20% of a given vaccine dose followed by a second shot with the remaining 80% of the dose 7 days later resulted in increased total GC B cells, 5-10-fold increased frequencies of antigen-specific GC B cells, and 10-fold increases in serum antibody titers compared to single bolus immunization. Computational modeling of the GC response suggested that this enhanced response is mediated by antigen delivered in the second dose being captured more efficiently as immune complexes in follicles, predictions we verified experimentally. Our computational and experimental results also highlight how properly designed reduced ED protocols enhance activation and antigen loading of dendritic cells and activation of T helper cells to amplify humoral responses. These results suggest that a two-shot priming approach can be used to substantially enhance responses to subunit vaccines.

Antigen presentation dynamics shape the response to emergent variants like SARS-CoV-2 Omicron strain after multiple vaccinations with wild type strain.

The Omicron variant of SARS-CoV-2 evades neutralization by most serum antibodies elicited by two doses of mRNA vaccines, but a third dose of the same vaccine increases anti-Omicron neutralizing antibodies. By combining computational modeling with data from vaccinated humans we reveal mechanisms underlying this observation. After the first dose, limited antigen availability in germinal centers results in a response dominated by B cells with high germline affinities for immunodominant epitopes that are significantly mutated in an Omicron-like variant. After the second dose, expansion of these memory cells and differentiation into plasma cells shape antibody responses that are thus ineffective for such variants. However, in secondary germinal centers, pre-existing higher affinity antibodies mediate enhanced antigen presentation and they can also partially mask dominant epitopes. These effects generate memory B cells that target subdominant epitopes that are less mutated in Omicron. The third dose expands these cells and boosts anti-variant neutralizing antibodies.

Insights into the Ring-Opening of Biomass-Derived Furanics over Carbon-Supported Ruthenium.

The selective ring-opening of cellulose-derived furanic molecules is a promising pathway for the production of industrially relevant linear oxygenates, such as 1,6-hexanediol. 2,5-Dimethylfuran (DMF) is employed as a model compound in a combined experimental and computational investigation to provide insights into the metal-catalyzed ring-opening. Ring-opening to 2-hexanol and 2-hexanone and ring-saturation to 2,5-dimethyltetrahydrofuran (DMTHF) are identified as two main parallel pathways. DFT calculations and microkinetic modeling indicate that DMF adsorbs on Ru in an open-ring configuration, which is potentially a common surface intermediate that leads to both ring-opening and ring-saturation products. Although the activation barriers for the two pathways are comparable, the formation of DMTHF is more thermodynamically favorable. In addition, steric interactions with co-adsorbed 2-propoxyl, derived from the solvent, and the oxophilic nature of Ru play key roles to determine the product distribution: the former favors less bulky, that is, ring-closed, intermediates, and the latter retards O-H bond formation. Finally, we show that the hydrodeoxygenation of oxygenated furanics, such as 5-methylfurfural and (5-methyl-2-furyl)methanol, on Ru occurs preferentially at oxygen-containing side groups to form DMF, followed by either ring-opening or ring-saturation.