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Background SARS-CoV-2 has induced a worldwide pandemic and subsequent non-pharmaceutical interventions (NPIs) to control the spread of the virus. As in many countries, the SARS-CoV-2 pandemic in Germany has led to a consecutive roll-out of different NPIs. As these NPIs have (largely unknown) adverse effects, targeting them precisely and monitoring their effectiveness are essential. We developed a compartmental infection dynamics model with specific features of SARS-CoV-2 that allows daily estimation of a time-varying reproduction number and published this information openly since the beginning of April 2020. Here, we present the transmission dynamics in Germany over time to understand the effect of NPIs and allow adaptive forecasts of the epidemic progression. Methods We used a data-driven estimation of the evolution of the reproduction number for viral spreading in Germany as well as in all its federal states using our model. Using parameter estimates from literature and, alternatively, with parameters derived from a fit to the initial phase of COVID-19 spread in different regions of Italy, the model was optimized to fit data from the Robert Koch Institute. Results The time-varying reproduction number ( R t ) in Germany decreased to <1 in early April 2020, 2–3 weeks after the implementation of NPIs. Partial release of NPIs both nationally and on federal state level correlated with moderate increases in R t until August 2020. Implications of state-specific R t on other states and on national level are characterized. Retrospective evaluation of the model shows excellent agreement with the data and usage of inpatient facilities well within the healthcare limit. While short-term predictions may work for a few weeks, long-term projections are complicated by unpredictable structural changes. Conclusions The estimated fraction of immunized population by August 2020 warns of a renewed outbreak upon release of measures. A low detection rate prolongs the delay reaching a low case incidence number upon release, showing the importance of an effective testing-quarantine strategy. We show that real-time monitoring of transmission dynamics is important to evaluate the extent of the outbreak, short-term projections for the burden on the healthcare system, and their response to policy changes.

A variety of B cell clones seed the germinal centers, where a selection stringency expands the fitter clones to generate higher affinity antibodies. However, recent experiments suggest that germinal centers often retain a diverse set of B cell clones with a range of affinities and concurrently carry out affinity maturation. Amid a tendency to flourish germinal centers with fitter clones, how several B cell clones with differing affinities can be concurrently selected remains poorly understood. Such a permissive selection may allow non-immunodominant clones, which are often rare and of low-affinity, to somatically hypermutate and result in a broad and diverse B cell response. How the constituent elements of germinal centers, their quantity and kinetics may modulate diversity of B cells, has not been addressed well. By implementing a state-of-the-art agent-based model of germinal center, here, we study how these factors impact temporal evolution of B cell clonal diversity and its underlying balance with affinity maturation. While we find that the extent of selection stringency dictates clonal dominance, limited antigen availability on follicular dendritic cells is shown to expedite the loss of diversity of B cells as germinal centers mature. Intriguingly, the emergence of a diverse set of germinal center B cells depends on high affinity founder cells. Our analysis also reveals a substantial number of T follicular helper cells to be essential in balancing affinity maturation with clonal diversity, as a low number of T follicular helper cells impedes affinity maturation and also contracts the scope for a diverse B cell response. Our results have implications for eliciting antibody responses to non-immunodominant specificities of the pathogens by controlling the regulators of the germinal center reaction, thereby pivoting a way for vaccine development to generate broadly protective antibodies.

The selection of high-affinity B cells and the production of high-affinity antibodies are mediated by T follicular helper cells (Tfhs) within germinal centres (GCs). Therein, somatic hypermutation and selection enhance B cell affinity but risk the emergence of self-reactive B cell clones. Despite being outnumbered compared to their helper counterpart, the ablation of T follicular regulatory cells (Tfrs) results in enhanced dissemination of self-reactive antibody-secreting cells (ASCs). The specific mechanisms by which Tfrs exert their regulatory action on self-reactive B cells are largely unknown. We developed computer simulations to investigate how Tfrs regulate either selection or differentiation of B cells to prevent auto-reactivity. We observed that Tfr-induced apoptosis of self-reactive B cells during the selection phase impedes self-reactivity with physiological Tfr numbers, especially when Tfrs can access centrocyte-enriched GC areas. While this aided in selecting non-self-reactive B cells by restraining competition, higher Tfr numbers distracted non-self-reactive B cells from receiving survival signals from Tfhs. Thus, the location and number of Tfrs must be regulated to circumvent such Tfr distraction and avoid disrupting GC evolution. In contrast, when Tfrs regulate differentiation of selected centrocytes by promoting recycling to the dark zone phenotype of self-reactive GC resident pre-plasma cells (GCPCs), higher Tfr numbers were required to impede the circulation of self-reactive ASCs (s–ASCs). On the other hand, Tfr-engagement with GCPCs and subsequent apoptosis of s–ASCs can control self-reactivity with low Tfr numbers, but does not confer selection advantage to non-self-reactive B cells. The simulations predict that to restrict auto-reactivity, natural redemption of self-reactive B cells is insufficient and that Tfrs should increase the mutation probability of self-reactive B cells.

Background During the first wave of COVID-19, hospital and intensive care unit beds got overwhelmed in Italy leading to an increased death burden. Based on data from Italian regions, we disentangled the impact of various factors contributing to the bottleneck situation of healthcare facilities, not well addressed in classical SEIR-like models. A particular emphasis was set on the undetected fraction (dark figure), on the dynamically changing hospital capacity, and on different testing, contact tracing, quarantine strategies. Methods We first estimated the dark figure for different Italian regions. Using parameter estimates from literature and, alternatively, with parameters derived from a fit to the initial phase of COVID-19 spread, the model was optimized to fit data (infected, hospitalized, ICU, dead) published by the Italian Civil Protection. Results We show that testing influenced the infection dynamics by isolation of newly detected cases and subsequent interruption of infection chains. The time-varying reproduction number ( R t ) in high testing regions decreased to <1 earlier compared to the low testing regions. While an early test and isolate (TI) scenario resulted in up to ~31% peak reduction of hospital occupancy, the late TI scenario resulted in an overwhelmed healthcare system. Conclusions An early TI strategy would have decreased the overall hospital usage drastically and, hence, death toll (∼34% reduction in Lombardia) and could have mitigated the lack of healthcare facilities in the course of the pandemic, but it would not have kept the hospitalization amount within the pre-pandemic hospital limit. Plain language summary Italy was heavily affected early in the COVID-19 pandemic, with healthcare facilities becoming overloaded. We use mathematical models to study COVID-19 transmission, and factors contributing to this, on a regional basis in Italy. We show that testing and lockdowns were effective in controlling disease spread. We use regional pre- and post-pandemic hospital/ICU bed occupancy to quantify the impact of the overwhelmed healthcare system upon the number of deaths. We find that increased isolation of cases could have reduced the effect of limited healthcare facilities but would not have kept hospitalizations within the pre-pandemic limit, and an improvement of hospital facilities would still have been required. We show that contact tracing and quarantine without testing could also be efficient strategies when test capacities are limited. Our findings help us to understand how to manage COVID-19 or other disease outbreaks in future. Bandyopadhyay, Schips et al. model the factors contributing to overloading of healthcare facilities during the first COVID-19 wave in Italy. They predict that an early test and isolate intervention could have reduced healthcare usage and death rates but would not have kept hospitalizations within pre-pandemic hospital limits.

Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of the GC reaction presumes that cMyc-dependent positive selection of LZ B cells is a competitive affinity-dependent process; however, this cannot explain the production of GC-derived lower-affinity MBCs or retention of GC B cells with varied affinities. Here, by combining single-cell/bulk RNA sequencing and flow cytometry, we identified and characterized temporally and functionally distinct positively selected cMyc⁺ GC B cell subpopulations. cMyc⁺ LZ B cell subpopulations enriched with either higher- or lower-affinity cells diverged soon after permissive positive selection. The former subpopulation contained PB precursors, whereas the latter comprised less proliferative MBC precursors and future DZ entrants. The overall affinity of future DZ entrants was enhanced in the LZ through preferential proliferation of higher-affinity cells. Concurrently, lower-affinity cells were retained in GCs and protected from apoptosis. These findings redefine positive selection as a dynamic process generating three distinct B cell fates and elucidate how positive selection ensures clonal diversity for broad protection.

BackgroundIn early March 2020, a SARS-CoV-2 outbreak in the ski resort Ischgl in Austria initiated the spread of SARS-CoV-2 throughout Austria and Northern Europe.MethodsBetween April 21st and 27th 2020, a cross-sectional epidemiologic study targeting the full population of Ischgl (n = 1867), of which 79% could be included (n = 1473, incl. 214 children), was performed. For each individual, the study involved a SARS-CoV-2 PCR, antibody testing and structured questionnaires. A mathematical model was used to help understand the influence of the determined seroprevalence on virus transmission.ResultsThe seroprevalence was 42.4% (95% confidence interval (CI) 39.8–44.7). Individuals under 18 showed a significantly lower seroprevalence of 27.1% (95% CI 21.3-33.6) than adults (45%; 95% CI 42.2–47.7; OR of 0.455, 95% CI 0.356–0.682, p < 0.001). Of the seropositive individuals, 83.7% had not been diagnosed to have had SARS-CoV-2 infection previously. The clinical course was generally mild. Over the previous two months, two COVID-19-related deaths had been recorded, corresponding to an infection fatality rate of 0.25% (95% CI 0.03–0.91). Only 8 (0.5 %) individuals were newly diagnosed to be infected with SARS-CoV-2 during this study.ConclusionsIschgl was hit early and hard by SARS-CoV-2 leading to a high local seroprevalence of 42.4%, which was lower in individuals below the age of 18 than in adults. Mathematical modeling suggests that a drastic decline of newly infected individuals in Ischgl by the end of April occurred due to the dual impact from the non-pharmacological interventions and a high immunization of the Ischgl population.Plain Language SummaryThe Austrian ski resort of Ischgl was a major hot-spot of SARS-CoV-2 infection early on in the pandemic. Here, we investigated the number of people that had been previously infected with the virus in Ischgl in April 2020, by measuring antibodies, blood proteins produced in response to the virus, against SARS-CoV-2. We found that these antibodies were present in 42.4% of the individuals tested and that the majority of these infections, which were generally mild, had not been previously detected. Children were less likely to have these antibodies compared to adults. Using mathematical models, we also found that the subsequent decline in SARS-CoV-2 infections was likely caused by a combination of immunity in the population of Ischgl and of non-pharmaceutical interventions. Our findings allow a better understanding of localised outbreaks of SARS-CoV-2 and how these might be controlled in future.

Immunization strategies are central to pathogen control, where efficacy relies on antigen uptake, distribution, persistence, and inflammatory context. We recently demonstrated that dermal lymphatic capillaries regulate antigen presentation in lymph nodes (LN) by restraining fluid and virion transport following vaccinia virus (VACV) infection by skin scarification. Concurrently, a perifollicular, LN lymphangiogenic response encapsulates expanding B cell follicles. Given the important role of antigen transport and uptake on humoral immunity, we tested the hypothesis that lymphatic remodeling in the skin and LNs regulates germinal center (GC)-dependent antibody responses during infection. Using a model of lymphatic-specific VEGFR2 inhibition, we found that inhibiting viral-induced lymphatic remodeling in skin and LNs prompted significant GC expansion but paradoxically decreases protective VACV-specific class-switched antibodies. While the larger GC responses appeared structurally normal, they failed to support a proliferative burst consistent with clonal selection. Mathematical modeling revealed that this disconnect between GC size and function arises from impaired productive T follicular cell interactions in larger GC volumes and consistent with this finding, the optimal GC size was evolutionarily conserved across diverse mammals. Finally, we found that the presence of virus in the LN initiates these changes in GC function, inhibits LN lymphangiogenesis, increases B cell follicle size, and reduces selection efficiency. Therefore, protecting LN lymphatic vessels from virus-induced interferons rescues perifollicular lymphatic growth and follicle size, indicating that LN lymphangiogenesis directly constrains the follicular response. In summary, this study underscores the central role of lymphatic remodeling in compartmentalizing antigen and inflammatory signals to optimize GC fitness and protective antibody responses.

The selection of high-affinity B cells and the production of high-affinity antibodies are mediated by T follicular helper cells (Tfhs) within germinal centres (GCs). Therein, somatic hypermutation and selection enhance B cell affinity but risk the emergence of self-reactive B cell clones. Despite being outnumbered compared to their helper counterpart, the ablation of T follicular regulatory cells (Tfrs) results in enhanced dissemination of self-reactive antibody-secreting cells (ASCs). The specific mechanisms by which Tfrs exert their regulatory action on self-reactive B cells are largely unknown. We developed computer simulations to investigate how Tfrs regulate either selection or differentiation of B cells to prevent auto-reactivity. We observed that Tfr-induced apoptosis of self-reactive B cells during the selection phase impedes self-reactivity with physiological Tfr numbers, especially when Tfrs can access centrocyte-enriched GC areas. While this aided in selecting non-self-reactive B cells by restraining competition, higher Tfr numbers distracted non-self-reactive B cells from receiving survival signals from Tfhs. Thus, the location and number of Tfrs must be regulated to circumvent such Tfr distraction and avoid disrupting GC evolution. In contrast, when Tfrs regulate differentiation of selected centrocytes by promoting recycling to the dark zone phenotype of self-reactive GC resident pre-plasma cells (GCPCs), higher Tfr numbers were required to impede the circulation of self-reactive ASCs (s–ASCs). On the other hand, Tfr-engagement with GCPCs and subsequent apoptosis of s–ASCs can control self-reactivity with low Tfr numbers, but does not confer selection advantage to non-self-reactive B cells. The simulations predict that to restrict auto-reactivity, natural redemption of self-reactive B cells is insufficient and that Tfrs should increase the mutation probability of self-reactive B cells.

A variety of B cell clones seed the germinal centers, where a selection stringency expands the fitter clones to generate higher affinity antibodies. However, recent experiments suggest that germinal centers often retain a diverse set of B cell clones with a range of affinities and concurrently carry out affinity maturation. Amid a tendency to flourish germinal centers with fitter clones, how several B cell clones with differing affinities can be concurrently selected remains poorly understood. Such a permissive selection may allow non-immunodominant clones, which are often rare and of low-affinity, to somatically hypermutate and result in a broad and diverse B cell response. How the constituent elements of germinal centers, their quantity and kinetics may modulate diversity of B cells, has not been addressed well. By implementing a state-of-the-art agent-based model of germinal center, here, we study how these factors impact temporal evolution of B cell clonal diversity and its underlying balance with affinity maturation. While we find that the extent of selection stringency dictates clonal dominance, limited antigen availability on follicular dendritic cells is shown to expedite the loss of diversity of B cells as germinal centers mature. Intriguingly, the emergence of a diverse set of germinal center B cells depends on high affinity founder cells. Our analysis also reveals a substantial number of T follicular helper cells to be essential in balancing affinity maturation with clonal diversity, as a low number of T follicular helper cells impedes affinity maturation and also contracts the scope for a diverse B cell response. Our results have implications for eliciting antibody responses to non-immunodominant specificities of the pathogens by controlling the regulators of the germinal center reaction, thereby pivoting a way for vaccine development to generate broadly protective antibodies. Competing Interest Statement The authors have declared no competing interest.

The Amyloid cascade hypothesis (ACH) for Alzheimer’s disease (AD) is modeled over the whole brain tissue with a set of partial differential equations. Our results show that the amyloid plaque formation is critically dependent on the secretion rate of amyloid β (Aβ), which is proportional to the product of neural density and neural activity. Neural atrophy is similarly related to the secretion rate of Aβ. Due to a heterogeneous distribution of neural density and brain activity throughout the brain, amyloid plaque formation and neural death occurs heterogeneously in the brain. The geometry of the brain and microglia migration in the parenchyma bring more complexity into the system and result in a diverse amyloidosis and dementia pattern of different brain regions. Although the pattern of amyloidosis in the brain cortex from in-silico results is similar to experimental autopsy findings, they mismatch at the central regions of the brain, suggesting that ACH is not able to explain the whole course of AD without considering other factors, such as tau-protein aggregation or neuroinflammation.