Modeling the impacts of antiviral prophylaxis strategies in mitigating seasonal influenza outbreaks in nursing homes.

BACKGROUND: Antiviral chemoprophylaxis is recommended for use during influenza outbreaks in nursing homes to prevent transmission and severe disease among non-ill residents. Centers for Disease Control and Prevention (CDC) guidance recommends prophylaxis be initiated for all non-ill residents once an influenza outbreak is detected and be continued for at least 14 days and until seven days after the last laboratory-confirmed influenza case is identified. However, not all facilities strictly adhere to this guidance and the impact of such partial adherence is not fully understood. METHODS: We developed a stochastic compartmental framework to model influenza transmission within an average-sized U.S. nursing home. We compared the number of symptomatic illnesses and hospitalizations under varying prophylaxis implementation strategies, in addition to different levels of prophylaxis uptake and adherence by residents and healthcare personnel (HCP). RESULTS: Prophylaxis implemented according to current guidance reduced total symptomatic illnesses and hospitalizations among residents by an average of 12% and 36%, respectively, compared with no prophylaxis. We did not find evidence that alternative implementations of prophylaxis were more effective: compared to full adoption of current guidance, partial adoption resulted in increased symptomatic illnesses and/or hospitalizations, and longer or earlier adoption offered no additional improvements. In addition, increasing uptake and adherence among nursing home residents was effective in reducing resident illnesses and hospitalizations, but increasing HCP uptake had minimal indirect impacts for residents. CONCLUSIONS: The greatest benefits of influenza prophylaxis during nursing home outbreaks will likely be achieved through increasing uptake and adherence among residents and following current CDC guidance.

The role of asymptomatic infections in influenza transmission: what do we really know.

Before the COVID-19 pandemic, the role of asymptomatic influenza virus infections in influenza transmission was uncertain. However, the importance of asymptomatic infection with SARS-CoV-2 for onward transmission of COVID-19 has led experts to question whether the role of asymptomatic influenza virus infections in transmission had been underappreciated. We discuss the existing evidence on the frequency of asymptomatic influenza virus infections, the extent to which they contribute to infection transmission, and remaining knowledge gaps. We propose priority areas for further evaluation, study designs, and case definitions to address existing knowledge gaps.

Medium-term scenarios of COVID-19 as a function of immune uncertainties and chronic disease.

As the SARS-CoV-2 trajectory continues, the longer-term immuno-epidemiology of COVID-19, the dynamics of Long COVID, and the impact of escape variants are important outstanding questions. We examine these remaining uncertainties with a simple modelling framework that accounts for multiple (antigenic) exposures via infection or vaccination. If immunity (to infection or Long COVID) accumulates rapidly with the valency of exposure, we find that infection levels and the burden of Long COVID are markedly reduced in the medium term. More pessimistic assumptions on host adaptive immune responses illustrate that the longer-term burden of COVID-19 may be elevated for years to come. However, we also find that these outcomes could be mitigated by the eventual introduction of a vaccine eliciting robust (i.e. durable, transmission-blocking and/or 'evolution-proof') immunity. Overall, our work stresses the wide range of future scenarios that still remain, the importance of collecting real-world epidemiological data to identify likely outcomes, and the crucial need for the development of a highly effective transmission-blocking, durable and broadly protective vaccine.

Evaluating Potential Impacts of a Preferential Vaccine Recommendation for Adults 65 Years of Age and Older on US Influenza Burden.

BACKGROUND: High-dose, adjuvanted, and recombinant influenza vaccines may offer improved effectiveness among older adults compared with standard-dose, unadjuvanted, inactivated vaccines. However, the Advisory Committee on Immunization Practices (ACIP) only recently recommended preferential use of these "higher-dose or adjuvanted" vaccines. One concern was that individuals might delay or decline vaccination if a preferred vaccine is not readily available. METHODS: We mathematically model how a recommendation for preferential use of higher-dose or adjuvanted vaccines in adults ≥65 years might impact influenza burden in the United States during exemplar "high-" and "low-"severity seasons. We assume higher-dose or adjuvanted vaccines are more effective than standard vaccines and that such a recommendation would increase uptake of the former but could cause (i) delays in administration of additional higher-dose or adjuvanted vaccines relative to standard vaccines and/or (ii) reductions in overall coverage if individuals only offered standard vaccines forego vaccination. RESULTS: In a best-case scenario, assuming no delay or coverage reduction, a new recommendation could decrease hospitalizations and deaths in adults ≥65 years by 0%-4% compared with current uptake. However, intermediate and worst-case scenarios, with assumed delays of 3 or 6 weeks and/or 10% or 20% reductions in coverage, included projections in which hospitalizations and deaths increased by over 7%. CONCLUSIONS: We estimate that increased use of higher-dose or adjuvanted vaccines could decrease influenza burden in adults ≥65 in the United States provided there is timely and adequate access to these vaccines, and that standard vaccines are administered when they are unavailable.

Healthy dynamics of CD4 T cells may drive HIV resurgence in perinatally-infected infants on antiretroviral therapy.

In 2019 there were 490,000 children under five living with HIV. Understanding the dynamics of HIV suppression and rebound in this age group is crucial to optimizing treatment strategies and increasing the likelihood of infants achieving and sustaining viral suppression. Here we studied data from a cohort of 122 perinatally-infected infants who initiated antiretroviral treatment (ART) early after birth and were followed for up to four years. These data included longitudinal measurements of viral load (VL) and CD4 T cell numbers, together with information regarding treatment adherence. We previously showed that the dynamics of HIV decline in 53 of these infants who suppressed VL within one year were similar to those in adults. However, in extending our analysis to all 122 infants, we find that a deterministic model of HIV infection in adults cannot explain the full diversity in infant trajectories. We therefore adapt this model to include imperfect ART adherence and natural CD4 T cell decline and reconstitution processes in infants. We find that individual variation in both processes must be included to obtain the best fits. We also find that infants with faster rates of CD4 reconstitution on ART were more likely to experience resurgences in VL. Overall, our findings highlight the importance of combining mathematical modeling with clinical data to disentangle the role of natural immune processes and viral dynamics during HIV infection.

Vaccine nationalism and the dynamics and control of SARS-CoV-2.

Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to exert globally, yet vaccine distribution remains unequal among countries. To examine the potential epidemiological and evolutionary impacts of "vaccine nationalism," we extend previous models to include simple scenarios of stockpiling between two regions. In general, when vaccines are widely available and the immunity they confer is robust, sharing doses minimizes total cases across regions. A number of subtleties arise when the populations and transmission rates in each region differ, depending on evolutionary assumptions and vaccine availability. When the waning of natural immunity contributes most to evolutionary potential, sustained transmission in low-access regions results in an increased potential for antigenic evolution, which may result in the emergence of novel variants that affect epidemiological characteristics globally. Overall, our results stress the importance of rapid, equitable vaccine distribution for global control of the pandemic.

Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19.

Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.

Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes.

Given vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two critical issues arise: How timing of delivery of the second dose will affect infection dynamics and how it will affect prospects for the evolution of viral immune escape via a buildup of partially immune individuals. Both hinge on the robustness of the immune response elicited by a single dose as compared with natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short term, focusing on one dose generally decreases infections, but that longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection and find that a one-dose policy may increase the potential for antigenic evolution under certain conditions of partial population immunity. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose and to ramp up vaccination efforts globally.

Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes.

As the threat of Covid-19 continues and in the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels. How timing of delivery of the second dose affects infection burden but also prospects for the evolution of viral immune escape are critical questions. Both hinge on the strength and duration (i.e. robustness) of the immune response elicited by a single dose, compared to natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short-term, focusing on one dose generally decreases infections, but longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection, evaluating how different second dose delays might drive immune escape via a build-up of partially immune individuals. Under certain scenarios, we find that a one-dose policy may increase the potential for antigenic evolution. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose, and to ramp up vaccination efforts throughout the world.

Analysis of respiratory and systemic immune responses in COVID-19 reveals mechanisms of disease pathogenesis.

Immune responses to respiratory viruses like SARS-CoV-2 originate and function in the lung, yet assessments of human immunity are often limited to blood. Here, we conducted longitudinal, high-dimensional profiling of paired airway and blood samples from patients with severe COVID-19, revealing immune processes in the respiratory tract linked to disease pathogenesis. Survival from severe disease was associated with increased CD4 + T cells and decreased monocyte/macrophage frequencies in the airway, but not in blood. Airway T cells and macrophages exhibited tissue-resident phenotypes and activation signatures, including high level expression and secretion of monocyte chemoattractants CCL2 and CCL3 by airway macrophages. By contrast, monocytes in blood expressed the CCL2-receptor CCR2 and aberrant CD163 + and immature phenotypes. Extensive accumulation of CD163 + monocyte/macrophages within alveolar spaces in COVID-19 lung autopsies suggested recruitment from circulation. Our findings provide evidence that COVID-19 pathogenesis is driven by respiratory immunity, and rationale for site-specific treatment and prevention strategies.

Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years.

The future trajectory of the coronavirus disease 2019 (COVID-19) pandemic hinges on the dynamics of adaptive immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, salient features of the immune response elicited by natural infection or vaccination are still uncertain. We use simple epidemiological models to explore estimates for the magnitude and timing of future COVID-19 cases, given different assumptions regarding the protective efficacy and duration of the adaptive immune response to SARS-CoV-2, as well as its interaction with vaccines and nonpharmaceutical interventions. We find that variations in the immune response to primary SARS-CoV-2 infections and a potential vaccine can lead to markedly different immune landscapes and burdens of critically severe cases, ranging from sustained epidemics to near elimination. Our findings illustrate likely complexities in future COVID-19 dynamics and highlight the importance of immunological characterization beyond the measurement of active infections for adequately projecting the immune landscape generated by SARS-CoV-2 infections.

Quantifying the Dynamics of HIV Decline in Perinatally Infected Neonates on Antiretroviral Therapy.

BACKGROUND: Mathematical modeling has provided important insights into HIV infection dynamics in adults undergoing antiretroviral treatment (ART). However, much less is known about the corresponding dynamics in perinatally infected neonates initiating early ART. SETTING: From 2014 to 2017, HIV viral load (VL) was monitored in 122 perinatally infected infants identified at birth and initiating ART within a median of 2 days. Pretreatment infant and maternal covariates, including CD4 T cell counts and percentages, were also measured. METHODS: From the initial cohort, 53 infants demonstrated consistent decline and suppressed VL below the detection threshold (20 copies mL) within 1 year. For 43 of these infants with sufficient VL data, we fit a mathematical model describing the loss of short-lived and long-lived infected cells during ART. We then estimated the lifespans of infected cells and the time to viral suppression, and tested for correlations with pretreatment covariates. RESULTS: Most parameters governing the kinetics of VL decline were consistent with those obtained previously from adults and other infants. However, our estimates of the lifespan of short-lived infected cells were longer than published values. This difference may reflect sparse sampling during the early stages of VL decline, when the loss of short-lived cells is most apparent. In addition, infants with higher pretreatment CD4 percentage or lower pretreatment VL trended toward more rapid viral suppression. CONCLUSIONS: HIV dynamics in perinatally infected neonates initiating early ART are broadly similar to those observed in other age groups. Accelerated viral suppression is also associated with higher CD4 percentage and lower VL.

ushr: Understanding suppression of HIV in R.

BACKGROUND: HIV/AIDS is responsible for the deaths of one million people every year. Although mathematical modeling has provided many insights into the dynamics of HIV infection, there is still a lack of accessible tools for researchers unfamiliar with modeling techniques to apply them to their own clinical data. RESULTS: Here we present ushr, a free and open-source R package that models the decline of HIV during antiretroviral treatment (ART) using a popular mathematical framework. ushr can be applied to longitudinal data of viral load measurements, and provides processing tools to prepare it for computational analysis. By mathematically fitting the data, important biological parameters can then be estimated, including the lifespans of short and long-lived infected cells, and the time to reach viral suppression below a defined detection threshold. The package also provides visualization and summary tools for fast assessment of model results. CONCLUSIONS: ushr enables researchers without a strong mathematical or computational background to model the dynamics of HIV using longitudinal clinical data. Increasing accessibility to such methods may facilitate quantitative analysis across a broader range of independent studies, so that greater insights on HIV infection and treatment dynamics may be gained.

Tissue-Resident Memory T Cells in Mice and Humans: Towards a Quantitative Ecology.

In recent years, tissue-resident memory T cells (TRM) have emerged as essential components of immunological memory. Following antigenic challenge, TRM remain in nonlymphoid tissues and defend against re-exposure. Although accumulating evidence suggests important roles for TRM in mediating protective immunity, fundamental aspects of the population biology of TRM remain poorly understood. In this article, we discuss how results from different systems shed light on the ecological dynamics of TRM in mice and humans. We highlight the importance of dissecting processes contributing to TRM maintenance, and how these might vary across phenotypically and spatially heterogeneous subsets. We also discuss how the diversity of TRM communities within specific tissues may evolve under competition and in response to antigenic perturbation. Throughout, we illustrate how mathematical models can clarify inferences obtained from experimental data and help elucidate the homeostatic mechanisms underpinning the ecology of TRM populations.

Modeling the measles paradox reveals the importance of cellular immunity in regulating viral clearance.

Measles virus (MV) is a highly contagious member of the Morbillivirus genus that remains a major cause of childhood mortality worldwide. Although infection induces a strong MV-specific immune response that clears viral load and confers lifelong immunity, transient immunosuppression can also occur, leaving the host vulnerable to colonization from secondary pathogens. This apparent contradiction of viral clearance in the face of immunosuppression underlies what is often referred to as the 'measles paradox', and remains poorly understood. To explore the mechanistic basis underlying the measles paradox, and identify key factors driving viral clearance, we return to a previously published dataset of MV infection in rhesus macaques. These data include virological and immunological information that enable us to fit a mathematical model describing how the virus interacts with the host immune system. In particular, our model incorporates target cell depletion through infection of host immune cells-a hallmark of MV pathology that has been neglected from previous models. We find the model captures the data well, and that both target cell depletion and immune activation are required to explain the overall dynamics. Furthermore, by simulating conditions of increased target cell availability and suppressed cellular immunity, we show that the latter causes greater increases in viral load and delays to MV clearance. Overall, this signals a more dominant role for cellular immunity in resolving acute MV infection. Interestingly, we find contrasting dynamics dominated by target cell depletion when viral fitness is increased. This may have wider implications for animal morbilliviruses, such as canine distemper virus (CDV), that cause fatal target cell depletion in their natural hosts. To our knowledge this work represents the first fully calibrated within-host model of MV dynamics and, more broadly, provides a new platform from which to explore the complex mechanisms underlying Morbillivirus infection.

Analysis of multi-level spatial data reveals strong synchrony in seasonal influenza epidemics across Norway, Sweden, and Denmark.

Population structure, spatial diffusion, and climatic conditions mediate the spatiotemporal spread of seasonal influenza in temperate regions. However, much of our knowledge of these dynamics stems from a few well-studied countries, such as the United States (US), and the extent to which this applies in different demographic and climatic environments is not fully understood. Using novel data from Norway, Sweden, and Denmark, we applied wavelet analysis and non-parametric spatial statistics to explore the spatiotemporal dynamics of influenza transmission at regional and international scales. We found the timing and amplitude of epidemics were highly synchronized both within and between countries, despite the geographical isolation of many areas in our study. Within Norway, this synchrony was most strongly modulated by population size, confirming previous findings that hierarchical spread between larger populations underlies seasonal influenza dynamics at regional levels. However, we found no such association when comparing across countries, suggesting that other factors become important at the international scale. Finally, to frame our results within a wider global context, we compared our findings from Norway to those from the US. After correcting for differences in geographic scale, we unexpectedly found higher levels of synchrony in Norway, despite its smaller population size. We hypothesize that this greater synchrony may be driven by more favorable and spatially uniform climatic conditions, although there are other likely factors we were unable to consider (such as reduced variation in school term times and differences in population movements). Overall, our results highlight the importance of comparing influenza spread at different spatial scales and across diverse geographic regions in order to better understand the complex mechanisms underlying disease dynamics.

Partially observed epidemics in wildlife hosts: modelling an outbreak of dolphin morbillivirus in the northwestern Atlantic, June 2013-2014.

Morbilliviruses cause major mortality in marine mammals, but the dynamics of transmission and persistence are ill understood compared to terrestrial counterparts such as measles; this is especially true for epidemics in cetaceans. However, the recent outbreak of dolphin morbillivirus in the northwestern Atlantic Ocean can provide new insights into the epidemiology and spatio-temporal spread of this pathogen. To deal with uncertainties surrounding the ecology of this system (only stranded animals were observed), we develop a statistical framework that can extract key information about the underlying transmission process given only sparse data. Our self-exciting Poisson process model suggests that individuals are infectious for at most 24 days and can transfer infection up to two latitude degrees (220 km) within this time. In addition, the effective reproduction number is generally below one, but reaches 2.6 during a period of heightened stranding numbers near Virginia Beach, Virginia, in summer 2013. Network analysis suggests local movements dominate spatial spread, with seasonal migration facilitating wider dissemination along the coast. Finally, a low virus transmission rate or high levels of pre-existing immunity can explain the lack of viral spread into the Gulf of Mexico. More generally, our approach illustrates novel methodologies for analysing very indirectly observed epidemics.

Demographic buffering: titrating the effects of birth rate and imperfect immunity on epidemic dynamics.

Host demography can alter the dynamics of infectious disease. In the case of perfectly immunizing infections, observations of strong sensitivity to demographic variation have been mechanistically explained through analysis of the susceptible-infected-recovered (SIR) model that assumes lifelong immunity following recovery from infection. When imperfect immunity is incorporated into this framework via the susceptible-infected-recovered-susceptible (SIRS) model, with individuals regaining full susceptibility following recovery, we show that rapid loss of immunity is predicted to buffer populations against the effects of demographic change. However, this buffering is contrary to the dependence on demography recently observed for partially immunizing infections such as rotavirus and respiratory syncytial virus. We show that this discrepancy arises from a key simplification embedded in the SIR(S) framework, namely that the potential for differential immune responses to repeat exposures is ignored. We explore the minimum additional immunological information that must be included to reflect the range of observed dependencies on demography. We show that including partial protection and lower transmission following primary infection is sufficient to capture more realistic reduced levels of buffering, in addition to changes in epidemic timing, across a range of partially and fully immunizing infections. Furthermore, our results identify key variables in this relationship, including R0.

Phocine distemper virus: current knowledge and future directions.

Phocine distemper virus (PDV) was first recognized in 1988 following a massive epidemic in harbor and grey seals in north-western Europe. Since then, the epidemiology of infection in North Atlantic and Arctic pinnipeds has been investigated. In the western North Atlantic endemic infection in harp and grey seals predates the European epidemic, with relatively small, localized mortality events occurring primarily in harbor seals. By contrast, PDV seems not to have become established in European harbor seals following the 1988 epidemic and a second event of similar magnitude and extent occurred in 2002. PDV is a distinct species within the Morbillivirus genus with minor sequence variation between outbreaks over time. There is now mounting evidence of PDV-like viruses in the North Pacific/Western Arctic with serological and molecular evidence of infection in pinnipeds and sea otters. However, despite the absence of associated mortality in the region, there is concern that the virus may infect the large Pacific harbor seal and northern elephant seal populations or the endangered Hawaiian monk seals. Here, we review the current state of knowledge on PDV with particular focus on developments in diagnostics, pathogenesis, immune response, vaccine development, phylogenetics and modeling over the past 20 years.