Induction of durable remission by dual immunotherapy in SHIV-infected ART-suppressed macaques.

The eradication of the viral reservoir represents the major obstacle to the development of a clinical cure for established HIV-1 infection. Here, we demonstrate that the administration of N-803 (brand name Anktiva) and broadly neutralizing antibodies (bNAbs) results in sustained viral control after discontinuation of antiretroviral therapy (ART) in simian-human AD8 (SHIV-AD8)-infected, ART-suppressed rhesus macaques. N-803+bNAbs treatment induced immune activation and transient viremia but only limited reductions in the SHIV reservoir. Upon ART discontinuation, viral rebound occurred in all animals, which was followed by durable control in approximately 70% of all N-803+bNAb-treated macaques. Viral control was correlated with the reprogramming of CD8+ T cells by N-803+bNAb synergy. Thus, complete eradication of the replication-competent viral reservoir is likely not a prerequisite for the induction of sustained remission after discontinuation of ART.

Estimation of introduction and transmission rates of SARS-CoV-2 in a prospective household study.

Household studies provide an efficient means to study transmission of infectious diseases, enabling estimation of susceptibility and infectivity by person-type. A main inclusion criterion in such studies is usually the presence of an infected person. This precludes estimation of the hazards of pathogen introduction into the household. Here we estimate age- and time-dependent household introduction hazards together with within household transmission rates using data from a prospective household-based study in the Netherlands. A total of 307 households containing 1,209 persons were included from August 2020 until March 2021. Follow-up of households took place between August 2020 and August 2021 with maximal follow-up per household mostly limited to 161 days. Almost 1 out of 5 households (59/307) had evidence of an introduction of SARS-CoV-2. We estimate introduction hazards and within-household transmission rates in our study population with penalized splines and stochastic epidemic models, respectively. The estimated hazard of introduction of SARS-CoV-2 in the households was lower for children (0-12 years) than for adults (relative hazard: 0.62; 95%CrI: 0.34-1.0). Estimated introduction hazards peaked in mid October 2020, mid December 2020, and mid April 2021, preceding peaks in hospital admissions by 1-2 weeks. Best fitting transmission models included increased infectivity of children relative to adults and adolescents, such that the estimated child-to-child transmission probability (0.62; 95%CrI: 0.40-0.81) was considerably higher than the adult-to-adult transmission probability (0.12; 95%CrI: 0.057-0.19). Scenario analyses indicate that vaccination of adults can strongly reduce household infection attack rates and that adding adolescent vaccination offers limited added benefit.

Estimation of introduction and transmission rates of SARS-CoV-2 in a prospective household study.

Household studies provide an efficient means to study transmission of infectious diseases, enabling estimation of individual susceptibility and infectivity. A main inclusion criterion in such studies is often the presence of an infected person. This precludes estimation of the hazards of pathogen introduction into the household. Here we use data from a prospective household-based study to estimate SARS-CoV-2 age- and time-dependent household introduction hazards together with within household transmission rates in the Netherlands from August 2020 to August 2021. Introduction hazards and within-household transmission rates are estimated with penalized splines and stochastic epidemic models, respectively. The estimated hazard of introduction of SARS-CoV-2 in the households was lower for children (0-12 years) than for adults (relative hazard: 0.62; 95%CrI: 0.34-1.0). Estimated introduction hazards peaked in mid October 2020, mid December 2020, and mid April 2021, preceding peaks in hospital admissions by 1-2 weeks. The best fitting transmission models include increased infectivity of children relative to adults and adolescents, such that the estimated child-to-child transmission probability (0.62; 95%CrI: 0.40-0.81) was considerably higher than the adult-to-adult transmission probability (0.12; 95%CrI: 0.057-0.19). Scenario analyses show that vaccination of adults could have strongly reduced infection attack rates in households and that adding adolescent vaccination would have offered limited added benefit.

Global estimates of the fitness advantage of SARS-CoV-2 variant Omicron.

New variants of SARS-CoV-2 show remarkable heterogeneity in their relative fitness over both time and space. In this paper we extend the tools available for estimating the selection strength for new SARS-CoV-2 variants to a hierarchical, mixed-effects, renewal equation model. This formulation allows us to estimate selection effects at the global level while incorporating both measured and unmeasured heterogeneity among countries. Applying this model to the spread of Omicron in forty countries, we find evidence for very strong but very heterogeneous selection effects. To test whether this heterogeneity is explained by differences in the immune landscape, we considered several measures of vaccination rates and recent population-level infection as covariates, finding moderately strong, statistically significant effects. We also found a significant positive correlation between the selection advantage of Delta and Omicron at the country level, suggesting that other region-specific explanatory variables of fitness differences do exist. Our method is implemented in the Stan programming language, can be run on standard consumer-grade computing resources, and will be straightforward to apply to future variants.

Global estimates of the fitness advantage of SARS-CoV-2 variant Omicron.

New variants of SARS-CoV-2 show remarkable heterogeneity in their relative fitness both over time and space. In this paper we extend a previously published model for estimating the selection strength for new SARS-CoV-2 variants to a hierarchical, mixed-effects, renewal equation model. This formulation allows us to globally estimate selection effects at different spatial levels while controlling for complex patterns of transmission and jointly inferring the effects of unit-level covariates in the spatial heterogeneity of SARS-CoV-2 selection effects. Applying this model to the spread of Omicron in 40 counties finding evidence for very strong (64%) but very heterogeneous selection effects at the country level. We further considered different measures of vaccination levels and measures of recent population-level infection as possible explanations. However, none of those variables were found to explain a significant proportion of the heterogeneity in country-level selection effects. We did find a significant positive correlation between the selection advantage of Delta and Omicron at the country level, suggesting that region-specific explanatory variables of fitness differences do exist. Our method is implemented in the Stan programming language, can be run on standard commercial-grade computing resources, and should be straightforward to apply to future variants.

Numerical methods and hypoexponential approximations for gamma distributed delay differential equations.

Gamma distributed delay differential equations (DDEs) arise naturally in many modelling applications. However, appropriate numerical methods for generic gamma distributed DDEs have not previously been implemented. Modellers have therefore resorted to approximating the gamma distribution with an Erlang distribution and using the linear chain technique to derive an equivalent system of ordinary differential equations (ODEs). In this work, we address the lack of appropriate numerical tools for gamma distributed DDEs in two ways. First, we develop a functional continuous Runge-Kutta (FCRK) method to numerically integrate the gamma distributed DDE without resorting to Erlang approximation. We prove the fourth-order convergence of the FCRK method and perform numerical tests to demonstrate the accuracy of the new numerical method. Nevertheless, FCRK methods for infinite delay DDEs are not widely available in existing scientific software packages. As an alternative approach to solving gamma distributed DDEs, we also derive a hypoexponential approximation of the gamma distributed DDE. This hypoexponential approach is a more accurate approximation of the true gamma distributed DDE than the common Erlang approximation but, like the Erlang approximation, can be formulated as a system of ODEs and solved numerically using standard ODE software. Using our FCRK method to provide reference solutions, we show that the common Erlang approximation may produce solutions that are qualitatively different from the underlying gamma distributed DDE. However, the proposed hypoexponential approximations do not have this limitation. Finally, we apply our hypoexponential approximations to perform statistical inference on synthetic epidemiological data to illustrate the utility of the hypoexponential approximation.

Controlling the pandemic during the SARS-CoV-2 vaccination rollout.

There is a consensus that mass vaccination against SARS-CoV-2 will ultimately end the COVID-19 pandemic. However, it is not clear when and which control measures can be relaxed during the rollout of vaccination programmes. We investigate relaxation scenarios using an age-structured transmission model that has been fitted to age-specific seroprevalence data, hospital admissions, and projected vaccination coverage for Portugal. Our analyses suggest that the pressing need to restart socioeconomic activities could lead to new pandemic waves, and that substantial control efforts prove necessary throughout 2021. Using knowledge on control measures introduced in 2020, we anticipate that relaxing measures completely or to the extent as in autumn 2020 could launch a wave starting in April 2021. Additional waves could be prevented altogether if measures are relaxed as in summer 2020 or in a step-wise manner throughout 2021. We discuss at which point the control of COVID-19 would be achieved for each scenario.

A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies.

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This "participant-derived xenograft" model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.

Estimating the strength of selection for new SARS-CoV-2 variants.

Controlling the SARS-CoV-2 pandemic becomes increasingly challenging as the virus adapts to human hosts through the continual emergence of more transmissible variants. Simply observing that a variant is increasing in frequency is relatively straightforward, but more sophisticated methodology is needed to determine whether a new variant is a global threat and the magnitude of its selective advantage. We present three methods for quantifying the strength of selection for new and emerging variants of SARS-CoV-2 relative to the background of contemporaneous variants. These methods range from a detailed model of dynamics within one country to a broad analysis across all countries, and they include alternative explanations such as migration and drift. We find evidence for strong selection favoring the D614G spike mutation and B.1.1.7 (Alpha), weaker selection favoring B.1.351 (Beta), and no advantage of R.1 after it spreads beyond Japan. Cutting back data to earlier time horizons reveals large uncertainty very soon after emergence, but that estimates of selection stabilize after several weeks. Our results also show substantial heterogeneity among countries, demonstrating the need for a truly global perspective on the molecular epidemiology of SARS-CoV-2.

Model-based evaluation of school- and non-school-related measures to control the COVID-19 pandemic.

The role of school-based contacts in the epidemiology of SARS-CoV-2 is incompletely understood. We use an age-structured transmission model fitted to age-specific seroprevalence and hospital admission data to assess the effects of school-based measures at different time points during the COVID-19 pandemic in the Netherlands. Our analyses suggest that the impact of measures reducing school-based contacts depends on the remaining opportunities to reduce non-school-based contacts. If opportunities to reduce the effective reproduction number (Re) with non-school-based measures are exhausted or undesired and Re is still close to 1, the additional benefit of school-based measures may be considerable, particularly among older school children. As two examples, we demonstrate that keeping schools closed after the summer holidays in 2020, in the absence of other measures, would not have prevented the second pandemic wave in autumn 2020 but closing schools in November 2020 could have reduced Re below 1, with unchanged non-school-based contacts.

Models of SIV rebound after treatment interruption that involve multiple reactivation events.

In order to assess the efficacy of novel HIV-1 treatments leading to a functional cure, the time to viral rebound is frequently used as a surrogate endpoint. The longer the time to viral rebound, the more efficacious the therapy. In support of such an approach, mathematical models serve as a connection between the size of the latent reservoir and the time to HIV-1 rebound after treatment interruption. The simplest of such models assumes that a single successful latent cell reactivation event leads to observable viremia after a period of exponential viral growth. Here we consider a generalization developed by Pinkevych et al. and Hill et al. of this simple model in which multiple reactivation events can occur, each contributing to the exponential growth of the viral load. We formalize and improve the previous derivation of the dynamics predicted by this model, and use the model to estimate relevant biological parameters from SIV rebound data. We confirm a previously described effect of very early antiretroviral therapy (ART) initiation on the rate of recrudescence and the viral load growth rate after treatment interruption. We find that every day ART initiation is delayed results in a 39% increase in the recrudescence rate (95% credible interval: [18%, 62%]), and a 11% decrease of the viral growth rate (95% credible interval: [4%, 20%]). We show that when viral rebound occurs early relative to the viral load doubling time, a model with multiple successful reactivation events fits the data better than a model with only a single successful reactivation event.

Estimating Transmission Parameters for Respiratory Syncytial Virus and Predicting the Impact of Maternal and Pediatric Vaccination.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract illness in young children and a major cause of hospital admissions globally. METHODS: Here we fit age-structured transmission models with immunity propagation to data from the Netherlands (2012-2017). Data included nationwide hospitalizations with confirmed RSV, general practitioner (GP) data on attendance for care from acute respiratory infection, and virological testing of acute respiratory infections at the GP. The transmission models, equipped with key parameter estimates, were used to predict the impact of maternal and pediatric vaccination. RESULTS: Estimates of the basic reproduction number were generally high (R0 > 10 in scenarios with high statistical support), while susceptibility was estimated to be low in nonelderly adults (<10% in persons 20-64 years) and was higher in older adults (≥65 years). Scenario analyses predicted that maternal vaccination reduces the incidence of infection in vulnerable infants (<1 year) and shifts the age of first infection from infants to young children. CONCLUSIONS: Pediatric vaccination is expected to reduce the incidence of infection in infants and young children (0-5 years), slightly increase incidence in 5 to 9-year-old children, and have minor indirect benefits.

Infectious reactivation of cytomegalovirus explaining age- and sex-specific patterns of seroprevalence.

Human cytomegalovirus (CMV) is a herpes virus with poorly understood transmission dynamics. Person-to-person transmission is thought to occur primarily through transfer of saliva or urine, but no quantitative estimates are available for the contribution of different infection routes. Using data from a large population-based serological study (n = 5,179), we provide quantitative estimates of key epidemiological parameters, including the transmissibility of primary infection, reactivation, and re-infection. Mixture models are fitted to age- and sex-specific antibody response data from the Netherlands, showing that the data can be described by a model with three distributions of antibody measurements, i.e. uninfected, infected, and infected with increased antibody concentration. Estimates of seroprevalence increase gradually with age, such that at 80 years 73% (95%CrI: 64%-78%) of females and 62% (95%CrI: 55%-68%) of males are infected, while 57% (95%CrI: 47%-67%) of females and 37% (95%CrI: 28%-46%) of males have increased antibody concentration. Merging the statistical analyses with transmission models, we find that models with infectious reactivation (i.e. reactivation that can lead to the virus being transmitted to a novel host) fit the data significantly better than models without infectious reactivation. Estimated reactivation rates increase from low values in children to 2%-4% per year in women older than 50 years. The results advance a hypothesis in which transmission from adults after infectious reactivation is a key driver of transmission. We discuss the implications for control strategies aimed at reducing CMV infection in vulnerable groups.

Long-term adaptation of the influenza A virus by escaping cytotoxic T-cell recognition.

The evolutionary adaptation of the influenza A virus (IAV) to human antibodies is well characterised. Much less is known about the long-term evolution of cytotoxic T lymphocyte (CTL) epitopes, which are important antigens for clearance of infection. We construct an antigenic map of IAVs of all human subtypes using a compendium of 142 confirmed CTL epitopes, and show that IAV evolved gradually in the period 1932-2015, with infrequent antigenic jumps in the H3N2 subtype. Intriguingly, the number of CTL epitopes per virus decreases with more than one epitope per three years in the H3N2 subtype (from 84 epitopes per virus in 1968 to 64 in 2015), mostly attributed to the loss of HLA-B epitopes. We confirm these observations with epitope predictions. Our findings indicate that selection pressures imposed by CTL immunity shape the long-term evolution of IAV.

Immuno-epidemiological modeling of HIV-1 predicts high heritability of the set-point virus load, while selection for CTL escape dominates virulence evolution.

It has been suggested that HIV-1 has evolved its set-point virus load to be optimized for transmission. Previous epidemiological models and studies into the heritability of set-point virus load confirm that this mode of adaptation within the human population is feasible. However, during the many cycles of replication between infection of a host and transmission to the next host, HIV-1 is under selection for escape from immune responses, and not transmission. Here we investigate with computational and mathematical models how these two levels of selection, within-host and between-host, are intertwined. We find that when the rate of immune escape is comparable to what has been observed in patients, immune selection within hosts is dominant over selection for transmission. Surprisingly, we do find high values for set-point virus load heritability, and argue that high heritability estimates can be caused by the 'footprints' left by differing hosts' immune systems on the virus.