Publications by authors named "Chadi M Saad-Roy"

13 Publications

  • Page 1 of 1

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

Science 2021 Sep 24;373(6562):eabj7364. Epub 2021 Sep 24.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08540, USA.

[Figure: see text].
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http://dx.doi.org/10.1126/science.abj7364DOI Listing
September 2021

Evolution of an asymptomatic first stage of infection in a heterogeneous population.

J R Soc Interface 2021 06 16;18(179):20210175. Epub 2021 Jun 16.

Department of Molecular Biology, Princeton University, Princeton, NJ, USA.

Pathogens evolve different life-history strategies, which depend in part on differences in their host populations. A central feature of hosts is their population structure (e.g. spatial). Additionally, hosts themselves can exhibit different degrees of symptoms when newly infected; this latency is a key life-history property of pathogens. With an evolutionary-epidemiological model, we examine the role of population structure on the evolutionary dynamics of latency. We focus on specific power-law-like formulations for transmission and progression from the first infectious stage as a function of latency, assuming that the across-group to within-group transmission ratio increases if hosts are less symptomatic. We find that simple population heterogeneity can lead to local evolutionarily stable strategies (ESSs) at zero and infinite latency in situations where a unique ESS exists in the corresponding homogeneous case. Furthermore, there can exist more than one interior evolutionarily singular strategy. We find that this diversity of outcomes is due to the (possibly slight) advantage of across-group transmission for pathogens that produce fewer symptoms in a first infectious stage. Thus, our work reveals that allowing individuals without symptoms to travel can have important unintended evolutionary effects and is thus fundamentally problematic in view of the evolutionary dynamics of latency.
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http://dx.doi.org/10.1098/rsif.2021.0175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205539PMC
June 2021

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

Science 2021 04 9;372(6540):363-370. Epub 2021 Mar 9.

Department of Bioengineering, McGill University, Montreal, QC H3A 0C3, Canada.

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.
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http://dx.doi.org/10.1126/science.abg8663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128287PMC
April 2021

Superinfection and the evolution of an initial asymptomatic stage.

R Soc Open Sci 2021 Jan 27;8(1):202212. Epub 2021 Jan 27.

Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.

Pathogens have evolved a variety of life-history strategies. An important strategy consists of successful transmission by an infected host before the appearance of symptoms, that is, while the host is still partially or fully asymptomatic. During this initial stage of infection, it is possible for another pathogen to superinfect an already infected host and replace the previously infecting pathogen. Here, we study the effect of superinfection during the first stage of an infection on the evolutionary dynamics of the degree to which the host is asymptomatic (host latency) in that same stage. We find that superinfection can lead to major differences in evolutionary behaviour. Most strikingly, the duration of immunity following infection can significantly influence pathogen evolutionary dynamics, whereas without superinfection the outcomes are independent of host immunity. For example, changes in host immunity can drive evolutionary transitions from a fully symptomatic to a fully asymptomatic first infection stage. Additionally, if superinfection relative to susceptible infection is strong enough, evolution can lead to a unique strategy of latency that corresponds to a local fitness minimum, and is therefore invasible by nearby mutants. Thus, this strategy is a branching point, and can lead to coexistence of pathogens with different latencies. Furthermore, in this new framework with superinfection, we also find that there can exist two interior singular strategies. Overall, new evolutionary outcomes can cascade from superinfection.
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http://dx.doi.org/10.1098/rsos.202212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890506PMC
January 2021

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

medRxiv 2021 Feb 3. Epub 2021 Feb 3.

Department of Bioengineering, McGill University, Montreal QC H3A 0C3, Canada.

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.
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http://dx.doi.org/10.1101/2021.02.01.21250944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872380PMC
February 2021

Trajectory of individual immunity and vaccination required for SARS-CoV-2 community immunity: a conceptual investigation.

J R Soc Interface 2021 02 3;18(175):20200683. Epub 2021 Feb 3.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA.

SARS-CoV-2 is an international public health emergency; high transmissibility and morbidity and mortality can result in the virus overwhelming health systems. Combinations of social distancing, and test, trace, and isolate strategies can reduce the number of new infections per infected individual below 1, thus driving declines in case numbers, but may be both challenging and costly. These interventions must also be maintained until development and (now likely) mass deployment of a vaccine (or therapeutics), since otherwise, many susceptible individuals are still at risk of infection. We use a simple analytical model to explore how low levels of infection, combined with vaccination, determine the trajectory to community immunity. Understanding the repercussions of the biological characteristics of the viral life cycle in this scenario is of considerable importance. We provide a simple description of this process by modelling the scenario where the effective reproduction number [Formula: see text] is maintained at 1. Since the additional complexity imposed by the strength and duration of transmission-blocking immunity is not yet clear, we use our framework to probe the impact of these uncertainties. Through intuitive analytical relations, we explore how the necessary magnitude of vaccination rates and mitigation efforts depends crucially on the durations of natural and vaccinal immunity. We also show that our framework can encompass seasonality or preexisting immunity due to epidemic dynamics prior to strong mitigation measures. Taken together, our simple conceptual model illustrates the importance of individual and vaccinal immunity for community immunity, and that the quantification of individuals immunized against SARS-CoV-2 is paramount.
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http://dx.doi.org/10.1098/rsif.2020.0683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086877PMC
February 2021

Economic and Behavioral Influencers of Vaccination and Antimicrobial Use.

Front Public Health 2020 21;8:614113. Epub 2020 Dec 21.

Princeton Environmental Institute, Princeton University, Princeton, NJ, United States.

Despite vast improvements in global vaccination coverage during the last decade, there is a growing trend in vaccine hesitancy and/or refusal globally. This has implications for the acceptance and coverage of a potential vaccine against COVID-19. In the United States, the number of children exempt from vaccination for "philosophical belief-based" non-medical reasons increased in 12 of the 18 states that allowed this policy from 2009 to 2017 (1). Meanwhile, the overuse and misuse of antibiotics, especially in young children, have led to increasing rates of drug resistance that threaten our ability to treat infectious diseases. Vaccine hesitancy and antibiotic overuse exist side-by-side in the same population of young children, and it is unclear why one modality (antibiotics) is universally seen as safe and effective, while the other (vaccines) is seen as potentially hazardous by some. In this review, we consider the drivers shaping the use of vaccines and antibiotics in the context of three factors: individual incentives, risk perceptions, and social norms and group dynamics. We illustrate how these factors contribute to the societal and individual costs of vaccine underuse and antimicrobial overuse. Ultimately, we seek to understand these factors that are at the nexus of infectious disease epidemiology and social science to inform policy-making.
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http://dx.doi.org/10.3389/fpubh.2020.614113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779682PMC
January 2021

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

Science 2020 11 21;370(6518):811-818. Epub 2020 Sep 21.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544, USA.

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.
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http://dx.doi.org/10.1126/science.abd7343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857410PMC
November 2020

Implications of localized charge for human influenza A H1N1 hemagglutinin evolution: Insights from deep mutational scans.

PLoS Comput Biol 2020 06 25;16(6):e1007892. Epub 2020 Jun 25.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.

Seasonal influenza A viruses of humans evolve rapidly due to strong selection pressures from host immune responses, principally on the hemagglutinin (HA) viral surface protein. Based on mouse transmission experiments, a proposed mechanism for immune evasion consists of increased avidity to host cellular receptors, mediated by electrostatic charge interactions with negatively charged cell surfaces. In support of this, the HA charge of the globally circulating H3N2 has increased over time since its pandemic. However, the same trend was not seen in H1N1 HA sequences. This is counter-intuitive, since immune escape due to increased avidity (due itself to an increase in charge) was determined experimentally. Here, we explore whether patterns of local charge of H1N1 HA can explain this discrepancy and thus further associate electrostatic charge with immune escape and viral evolutionary dynamics. Measures of site-wise functional selection and expected charge computed from deep mutational scan data on an early H1N1 HA yield a striking division of residues into three groups, separated by charge. We then explored evolutionary dynamics of these groups from 1918 to 2008. In particular, one group increases in net charge over time and consists of sites that are evolving the fastest, that are closest to the receptor binding site (RBS), and that are exposed to solvent (i.e., on the surface). By contrast, another group decreases in net charge and consists of sites that are further away from the RBS and evolving slower, but also exposed to solvent. The last group consists of those sites in the HA core, with no change in net charge and that evolve very slowly. Thus, there is a group of residues that follows the same trend as seen for the entire H3N2 HA. It is possible that the H1N1 HA is under other biophysical constraints that result in compensatory decreases in charge elsewhere on the protein. Our results implicate localized charge in HA interactions with host cells, and highlight how deep mutational scan data can inform evolutionary hypotheses.
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http://dx.doi.org/10.1371/journal.pcbi.1007892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316228PMC
June 2020

Stochastic Model of Bovine Babesiosis with Juvenile and Adult Cattle.

Bull Math Biol 2020 05 19;82(6):64. Epub 2020 May 19.

Department of Mathematics and Statistics, University of Victoria, Victoria, Canada.

A stochastic model for Bovine Babesiosis (BB) including ticks, and both juvenile and adult cattle is developed. This model is formulated by a system of continuous-time Markov chains (CTMCs) that is derived based on an extension of the deterministic ordinary differential equation model developed by Saad-Roy et al. (Bull Math Biol 77:514-547, 2015). The nonlinear CTMC model is approximated by a multitype branching process, giving a theoretical estimate of the probability of an outbreak of BB. Unlike the deterministic dynamics where the basic reproduction number is a sharp threshold parameter, the stochastic model indicates that there is always a positive probability of disease extinction within the cattle population. For parameter values from Colombia data, conditional probability distributions are numerically obtained for the time to disease extinction or outbreak, and are found to depend on the host type at the initiation of infection. The models with and without the inclusion of juvenile cattle are compared, and our result highlights that neglecting juvenile bovine in the models may lead to faulty predictions of critical disease statistics: particularly, it may underestimate the risk of infection. Endemic disease prevalence in adult cattle is examined for certain parameter values in the corresponding deterministic model. Notably, with long-lasting immunity, increased tick to juvenile infectivity decreases the proportion of infectious adults.
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http://dx.doi.org/10.1007/s11538-020-00734-xDOI Listing
May 2020

Dynamics in a simple evolutionary-epidemiological model for the evolution of an initial asymptomatic infection stage.

Proc Natl Acad Sci U S A 2020 05 8;117(21):11541-11550. Epub 2020 May 8.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544;

Pathogens exhibit a rich variety of life history strategies, shaped by natural selection. An important pathogen life history characteristic is the propensity to induce an asymptomatic yet productive (transmissive) stage at the beginning of an infection. This characteristic is subject to complex trade-offs, ranging from immunological considerations to population-level social processes. We aim to classify the evolutionary dynamics of such asymptomatic behavior of pathogens (hereafter "latency") in order to unify epidemiology and evolution for this life history strategy. We focus on a simple epidemiological model with two infectious stages, where hosts in the first stage can be partially or fully asymptomatic. Immunologically, there is a trade-off between transmission and progression in this first stage. For arbitrary trade-offs, we derive different conditions that guarantee either at least one evolutionarily stable strategy (ESS) at zero, some, or maximal latency of the first stage or, perhaps surprisingly, at least one unstable evolutionarily singular strategy. In this latter case, there is bistability between zero and nonzero (possibly maximal) latency. We then prove the uniqueness of interior evolutionarily singular strategies for power-law and exponential trade-offs: Thus, bistability is always between zero and maximal latency. Overall, previous multistage infection models can be summarized with a single model that includes evolutionary processes acting on latency. Since small changes in parameter values can lead to abrupt transitions in evolutionary dynamics, appropriate disease control strategies could have a substantial impact on the evolution of first-stage latency.
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http://dx.doi.org/10.1073/pnas.1920761117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261016PMC
May 2020

Dynamic Perspectives on the Search for a Universal Influenza Vaccine.

J Infect Dis 2019 04;219(Suppl_1):S46-S56

Department of Ecology and Evolutionary Biology, Princeton University, New Jersey.

A universal influenza vaccine (UIV) could considerably alleviate the public health burden of both seasonal and pandemic influenza. Although significant progress has been achieved in clarifying basic immunology and virology relating to UIV, several important questions relating to the dynamics of infection, immunity, and pathogen evolution remain unsolved. In this study, we review these gaps, which span integrative levels, from cellular to global and timescales from molecular events to decades. We argue that they can be best addressed by a tight integration of empirical (laboratory, epidemiological) research and theory and suggest fruitful areas for this synthesis. In particular, quantifying natural and vaccinal limitations on viral transmission are central to this effort.
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http://dx.doi.org/10.1093/infdis/jiz044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452315PMC
April 2019
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