COVID-19 Adaptive Humoral Immunity Models: Weakly Neutralizing Versus Antibody-Disease Enhancement Scenarios.

The interplay between the virus, infected cells and immune responses to SARS-CoV-2 is still under debate. By extending the basic model of viral dynamics, we propose here a formal approach to describe neutralisation versus weak (or non-)neutralisation scenarios and compare them with the possible effects of antibody-dependent enhancement (ADE). The theoretical model is consistent with the data available in the literature; we show that both weakly neutralising antibodies and ADE can result in final viral clearance or disease progression, but that the immunodynamics are different in each case. As a significant proportion of the world's population is already naturally immune or vaccinated, we also discuss the implications for secondary infections after vaccination or in the presence of immune system dysfunctions.

Heterogeneous social interactions and the COVID-19 lockdown outcome in a multi-group SEIR model

We study variants of the SEIR model for interpreting some qualitative features of the statistics of the Covid-19 epidemic in France. Standard SEIR models distinguish essentially two regimes: either the disease is controlled and the number of infected people rapidly decreases, or the disease spreads and contaminates a significant fraction of the population until herd immunity is achieved. After lockdown, at first sight it seems that social distancing is not enough to control the outbreak. We discuss here a possible explanation, namely that the lockdown is creating social heterogeneity: even if a large majority of the population complies with the lockdown rules, a small fraction of the population still has to maintain a normal or high level of social interactions, such as health workers, providers of essential services, etc. This results in an apparent high level of epidemic propagation as measured through re-estimations of the basic reproduction ratio. However, these measures are limited to averages, while variance inside the population plays an essential role on the peak and the size of the epidemic outbreak and tends to lower these two indicators. We provide theoretical and numerical results to sustain such a view.

A New Transmission Route for the Propagation of the SARS-CoV-2 Coronavirus.

BACKGROUND: Starting late 2019, a novel coronavirus spread from the capital of the Hubei province in China to the rest of the country, then to most of the world. To anticipate future trends in the development of the pandemic, we explore here, based on public records of infected persons, how variation in the virus tropism could end up in different patterns, warranting a specific strategy to handle the epidemic. METHODS: We use a compartmental model to describe the evolution of an individual through several possible states: susceptible, infected, alternative infection, detected, and removed. We fit the parameters of the model to the existing data, taking into account significant quarantine changes where necessary. RESULTS: The model indicates that Wuhan quarantine measures were effective, but that alternative virus forms and a second propagation route are compatible with available data. For the Hong Kong, Singapore, and Shenzhen regions, the secondary route does not seem to be active. CONCLUSIONS: Hypotheses of an alternative infection tropism (the gut tropism) and a secondary propagation route are discussed using a model fitted by the available data. Corresponding prevention measures that take into account both routes should be implemented to the benefit of epidemic control.

A New Transmission Route for the Propagation of the SARS-CoV-2 Coronavirus

Background: Starting late 2019, a novel coronavirus spread from the capital of the Hubei province in China to the rest of the country, then to most of the world. To anticipate future trends in the development of the pandemic, we explore here, based on public records of infected persons, how variation in the virus tropism could end up in different patterns, warranting a specific strategy to handle the epidemic. Methods: We use a compartmental model to describe the evolution of an individual through several possible states: susceptible, infected, alternative infection, detected, and removed. We fit the parameters of the model to the existing data, taking into account significant quarantine changes where necessary. Results: The model indicates that Wuhan quarantine measures were effective, but that alternative virus forms and a second propagation route are compatible with available data. For the Hong Kong, Singapore, and Shenzhen regions, the secondary route does not seem to be active. Conclusions: Hypotheses of an alternative infection tropism (the gut tropism) and a secondary propagation route are discussed using a model fitted by the available data. Corresponding prevention measures that take into account both routes should be implemented to the benefit of epidemic control.

Immunity after COVID-19: Protection or sensitization?

Motivated by historical and present clinical observations, we discuss the possible unfavorable evolution of the immunity (similar to documented antibody-dependent enhancement scenarios) after a first infection with COVID-19. More precisely we ask the question of how the epidemic outcomes are affected if the initial infection does not provide immunity but rather sensitization to future challenges. We first provide background comparison with the 2003 SARS epidemic. Then we use a compartmental epidemic model structured by immunity level that we fit to available data; using several scenarios of the fragilization dynamics, we derive quantitative insights into the additional expected numbers of severe cases and deaths.

[Biochemical and statistical lessons from the evolution of the SARS-CoV-2 virus: paths for novel antiviral warfare]. / Leçons biochimiques et statistiques de l'évolution du virus SARS-CoV-2 : nouveaux chemins pour combattre les virus.

In the fight against the spread of COVID-19 the emphasis is on vaccination or on reactivating existing drugs used for other purposes. The tight links that necessarily exist between the virus as it multiplies and the metabolism of its host are systematically ignored. Here we show that the metabolism of all cells is coordinated by the availability of a core building block of the cell's genome, cytidine triphosphate (CTP). This metabolite is also the key to the synthesis of the viral envelope and to the translation of its genome into proteins. This unique role explains why evolution has led to the early emergence in animals of an antiviral immunity enzyme, viperin, that synthesizes a toxic analogue of CTP. The constraints arising from this dependency guide the evolution of the virus. With this in mind, we explored the real-time experiment taking place before our eyes using probabilistic modelling approaches to the molecular evolution of the virus. We have thus followed, almost on a daily basis, the evolution of the composition of the viral genome to link it to the progeny produced over time, particularly in the form of blooms that sparked a firework of viral mutations. Some of those certainly increase the propagation of the virus. This led us to make out the critical role in this evolution of several proteins of the virus, such as its nucleocapsid N, and more generally to begin to understand how the virus ties up the host metabolism to its own benefit. A way for the virus to escape CTP-dependent control in cells would be to infect cells that are not expected to grow, such as neurons. This may account for unexpected body sites of viral development in the present epidemic.

Dans la lutte contre la propagation de la COVID-19 l'accent est mis sur la vaccination, d'une part, et sur le redéploiement de traitements utilisés pour d'autres usages, d'autre part. Les liens qui existent nécessairement entre la multiplication du virus et le métabolisme de l'hôte sont systématiquement ignorés. Ici nous montrons que le métabolisme de toutes les cellules est coordonné par l'accessibilité d'un composant central du génome cellulaire, le triphosphate de cytidine (CTP). Ce métabolite est aussi la clé de la synthèse de l'enveloppe virale et de la traduction de son génome en protéines. Ce rôle unique explique pourquoi l'évolution a fait apparaître très tôt chez les animaux une activité enzymatique de l'immunité antivirale, la vipérine, destinée à synthétiser un analogue toxique du CTP. Les contraintes nées de cette dépendance orientent l'évolution du virus. Avec cette servitude à l'esprit, nous avons exploré l'expérience en vraie grandeur qui se déroule sous nos yeux au moyen d'approches de modélisation probabiliste de l'évolution moléculaire du virus. Nous avons ainsi suivi, presque au jour le jour, le devenir de la composition du génome viral pour la relier à la descendance produite au cours du temps, en particulier sous la forme d'efflorescences où apparaît un véritable feu d'artifice de mutations virales. Certaines d'entre elles augmentent certainement la propagation du virus. Cela nous conduit à proposer un rôle important dans cette évolution à certaines protéines du virus, comme celle de la nucléocapside N et plus généralement de commencer à comprendre comment le virus asservit à son bénéfice le métabolisme de l'hôte. L'un des moyens possibles pour le virus d'échapper au contrôle par le CTP serait d'infecter des cellules qui ne se multiplient pas, comme les neurones. Cela pourrait expliquer les sites de développement viral inattendus qu'on observe dans l'épidémie actuelle.

Contact rate epidemic control of COVID-19: An equilibrium view

We consider the control of the COVID-19 pandemic through a standard SIR compartmental model. This control is induced by the aggregation of individuals' decisions to limit their social interactions: when the epidemic is ongoing, an individual can diminish his/her contact rate in order to avoid getting infected, but this effort comes at a social cost. If each individual lowers his/her contact rate, the epidemic vanishes faster, but the effort cost may be high. A Mean Field Nash equilibrium at the population level is formed, resulting in a lower effective transmission rate of the virus. We prove theoretically that equilibrium exists and compute it numerically. However, this equilibrium selects a sub-optimal solution in comparison to the societal optimum (a centralized decision respected fully by all individuals), meaning that the cost of anarchy is strictly positive. We provide numerical examples and a sensitivity analysis, as well as an extension to a SEIR compartmental model to account for the relatively long latent phase of the COVID-19 disease. In all the scenario considered, the divergence between the individual and societal strategies happens both before the peak of the epidemic, due to individuals' fears, and after, when a significant propagation is still underway.