Drivers and impact of the early silent invasion of SARS-CoV-2 Alpha (preprint)

SARS-CoV-2 variants of concern (VOCs) circulated cryptically before being identified as a threat, delaying interventions. Understanding the drivers of such silent spread and its epidemic impact is critical to inform future response planning. Here, we integrated spatio-temporal records of international mobility, local epidemic growth and genomic surveillance into a Bayesian framework to reconstruct the early dissemination of Alpha out of the UK in the first three months after emergence. We found that silent circulation lasted from days to months and was logarithmically associated with sequencing coverage. Social restrictions in certain countries likely slowed down the seeding of local transmission by weeks, mitigating the negative consequences of late detection. Revisiting the initial spread of Alpha supports local mitigation at the destination in case of emerging events.

Epidemic graph diagrams as analytics for epidemic control in the data-rich era (preprint)

COVID-19 highlighted how modeling is an integral part of pandemic response. But it also exposed fundamental methodological challenges. As high-resolution data on disease progression, epidemic surveillance, and host behavior are now available, can models turn them into accurate epidemic estimates and reliable public health recommendations? Take the epidemic threshold, which estimates the potential for an infection to spread in a host population, quantifying epidemic risk throughout epidemic emergence, mitigation, and control. While models increasingly integrated realistic host contacts, no parallel development occurred with matching detail in disease progression and interventions. This narrowed the use of the epidemic threshold to oversimplified disease and control descriptions. Here, we introduce the epidemic graph diagrams (EGDs), novel representations to compute the epidemic threshold directly from arbitrarily complex data on contacts, disease and control efforts. We define a grammar of diagram operations to decompose, compare, simplify models, extracting new theoretical understanding and improving computational efficiency. We test EGDs on two public health challenges, influenza and sexually-transmitted infections, to (i) explain the emergence of resistant influenza variants in the 2007-2008 season, and (ii) demonstrate that neglecting non-infectious prodromic stages biases the predicted epidemic risk, compromising control. EGDs are however general, and increase the performance of mathematical modeling to respond to present and future public health challenges.

Global patterns and drivers of influenza decline during the COVID-19 pandemic (preprint)

Influenza circulation declined during the COVID-19 pandemic. The timing and extent of decline and its association with interventions against COVID-19 were described for some regions. Here, we provide a global analysis of the influenza decline between March 2020 and September 2021 and investigate its potential drivers. We computed influenza change by country and trimester relative to the 2014-2019 period using the number of samples in the FluNet database. We used random forests to determine important predictors in a list of 20 covariates including demography, weather, pandemic preparedness, COVID-19 incidence, and COVID-19 pandemic response. With a regression tree we then classified observations according to these predictors. We found that influenza circulation decreased globally, with COVID-19 incidence and pandemic preparedness being the two most important predictors of this decrease. The regression tree showed interpretable groups of observations by country and trimester: Europe and North America clustered together in spring 2020, with limited influenza decline despite strong COVID-19 restrictions; in the period afterwards countries of temperate regions, with high pandemic preparedness, high COVID-19 incidence and stringent social restrictions grouped together having strong influenza decline. Conversely, countries in the tropics, with altogether low pandemic preparedness, low reported COVID-19 incidence and low strength of COVID-19 response showed low influenza decline overall. A final group singled out four "zero-Covid" countries, with the lowest residual influenza levels. The spatiotemporal decline of influenza during the COVID-19 pandemic was global, yet heterogeneous. The sociodemographic context and stage of the COVID-19 pandemic showed non-linear associations with this decline. Zero-Covid countries maintained the lowest levels of reduction with strict border controls and despite close-to-normal social activity. These results suggest that the resurgence of influenza could take equally diverse paths. It also emphasizes the importance of influenza reseeding in driving countries' seasonal influenza epidemics.

Retrospective analysis of SARS-CoV-2 omicron invasion over delta in French regions in 2021-22: a status-based multi-variant model (preprint)

Background SARS-CoV-2 is a rapidly spreading disease affecting human life and the economy on a global scale. The disease has caused so far more then 5.5 million deaths. The omicron outbreak that emerged in Botswana in the south of Africa spread around the globe at further increased rates, and caused unprecedented SARS-CoV-2 infection incidences in several countries. At the start of December 2021 the first omicron cases were reported in France. Methods In this paper we investigate the contagiousness of this novel variant relatively to the delta variant that was also in circulation in France at that time. Using a dynamic multi-variant model accounting for cross-immunity through a status-based approach, we analyze screening data reported by Santé Publique France over 13 metropolitan French regions between 1st of December 2021 and the 30th of January 2022. During the investigated period, the delta variant was replaced by omicron in all metropolitan regions in approximately three weeks. The analysis conducted retrospectively allows us to consider the whole replacement time window and compare regions with different times of omicron introduction and baseline levels of variants’ transmission potential. As large uncertainties regarding cross-immunity among variants persist, uncertainty analyses were carried out to assess its impact on our estimations. Results Assuming that 80% of the population was immunized against delta, a cross delta/omicron cross-immunity of 25% and omicron generation time was 3.5 days, the relative strength of omicron to delta, expressed as the ratio of their respective reproduction rates, , was found to range between 1.51 and 1.86 across regions. Uncertainty analysis on epidemiological parameters led ranging over 1.57-2.13 when averaged over the metropolitan French regions, weighting by population size. Conclusions Upon introduction, omicron spread rapidly through the French territory and showed a high fitness relative to delta. We documented considerable geographical heterogeneities on the spreading dynamics. The historical reconstruction of variant emergence dynamics provide valuable ground knowledge to face future variant emergence events.

Reactive vaccination of workplaces and schools against COVID-19 (preprint)

As vaccination against COVID-19 stalls in some countries, increased accessibility and more adaptive approaches may be useful to keep the epidemic under control. Here we study the impact of reactive vaccination targeting schools and workplaces where cases have been detected, with an agent-based model accounting for COVID-19 natural history, vaccine characteristics, individuals' demography and behaviour and social distancing. We study epidemic scenarios ranging from sustained spread to flare-up of cases, and we consider reactive vaccination alone and in combination with mass vaccination. With the same number of doses, reactive vaccination reduces cases more than non-reactive approaches, but may require concentrating a high number of doses over a short time in case of sustained spread. In case of flare-ups, quick implementation of reactive vaccination supported by enhanced test-trace-isolate practices would limit further spread. These results provide key information to promote an adaptive vaccination plan in the months to come.

Adherence and sustainability of interventions informing optimal control against COVID-19 pandemic (preprint)

After one year of stop-and-go COVID-19 mitigation, some European countries still experience sustained viral circulation due to the B.1.1.7 variant. As the prospect of phasing out this stage through vaccination draws closer, it is critical to balance the efficacy of long-lasting interventions and their impact on the quality of life. Focusing on the current situation in France, we show that moderate interventions require a much longer time to achieve the same result as high intensity lockdowns, with the additional risk of deteriorating control as adherence wanes. Integrating intensity and duration of social distancing in a data-driven "distress" index, we show that shorter strict lockdowns are largely more performant than longer moderate lockdowns, for similar intermediate distress and infringement on individual freedom. Our study shows that favoring milder interventions over more stringent short approaches on the basis of perceived acceptability could be detrimental in the long term, especially with waning adherence.

SARS-CoV-2 European resurgence foretold: interplay of introductions and persistence by leveraging genomic and mobility data (preprint)

Following the first wave of SARS-CoV-2 infections in spring 2020, Europe experienced a resurgence of the virus starting late summer that was deadlier and more difficult to contain. Relaxed intervention measures and summer travel have been implicated as drivers of the second wave. Here, we build a phylogeographic model to evaluate how newly introduced lineages, as opposed to the rekindling of persistent lineages, contributed to the COVID-19 resurgence in Europe. We inform this model using genomic, mobility and epidemiological data from 10 West European countries and estimate that in many countries more than 50% of the lineages circulating in late summer resulted from new introductions since June 15th. The success in onwards transmission of these lineages is predicted by SARS-CoV-2 incidence during this period. Relatively early introductions from Spain into the United Kingdom contributed to the successful spread of the 20A.EU1/B.1.177 variant. The pervasive spread of variants that have not been associated with an advantage in transmissibility highlights the threat of novel variants of concern that emerged more recently and have been disseminated by holiday travel. Our findings indicate that more effective and coordinated measures are required to contain spread through cross-border travel.

Anatomy of digital contact tracing: role of age, transmission setting, adoption and case detection (preprint)

The efficacy of digital contact tracing against COVID-19 epidemic is debated: smartphone penetration is limited in many countries, non-uniform across age groups, with low coverage among elderly, the most vulnerable to SARS-CoV-2. We developed an agent-based model to precise the impact of digital contact tracing and household isolation on COVID-19 transmission. The model, calibrated on French population, integrates demographic, contact-survey and epidemiological information to describe the risk factors for exposure and transmission of COVID-19. We explored realistic levels of case detection, app adoption, population immunity and transmissibility. Assuming a reproductive ratio R = 2.6 and 50% detection of clinical cases, a ~20% app adoption reduces peak incidence by ~35%. With R = 1.7, >30% app adoption lowers the epidemic to manageable levels. Higher coverage among adults, playing a central role in COVID-19 transmission, yields an indirect benefit for elderly. These results may inform the inclusion of digital contact tracing within a COVID-19 response plan.

Accommodating individual travel history, global mobility, and unsampled diversity in phylogeography: a SARS-CoV-2 case study. (preprint)

Spatiotemporal bias in genome sequence sampling can severely confound phylogeographic inference based on discrete trait ancestral reconstruction. This has impeded our ability to accurately track the emergence and spread of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Despite the availability of unprecedented numbers of SARS-CoV-2 genomes on a global scale, evolutionary reconstructions are hindered by the slow accumulation of sequence divergence over its relatively short transmission history. When confronted with these issues, incorporating additional contextual data may critically inform phylodynamic reconstructions. Here, we present a new approach to integrate individual travel history data in Bayesian phylogeographic inference and apply it to the early spread of SARS-CoV-2, while also including global air transportation data. We demonstrate that including travel history data for each SARS-CoV-2 genome yields more realistic reconstructions of virus spread, particularly when travelers from undersampled locations are included to mitigate sampling bias. We further explore methods to ameliorate the impact of sampling bias by augmenting the phylogeographic analysis with lineages from undersampled locations in the analyses. Our reconstructions reinforce specific transmission hypotheses suggested by the inclusion of travel history data, but also suggest alternative routes of virus migration that are plausible within the epidemiological context but are not apparent with current sampling efforts. Although further research is needed to fully examine the performance of our travel-aware phylogeographic analyses with unsampled diversity and to further improve them, they represent multiple new avenues for directly addressing the colossal issue of sample bias in phylogeographic inference.

Lessons learnt from 288 COVID-19 international cases: importations over time, effect of interventions, underdetection of imported cases (preprint)

288 cases have been confirmed out of China from January 3 to February 13, 2020. We collected and synthesized all available information on these cases from official sources and media. We analyzed importations that were successfully isolated and those leading to onward transmission. We modeled their number over time, in relation to the origin of travel (Hubei province, other Chinese provinces, other countries) and interventions. We characterized importations timeline to assess the rapidity of isolation, and epidemiologically linked clusters to estimate the rate of detection. We found a rapid exponential growth of importations from Hubei, combined with a slower growth from the other areas. We predicted a rebound of importations from South East Asia in the upcoming weeks. Time from travel to detection has considerably decreased since the first importation, however 6 cases out of 10 were estimated to go undetected. Countries outside China should be prepared for the possible emergence of several undetected clusters of chains of local transmissions.

Preparedness and vulnerability of African countries against introductions of 2019-nCoV (preprint)

The novel coronavirus (2019-nCoV) epidemic has spread to 23 countries from China. Local cycles of transmission already occurred in 7 countries following case importation. No African country has reported cases yet. The management and control of 2019-nCoV introductions heavily relies on the public health capacity of a country. Here we evaluate the preparedness and vulnerability of African countries against their risk of importation of 2019-nCoV. We used data on air travel volumes departing from airports in the infected provinces in China and directed to Africa to estimate the risk of introduction per country. We determined the countries capacity to detect and respond to cases with two indicators: preparedness, using the WHO International Health Regulation Monitoring and Evaluation Framework; and vulnerability, with the Infectious Disease Vulnerability Index. Countries were clustered according to the Chinese regions contributing the most to their risk. Findings: Countries at the highest importation risk (Egypt, Algeria, Republic of South Africa) have moderate to high capacity to respond to outbreaks. Countries at moderate risk (Nigeria, Ethiopia, Sudan, Angola, Tanzania, Ghana, Kenya) have variable capacity and high vulnerability. Three clusters of countries are identified that share the same exposure to the risk originating from the provinces of Guangdong, Fujian, and Beijing, respectively. Interpretation: Several countries in Africa are stepping up their preparedness to detect and cope with 2019-nCoV importations. Resources and intensified surveillance and capacity capacity should be urgently prioritized towards countries at moderate risk that may be ill-prepared to face the importation and to limit onward transmission.