Genomic assessment of invasion dynamics of SARS-CoV-2 Omicron BA.1 (preprint)

SARS-CoV-2 variants of concern (VOCs) arise against the backdrop of increasingly heterogeneous human connectivity and population immunity. Through a large-scale phylodynamic analysis of 115,622 Omicron genomes, we identified >6,000 independent introductions of the antigenically distinct virus into England and reconstructed the dispersal history of resulting local transmission. Travel restrictions on southern Africa did not reduce BA.1 importation intensity as secondary hubs became major exporters. We explored potential drivers of BA.1 spread across England and discovered an early period during which viral lineage movements mainly occurred between larger cities, followed by a multi-focal spatial expansion shaped by shorter distance mobility patterns. We also found evidence that disease incidence impacted human commuting behaviours around major travel hubs. Our results offer a detailed characterisation of processes that drive the invasion of an emerging VOC across multiple spatial scales and provide unique insights on the interplay between disease spread and human mobility.

The effect of variation of individual infectiousness on SARS-CoV-2 transmission in households (preprint)

Quantifying variation of individual infectiousness is critical to inform disease control. Previous studies reported substantial heterogeneity in transmission of many infectious diseases (including SARS-CoV-2). However, those results are difficult to interpret since the number of contacts is rarely considered in such approaches. Here, we analyze data from 17 SARS-CoV-2 household transmission studies conducted in periods dominated by ancestral strains, in which the number of contacts was known. By fitting individual-based household transmission models to these data, accounting for number of contacts and baseline transmission probabilities, the pooled estimate suggests that the 20% most infectious cases have 3.1-fold (95% confidence interval: 2.2-4.2 fold) higher infectiousness than average cases, which is consistent with the observed heterogeneity in viral shedding. Household data can inform the estimation of transmission heterogeneity, which is important for epidemic management.

SARS-CoV-2 IgG seroprevalence surveys in blood donors before the vaccination campaign, France 2020-2021 (preprint)

SUMMARY We conducted a cross-sectional study for SARS-CoV-2 anti-S1 IgG prevalence in French blood donors (n=32605), from May-2020 to January-2021. A mathematical model combined seroprevalence with daily number of hospital admissions to estimate the probability of hospitalization upon infection and determine the number of infections while correcting for antibody decay. There was an overall seroprevalence increase over the study period and we estimate that ∼15% of the French population had been infected by SARS-CoV-2 by January-2021. The infection/hospitalization ratio increased with age, from 0.56% (18-30yo) to 6.75% (61-70yo). Half of the IgG-S1 positive individuals had no detectable antibodies 4 to 5 months after infection. The seroprevalence in group O donors (7.43%) was lower (p=0.003) than in A, B and AB donors (8.90%). We conclude, based on seroprevalence data and mathematical modelling, that the overall immunity in the French population before the vaccination campaign started was too low to achieve herd immunity.

Impact and mitigation of sampling bias to determine viral spread: evaluating discrete phylogeography through CTMC modeling and structured coalescent model approximations (preprint)

Bayesian phylogeographic inference is a powerful tool in molecular epidemiological studies that enables reconstructing the origin and subsequent geographic spread of pathogens. Such inference is, however, potentially affected by geographic sampling bias. Here, we investigated the impact of sampling bias on the spatiotemporal reconstruction of viral epidemics using Bayesian discrete phylogeographic models and explored different operational strategies to mitigate this impact. We considered the continuous-time Markov chain (CTMC) model and two structured coalescent approximations (BASTA and MASCOT). For each approach, we compared the estimated and simulated spatiotemporal histories in biased and unbiased conditions based on simulated epidemics of rabies virus (RABV) in dogs in Morocco. While the reconstructed spatiotemporal histories were impacted by sampling bias for the three approaches, BASTA and MASCOT reconstructions were also biased when employing unbiased samples. Increasing the number of analyzed genomes led to more robust estimates at low sampling bias for CTMC. Alternative sampling strategies that maximize the spatiotemporal coverage greatly improved the inference at intermediate sampling bias for CTMC, and to a lesser extent, for BASTA and MASCOT. In contrast, allowing for time-varying population sizes in MASCOT resulted in robust inference. We further applied these approaches to two empirical datasets: a RABV dataset from the Philippines and a SARS-CoV-2 dataset describing its early spread across the world. In conclusion, sampling biases are ubiquitous in phylogeographic analyses but may be accommodated by increasing sample size, balancing spatial and temporal composition in the samples, and informing structured coalescent models with reliable case count data.

Humoral Immunity to SARS-CoV-2 and Inferred Protection from Infection in a French Longitudinal Community Cohort (preprint)

Population-level immunity to SARS-CoV-2 is growing through vaccination as well as ongoing circulation. Given waning immunity and emergence of new variants, it is important to dynamically determine the risk of re-infection in the population. For estimating immune protection, neutralization titers are most informative, but these assays are difficult to conduct at a population level. Measurement of antibody levels can be implemented at high throughput, but has not been robustly validated as a correlate of protection. Here, we have developed a method that predicts neutralization and protection based on variant-specific antibody measurements to SARS-CoV-2 antigens. This approach allowed us to estimate population-immunity in a longitudinal cohort from France followed for up to 2 years. Participants with a single vaccination or immunity caused by infection only are especially vulnerable to COVID-19 or hospitalization due to SARS-CoV-2. While the median reduced risk to COVID-19 in participants with 3 vaccinations was 96%, the median reduced risk among participants with infection-acquired immunity only was 42%. The results presented here are consistent with data from vaccine-effectiveness studies indicating robustness of our approach. Our multiplex serological assay can be readily optimized and employed to study any new variant and provides a framework for development of an assay that would include protection estimates.

Prophylactic and reactive vaccination strategies for healthcare workers against MERS-CoV (preprint)

Several vaccines candidates are in development against Middle East respiratory syndrome–related coronavirus (MERS-CoV), which remains a major public health concern. Using individual-level data on the 2013-2014 Kingdom of Saudi Arabia epidemic, we employ counterfactual analysis on inferred transmission trees (“who-infected-whom”) to assess potential vaccine impact. We investigate the conditions under which prophylactic “proactive” campaigns would outperform “reactive” campaigns (i.e. vaccinating either before or in response to the next outbreak), focussing on healthcare workers. Spatial scale is crucial: if vaccinating healthcare workers in response to outbreaks at their hospital only, proactive campaigns perform better, unless efficacy has waned significantly. However, campaigns that react at regional or national level consistently outperform proactive campaigns. Measures targeting the animal reservoir reduce transmission linearly, albeit with wide uncertainty. Substantial reduction of MERS-CoV morbidity and mortality is possible when vaccinating healthcare workers, underlining the need for at-risk countries to stockpile vaccines when available.

Time-varying transmission heterogeneity of SARS and COVID-19 in Hong Kong (preprint)

Transmission heterogeneity is a notable feature of the severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) epidemics, though previous efforts to estimate how heterogeneity changes over time are limited. Using contact tracing data, we compared the epidemiology of SARS and COVID-19 infection in Hong Kong in 2003 and 2020-21 and estimated time-varying transmission heterogeneity (kt) by fitting negative binomial models to offspring distributions generated across variable observation windows. kt fluctuated over time for both COVID-19 and SARS on a continuous scale though SARS exhibited significantly greater (p < 0.001) heterogeneity compared to COVID-19 overall and in-time. For COVID-19, kt declined over time and was significantly associated with increasingly stringent non-pharmaceutical interventions though similar evidence for SARS was inconclusive. Underdetection of sporadic COVID-19 cases led to a moderate overestimation of kt, indicating COVID-19 heterogeneity of could be greater than observed. Time-varying or real-time estimates of transmission heterogeneity could become a critical indicator for epidemic intelligence in the future.

Selection for infectivity profiles in slow and fast epidemics, and the rise of SARS-CoV-2 variants (preprint)

Evaluating the characteristics of emerging SARS-CoV-2 variants of concern is essential to inform pandemic risk assessment. A variant may grow faster if it produces a larger number of secondary infections (transmissibility advantage) or if the timing of secondary infections (generation time) is better. So far, assessments have largely focused on deriving the transmissibility advantage assuming the generation time was unchanged. Yet, knowledge of both is needed to anticipate impact. Here we develop an analytical framework to investigate the contribution of both the transmissibility advantage and generation time to the growth advantage of a variant. We find that the growth advantage depends on the epidemiological context (level of epidemic control). More specifically, variants conferring earlier transmission are more strongly favoured when the historical strains have fast epidemic growth, while variants conferring later transmission are more strongly favoured when historical strains have slow or negative growth. We develop these conceptual insights into a statistical framework to infer both the transmissibility advantage and generation time of a variant. On simulated data, our framework correctly estimates both parameters when it covers time periods characterized by different epidemiological contexts. Applied to data for the Alpha and Delta variants in England and in Europe, we find that Alpha confers a +54% [95% CI, 45-63%] transmissibility advantage compared to previous strains, and Delta +140% [98-182%] compared to Alpha, and mean generation times are similar to historical strains for both variants. This work helps interpret variant frequency and will strengthen risk assessment for future variants of concern.

How well does SARS-CoV-2 spread in hospitals? (preprint)

Covid-19 poses significant risk of nosocomial transmission, and preventing this requires good estimates of the basic reproduction number R0 in hospitals and care facilities, but these are currently lacking. Such estimates are challenging due to small population sizes in these facilities and inconsistent testing practices. We estimate the patient-to-patient R0 and daily transmission rate of SARS-CoV-2 using data from a closely monitored hospital outbreak in Paris 2020 during the first wave. We use a realistic epidemic model which accounts for progressive stages of infection, stochastic effects and a large proportion of asymptomatic infections. Innovatively, we explicitly include changes in testing capacity over time, as well as the evolving sensitivity of PCR testing at different stages of infection. We conduct rigorous statistical inference using iterative particle filtering to fit the model to the observed patient data and validate this methodology using simulation. We provide estimates for R0 across the entire hospital (2.6) and in individual wards (from 3 to 15), possibly reflecting heterogeneity in contact patterns or control measures. An obligatory mask-wearing policy introduced during the outbreak is likely to have changed the R0, and we estimate values before (8.7) and after (1.3) its introduction, corresponding to a policy efficacy of 85%.

Self-testing and vaccination against COVID-19 to minimize school closure (preprint)

Schools were largely closed in 2020-2021 to counter COVID-19 spread, impacting students education and well-being. With highly contagious variants expanding in Europe while vaccine hesitancy persists, safe options to maintain schools open are urgently needed. We developed an agent-based model of SARS-CoV-2 transmission in school. We used empirical contact data measured in a primary and a secondary school in France, and field estimates for adherence to screening from 683 schools during the spring 2021 wave. Examining different screening protocols, we performed a cost-benefit analysis for varying epidemic conditions and vaccination scenarios. In a partially immunized school population, weekly screening would reduce the number of cases on average by 24% in the primary and 53% in the secondary school compared to symptom-based testing alone, if R=1.3 and 50% adhered to screening. This adherence was met in primary schools (53% (95% confidence interval 21-85%)), but insufficient participation was recorded in secondary schools (10% (1-38%) in middle schools, 6% (2-12%) in high schools). Regular screening would also reduce by 90% the number of student-days lost compared to reactive class closure. No difference was predicted when fully vaccinating teachers, due to their limited number and mixing. Partially vaccinating adolescents would still require regular screening for additional control (20% case reduction with 50% vaccinated students). In the upcoming fall, COVID-19 epidemic will likely continue to pose a risk to the safe opening of schools. Increasing vaccination coverage in adolescents and implementing regular testing while largely incentivizing adherence are essential steps to keep schools open.

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.

Impact of BNT162b2 vaccination and isolation on SARS-CoV-2 transmission in Israeli households: an observational study (preprint)

Background Massive vaccination rollouts against SARS-CoV-2 infections have facilitated the easing of control measures in countries like Israel. While several studies have characterized the effectiveness of vaccines against severe forms of COVID-19 or SARS-CoV-2 infection, estimates of their impact on transmissibility remain limited. Here, we evaluated the role of vaccination and isolation on SARS-CoV-2 transmission within Israeli households. Methods From December 2020 to April 2021, confirmed cases were identified among healthcare workers of the Sheba Medical Centre and their family members. Households were recruited and followed up with repeated PCR for a minimum of ten days after case confirmation. Symptoms and vaccination information were collected at the end of follow-up. We developed a data augmentation Bayesian framework to ascertain how age, isolation and BNT162b2 vaccination with more than 7 days after the 2 nd dose impacted household transmission of SARS-CoV-2. Findings 210 households with 215 index cases were enrolled. 269 out of 687 (39%) household contacts developed a SARS-CoV-2 infection. Of those, 170 (63%) developed symptoms. Children below 12 years old were less susceptible than adults/teenagers (Relative Risk RR=0·50, 95% Credible Interval CI 0·32-0·79). Vaccination reduced the risk of infection among adults/teenagers (RR=0·19, 95% CI 0·07-0·40). Isolation reduced the risk of infection of unvaccinated adult/teenager (RR=0·11, 95% CI 0·05-0·19) and child contacts (RR=0·16, 95% CI 0·07-0·31) compared to unvaccinated adults/teenagers that did not isolate. Infectivity was significantly reduced in vaccinated cases (RR=0·22, 95% CI 0·06-0·70). Interpretation Within households, vaccination reduces both the risk of infection and of transmission if infected. When contacts were not vaccinated, isolation also led to important reductions in the risk of transmission. Vaccinated contacts might reduce their risk of infection if they isolate, although this requires confirmation with additional data. Funding Sheba Medical Center. Research in context Evidence before this study The efficacy of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmissions in households remains understudied. On June 28, 2021, we searched PubMed and medRxiv for articles published between December 1, 2020, and June 28, 2021, using the following combination of search terms: (“COVID-19” OR “SARS-CoV-2”) AND (“household*” OR “famil*”) AND “transmission” AND “vaccination”. Our search yielded two articles that investigated the effect of vaccination on SARS-CoV-2 transmission in households. They showed a lower risk of infection in households with vaccinees. Vaccine efficacy on the risk of infection was estimated to 80% after the 2 nd dose, and vaccine efficacy on the risk of transmission if infected was estimated to 49% 21 days after the 1 st dose. However, these estimates are derived from surveillance data with no active follow-up of the households. In addition, the impact of isolation precautions has not been assessed. Added value of this study Based on the active follow-up of households of health care workers from the Sheba Medical Center in Israel, we estimated the effect of vaccination on household transmission. To our knowledge, our study is the first to conjointly investigate the effect of vaccination, age, and isolation precautions on the risk of infection and the risk of transmission in households while accounting for tertiary infections in the household, infections within the community, the reduced infectivity of asymptomatic cases, misidentification of index cases, and household size. Our study confirmed the high efficacy of BNT-162b2 vaccination to reduce infection risk and transmission risk. It also suggests that isolation might remain beneficial to vaccinated contacts. Implications of all the available evidence Vaccination reduces susceptibility to infection and case infectivity in households. Isolation precautions also mitigate the risk of infection and should be implemented whenever a household member is infected. They might remain beneficial to vaccinated contacts.

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.

Impact of national and regional lockdowns on COVID-19 epidemic waves: Application to the 2020 spring wave in France (preprint)

Several countries have implemented lockdowns to control their COVID-19 epidemic. However, questions like “where” and “when” still require answers. We assessed the impact of national and regional lockdowns considering the French first epidemic wave of COVID-19 as a case study. In a regional lockdown scenario aimed at preventing intensive care units (ICU) saturation, almost all French regions would have had to implement a lockdown within 10 days and 96% of ICU capacities would have been used. For slowly growing epidemics, with a lower reproduction number, the expected delays between regional lockdowns increases. However, the public health costs associated with these delays tend to grow exponentially with time. In a quickly growing pandemic wave, defining the timing of lockdowns at a regional rather than national level delays by a few days the implementation of a nationwide lockdown but leads to substantially higher morbidity, mortality and stress on the healthcare system.

Colder and drier winter conditions are associated with greater SARS-CoV-2 transmission: a regional study of the first epidemic wave in north-west hemisphere countries. (preprint)

Higher transmissibility of SARS-CoV-2 in cold and dry weather conditions has been hypothesized since the onset of the COVID-19 pandemic but the level of epidemiological evidence remains low. During the first wave of the pandemic, Spain, Italy, France, Portugal, Canada and USA presented an early spread, a heavy COVID-19 burden, and low initial public health response until lockdowns. In a context when testing was limited, we calculated the basic reproduction number (R0) in 63 regions from the growth in regional death counts. After adjusting for population density, early spread of the epidemic, and age structure, temperature and humidity were negatively associated to SARS-CoV-2 transmissibility. A reduction of mean absolute humidity by 1g/m3 was associated with a 0.15-unit increase of R0. Below 10{degrees}C, a temperature reduction of 1{degrees}C was associated with a 0.16-unit increase of R0. Our results confirm a dependency of SARS-CoV-2 transmissibility to weather conditions in the absence of control measures during the first wave. The transition from summer-to winter-like conditions likely contributed to the intensification of the second wave in north-west hemisphere countries. Adjustments of the levels of social mobility restrictions need to account for increased SARS-CoV-2 transmissibility in winter conditions.

Monitoring the proportion infected by SARS-CoV-2 from age-stratified hospitalisation and serological data (preprint)

BackgroundRegional monitoring of the proportion infected by SARS-CoV-2 is important to guide local management of the epidemic, but is difficult in the absence of regular nationwide serosurveys. MethodsWe developed a method to reconstruct in real-time the proportion infected by SARS-CoV-2 and the proportion of infections being detected from the joint analysis of age-stratified seroprevalence, hospitalisation and case data. We applied our approach to the 13 French metropolitan regions. FindingsWe estimate that 5.7% [5.1%-6.4%] of adults in metropolitan France had been infected by SARS-CoV-2 by May 2020. This proportion remained stable until August and increased to 12.6% [11.2%-14.3%] by the end of November. With 23.8% [21.2%-26.8%] infected in the Paris region compared to 4.0% [3.5% - 4.6%] in Brittany, regional variations remained large (Coefficient of Variation CV: 0.53) although less so than in May (CV: 0.74). The proportion infected was twice higher (17.6% [13.4%-22.7%]) in 20-49 y.o. than in 50+ y.o (8.0% [5.7% - 11.5%]). Forty percent [33.7% - 45.4%] of infections in adults were detected in June-August compared to 55.7% [48.7% - 63.1%] in September-November. Our method correctly predicted seroprevalence in 11 regions in which only hospitalisation data were used. InterpretationIn the absence of contemporary serosurvey, our real-time monitoring indicates that the proportion infected by SARS-CoV-2 may be above 20% in some French regions. FundingEU RECOVER, ANR, Fondation pour la Recherche Medicale, Inserm.

Comparing the age and sex trajectories of SARS-CoV-2 morbidity with other respiratory pathogens points to potential immune mechanisms. (preprint)

Comparing age and sex differences in SARS-CoV-2 hospitalization and mortality with influenza and other health outcomes opens the way to generating hypotheses as to the underlying mechanisms, building on the extraordinary advances in immunology and physiology that have occurred over the last year. Notable departures in health outcomes starting around puberty suggest that burdens associated with influenza and other causes are reduced relative to the two emergent coronaviruses over much of adult life. Two possible hypotheses could explain this: protective adaptive immunity for influenza and other infections, or greater sensitivity to immunosenescence in the coronaviruses. Comparison of sex differences suggest an important role for adaptive immunity; but immunosenescence might also be relevant, if males experience faster immunosenescence. Involvement of the renin-angiotensin-system in SARS-CoV-2 infection might drive high sensitivity to disruptions of homeostasis. Overall, these results highlight the long tail of vulnerability in the age profile relevant to the emergent coronaviruses, which more transmissible variants have the potential to uncover at the younger end of the scale, and aging populations will expose at the other end of the scale.

Early chains of transmission of COVID-19 in France (preprint)

IntroductionSARS-CoV-2, which causes COVID-19, has spread rapidly across the world. A dedicated surveillance system was implemented in France in January 2020 to improve early detection of cases and their contacts and limit secondary transmission. Our objective was to use contact-tracing data collected during this initial phase of the epidemic to better characterize SARS-CoV-2 transmission. MethodsWe analysed data collected during contact tracing and retrospective epidemiological investigations in France from 24 January to 30 March 2020. We assessed the secondary clinical attack rate and characterized the risk of a contact becoming a case. We described chains of transmission and estimated key parameters of spread. ResultsOver the study period, 6,082 contacts of 735 confirmed cases were traced. The overall secondary clinical attack rate was 4.1% (95%CI 3.6-4.6) and increased with age of the index case and of the contact. Family contacts were at higher risk of becoming cases (adjusted odds ratio 2.1 (95%CI 1.4-3.0)) while nosocomial contacts were at lower risk (adjusted odds ratio 0.3 (95%CI 0.1-0.7)), compared to coworkers/friends. We identified 328 infector/infectee pairs, 49% of which were family members. The distribution of secondary cases was highly over-dispersed with 80% of secondary cases being caused by 10% of cases. The mean serial interval was 5.1 days (interquartile range 2-8 days) in contact-tracing pairs where late transmission events may be censored, and 6.8 (3-8) days in pairs investigated retrospectively. ConclusionThis study contributes to improving our knowledge of SARS-CoV-2 transmission, such as the importance of superspreading events. Contact-tracing data are challenging to collect but are key to better understand emerging pathogens. Funding statementThis work was supported by the LabEx "Integrative Biology of Emerging Infectious Diseases (IBEID)" (Grant Number ANR-10-LABX-62-IBEID), Sante Publique France, the INCEPTION project (PIA/ANR-16-CONV-0005), and the European Unions Horizon 2020 research and innovation program under grants 101003589 (RECOVER) and 874735 (VEO).

Ready for a BASE jump? Do not neglect SARS-CoV-2 hospitalization and fatality risks in the middle-aged adult population. (preprint)

Seroprevalence results coupled with surveillance data were used to estimate the SARS-CoV-2 infection hospitalization (IHR) and infection fatality ratios (IFR) in France. IHR and IFR were dramatically high in the very elderly (80-90 years: IHR: 30%, IFR: 11%), but also substantial in middle-aged adults (40-50 years: IHR: 1.2%, IFR: 0.05%).