Accounting for assay performance when estimating the temporal dynamics in SARS-CoV-2 seroprevalence in the U.S. (preprint)

Estimating the incidence of SARS-CoV-2 infection is central to understanding the state of the pandemic. Seroprevalence studies are often used to assess cumulative infections as they can identify asymptomatic infection. Since July 2020, commercial laboratories have conducted nationwide serosurveys for the U.S. CDC. They employed three assays, with different sensitivities and specificities, potentially introducing biases in seroprevalence estimates. Using mechanistic models, we show that accounting for assays explains some of the observed state-to-state variation in seroprevalence, and when integrating case and death surveillance data, we show that when using the Abbott assay, estimates of proportions infected can differ substantially from seroprevalence estimates. We also found that states with higher proportions infected (before or after vaccination) had lower vaccination coverages, a pattern corroborated using a separate dataset. Finally, to understand vaccination rates relative to the increase in cases, we estimated the proportions of the population that received a vaccine prior to infection.

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).

Evaluating the impact of curfews and other measures on SARS-CoV-2 transmission in French Guiana (preprint)

While general lockdowns have proven effective to control SARS-CoV-2 epidemics, they come with enormous costs for society. It is therefore essential to identify control strategies with lower social and economic impact. Here, we report and evaluate the control strategy implemented during a large SARS-CoV-2 epidemic in June-July 2020 in French Guiana that relied on curfews, targeted lockdowns and other measures. We find that the combination of these interventions reduced the basic reproduction number of SARS-CoV-2 from 1.7 to 1.1, which was sufficient to avoid saturation of hospitals. We estimate that thanks to the young demographics across the territory, the risk of hospitalisation following infection was 0.3 times that of metropolitan France and that about 20% of the population was infected by July. Our model projections are consistent with a recent seroprevalence study. The study showcases how mathematical modeling can be used to support healthcare planning and decision making in a context of high uncertainty.

Lockdown impact on age-specific contact patterns and behaviours in France (preprint)

In the first trimester 2020, a significant number of countries implemented general lockdowns of their populations to contain the quickly expanding SARS-CoV-2 epidemic and avoid major saturation of health care capacity. Understanding how these unprecedented measures impacted population behaviour and contact patterns is key to predict more accurately the health, social and economic impacts of such extreme actions if they were to be applied to future outbreaks. We set up an online survey to measure how the lockdown affected social contact patterns in France, and collected information from 42,036 participants aged 18 years and over between April 10 and April 28, 2020. Among the participants who normally worked outside home prior to the lockdown (72% of the survey population), 68% reported that they had moved to working from home and 17% reported being unemployed during the lockdown. Only 2% of participants used public transport during lockdown, as opposed to 37% before it. Participants reported increased frequency of washing hands, switch in greeting behaviour, but generally limited use of masks outside home. 138,934 contacts were reported, with an average 3.3 contacts per individual per day (1.7 for individuals aged >65 years old compared to 3.6 for younger age-groups). This represented a 70% reduction compared with previous surveys, consistent with reductions in transmission rates measured during the lockdown. Contacts in workplaces, shops, and transports on the previous day were respectively reported in only 11%, 31% and 0.5% of the participants. For those who maintained a professional activity outside home, the frequency of contacts at work dropped by 79%. This study shows that the lockdown dramatically affected population's behavior, work, risk perception and contact patterns. Both frequency and heterogeneity of contacts were affected, impacting potential important features of virus dissemination. Such surveys are essential to evaluate more accurately the impact of past or future lockdowns and anticipate epidemic dynamics in these conditions.

Seroprevalence of anti-SARS-CoV-2 IgG at the epidemic peak in French Guiana (preprint)

Background SARS-CoV-2 seroprevalence studies are crucial for clarifying dynamics in affected countries and determining the route that has already been achieved towards herd immunity. While Latin America has been heavily affected by the pandemic, only a few seroprevalence studies have been conducted there. Methods A cross-sectional survey was performed between 15 July 2020 and 23 July 2020 in 4 medical biology laboratories and 5 health centers of French Guiana, representing a period shortly after the epidemic peak. Samples were screened for the presence of anti-SARS-CoV-2 IgG directed against domain S1 of the SARS-CoV-2 spike protein using the anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) from Euroimmun. Results The overall seroprevalence was 15.4% [9.3%-24.4%] among 480 participants, ranging from 4.0% to 25.5% across the different municipalities. The seroprevalence did not differ according to gender (p=0.19) or age (p=0.51). Among SARS-CoV-2 positive individuals, we found that 24.6% [11.5%-45.2%] reported symptoms consistent with COVID-19. Conclusions Our findings revealed high levels of infection across the territory but a low number of resulting deaths, which can be explained by the young population structure.

Age-specific mortality and immunity patterns of SARS-CoV-2 infection in 45 countries (preprint)

The number of COVID-19 deaths is often used as a key indicator of SARS-CoV-2 epidemic size. However, heterogeneous burdens in nursing homes and variable reporting of deaths in elderly individuals can hamper comparisons of deaths and the number of infections associated with them across countries. Using age-specific death data from 45 countries, we find that relative differences in the number of deaths by age amongst individuals aged <65 years old are highly consistent across locations. Combining these data with data from 15 seroprevalence surveys we demonstrate how age-specific infection fatality ratios (IFRs) can be used to reconstruct infected population proportions. We find notable heterogeneity in overall IFR estimates as suggested by individual serological studies and observe that for most European countries the reported number of deaths amongst [≥]65s are significantly greater than expected, consistent with high infection attack rates experienced by nursing home populations in Europe. Age-specific COVID-19 death data in younger individuals can provide a robust indicator of population immunity.

Estimating the burden of SARS-CoV-2 in France (preprint)

France has been heavily affected by the SARS-CoV-2 epidemic and went into lockdown on the 17th March 2020. Using models applied to hospital and death data, we estimate the impact of the lockdown and current population immunity. We find 2.6% of infected individuals are hospitalized and 0.53% die, ranging from 0.001% in those <20y to 8.3% in those >80y. Across all ages, men are more likely to be hospitalized, enter intensive care, and die than women. The lockdown reduced the reproductive number from 3.3 to 0.5 (84% reduction). By 11 May, when interventions are scheduled to be eased, we project 3.7 million (range: 2.3-6.7) people, 5.7% of the population, will have been infected. Population immunity appears insufficient to avoid a second wave if all control measures are released at the end of the lockdown.

A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease (preprint)

The duration and nature of immunity generated in response to SARS-CoV-2 infection is unknown. Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The timescale of protection is a critical determinant of the future impact of the pathogen. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. The dynamics of immunity and nature of protection are relevant to discussions surrounding therapeutic use of convalescent sera as well as efforts to identify individuals with protective immunity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV-1, MERS-CoV and human endemic coronaviruses (HCoVs). We reviewed 1281 abstracts and identified 322 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While studies of SARS-CoV-2 are necessary to determine immune responses to it, evidence from other coronaviruses can provide clues and guide future research.