Cryo-EM Structure of the N501Y SARS-CoV-2 Spike Protein in Complex with a Potent Neutralizing Antibody (preprint)

The recently reported ''UK variant'' of SARS-CoV-2 is thought to be more infectious than previously circulating strains as a result of several changes, including the N501Y mutation. Here, we report cryo-EM structures of SARS-CoV-2 spike protein ectodomains with and without the N501Y mutation, in complex with the VH fragment of the potent neutralizing antibody, VH -Fc ab8. The mutation results in localized structural perturbations near Y501, but VH -Fc ab8 retains the ability to bind and neutralize pseudotyped viruses expressing the N501Y mutant with efficiencies comparable to that of unmutated viruses. Our results show that despite the higher affinity of ACE2 for the N501Y mutant, it can still be neutralized efficiently by an antibody that binds epitopes in the receptor binding domain of the SARS-CoV-2 spike protein.

Snake venom phospholipases A2 possess a strong virucidal activity against SARS-CoV-2 in vitro and block the cell fusion mediated by spike glycoprotein interaction with the ACE2 receptor (preprint)

A new coronavirus was recently discovered and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the absence of specific therapeutic and prophylactic agents, the virus has infected almost hundred million people, of whom nearly two million have died from the viral disease COVID-19. The ongoing COVID-19 pandemic is a global threat requiring new therapeutic strategies. Among them, antiviral studies based on natural molecules are a promising approach. The superfamily of phospholipases A2 (PLA2s) consists of a large number of members that catalyze the hydrolysis of phospholipids at a specific position. Here we show that secreted PLA2s from the venom of various snakes protect to varying degrees the Vero E6 cells widely used for the replication of viruses with evident cytopathic action, from SARS-CoV-2 infection PLA2s showed low cytotoxicity to Vero E6 cells and the high antiviral activity against SARS-CoV-2 with IC50 values ranged from 0.06 to 7.71 ug/ml. Dimeric PLA2 HDP-2 from the viper Vipera nikolskii, as well as its catalytic and inhibitory subunits, had potent virucidal (neutralizing) activity against SARS-CoV-2. Inactivation of the enzymatic activity of the catalytic subunit of dimeric PLA2 led to a significant decrease in antiviral activity. In addition, dimeric PLA2 inhibited cell-cell fusion mediated by SARS-CoV-2 spike glycoprotein. These results suggest that snake PLA2s, in particular dimeric ones, are promising candidates for the development of antiviral drugs that target lipid bilayers of the viral envelope and may be good tools to study the interaction of viruses with host cell membranes.

Novel RT-ddPCR assays for determining the transcriptional profile of SARS-CoV-2 (preprint)

The exact mechanism of coronavirus replication and transcription is not fully understood; however, a hallmark of coronavirus transcription is the generation of negative-sense RNA intermediates that serve as the templates for the synthesis of positive-sense genomic RNA (gRNA) and an array of subgenomic mRNAs (sgRNAs) encompassing sequences arising from discontinuous transcription. Existing PCR-based diagnostic assays for SAR-CoV-2 are qualitative or semi-quantitative and do not provide the resolution needed to assess the complex transcription dynamics of SARS-CoV-2 over the course of infection. We developed and validated a novel panel of specially designed SARS-CoV-2 ddPCR-based assays to map the viral transcription profile. Application of these assays to clinically relevant samples will enhance our understanding of SARS-CoV-2 replication and transcription and may also inform the development of improved diagnostic tools and therapeutics.

Inhibitor Binding Modulates Protonation States in the Active Site of SARS-CoV-2 Main Protease (preprint)

The main protease (3CL Mpro) from SARS-CoV-2, the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. Although drugs have been developed to inhibit the proteases from HIV, hepatitis C and other viruses, no such therapeutic is available to inhibit the main protease of SARS-CoV-2. To directly observe the protonation states in SARS-CoV-2 Mpro and to elucidate their importance in inhibitor binding, we determined the structure of the enzyme in complex with the -ketoamide inhibitor telaprevir using neutron protein crystallography at near-physiological temperature. We compared protonation states in the inhibitor complex with those determined for a ligand-free neutron structure of Mpro. This comparison revealed that three active-site histidine residues (His41, His163 and His164) adapt to ligand binding, altering their protonation states to accommodate binding of telaprevir. We suggest that binding of other -ketoamide inhibitors can lead to the same protonation state changes of the active site histidine residues. Thus, by studying the role of active site protonation changes induced by inhibitors we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 Mpro.

Epidemiological impact of prioritizing SARS-CoV-2 vaccination by antibody status: Mathematical modeling analyses (preprint)

Background: Vaccines against SARS-CoV-2 have been developed, but their availability falls far short of global needs. This study aimed to investigate the impact of prioritizing available doses on the basis of recipient antibody status, that is by exposure status, using Qatar as an example. Methods: Vaccination impact was assessed under different scale-up scenarios using a deterministic meta-population mathematical model describing SARS-CoV-2 transmission and disease progression in the presence of vaccination. Results: For a vaccine that protects against infection with an efficacy of 95%, half as many vaccinations were needed to avert one infection, disease outcome, or death by prioritizing antibody-negative individuals for vaccination. Prioritization by antibody status reduced incidence at a faster rate and led to faster elimination of infection and return to normalcy. Further prioritization by age group amplified the gains of prioritization by antibody status. Gains from prioritization by antibody status were largest in settings where the proportion of the population already infected at the commencement of vaccination was 30-60%, which is perhaps where most countries will be by the time vaccination programs are up and running. For a vaccine that only protects against disease and not infection, vaccine impact was reduced by half, whether this impact was measured in terms of averted infections or disease outcomes, but the relative gains from using antibody status to prioritize vaccination recipients were similar. Conclusions: Major health, societal, and economic gains can be achieved more quickly by prioritizing those who are antibody-negative while doses of the vaccine remain in short supply.

SARS-CoV-2 seroprevalence in the urban population of Qatar: An analysis of antibody testing on a sample of 112,941 individuals (preprint)

Background: Qatar has experienced a large SARS-CoV-2 epidemic. Our first objective was to assess the proportion of the urban population that has been infected with SARS-CoV-2, by measuring the prevalence of detectable antibodies. Our second objective was to identify predictors for infection and for having higher antibody titers. Methods: Residual blood specimens from individuals receiving routine and other clinical care between May 12-September 9, 2020 were tested for anti-SARS-CoV-2 antibodies. Associations with seropositivity and higher antibody titers were identified through regression analyses. Probability weights were applied in deriving the epidemiological measures. Results: We tested 112,941 individuals (~10% of Qatar urban population), of whom 51.6% were men and 66.0% were 20-49 years of age. Seropositivity was 13.3% (95% CI: 13.1-13.6%) and was significantly associated with sex, age, nationality, clinical-care type, and testing date. The proportion with higher antibody titers varied by age, nationality, clinical-care type, and testing date. There was a strong correlation between higher antibody titers and seroprevalence in each nationality, with a Pearson correlation coefficient of 0.85 (95% CI: 0.47-0.96), suggesting that higher antibody titers may indicate repeated exposure to the virus. The percentage of antibody-positive persons with prior PCR-confirmed diagnosis was 47.1% (95% CI: 46.1-48.2%), severity rate was 3.9% (95% CI: 3.7-4.2%), criticality rate was 1.3% (95% CI: 1.1-1.4%), and fatality rate was 0.3% (95% CI: 0.2-0.3%). Conclusions: Fewer than two in every 10 individuals in Qatar urban population had detectable antibodies against SARS-CoV-2 between May 12-September 9, 2020, suggesting that this population is still far from the herd immunity threshold and at risk from a subsequent epidemic wave.

Are commercial antibody assays substantially underestimating SARS-CoV-2 ever infection? An analysis on a population-based sample in a high exposure setting (preprint)

BackgroundPerformance of three automated commercial serological IgG-based assays was investigated for assessing SARS-CoV-2 ever (past or current) infection in a population-based sample in a high exposure setting. MethodsPCR and serological testing was performed on 394 individuals. ResultsSARS-CoV-2-IgG seroprevalence was 42.9% (95% CI 38.1%-47.8%), 40.6% (95% CI 35.9%-45.5%), and 42.4% (95% CI 37.6%-47.3%) using the CL-900i, VidasIII, and Elecsys assays, respectively. Between the three assays, overall, positive, and negative percent agreements ranged between 93.2%-95.7%, 89.3%-92.8%, and 93.8%-97.8%, respectively; Cohen kappa statistic ranged from 0.86-0.91; and 35 specimens (8.9%) showed discordant results. Among all individuals, 12.5% (95% CI 9.6%-16.1%) had current infection, as assessed by PCR. Of these, only 34.7% (95% CI 22.9%-48.7%) were seropositive by at least one assay. A total of 216 individuals (54.8%; 95% CI 49.9%-59.7%) had evidence of ever infection using antibody testing and/or PCR during or prior to this study. Of these, only 78.2%, 74.1%, and 77.3% were seropositive in the CL-900i, VidasIII, and Elecsys assays, respectively. ConclusionsAll three assays had comparable performance and excellent agreement, but missed at least 20% of individuals with past or current infection. Commercial antibody assays can substantially underestimate ever infection, more so when infection rates are high.

SARS-CoV-2 infection hospitalization, severity, criticality, and fatality rates (preprint)

BackgroundThis study aimed to estimate the age-stratified and overall morbidity and mortality rates of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on an analysis of the pervasive SARS-CoV-2 epidemic in Qatar, a country with <9% of the population being [≥]50 years of age. MethodsInfection disease outcomes were investigated using a Bayesian approach applied to an age-structured mathematical model describing SARS-CoV-2 transmission and disease progression in the population. The model was fitted to infection and disease time-series and age-stratified data. Two separate criteria for classifying morbidity were used: one based on actual recorded hospital admission (acute-care or intensive-care-unit hospitalization) and one based on clinical presentation as per World Health Organization classification of disease severity or criticality. ResultsAll outcomes showed very strong age dependence, with low values for those <50 years of age, but rapidly growing rates for those [≥]50 years of age. The strong age dependence was particularly pronounced for infection criticality rate and infection fatality rate. Infection acute-care and intensive-care-unit bed hospitalization rates were estimated at 13.10 (95% CI: 12.82-13.24) and 1.60 (95% CI: 1.58-1.61) per 1,000 infections, respectively. Infection severity and criticality rates were estimated at 3.06 (95% CI: 3.01-3.10) and 0.68 (95% CI: 0.67-0.68) per 1,000 infections, respectively. Infection fatality rate was estimated at 1.85 (95% CI: 1.74-1.95) per 10,000 infections. ConclusionsSARS-CoV-2 severity and fatality in Qatar was not high and demonstrated a very strong age dependence with <4 infections in every 1,000 being severe or critical and <2 in every 10,000 being fatal. Epidemic expansion in nations with young populations may lead to lower disease burden than previously thought.

Mutations in SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk (preprint)

SARS-CoV-2 mortality has been extensively studied in relationship to a patient's predisposition to the disease. However, how sequence variations in the SARS-CoV-2 genome affect mortality is not understood. To address this issue, we used a whole-genome sequencing (WGS) association study to directly link death of SARS-CoV-2 patients with sequence variation in the viral genome. Specifically, we analyzed 3,626 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) with reported patient's health status from COVID-19, i.e. deceased versus non-deceased. In total, evaluating 28,492 loci of the viral genome for association with patient/host mortality, two loci, 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 1.24e-12, and 1.24e-26, respectively). Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development.

LinearTurboFold: Linear-Time RNA Structural Alignment and Conserved Structure Prediction with Applications to Coronaviruses (preprint)

Many functional RNA structures are conserved across evolution, and such conserved structures provide critical targets for diagnostics and treatment. TurboFold II is a state-of-the-art software that can predict conserved structures and alignments given homologous sequences, but its cubic runtime and quadratic memory usage with sequence length prevent it from being applied to most full-length viral genomes. As the COVID-19 outbreak spreads, there is a growing need to have a fast and accurate tool to identify conserved regions of SARS-CoV-2. To address this issue, we present LinearTurboFold, which successfully accelerates TurboFold II without sacrificing accuracy on secondary structure and multiple sequence alignment prediction. LinearTurboFold is orders of magnitude faster than TurboFold II, e.g., 372 times faster (12 minutes vs. 3.1 days) on a group of five HIV-1 homologs with average length 9,686 nt. LinearTurboFold is able to scale up to the full sequence of SARS-CoV-2, and identifies conserved structures that have been supported by previous studies. Additionally, LinearTurboFold finds a list of novel conserved regions, including long-range base pairs, which may be useful for better understanding the virus.

Seroprevalence of SARS-CoV-2 infection in the craft and manual worker population of Qatar (preprint)

Background: Qatar experienced a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic that disproportionately affected the craft and manual worker (CMW) population who comprise 60% of the total population. This study aimed to assess the proportions of ever and/or current infection in this population. Methods: A cross-sectional population-based survey was conducted during July 26-September 09, 2020 to assess both anti-SARS-CoV-2 positivity through serological testing and polymerase chain reaction (PCR) positivity through PCR testing. Associations with antibody and PCR positivity were identified through regression analyses. Results: Study included 2,641 participants, 69.3% of whom were <40 years of age. Anti-SARS-CoV-2 positivity was estimated at 55.3% (95% CI: 53.3-57.3%) and was significantly associated with nationality, geographic location, educational attainment, occupation, presence of symptoms in the two weeks preceding the survey, and previous infection diagnosis. PCR positivity was assessed at 11.3% (95% CI: 9.9-12.8%) and was significantly associated with geographic location, contact with an infected person, and reporting two or more symptoms. Infection positivity (antibody and/or PCR positive) was assessed at 60.6% (95% CI: 9.9-12.8%). The proportion of antibody-positive CMWs that had a prior SARS-CoV-2 diagnosis was 9.3% (95% CI: 7.9-11.0%). Only seven infections were ever severe and one was ever critical - an infection severity rate of 0.5% (95% CI: 0.2-1.0%). Conclusions: Six in every 10 CMWs have been infected, suggestive of reaching the herd immunity threshold. Infection severity was low with only one in every 200 infections progressing to be severe or critical. Only one in every 10 infections had been previously diagnosed suggestive of mostly asymptomatic or minimally mild infections.

Timing the SARS-CoV-2 Index Case in Hubei Province (preprint)

Understanding when SARS-CoV-2 emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We employed a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated prior to the time of the most recent common ancestor. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province. By characterizing the likely dynamics of the virus before it was discovered, we show that over two-thirds of SARS-CoV-2-like zoonotic events would be self-limited, dying out without igniting a pandemic. Our findings highlight the shortcomings of zoonosis surveillance approaches for detecting highly contagious pathogens with moderate mortality rates.

The rocaglate CR-31-B (-) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrations in vitro and ex vivo (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a betacoronavirus in the subgenus Sarbecovirus causes a respiratory disease with varying symptoms referred to as coronavirus disease 2019 (COVID-19) and is responsible for a pandemic that started in early 2020. With no vaccines or effective antiviral treatments available, and infection and fatality numbers continuing to increase globally, the quest for novel therapeutic solutions remains an urgent priority. Rocaglates, a class of plant-derived cyclopenta[b]benzofurans, exhibit broad-spectrum antiviral activity against positive- and negative-sense RNA viruses. This compound class inhibits eukaryotic initiation factor 4A (eIF4A)-dependent mRNA translation initiation, resulting in strongly reduced viral RNA translation. The synthetic rocaglate CR-31-B (-) has previously been shown to inhibit the replication of human coronaviruses, such as HCoV-229E and MERS-CoV, as well as Zika-, Lassa-, Crimean Congo hemorrhagic fever virus in primary cells. Here, we assessed the antiviral activity of CR-31-B (-) against SARS-CoV-2 using both in vitro and ex vivo cell culture models. In African green monkey Vero E6 cells, CR-31-B (-) inhibited SARS-CoV-2 replication with an EC50 of ~1.8 nM. In line with this, viral protein accumulation and replication/transcription complex formation were found to be strongly reduced by this compound. In an ex vivo infection system using human airway epithelial cells, CR-31-B (-) was found to cause a massive reduction of SARS-CoV-2 titers by about 4 logs to nearly non-detectable levels. The data reveal a potent anti-SARS-CoV-2 activity by CR-31-B (-), corroborating previous results obtained for other coronaviruses and supporting the idea that rocaglates may be used in first-line antiviral intervention strategies against novel and emerging RNA virus outbreaks.

In Vitro Efficacy of "Essential Iodine Drops" Against Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) (preprint)

Background: Aerosolization of respiratory droplets is considered the main route of coronavirus disease 2019 (COVID-19). Therefore, reducing the viral load of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) shed via respiratory droplets is potentially an ideal strategy to prevent the spread of the pandemic. The in vitro virucidal activity of intranasal Povidone-Iodine (PVP-I) has been demonstrated recently to reduce SARS-CoV-2 viral titres. This study evaluated the virucidal activity of the aqueous solution of Iodine-V (a clathrate complex formed by elemental iodine and fulvic acid) as in Essential Iodine Drops (EID) with 200 microgram elemental iodine/ml content against SARS-CoV-2 to ascertain whether it is a better alternative to PVP-I. Methods: SARS-CoV-2 (USAWA1/2020 strain) virus stock was prepared by infecting Vero 76 cells (ATCC CRL-1587) until cytopathic effect (CPE). The virucidal activity of EID against SARS-CoV-2 was tested in three dilutions (1:1; 2:1 and 3:1) in triplicates by incubating at room temperature (22 +/- 2 Celsius) for either 60 or 90 seconds. The surviving viruses from each sample were quantified by a standard end-point dilution assay. Results: EID (200 microgram iodine/ml) after exposure for 60 and 90 seconds was compared to controls. In both cases, the viral titre was reduced by 99% (LRV 2.0). The 1:1 dilution of EID with virus reduced SARS-CoV-2 virus from 31,623 cell culture infectious dose 50% (CCCID50) to 316 CCID50 within 90 seconds. Conclusion: Substantial reductions in LRV by Iodine-V in EID confirmed the activity of EID against SARS-CoV-2 in vitro, demonstrating that Iodine-V in EID is effective at inactivating the virus in vitro and therefore suggesting its potential application intranasally to reduce SARS-CoV-2 transmission from known or suspected COVID-19 patients.

Mathematical modeling of the SARS-CoV-2 epidemic in Qatar and its impact on the national response to COVID-19 (preprint)

Background: Mathematical modeling constitutes an important tool for planning robust responses to epidemics. This study was conducted to guide the Qatari national response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic. The study investigated the time course of the epidemic, forecasted healthcare needs, predicted the impact of social and physical distancing restrictions, and rationalized and justified easing of restrictions. Methods: An age-structured deterministic model was constructed to describe SARS-CoV-2 transmission dynamics and disease progression throughout the population. Results: The enforced social and physical distancing interventions flattened the epidemic curve, reducing the peaks for incidence, prevalence, acute-care hospitalization, and intensive care unit (ICU) hospitalizations by 87%, 86%, 76%, and 78%, respectively. The daily number of new infections was predicted to peak at 12,750 on May 23, and active-infection prevalence was predicted to peak at 3.2% on May 25. Daily acute-care and ICU-care hospital admissions and occupancy were forecast accurately and precisely. By October 15, 2020, the basic reproduction number R0 had varied between 1.07-2.78, and 50.8% of the population were estimated to have been infected (1.43 million infections). The proportion of actual infections diagnosed was estimated at 11.6%. Applying the concept of Rt tuning, gradual easing of restrictions was rationalized and justified to start on June 15, 2020, when Rt declined to 0.7, to buffer the increased interpersonal contact with easing of restrictions and to minimize the risk of a second wave. No second wave has materialized as of October 15, 2020, five months after the epidemic peak. Conclusions: Use of modeling and forecasting to guide the national response proved to be a successful strategy, reducing the toll of the epidemic to a manageable level for the healthcare system.

Evidence for and level of herd immunity against SARS-CoV-2 infection: the ten-community study (preprint)

Background: Qatar experienced a large severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic that disproportionately affected the craft and manual workers (CMWs) who constitute 60% of the population. This study aimed to investigate level of immunity in communities within this population as well as infection exposure required to achieve herd immunity. Methods: Anti-SARS-CoV-2 seropositivity was assessed in ten CMW communities between June 21 and September 9, 2020. PCR positivity, infection positivity (antibody and/or PCR positive), and infection severity rate were also estimated. Associations with anti-SARS-CoV-2 positivity were investigated using regression analyses. Results: Study included 4,970 CMWs who were mostly men (95.0%) and <40 years of age (71.5%). Seropositivity ranged from 54.9% (95% CI: 50.2-59.4%) to 83.8% (95% CI: 79.1-87.7%) in the different CMW communities. Pooled mean seropositivity across all communities was 66.1% (95% CI: 61.5-70.6%). PCR positivity ranged from 0.0% to 10.5% (95% CI: 7.4-14.8%) in the different CMW communities. Pooled mean PCR positivity was 3.9% (95% CI: 1.6-6.9%). Median cycle threshold (Ct) value was 34.0 (range: 15.8-37.4). The majority (79.5%) of PCR-positive individuals had Ct value >30 indicative of earlier rather than recent infection. Infection positivity (antibody and/or PCR positive) ranged from 62.5% (95% CI: 58.3-66.7%) to 83.8% (95% CI: 79.1-87.7%) in the different CMW communities. Pooled mean infection positivity was 69.5% (95% CI: 62.8-75.9%). Only five infections were ever severe and one was ever critical, an infection severity rate of 0.2% (95% CI: 0.1-0.4%). Conclusions: Based on an extended range of epidemiological measures, active infection is rare in these communities with limited if any sustainable infection transmission for clusters to occur. At least some CMW communities in Qatar have reached or nearly reached herd immunity for SARS-CoV-2 infection at a proportion of ever infection of 65-70%.

Characterizing the Qatar advanced-phase SARS-CoV-2 epidemic (preprint)

ABSTRACT Background: Qatar has a population of 2.8 million, over half of whom are expatriate craft and manual workers (CMW). We aimed to characterize the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic in Qatar. Methods: A series of epidemiologic studies were conducted including analysis of the national SARS-CoV-2 PCR testing and hospitalization database, community surveys assessing current infection, ad-hoc PCR testing campaigns in workplaces and residential areas, serological testing for antibody on blood specimens collected for routine clinical screening/management, national Coronavirus Diseases 2019 (COVID-19) death registry, and a mathematical model. Results: By July 10, 397,577 individuals had been PCR tested for SARS-CoV-2, of whom 110,986 were positive, a positivity cumulative rate of 27.9% (95% CI: 27.8-28.1%). PCR positivity of nasopharyngeal swabs in a national community survey (May 6-7) including 1,307 participants was 14.9% (95% CI: 11.5-19.0%); 58.5% of those testing positive were asymptomatic. Across 448 ad-hoc PCR testing campaigns in workplaces and residential areas including 26,715 individuals, pooled mean PCR positivity was 15.6% (95% CI: 13.7-17.7%). SARS-CoV-2 antibody prevalence was 24.0% (95% CI: 23.3-24.6%) in 32,970 residual clinical blood specimens. Antibody prevalence was only 47.3% (95% CI: 46.2-48.5%) in those who had at least one PCR positive result, but it was 91.3% (95% CI: 89.5-92.9%) among those who were PCR positive >3 weeks before serology testing. There were substantial differences in exposure to infection by nationality and sex, reflecting risk differentials between the craft/manual workers and urban populations. As of July 5, case severity rate, based on the WHO severity classification, was 3.4% and case fatality rate was 1.4 per 1,000 persons. Model-estimated daily number of infections and active-infection prevalence peaked at 22,630 and 5.7%, respectively, on May 21 and May 23. Attack rate (ever infection) was estimated at 53.5% on July 12. R0 ranged between 1.45-1.68 throughout the epidemic. Rt was estimated at 0.70 on June 15, which was hence set as onset date for easing of restrictions. Age was by far the strongest predictor of severe, critical, or fatal infection. Conclusions: Qatar has experienced a large SARS-CoV-2 epidemic that is rapidly declining, apparently due to exhaustion of susceptibles. The epidemic demonstrated a classic susceptible-infected-recovered 'SIR' dynamics with a rather stable R0 of about 1.6. The young demographic structure of the population, in addition to a resourced public health response, yielded a milder disease burden and lower mortality than elsewhere.