Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection. METHODS: In an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated. RESULTS: A total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR-confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups. CONCLUSIONS: A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596.).

Trends in Clostridioides difficile infection rates in Canadian hospitals during the coronavirus disease 2019 (COVID-19) pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has placed significant burden on healthcare systems. We compared Clostridioides difficile infection (CDI) epidemiology before and during the pandemic across 71 hospitals participating in the Canadian Nosocomial Infection Surveillance Program. Using an interrupted time series analysis, we showed that CDI rates significantly increased during the COVID-19 pandemic.

Vaccine regulation should require and enforce the inclusion of pregnant and breastfeeding women in prelicensure clinical trials.

Exclusion of pregnant and breastfeeding women from the pivotal randomized controlled trials for COVID-19 vaccines that led to emergency regulatory approval created gaps in data needed for vaccine policy, healthcare provider recommendations, and women's decisions about vaccination. We argue that such knowledge gaps increase potential for vaccine hesitancy and misinformation relating to the health of women and infants, and that these gaps in evidence are avoidable. Over several decades, ethical and scientific guidance, scholarship, and advocacy in favor of pregnant and breastfeeding women's participation in clinical development of vaccines has accumulated. Guidance on how to include pregnant and breastfeeding women in vaccine trials ethically and safely predates the COVID-19 pandemic but has yet to be routinely incorporated in vaccine development. We highlight the important role regulatory authorities could play in requiring that pregnant and breastfeeding women be eligible as volunteer participants in prelicensure vaccine trials for products that are expected to be used in this population. Inclusion of pregnant and breastfeeding populations in clinical trials leading to market approval or emergency use authorization should be undertaken early or concurrently at the time of trials in the general population.

Operationalizing integrated needs-based workforce planning at Nova Scotia Health in response to the COVID-19 pandemic.

This paper documents Nova Scotia Health's progress in operationalizing integrated needs-based workforce planning as part of its ongoing response to the pandemic. A multidisciplinary workforce planning team with representation spanning key portfolios was created to facilitate the organization's response to the pandemic. Analyses applied early in Wave 3 of the pandemic showed large projected shortages in several professions and identified which services would likely be scarcest among the available workforce relative to patient need. Based on these results, the workforce planning team recommended and supported operational teams in implementing a multi-faceted set of interventions aimed at increasing the availability of individuals with these competencies. These interventions collectively yielded an adequate supply of additional competent personnel to meet the needs of COVID-19 inpatients across the province through the third wave of the pandemic. Lessons learned are proving critical to maintaining core operations during Wave 4 of the pandemic.

Impact of non-pharmaceutical interventions and vaccination on COVID-19 outbreaks in Nunavut, Canada: a Canadian Immunization Research Network (CIRN) study.

BACKGROUND: Nunavut, the northernmost Arctic territory of Canada, experienced three community outbreaks of the coronavirus disease 2019 (COVID-19) from early November 2020 to mid-June 2021. We sought to investigate how non-pharmaceutical interventions (NPIs) and vaccination affected the course of these outbreaks. METHODS: We used an agent-based model of disease transmission to simulate COVID-19 outbreaks in Nunavut. The model encapsulated demographics and household structure of the population, the effect of NPIs, and daily number of vaccine doses administered. We fitted the model to inferred, back-calculated infections from incidence data reported from October 2020 to June 2021. We then compared the fit of the scenario based on case count data with several counterfactual scenarios without the effect of NPIs, without vaccination, and with a hypothetical accelerated vaccination program whereby 98% of the vaccine supply was administered to eligible individuals. RESULTS: We found that, without a territory-wide lockdown during the first COVID-19 outbreak in November 2020, the peak of infections would have been 4.7 times higher with a total of 5,404 (95% CrI: 5,015-5,798) infections before the start of vaccination on January 6, 2021. Without effective NPIs, we estimated a total of 4,290 (95% CrI: 3,880-4,708) infections during the second outbreak under the pace of vaccination administered in Nunavut. In a hypothetical accelerated vaccine rollout, the total infections during the second Nunavut outbreak would have been 58% lower, to 1,812 (95% CrI: 1,593-2,039) infections. Vaccination was estimated to have the largest impact during the outbreak in April 2021, averting 15,196 (95% CrI: 14,798-15,591) infections if the disease had spread through Nunavut communities. Accelerated vaccination would have further reduced the total infections to 243 (95% CrI: 222-265) even in the absence of NPIs. CONCLUSIONS: NPIs have been essential in mitigating pandemic outbreaks in this large, geographically distanced and remote territory. While vaccination has the greatest impact to prevent infection and severe outcomes, public health implementation of NPIs play an essential role in the short term before attaining high levels of immunity in the population.

Final efficacy analysis, interim safety analysis, and immunogenicity of a single dose of recombinant novel coronavirus vaccine (adenovirus type 5 vector) in adults 18 years and older: an international, multicentre, randomised, double-blinded, placebo-controlled phase 3 trial.

BACKGROUND: The Ad5-nCoV vaccine is a single-dose adenovirus type 5 (Ad5) vectored vaccine expressing the SARS-CoV-2 spike protein that was well-tolerated and immunogenic in phase 1 and 2 studies. In this study, we report results on the final efficacy and interim safety analyses of the phase 3 trial. METHODS: This double-blind, randomised, international, placebo-controlled, endpoint-case driven, phase 3, clinical trial enrolled adults aged 18 years older at study centres in Argentina, Chile, Mexico, Pakistan, and Russia. Participants were eligible for the study if they had no unstable or severe underlying medical or psychiatric conditions; had no history of a laboratory-confirmed SARS-CoV-2 infection; were not pregnant or breastfeeding; and had no previous receipt of an adenovirus-vectored, coronavirus, or SARS-CoV-2 vaccine. After informed consent was obtained, 25 mL of whole blood was withdrawn from all eligible participants who were randomised in a 1:1 ratio to receive a single intramuscular dose of 0·5 mL placebo or a 0·5 mL dose of 5 × 1010 viral particle (vp)/mL Ad5-nCoV vaccine; study staff and participants were blinded to treatment allocation. All participants were contacted weekly by email, telephone, or text message to self-report any symptoms of COVID-19 illness, and laboratory testing for SARS-CoV-2 was done for all participants with any symptoms. The primary efficacy objective evaluated Ad5-nCoV in preventing symptomatic, PCR-confirmed COVID-19 infection occurring at least 28 days after vaccination in all participants who were at least 28 days postvaccination on Jan 15, 2021. The primary safety objective evaluated the incidence of any serious adverse events or medically attended adverse events postvaccination in all participants who received a study injection. This trial is closed for enrolment and is registered with ClinicalTrials.gov (NCT04526990). FINDINGS: Study enrolment began on Sept 22, 2020, in Pakistan, Nov 6, 2020, in Mexico, Dec 2, 2020, in Russia and Chile, and Dec 17, 2020, in Argentina; 150 endpoint cases were reached on Jan 15, 2021, triggering the final primary efficacy analysis. One dose of Ad5-nCoV showed a 57·5% (95% CI 39·7-70·0, p=0·0026) efficacy against symptomatic, PCR-confirmed, COVID-19 infection at 28 days or more postvaccination (21 250 participants; 45 days median duration of follow-up [IQR 36-58]). In the primary safety analysis undertaken at the time of the efficacy analysis (36 717 participants), there was no significant difference in the incidence of serious adverse events (14 [0·1%] of 18 363 Ad5-nCoV recipients and 10 [0·1%] of 18 354 placebo recipients, p=0·54) or medically attended adverse events (442 [2·4%] of 18 363 Ad5-nCoV recipients and 411 [2·2%] of 18 354 placebo recipients, p=0·30) between the Ad5-nCoV or placebo groups, or any serious adverse events considered related to the study product (none in both Ad5-nCoV and placebo recipients). In the extended safety cohort, 1004 (63·5%) of 1582 of Ad5-nCoV recipients and 729 (46·4%) of 1572 placebo recipients reported a solicited systemic adverse event (p<0·0001), of which headache was the most common (699 [44%] of Ad5-nCoV recipients and 481 [30·6%] of placebo recipients; p<0·0001). 971 (61·3%) of 1584 Ad5-nCoV recipients and 314 (20·0%) of 1573 placebo recipients reported an injection-site adverse event (p<0·0001), of which pain at the injection site was the most frequent; reported by 939 (59%) Ad5-nCoV recipients and 303 (19%) placebo recipients. INTERPRETATION: One dose of Ad5-nCoV is efficacious and safe in healthy adults aged 18 years and older. FUNDING: CanSino Biologics and the Beijing Institute of Biotechnology.

The Impact of Vaccination on Coronavirus Disease 2019 (COVID-19) Outbreaks in the United States.

BACKGROUND: Global vaccine development efforts have been accelerated in response to the devastating coronavirus disease 2019 (COVID-19) pandemic. We evaluated the impact of a 2-dose COVID-19 vaccination campaign on reducing incidence, hospitalizations, and deaths in the United States. METHODS: We developed an agent-based model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and parameterized it with US demographics and age-specific COVID-19 outcomes. Healthcare workers and high-risk individuals were prioritized for vaccination, whereas children under 18 years of age were not vaccinated. We considered a vaccine efficacy of 95% against disease following 2 doses administered 21 days apart achieving 40% vaccine coverage of the overall population within 284 days. We varied vaccine efficacy against infection and specified 10% preexisting population immunity for the base-case scenario. The model was calibrated to an effective reproduction number of 1.2, accounting for current nonpharmaceutical interventions in the United States. RESULTS: Vaccination reduced the overall attack rate to 4.6% (95% credible interval [CrI]: 4.3%-5.0%) from 9.0% (95% CrI: 8.4%-9.4%) without vaccination, over 300 days. The highest relative reduction (54%-62%) was observed among individuals aged 65 and older. Vaccination markedly reduced adverse outcomes, with non-intensive care unit (ICU) hospitalizations, ICU hospitalizations, and deaths decreasing by 63.5% (95% CrI: 60.3%-66.7%), 65.6% (95% CrI: 62.2%-68.6%), and 69.3% (95% CrI: 65.5%-73.1%), respectively, across the same period. CONCLUSIONS: Our results indicate that vaccination can have a substantial impact on mitigating COVID-19 outbreaks, even with limited protection against infection. However, continued compliance with nonpharmaceutical interventions is essential to achieve this impact.

Rapid disappearance of influenza following the implementation of COVID-19 mitigation measures in Hamilton, Ontario.

BACKGROUND: Public health measures, such as physical distancing and closure of schools and non-essential services, were rapidly implemented in Canada to interrupt the spread of the coronavirus disease 2019 (COVID-19). We sought to investigate the impact of mitigation measures during the spring wave of COVID-19 on the incidence of other laboratory-confirmed respiratory viruses in Hamilton, Ontario. METHODS: All nasopharyngeal swab specimens (n=57,503) submitted for routine respiratory virus testing at a regional laboratory serving all acute-care hospitals in Hamilton between January 2010 and June 2020 were reviewed. Testing for influenza A and B, respiratory syncytial virus, human metapneumovirus, parainfluenza I-III, adenovirus, and rhinovirus/enterovirus was done routinely using a laboratory-developed polymerase chain reaction multiplex respiratory viral panel. A Bayesian linear regression model was used to determine the trend of positivity rates of all influenza samples for the first 26 weeks of each year from 2010 to 2019. The mean positivity rate of Bayesian inference was compared with the weekly reported positivity rate of influenza samples in 2020. RESULTS: The positivity rate of influenza in 2020 diminished sharply following the population-wide implementation of COVID-19 interventions. Weeks 12-26 reported 0% positivity for influenza, with the exception of 0.1% reported in week 13. CONCLUSION: Public health measures implemented during the COVID-19 pandemic were associated with a reduced incidence of other respiratory viruses and should be considered to mitigate severe seasonal influenza and other respiratory virus pandemics.

Multifaceted strategies for the control of COVID-19 outbreaks in long-term care facilities in Ontario, Canada.

The novel coronavirus disease 2019 (COVID-19) has caused severe outbreaks in Canadian long-term care facilities (LTCFs). In Canada, over 80% of COVID-19 deaths during the first pandemic wave occurred in LTCFs. We sought to evaluate the effect of mitigation measures in LTCFs including frequent testing of staff, and vaccination of staff and residents. We developed an agent-based transmission model and parameterized it with disease-specific estimates, temporal sensitivity of nasopharyngeal and saliva testing, results of vaccine efficacy trials, and data from initial COVID-19 outbreaks in LTCFs in Ontario, Canada. Characteristics of staff and residents, including contact patterns, were integrated into the model with age-dependent risk of hospitalization and death. Estimates of infection and outcomes were obtained and 95% credible intervals were generated using a bias-corrected and accelerated bootstrap method. Weekly routine testing of staff with 2-day turnaround time reduced infections among residents by at least 25.9% (95% CrI: 23.3%-28.3%), compared to baseline measures of mask-wearing, symptom screening, and staff cohorting alone. A similar reduction of hospitalizations and deaths was achieved in residents. Vaccination averted 2-4 times more infections in both staff and residents as compared to routine testing, and markedly reduced hospitalizations and deaths among residents by 95.9% (95% CrI: 95.4%-96.3%) and 95.8% (95% CrI: 95.5%-96.1%), respectively, over 200 days from the start of vaccination. Vaccination could have a substantial impact on mitigating disease burden among residents, but may not eliminate the need for other measures before population-level control of COVID-19 is achieved.

Projecting the impact of a two-dose COVID-19 vaccination campaign in Ontario, Canada.

BACKGROUND: A number of highly effective COVID-19 vaccines have been developed and approved for mass vaccination. We evaluated the impact of vaccination on COVID-19 outbreak and disease outcomes in Ontario, Canada. METHODS: We used an agent-based transmission model and parameterized it with COVID-19 characteristics, demographics of Ontario, and age-specific clinical outcomes. We implemented a two-dose vaccination program according to tested schedules in clinical trials for Pfizer-BioNTech and Moderna vaccines, prioritizing healthcare workers, individuals with comorbidities, and those aged 65 and older. Daily vaccination rate was parameterized based on vaccine administration data. Using estimates of vaccine efficacy, we projected the impact of vaccination on the overall attack rate, hospitalizations, and deaths. We further investigated the effect of increased daily contacts at different stages during vaccination campaigns on outbreak control. RESULTS: Maintaining non-pharmaceutical interventions (NPIs) with an average of 74% reduction in daily contacts, vaccination with Pfizer-BioNTech and Moderna vaccines was projected to reduce hospitalizations by 27.3% (95% CrI: 22.3% - 32.4%) and 27.0% (95% CrI: 21.9% - 32.6%), respectively, over a one-year time horizon. The largest benefits of vaccination were observed in preventing deaths with reductions of 31.5% (95% CrI: 22.5% - 39.7%) and 31.9% (95% CrI: 22.0% - 41.4%) for Pfizer-BioNTech and Moderna vaccines, respectively, compared to no vaccination. We found that an increase of only 10% in daily contacts at the end of lockdown, when vaccination coverage with only one dose was 6%, would trigger a surge in the outbreak. Early relaxation of population-wide measures could lead to a substantial increase in the number of infections, potentially reaching levels observed during the peak of the second wave in Ontario. CONCLUSIONS: Vaccination can substantially mitigate ongoing COVID-19 outbreaks. Sustaining population-wide NPIs, to allow for a sufficient increase in population-level immunity through vaccination, is essential to prevent future outbreaks.

Routine saliva testing for the identification of silent coronavirus disease 2019 (COVID-19) in healthcare workers.

OBJECTIVE: Current COVID-19 guidelines recommend symptom-based screening and regular nasopharyngeal (NP) testing for healthcare personnel in high-risk settings. We sought to estimate case detection percentages with various routine NP and saliva testing frequencies. DESIGN: Simulation modeling study. METHODS: We constructed a sensitivity function based on the average infectiousness profile of symptomatic coronavirus disease 2019 (COVID-19) cases to determine the probability of being identified at the time of testing. This function was fitted to reported data on the percent positivity of symptomatic COVID-19 patients using NP testing. We then simulated a routine testing program with different NP and saliva testing frequencies to determine case detection percentages during the infectious period, as well as the presymptomatic stage. RESULTS: Routine biweekly NP testing, once every 2 weeks, identified an average of 90.7% (SD, 0.18) of cases during the infectious period and 19.7% (SD, 0.98) during the presymptomatic stage. With a weekly NP testing frequency, the corresponding case detection percentages were 95.9% (SD, 0.18) and 32.9% (SD, 1.23), respectively. A 5-day saliva testing schedule had a similar case detection percentage as weekly NP testing during the infectious period, but identified ~10% more cases (mean, 42.5%; SD, 1.10) during the presymptomatic stage. CONCLUSION: Our findings highlight the utility of routine noninvasive saliva testing for frontline healthcare workers to protect vulnerable patient populations. A 5-day saliva testing schedule should be considered to help identify silent infections and prevent outbreaks in nursing homes and healthcare facilities.

Estimations du taux de létalité de la COVID-19 au Canada et aux États-Unis sur une période donnée.

CONTEXTE: Les estimations du taux de létalité de la maladie à coronavirus 2019 (COVID-19) varient grandement selon les populations. L'objectif était d'estimer et de comparer ce taux pour le Canada et les États-Unis en tenant compte de 2 sources de biais potentiel du taux brut. MÉTHODES: Pour ce faire, nous sommes partis du nombre quotidien de cas confirmés et de décès au Canada et aux États-Unis pour la période du 31 janvier au 22 avril 2020. Nous y avons appliqué une méthode statistique qui réduit au minimum les biais du taux de létalité brut de 2 façons : en intégrant la durée de survie, soit le délai entre le début de la maladie et le décès, et en considérant que moins de 50 % des cas de COVID-19 sont confirmés (intervalle de confiance à 95 % 10 %­50 %). RÉSULTATS: À partir du nombre de cas confirmés au Canada, nous avons évalué le taux brut en date en 22 avril 2020 à 4,9 %, et le taux ajusté à 5,5 % (intervalle de crédibilité [ICr] 4,9 %­6,4 %). En appliquant divers taux de cas confirmés inférieurs à 50 %, nous avons obtenu un taux ajusté de 1,6 % (ICr 0,7 %­3,1 %). Pour les États-Unis, le taux brut en date du 20 avril 2020 était de 5,4 %, et le taux ajusté, de 6,1 % (ICr 5,4 %­6,9 %). Combiné à des taux de cas confirmés inférieurs à 50 %, le taux ajusté est passé à 1,78 % (ICr 0,8 %­3,6 %). INTERPRÉTATION: Nos estimations montrent que si le taux de cas confirmés est de moins de 50 %, le taux de létalité ajusté de la COVID-19 est vraisemblablement inférieur à 2 % au Canada. Aux États-Unis, les estimations sont plus élevées, mais le taux ajusté reste sous la barre des 2 %. Si le taux de cas confirmés était connu, nous pourrions mieux évaluer la virulence du coronavirus du syndrome respiratoire aigu sévère 2 et la charge associée.

Projection de la demande de lits de soins intensifs durant l'épidémie de COVID-19 au Canada.

CONTEXTE: La hausse des cas de maladie à coronavirus 2019 (COVID-19) au Canada peut créer une forte demande de soins hospitaliers et de soins intensifs. Nous avons évalué la mesure dans laquelle l'isolement volontaire des personnes présentant des symptômes légers retarde le sommet épidémique et réduit la demande de soins dans chaque province canadienne. MÉTHODES: Nous avons conçu un modèle de calcul et fait des simulations de la propagation de la COVID-19 dans chaque province. À partir des estimations des caractéristiques de la COVID-19, nous avons évalué la demande de lits d'hôpital et de lits de soins intensifs en l'absence d'isolement volontaire en supposant une moyenne de 2,5 cas secondaires, et avons comparé des scénarios en faisant varier le taux d'isolement volontaire des cas légers 24 heures après l'apparition des symptômes. RÉSULTATS: En l'absence d'isolement volontaire, l'épidémie atteindrait son sommet dans la première moitié de juin, et il faudrait en moyenne 569 jours-lits de soins intensifs par 10 000 habitants. Avec un taux d'isolement volontaire de 20 %, l'atteinte du sommet serait repoussée de 2 à 4 semaines, et la demande de lits diminuerait de 23,5 %; avec un taux de 40 %, le sommet serait repoussé de 2 à 4 semaines supplémentaires, et la demande de lits connaîtrait une baisse de 53,6 %. En fixant le taux d'occupation actuel des lits de soins intensifs à plus de 80 % et le taux d'isolement volontaire à 40 %, la demande de lits demeure supérieure au nombre de lits disponibles. INTERPRÉTATION: Au sommet de l'épidémie de COVID-19 au Canada, la demande de lits de soins intensifs excédera le nombre total de lits disponibles, même avec un taux d'isolement volontaire de 40 %. Nos résultats montrent que la situation sera difficile pour le système de santé et que l'isolement volontaire pourrait réduire la demande de soins hospitaliers et de soins intensifs.

Routine saliva testing for the identification of silent COVID-19 infections in healthcare workers.

Objective: Current COVID-19 guidelines recommend symptom-based screening and regular nasopharyngeal (NP) testing for healthcare personnel in high-risk settings. We sought to estimate case detection percentages with various routine NP and saliva testing frequencies. Design: Simulation modelling study. Methods: We constructed a sensitivity function based on the average infectiousness profile of symptomatic COVID-19 cases to determine the probability of being identified at the time of testing. This function was fitted to reported data on the percent positivity of symptomatic COVID-19 patients using NP testing. We then simulated a routine testing program with different NP and saliva testing frequencies to determine case detection percentages during the infectious period, as well as the pre-symptomatic stage. Results: Routine bi-weekly NP testing, once every two weeks, identified an average of 90.7% (SD: 0.18) of cases during the infectious period and 19.7% (SD: 0.98) during the pre-symptomatic stage. With a weekly NP testing frequency, the corresponding case detection percentages were 95.9% (SD: 0.18) and 32.9% (SD: 1.23), respectively. A 5-day saliva testing schedule had a similar case detection percentage as weekly NP testing during the infectious period, but identified about 10% more cases (mean: 42.5%; SD: 1.10) during the pre-symptomatic stage. Conclusion: Our findings highlight the utility of routine non-invasive saliva testing for frontline healthcare workers to protect vulnerable patient populations. A 5-day saliva testing schedule should be considered to help identify silent infections and prevent outbreaks in nursing homes and healthcare facilities.

The impact of vaccination on COVID-19 outbreaks in the United States.

BACKGROUND: Global vaccine development efforts have been accelerated in response to the devastating COVID-19 pandemic. We evaluated the impact of a 2-dose COVID-19 vaccination campaign on reducing incidence, hospitalizations, and deaths in the United States (US). METHODS: We developed an agent-based model of SARS-CoV-2 transmission and parameterized it with US demographics and age-specific COVID-19 outcomes. Healthcare workers and high-risk individuals were prioritized for vaccination, while children under 18 years of age were not vaccinated. We considered a vaccine efficacy of 95% against disease following 2 doses administered 21 days apart achieving 40% vaccine coverage of the overall population within 284 days. We varied vaccine efficacy against infection, and specified 10% pre-existing population immunity for the base-case scenario. The model was calibrated to an effective reproduction number of 1.2, accounting for current non-pharmaceutical interventions in the US. RESULTS: Vaccination reduced the overall attack rate to 4.6% (95% CrI: 4.3% - 5.0%) from 9.0% (95% CrI: 8.4% - 9.4%) without vaccination, over 300 days. The highest relative reduction (54-62%) was observed among individuals aged 65 and older. Vaccination markedly reduced adverse outcomes, with non-ICU hospitalizations, ICU hospitalizations, and deaths decreasing by 63.5% (95% CrI: 60.3% - 66.7%), 65.6% (95% CrI: 62.2% - 68.6%), and 69.3% (95% CrI: 65.5% - 73.1%), respectively, across the same period. CONCLUSIONS: Our results indicate that vaccination can have a substantial impact on mitigating COVID-19 outbreaks, even with limited protection against infection. However, continued compliance with non-pharmaceutical interventions is essential to achieve this impact.

Simulating the effect of school closure during COVID-19 outbreaks in Ontario, Canada.

BACKGROUND: The province of Ontario, Canada, has instituted indefinite school closures (SC) as well as other social distancing measures to mitigate the impact of the novel coronavirus disease 2019 (COVID-19) pandemic. We sought to evaluate the effect of SC on reducing attack rate and the need for critical care during COVID-19 outbreaks, while considering scenarios with concurrent implementation of self-isolation (SI) of symptomatic cases. METHODS: We developed an age-structured agent-based simulation model and parameterized it with the demographics of Ontario stratified by age and the latest estimates of COVID-19 epidemiologic characteristics. Disease transmission was simulated within and between different age groups by considering inter- and intra-group contact patterns. The effect of SC of varying durations on the overall attack rate, magnitude and peak time of the outbreak, and requirement for intensive care unit (ICU) admission in the population was estimated. Secondly, the effect of concurrent community-based voluntary SI of symptomatic COVID-19 cases was assessed. RESULTS: SC reduced attack rates in the range of 7.2-12.7% when the duration of SC increased from 3 to 16 weeks, when contacts among school children were restricted by 60-80%, and in the absence of SI by mildly symptomatic persons. Depending on the scenario, the overall reduction in ICU admissions attributed to SC throughout the outbreak ranged from 3.3 to 6.7%. When SI of mildly symptomatic persons was included and practiced by 20%, the reduction of attack rate and ICU admissions exceeded 6.3% and 9.1% (on average), respectively, in the corresponding scenarios. CONCLUSION: Our results indicate that SC may have limited impact on reducing the burden of COVID-19 without measures to interrupt the chain of transmission during both pre-symptomatic and symptomatic stages. While highlighting the importance of SI, our findings indicate the need for better understanding of the epidemiologic characteristics of emerging diseases on the effectiveness of social distancing measures.

Temporal estimates of case-fatality rate for COVID-19 outbreaks in Canada and the United States.

BACKGROUND: Estimates of the case-fatality rate (CFR) associated with coronavirus disease 2019 (COVID-19) vary widely in different population settings. We sought to estimate and compare the COVID-19 CFR in Canada and the United States while adjusting for 2 potential biases in crude CFR. METHODS: We used the daily incidence of confirmed COVID-19 cases and deaths in Canada and the US from Jan. 31 to Apr. 22, 2020. We applied a statistical method to minimize bias in the crude CFR by accounting for the survival interval as the lag time between disease onset and death, while considering reporting rates of COVID-19 cases less than 50% (95% confidence interval 10%-50%). RESULTS: Using data for confirmed cases in Canada, we estimated the crude CFR to be 4.9% on Apr. 22, 2020, and the adjusted CFR to be 5.5% (credible interval [CrI] 4.9%-6.4%). After we accounted for various reporting rates less than 50%, the adjusted CFR was estimated at 1.6% (CrI 0.7%-3.1%). The US crude CFR was estimated to be 5.4% on Apr. 20, 2020, with an adjusted CFR of 6.1% (CrI 5.4%-6.9%). With reporting rates of less than 50%, the adjusted CFR for the US was 1.78 (CrI 0.8%-3.6%). INTERPRETATION: Our estimates suggest that, if the reporting rate is less than 50%, the adjusted CFR of COVID-19 in Canada is likely to be less than 2%. The CFR estimates for the US were higher than those for Canada, but the adjusted CFR still remained below 2%. Quantification of case reporting can provide a more accurate measure of the virulence and disease burden of severe acute respiratory syndrome coronavirus 2.

Projecting demand for critical care beds during COVID-19 outbreaks in Canada.

BACKGROUND: Increasing numbers of coronavirus disease 2019 (COVID-19) cases in Canada may create substantial demand for hospital admission and critical care. We evaluated the extent to which self-isolation of mildly ill people delays the peak of outbreaks and reduces the need for this care in each Canadian province. METHODS: We developed a computational model and simulated scenarios for COVID-19 outbreaks within each province. Using estimates of COVID-19 characteristics, we projected the hospital and intensive care unit (ICU) bed requirements without self-isolation, assuming an average number of 2.5 secondary cases, and compared scenarios in which different proportions of mildly ill people practised self-isolation 24 hours after symptom onset. RESULTS: Without self-isolation, the peak of outbreaks would occur in the first half of June, and an average of 569 ICU bed days per 10 000 population would be needed. When 20% of cases practised self-isolation, the peak was delayed by 2-4 weeks, and ICU bed requirement was reduced by 23.5% compared with no self-isolation. Increasing self-isolation to 40% reduced ICU use by 53.6% and delayed the peak of infection by an additional 2-4 weeks. Assuming current ICU bed occupancy rates above 80% and self-isolation of 40%, demand would still exceed available (unoccupied) ICU bed capacity. INTERPRETATION: At the peak of COVID-19 outbreaks, the need for ICU beds will exceed the total number of ICU beds even with self-isolation at 40%. Our results show the coming challenge for the health care system in Canada and the potential role of self-isolation in reducing demand for hospital-based and ICU care.