BackgroundIn 2014–2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations.Methods and findingsPre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient’s individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient’s characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p<10−6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality.ConclusionsFavipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses.Trial registrationClinicalTrials.gov NCT02329054

ImportanceOmicron is phylogenetically- and antigenically-distinct from earlier SARS-CoV-2 variants and the original vaccine strain. Protection conferred by prior SARS-CoV-2 infection against Omicron re-infection, and the added value of vaccination, require quantification.ObjectiveTo estimate protection against Omicron re-infection and hospitalization conferred by prior heterologous SARS-CoV-2 (non-Omicron) infection and/or up to three doses of (ancestral, Wuhan-like) mRNA vaccine.DesignTest-negative study between December 26 (epi-week 52), 2021 and March 12 (epi-week 10), 2022.SettingPopulation-based, province of Quebec, CanadaParticipantsCommunity-dwelling ≥12-year-olds tested for SARS-CoV-2.ExposuresPrior laboratory-confirmed infection with/without mRNA vaccination.OutcomesLaboratory-confirmed SARS-CoV-2 re-infection and hospitalization, presumed Omicron by genomic surveillance. The odds of prior non-Omicron infection with/without vaccination were compared among Omicron cases/hospitalizations versus test-negative controls (single randomly-selected per individual). Adjusted odds ratios controlled for age, sex, testing-indication and epi-week. Analyses were stratified by severity and time since last non-Omicron infection or vaccine dose.ResultsWithout vaccination, prior non-Omicron infection reduced the Omicron re-infection risk by 44% (95%CI:38-48), decreasing from 66% (95%CI:57-73) at 3-5 months to 35% (95%CI:21-47) at 9-11 months post-infection and <30% thereafter. The more severe the prior infection, the greater the risk reduction: 8% (95%CI:17-28), 43% (95%CI:37-49) and 68% (95%CI:51-80) for prior asymptomatic, symptomatic ambulatory or hospitalized infections. mRNA vaccine effectiveness against Omicron infection was consistently significantly higher among previously-infected vs. non-infected individuals at 65% (95%CI:63-67) vs. 20% (95%CI:16-24) for one-dose; 68% (95%CI:67-70) vs. 42% (95%CI:41-44) for two doses; and 83% (95%CI:81-84) vs. 73% (95%CI:72-73) for three doses.Infection-induced protection against Omicron hospitalization was 81% (95%CI: 66-89) increasing to 86% (95%CI:77-99) with one, 94% (95%CI:91-96) with two and 97%(95%CI:94-99) with three mRNA vaccine doses. Two-dose effectiveness against hospitalization among previously-infected individuals did not wane across 11 months and did not significantly differ from three-dose effectiveness despite longer follow-up (median 158 and 27 days, respectively).Conclusions and relevancePrior heterologous SARS-CoV-2 infection provided substantial and sustained protection against Omicron hospitalization, greatest among those also vaccinated. In the context of program goals to prevent severe outcomes and preserve healthcare system capacity, >2 doses of ancestral Wuhan-like vaccine may be of marginal incremental value to previously-infected individuals.

As previously noted among infants born to mothers with history of wild-type measles, antibody responses among children born to vaccinated mothers were reduced based on earlier administration of their first measles vaccine dose at ≤12 vs ≥15 months of age. Negative effects of earlier age at first measles vaccine dose persisted after the second dose. The measles elimination goal may require a careful balance between earlier infant protection and the risk of reduced antibody responses and secondary vaccine failure among successive birth cohorts systematically initiated to measles vaccination <15 months of age.

Objectives: To estimate the SARS-CoV-2 infection rate and the secondary attack rate among healthcare workers (HCWs) in Quebec, the most affected province of Canada during the first wave; to describe the evolution of work-related exposures and infection prevention and control (IPC) practices in infected HCWs; and to compare the exposures and practices between acute care hospitals (ACHs) and long-term care facilities (LTCFs). Design: Survey of cases Participants: Quebec HCWs from private and public institutions with laboratory-confirmed COVID-19 diagnosed between 1st March and 14th June 2020. HCWs ≥18 years old, having worked during the exposure period and survived their illness were eligible for the survey. Methods: After obtaining consent, 4542 HCWs completed a standardized questionnaire. COVID-19 rates and proportions of exposures and practices were estimated and compared between ACHs and LTCFs. Results: HCWs represented 25% (13,726/54,005) of all reported COVID-19 cases in Quebec and had an 11-times greater rate than non-HCWs. Their secondary household attack rate was 30%. Most affected occupations were healthcare support workers, nurses and nurse assistants, working in LTCFs (45%) and ACHs (30%). Compared to ACHs, HCWs of LTCFs had less training, higher staff mobility between working sites, similar PPE use but better self-reported compliance with at-work physical distancing. Sub-optimal IPC practices declined over time but were still present at the end of the first wave. Conclusion: Quebec HCWs and their families were severely affected during the first wave of COVID-19. Insufficient pandemic preparedness and suboptimal IPC practices likely contributed to high transmission in both LTCFs and ACHs.

Author summaryDuring the large Ebola outbreak that affected West Africa in 2014 and 2015, studies were launched to evaluate potential treatments for the disease. A clinical trial to evaluate the effectiveness of the antiviral drug favipiravir was conducted in Guinea. This paper describes the main challenges of the implementation of the trial in the Ebola treatment center of Guéckédou. Following the principles of the Good Clinical Research Practices, we explored the aspects of the community’s communication and engagement, ethical conduct, trial protocol compliance, informed consent of participants, ongoing benefit/risk assessment, record keeping, confidentiality of patients and study data, and roles and responsibilities of the actors involved. We concluded that several challenges have to be addressed to successfully implement a clinical trial during an international medical emergency but that the potential for collaboration between research teams and humanitarian organizations needs to be highlighted.

Background The prevalence of post-COVID conditions (PCC) and associated physical, psychological and cognitive symptoms was assessed among Quebec healthcare workers (HCWs) with COVID-19. Methods This case-control study compared 6061 symptomatic HCWs with PCR-confirmed COVID-19 between July 2020 and May 2021 with a random sample of 4390 symptomatic HCWs who were test-negative controls. The prevalence of physical symptoms lasting ≥4 weeks (PCC4w) or ≥12 weeks (PCC12w) was estimated among hospitalized and non-hospitalized cases. In multivariate models, sociodemographic and clinical characteristics, as well as vaccine history, were evaluated as potential risk factors. Prevalence ratios compared four aspects of self-reported cognitive dysfunction among PCC cases to controls, adjusting for psychological distress and fatigue. Results PCC4w and PCC12w prevalences of 46% (2,746/5,943) and 40% (653/1,746), respectively, were observed among non-hospitalized cases and 76% (90/118) and 68% (27/37), respectively, among hospitalized cases. Hospitalization, female sex and age were associated with higher PCC risk. A substantial proportion of non-hospitalized PCC4w cases often or very often reported cognitive dysfunction, including concentration (33%) or organizing (23%) difficulties, forgetfulness (20%) and loss of necessary items (10%). All four aspects of cognitive dysfunction were associated with PCC4w symptoms, psychological distress and fatigue. Conclusion PCC may be a frequent sequela of ambulatory COVID-19 in working-age adults, with important effects on cognition. With so many HCWs infected, the implications for quality healthcare delivery could be profound if cognitive dysfunction and other severe PCC symptoms persist in a professionally-disabling way. Further evaluation of PCC prevalence and prognosis is warranted.

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Olfactory and gustatory dysfunctions (OD, GD) are prevalent symptoms following COVID-19 and persist in 6%–44% of individuals post-infection. As only few reports have described their prognosis after 6 months, our main objective was to assess the prevalence of OD and GD 11-month post-COVID-19. We also aimed to determine intraclass correlation coefficients (ICC) of chemosensory self-ratings for the follow-up of chemosensory sensitivity. We designed an observational study and distributed an online questionnaire assessing chemosensory function to healthcare workers with a RT-PCR-confirmed SARS-CoV-2 infection 5- and 11-month post-COVID-19. Specifically, we assessed olfaction, gustation, and trigeminal sensitivity (10-point visual analog scale) and function (4-point Likert scale). We further measured clinically relevant OD using the Chemosensory Perception Test, a psychophysical test designed to provide a reliable remote olfactory evaluation. We included a total of 366 participants (mean [SD] age of 44.8 (11.7) years old). They completed the last online questionnaire 10.6 months (0.7) after the onset of COVID-19 symptoms. Of all participants, 307 (83.9%) and 301 (82.2%) individuals retrospectively reported lower olfactory or gustatory sensitivity during the acute phase of COVID-19. At the time of evaluation, 184 (50.3%) and 163 (44.5%) indicated reduced chemosensory sensitivity, 32.2% reported impairment of olfactory function while 24.9% exhibited clinically relevant OD. Olfactory sensitivity had a high test–retest reliability (ICC: 0.818; 95% CI: 0.760–0.860). This study suggests that chemosensory dysfunctions persist in a third of COVID-19 patients 11 months after COVID-19. OD appears to be a common symptom of post-COVID-19 important to consider when treating patients.