Résumé
Point-of-care (POC) nucleic acid detection technologies are poised to aid gold-standard technologies in controlling the COVID-19 pandemic, yet shortcomings in the capability to perform critically needed complex detection, such as multiplexed detection for viral variant surveillance, may limit their widespread adoption. Herein, we developed a robust multiplexed CRISPR-based detection using LwaCas13a and PsmCas13b to simultaneously diagnose SARS-CoV-2 infection and pinpoint the causative SARS-CoV-2 variant of concern (VOC)-including globally dominant VOCs Delta (B.1.617.2) and Omicron (B.1.1.529)-all while maintaining high levels of accuracy upon the detection of multiple SARS-CoV-2 gene targets. The platform has several attributes suitable for POC use: premixed, freeze-dried reagents for easy use and storage; convenient direct-to-eye or smartphone-based readouts; and a one-pot variant of the multiplexed detection. To reduce reliance on proprietary reagents and enable sustainable use of such a technology in low- and middle-income countries, we locally produced and formulated our own recombinase polymerase amplification reaction and demonstrated its equivalent efficiency to commercial counterparts. Our tool, CRISPR-based detection for simultaneous COVID-19 diagnosis and variant surveillance which can be locally manufactured, may enable sustainable use of CRISPR diagnostics technologies for COVID-19 and other diseases in POC settings.
Sujets)
COVID-19Résumé
The appropriate COVID-19 booster vaccine following inactivated or adenoviral vector COVID-19 vaccination is unclear. We evaluated the safety and immunogenicity of different booster vaccines, inactivated (BBIBP-CorV), chimpanzee adenoviral vector (ChAdOx1), or mRNA (BNT162b2 at full (30 µg), or half (15 µg) dose) in healthy adults who received 2-dose primary series of either inactivated vaccine (CoronaVac) or ChAdOx1 8-12 weeks earlier. Overall, the adverse events for all booster vaccines were mild and moderate. Two weeks post-booster dose, the neutralising antibody titres against Delta variant in CoronaVac-prime and ChAdOx1-prime were highest with for 30µg-BNT162b2 (411 vs 470) and 15µg-BNT162b2 (499 vs 358); followed by ChAdOx1 (271 vs 69), and BBIBP-CorV (61.3 vs 49). BNT162b2 also induced higher interferon gamma response. Heterologous COVID-19 boosting vaccination with BNT162b2 is the most immunogenic following CoronaVac or ChAdOx1 primary series. A lower dose BNT162b2 may be used as booster in settings with limited vaccine supply.
Sujets)
COVID-19Résumé
The appropriate COVID-19 booster vaccine following inactivated or adenoviral vector COVID-19 vaccination is unclear. We evaluated the safety and immunogenicity of different booster vaccines, inactivated (BBIBP-CorV), chimpanzee adenoviral vector (ChAdOx1), or mRNA (BNT162b2 at full (30 g), or half (15 g) dose) in healthy adults who received 2-dose primary series of either inactivated vaccine (CoronaVac) or ChAdOx1 8-12 weeks earlier. Overall, the adverse events for all booster vaccines were mild and moderate. Two weeks post-booster dose, the neutralising antibody titres against Delta variant in CoronaVac-prime and ChAdOx1-prime were highest with for 30g-BNT162b2 (411 vs 470) and 15g-BNT162b2 (499 vs 358); followed by ChAdOx1 (271 vs 69), and BBIBP-CorV (61.3 vs 49). BNT162b2 also induced higher interferon gamma response. Heterologous COVID-19 boosting vaccination with BNT162b2 is the most immunogenic following CoronaVac or ChAdOx1 primary series. A lower dose BNT162b2 may be used as booster in settings with limited vaccine supply.
Sujets)
COVID-19Résumé
Importance: Inactivated vaccine (CoronaVac) and chimpanzee adenovirus-vector vaccine (ChAdOx1) have been more available in resource-limited settings. However, the data comparing between these two vaccines in the same setting are limited. Objectives: To determine adverse events (AEs) and immunogenicity of CoronaVac and ChAdOx1 in health care workers (HCWs). Design: This prospective study was conducted from February to July 2021. Setting: A single center, university-based tertiary care center in Bangkok. Participants: Healthy HCWs. Exposure: Two doses of CoronaVac (4 weeks apart) or ChAdOx1 (8 weeks apart) intramuscularly. Main Outcomes and Measures: Self-reported AEs were collected for 7 days following each vaccination using electronic diary. The immunogenicity was determined by the level of IgG antibodies against receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S1 subunit). The 50% plaque reduction neutralization tests against original Wuhan strain and circulating VOCs were performed in subset of samples at 2 weeks after the second dose. Results: Of the 360 HCWs, 180 received each vaccine. The median (interquartile range: IQR) age was 35 (29-44) years old and 84.2% were female. Participants who received ChAdOx1 reported higher frequency of AEs than those received CoronaVac after both the first dose (84.4% vs. 66.1%, P < 0.001) and second dose (75.6% vs. 60.6%, P = 0.002), with more AEs in those younger than 30 years of age for both vaccines. The seroconversion rate was 75.6% and 100% following the first dose of CoronaVac and ChAdOx1, respectively. All participants seroconverted at 2 weeks after the second dose. The anti-SARS-CoV-2 RBD IgG levels induced by CoronaVac was lower than ChAdOX1 with geometric means of 164.4 and 278.5 BAU/mL, respectively (P = 0.0066). Both vaccines induced similar levels of neutralizing antibodies against the Wuhan strain, geometric mean titer (GMT) of 337.4 vs 331.2; however, CoronaVac induced significantly lower GMT against Alpha (23.1 vs. 92.5), Delta (21.2 vs. 69.7), and Beta (10.2 vs. 43.6) variants, respectively. Conclusions and Relevance: CoronaVac induces lower measurable antibodies but with lower frequency of AEs than ChAdOx1. The low neutralizing antibodies against the circulating VOCs induced by CoronaVac supports the need for earlier boosting to prevent breakthrough infections. Trial Registration: TCTR20210720002 https://www.thaiclinicaltrials.org/
Sujets)
Douleur paroxystiqueRésumé
Background The unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Methods and Findings We develop a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care to explore the potential public-health impact of a range of different potential therapeutics, under a range of different scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) drug efficacy in the absence of supportive care. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. We find the impact of drugs like dexamethasone (which are delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Conclusions There is a global asymmetry in who is likely to benefit from advances in the treatment of COVID-19 to date, which have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.
Sujets)
COVID-19Résumé
Background: The unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of current and proposed treatments, and consequently research and procurement priorities, have not been clear. Methods: First, we used a model of SARS-CoV-2 transmission, COVID-19 disease and clinical care pathways to explore the potential impact of dexamethasone - the main treatment currently for hospitalised COVID-19 patients - under scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) the efficacy of dexamethasone in the absence of supportive care. We then fit the model to the observed epidemic trajectory to-date in 165 countries and analysed the potential future impact of dexamethasone in different countries, regions, and country-income strata. Finally, we constructed hypothetical profiles of novel therapeutics based on current trials, and compared the potential impact of each under different circumstances. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. Findings: We find the potential benefit dexamethasone is severely limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). However, therapeutics for different patient populations (in particular, those not in hospital and early in the course of infection) and types of benefit (in particular, reducing disease severity or infectiousness) could have much greater benefits. Such therapeutics would have particular value in resource-poor settings facing large epidemics, even if the efficacy or achievable coverage of such therapeutics is lower in comparison to other types. Interpretation: People in low-income countries will benefit the least from advances in the treatment of COVID-19 to date, which have focussed on hospitalised-patients with adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have much greater impact. Such therapeutics may be feasible and research into their efficacy and means of delivery should be a priority. Funding: None to declare. Declaration of Interest: None to declare.
Sujets)
COVID-19Résumé
Background: The epidemiology and outcomes of COVID-19 patients in Thailand are scarce. Methods: This retrospective cohort study included adult hospitalized patients who were diagnosed with COVID-19 at Siriraj Hospital during February 2020 to April 2020. Results: Of 1,409 patients who underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2, 1,029 patients (73%) had risk factors for COVID-19 acquisition of which 107 patients had laboratory-confirmed COVID-19. Among the 104 patients who were treated with antiviral medications, 78 (75%) received 2-drug regimen (lopinavir/ritonavir or darunavir/ritonavir plus chloroquine or hydroxychloroquine), and 26 (25%) received a 3-drug regimen with favipiravir added to the 2-drug regimen. Disease progression was observed in 18 patients (16.8%). All patients with COVID-19 were discharged alive. Conclusions: The prevalence of COVID-19 was 7.5% among patients who underwent RT-PCR testing, and 10% among those having risk factors for COVID-19 acquisition. Combination antiviral therapies for COVID-19 patients were well-tolerated and produced a favorable outcome.