From the New England Journal of Medicine

Phase 1–2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine: “After randomization, 83 participants were assigned to receive the [NVX-CoV2373] vaccine with adjuvant and 25 without adjuvant, and 23 participants were assigned to receive placebo. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean, ≤ 2 days). One participant had mild fever that lasted 1 day. Unsolicited adverse events were mild in most participants; there were no severe adverse events. The addition of adjuvant resulted in enhanced immune responses, was antigen dose–sparing, and induced a T helper 1 (Th1) response. The two-dose 5-μg adjuvanted regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic COVID-19 patients (8344 and 983, respectively). At 35 days, NVX-CoV2373 appeared to be safe, and it elicited immune responses that exceeded levels in COVID-19 convalescent serum. The Matrix-M1 adjuvant induced CD4+ T-cell responses that were biased toward a Th1 phenotype.”

An mRNA vaccine against SARS-CoV-2 — preliminary report: “After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40 227 in the 25-μg group, 109 209 in the 100-μg group, and 213 526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299 751, 782 719, and 1 192 154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events. The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.”

Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates: “The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-μg dose group and 3481 in the 100-μg dose group. Vaccination induced type 1 helper T-cell (Th1)–biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in [bronchoalveolar lavage] fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-μg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group. Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralising activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung.”

Humoral immune response to SARS-CoV-2 in Iceland: “Of the 1797 persons who had recovered from SARS-CoV-2 infection, 1107 of the 1215 who were tested (91.1%) were seropositive; antiviral antibody titers assayed by two pan-Ig assays increased during 2 months after diagnosis by qPCR and remained on a plateau for the remainder of the study. Of quarantined persons, 2.3% were seropositive; of those with unknown exposure, 0.3% were positive. We estimate that 0.9% of Icelanders were infected with SARS-CoV-2 and that the infection was fatal in 0.3%. We also estimate that 56% of all SARS-CoV-2 infections in Iceland had been diagnosed with qPCR, 14% had occurred in quarantined persons who had not been tested with qPCR (or who had not received a positive result, if tested), and 30% had occurred in persons outside quarantine and not tested with qPCR. Our results indicate that antiviral antibodies against SARS-CoV-2 did not decline within 4 months after diagnosis. We estimate that the risk of death from infection was 0.3% and that 44% of persons infected with SARS-CoV-2 in Iceland were not diagnosed by qPCR.”

From the BMJ

Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis: “77 studies were included. Overall, 10% of pregnant and recently pregnant women attending or admitted to hospital for any reason were diagnosed as having suspected or confirmed COVID-19. The most common clinical manifestations of COVID-19 in pregnancy were fever (40%) and cough (39%). Compared with non-pregnant women of reproductive age, pregnant and recently pregnant women with COVID-19 were less likely to report symptoms of fever and myalgia and were more likely to need admission to an intensive care unit and invasive ventilation. 73 pregnant women (0.1%) with confirmed COVID-19 died from any cause. Increased maternal age, high body mass index, chronic hypertension, and pre-existing diabetes were associated with severe COVID-19 in pregnancy. Pre-existing maternal comorbidity was a risk factor for admission to an intensive care unit and invasive ventilation. Spontaneous preterm birth rate was 6% in women with COVID-19. The odds of any preterm birth was high in pregnant women with COVID-19 compared with those without the disease. A quarter of all neonates born to mothers with COVID-19 were admitted to the neonatal unit (25%) and were at increased risk of admission than those born to mothers without COVID-19. Conclusion: Pregnant and recently pregnant women are less likely to manifest COVID-19 related symptoms of fever and myalgia than non-pregnant women of reproductive age and are potentially more likely to need intensive care treatment for COVID-19. Pre-existing comorbidities, high maternal age, and high body mass index seem to be risk factors for severe COVID-19. Preterm birth rates are high in pregnant women with COVID-19 than in pregnant women without the disease.”

Clinical characteristics of children and young people admitted to hospital with COVID-19 in United Kingdom: prospective multicentre observational cohort study: “A systemic mucocutaneous-enteric cluster of symptoms was identified, which encompassed the symptoms for the WHO multisystem inflammatory syndrome in children (MIS-C) criteria. 18% (116/632) of children were admitted to critical care. On multivariable analysis, this was associated with age under 1 month, age 10–14 years, and black ethnicity. Six (1%) of 627 patients died in hospital, all of whom had profound comorbidity. 11% (52/456) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Children meeting MIS-C criteria were older (median age 10.7 years) and more likely to be of non-white ethnicity (64% v 42%). Children with MIS-C were five times more likely to be admitted to critical care (73% v 15%). In addition to the WHO criteria, children with MIS-C were more likely to present with fatigue (51% v 28%), headache (34% v 10%), myalgia (34% v 8%), sore throat (30% v 12%), and lymphadenopathy (20% v 3%) and to have a platelet count of less than 150 × 109/L (32% v 11%) than children who did not have MIS-C. No deaths occurred in the MIS-C group. Conclusions: Children and young people have less severe acute COVID-19 than adults. A systemic mucocutaneous-enteric symptom cluster was also identified in acute cases that shares features with MIS-C. This study provides additional evidence for refining the WHO MIS-C preliminary case definition. Children meeting the MIS-C criteria have different demographic and clinical features depending on whether they have acute SARS-CoV-2 infection (polymerase chain reaction positive) or are post-acute (antibody positive).”

Drug treatments for COVID-19: living systematic review and network meta-analysis: “23 randomised controlled trials were included in the analysis performed on 26 June 2020. The certainty of the evidence for most comparisons was very low because of risk of bias (lack of blinding) and serious imprecision. Glucocorticoids were the only intervention with evidence for a reduction in death compared with standard care (risk difference 37 fewer per 1000 patients, 95% credible interval 63 fewer to 11 fewer, moderate certainty) and mechanical ventilation (31 fewer per 1000 patients, 47 fewer to 9 fewer, moderate certainty). These estimates are based on direct evidence; network estimates for glucocorticoids compared with standard care were less precise because of network heterogeneity. Three drugs might reduce symptom duration compared with standard care: hydroxychloroquine (mean difference −4.5 days, low certainty), remdesivir (−2.6 days, moderate certainty), and lopinavir-ritonavir (−1.2 days, low certainty). Hydroxychloroquine might increase the risk of adverse events compared with the other interventions, and remdesivir probably does not substantially increase the risk of adverse effects leading to drug discontinuation. No other interventions included enough patients to meaningfully interpret adverse effects leading to drug discontinuation. Conclusion: Glucocorticoids probably reduce mortality and mechanical ventilation in patients with COVID-19 compared with standard care. The effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.”


Effect of hydrocortisone on 21-Day mortality or respiratory support among critically ill patients with COVID-19: “The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group. Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment. Conclusions: In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome.”

Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: “A total of 299 patients were enrolled and all completed follow-up. Patients randomised to the dexamethasone group had a mean 6.6 ventilator-free days during the first 28 days vs 4.0 ventilator-free days in the standard care group. At 7 days, patients in the dexamethasone group had a mean sequential organ failure assessment score of 6.1 vs 7.5 in the standard care group. There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events. Conclusions: Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.”

Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: “After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%–71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (–1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support–free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.”

Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis: “A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as ‘low’ for 6 of the 7 mortality results and as ‘some concerns’ in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomised to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53–0.82]; P < 0.001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = 0.31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48–1.01; P = 0.053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50–0.82; P < 0.001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43–1.12; P = 0.13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29–2.87; P = 0.87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomised to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo. Conclusions: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.”

From the Lancet

Comparison of molecular testing strategies for COVID-19 control: a mathematical modelling study: “If all individuals with symptoms compatible with COVID-19 self-isolated and self-isolation was 100% effective in reducing onwards transmission, self-isolation of symptomatic individuals would result in a reduction in R of 47% (95% uncertainty interval [UI] 32–55). PCR testing to identify SARS-CoV-2 infection soon after symptom onset could reduce the number of individuals needing to self-isolate, but would also reduce the effectiveness of self-isolation (around 10% would be false negatives). Weekly screening of health-care workers and other high-risk groups irrespective of symptoms by use of PCR testing is estimated to reduce their contribution to SARS-CoV-2 transmission by 23% (95% UI 16–40), on top of reductions achieved by self-isolation following symptoms, assuming results are available at 24 h. The effectiveness of test and trace depends strongly on coverage and the timeliness of contact tracing, potentially reducing R by 26% (95% UI 14–35) on top of reductions achieved by self-isolation following symptoms, if 80% of cases and contacts are identified and there is immediate testing following symptom onset and quarantine of contacts within 24 h. Among currently available antibody tests, performance has been highly variable, with specificity around 90% or lower for rapid diagnostic tests and 95–99% for laboratory-based ELISA and chemiluminescent assays. Conclusion: Molecular testing can play an important role in prevention of SARS-CoV-2 transmission, especially among health-care workers and other high-risk groups, but no single strategy will reduce R below 1 at current levels of population immunity. Immunity passports based on antibody tests or tests for infection face substantial technical, legal, and ethical challenges.”

COVID-19 and multisystem inflammatory syndrome in children and adolescents: “As the COVID-19 outbreak evolves, the scientific community needs to generate good evidence for the diagnosis and treatment of MIS-C. A recent report from the US CDC describes in detail the clinical characteristics and treatment modalities available for patients with MIS-C in a large case series of the US population. However, epidemiological data using cohort or case-control designs are urgently needed to establish the cause and causality between COVID-19 and MIS-C. Clinical management and potential treatment protocols should be tested in randomised controlled trials or cohort designs to compare clinical outcomes and changes in inflammatory markers. It is also important to understand whether Kawasaki disease-type morbidities, including coronary artery dilatation, occur in patients with MIS-C and how frequently they occur, and whether the use of aspirin or other interventions can reduce this risk and long-term morbidities. Laboratory investigations into the pathophysiological and immunological mechanisms of the disease are urgently needed to provide insights into potential treatment targets and to inform strategies for vaccine development. Finally, with the small number of cases globally, establishing an international research collaboration is vital to rapidly conduct these studies in a coordinated and effective way.”

Risk of COVID-19 in health-care workers in Denmark: an observational cohort study: “Between April 15 and April 23, 2020, we screened 29 295 health-care workers, of whom 28 792 (98.28%) provided their test results. We identified 1163 (4.04% [95% CI, 3.82–4.27]) seropositive health-care workers. Seroprevalence was higher in health-care workers than in blood donors (142 [3.04%] of 4672). Seroprevalence was higher in male health-care workers (331 [5.45%] of 6077) than in female health-care workers (832 [3.66%] of 22 715). Frontline health-care workers working in hospitals had a significantly higher seroprevalence (779 [4.55%] of 16 356) than health-care workers in other settings (384 [3.29%] of 11 657). Health-care workers working on dedicated COVID-19 wards (95 [7·19%] of 1321) had a significantly higher seroprevalence than other frontline health-care workers working in hospitals (696 [4·35%] of 15 983). 622 [53·5%] of 1163 seropositive participants reported symptoms attributable to SARS-CoV-2. Loss of taste or smell was the symptom that was most strongly associated with seropositivity (377 [32·39%] of 1164 participants with this symptom were seropositive vs 786 [2·84%] of 27 628 without this symptom). Conclusion: The prevalence of health-care workers with antibodies against SARS-CoV-2 was low but higher than in blood donors. The risk of SARS-CoV-2 infection in health-care workers was related to exposure to infected patients. More than half of seropositive health-care workers reported symptoms attributable to COVID-19.”

From the MJA

Victoria’s response to a resurgence of COVID-19 has averted 9000-37000 cases in July 2020: “In conclusion, the control measures introduced in Victoria from 1 July reduced the transmission of COVID-19, averting 9000–37 000 infections between 2 and 30 July. Importantly, however, there remains small but significant ongoing growth with further work needed to bring the Victorian epidemic under control. A broader and sustainable effort, involving community and government together is needed to optimise the uptake of all of the non-pharmaceutical interventions available to us.”

Modelling the impact of reducing control measures on the COVID-19 pandemic in a low transmission setting: “Policy changes leading to the gathering of large, unstructured groups with unknown individuals (e.g. bars opening, increased public transport use) posed the greatest risk of epidemic rebound, while policy changes leading to smaller, structured gatherings with known individuals (e.g. small social gatherings) posed least risk of epidemic rebound. In the model, epidemic rebound following some policy changes took more than two months to occur. Model outcomes support continuation of working from home policies to reduce public transport use, and risk mitigation strategies in the context of social venues opening. Conclusions: Care should be taken to avoid lifting sequential COVID-19 policy restrictions within short time periods, as it could take more than two months to detect the consequences of any changes.”


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