COVID-19 research news in brief

From the New England Journal of Medicine

Safety of the BNT162b2 mRNA COVID-19 Vaccine in a nationwide setting: “In the vaccination analysis, the vaccinated and control groups each included a mean of 884 828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100 000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100 000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100 000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100 000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100 000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia. Conclusions: In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100 000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection.”

Clinical features of vaccine-induced immune thrombocytopenia and thrombosis: “Among 294 patients who were evaluated, we identified 170 definite and 50 probable cases of VITT. All the patients had received the first dose of ChAdOx1 nCoV-19 vaccine and presented 5 to 48 days (median, 14) after vaccination. The age range was 18 to 79 years (median, 48), with no sex preponderance and no identifiable medical risk factors. Overall mortality was 22%. The odds of death increased by a factor of 2.7 (95% confidence interval [CI], 1.4 to 5.2) among patients with cerebral venous sinus thrombosis, by a factor of 1.7 (95% CI, 1.3 to 2.3) for every 50% decrease in the baseline platelet count, by a factor of 1.2 (95% CI, 1.0 to 1.3) for every increase of 10,000 fibrinogen-equivalent units in the baseline d-dimer level, and by a factor of 1.7 (95% CI, 1.1 to 2.5) for every 50% decrease in the baseline fibrinogen level. Multivariate analysis identified the baseline platelet count and the presence of intracranial hemorrhage as being independently associated with death; the observed mortality was 73% among patients with platelet counts below 30,000 per cubic millimeter and intracranial hemorrhage. Conclusions: The high mortality associated with VITT was highest among patients with a low platelet count and intracranial hemorrhage. Treatment remains uncertain, but identification of prognostic markers may help guide effective management.”

Early convalescent plasma for high-risk outpatients with COVID-19: “A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, −6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups. Conclusions: The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression.”

Evaluation of mRNA-1273 SARS-CoV-2 vaccine in adolescents: “A total of 3732 participants were randomly assigned to receive mRNA-1273 (2489 participants) or placebo (1243 participants). In the mRNA-1273 group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 93.1% and 92.4%, respectively), headache (in 44.6% and 70.2%, respectively), and fatigue (in 47.9% and 67.8%, respectively); in the placebo group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 34.8% or 30.3%, respectively), headache (in 38.5% and 30.2%, respectively), and fatigue (in 36.6% and 28.9%, respectively). No serious adverse events related to mRNA-1273 or placebo were noted. The geometric mean titer ratio of pseudovirus neutralizing antibody titers in adolescents relative to young adults was 1.08 (95% confidence interval [CI], 0.94 to 1.24), and the absolute difference in serologic response was 0.2 percentage points (95% CI, −1.8 to 2.4), which met the noninferiority criterion. No cases of Covid-19 with an onset of 14 days after the second injection were reported in the mRNA-1273 group, and four cases occurred in the placebo group. Conclusions: The mRNA-1273 vaccine had an acceptable safety profile in adolescents. The immune response was similar to that in young adults, and the vaccine was efficacious in preventing COVID-19.”

From the BMJ

Risk of hospital admission with COVID-19 among teachers compared with healthcare workers and other adults of working age in Scotland, March 2020 to July 2021: “Most teachers were young (mean age 42), were women (80%), and had no comorbidities (84%). The risk (cumulative incidence) of hospital admission with COVID-19 was <1% for all adults of working age in the general population. Over the study period, in conditional logistic regression models adjusted for age, sex, general practice, race/ethnicity, deprivation, number of comorbidities, and number of adults in the household, teachers showed a lower risk of hospital admission with COVID-19 (rate ratio 0.77, 95% confidence interval 0.64 to 0.92) and of severe COVID-19 (0.56, 0.33 to 0.97) than the general population. In the first period when schools in Scotland reopened, in autumn 2020, the rate ratio for hospital admission in teachers was 1.20 (0.89 to 1.61) and for severe COVID-19 was 0.45 (0.13 to 1.55). The corresponding findings for household members of teachers were 0.91 (0.67 to 1.23) and 0.73 (0.37 to 1.44), and for patient facing healthcare workers were 2.08 (1.73 to 2.50) and 2.26 (1.43 to 3.59). Similar risks were seen for teachers in the second period, when schools reopened in summer 2021. These values were higher than those seen in spring/summer 2020, when schools were mostly closed. Conclusion: Compared with adults of working age who are otherwise similar, teachers and their household members were not found to be at increased risk of hospital admission with COVID-19 and were found to be at lower risk of severe COVID-19. These findings should reassure those who are engaged in face-to-face teaching.”

Risk of thrombocytopenia and thromboembolism after COVID-19 vaccination and SARS-CoV-2 positive testing: “The study found increased risk of thrombocytopenia after ChAdOx1 nCoV-19 vaccination (incidence rate ratio 1.33, 95% confidence interval 1.19 to 1.47 at 8–14 days) and after a positive SARS-CoV-2 test (5.27, 4.34 to 6.40 at 8–14 days); increased risk of venous thromboembolism after ChAdOx1 nCoV-19 vaccination (1.10, 1.02 to 1.18 at 8–14 days) and after SARS-CoV-2 infection (13.86, 12.76 to 15.05 at 8–14 days); and increased risk of arterial thromboembolism after BNT162b2 mRNA vaccination (1.06, 1.01 to 1.10 at 15–21 days) and after SARS-CoV-2 infection (2.02, 1.82 to 2.24 at 15–21 days). Secondary analyses found increased risk of CVST after ChAdOx1 nCoV-19 vaccination (4.01, 2.08 to 7.71 at 8–14 days), after BNT162b2 mRNA vaccination (3.58, 1.39 to 9.27 at 15–21 days), and after a positive SARS-CoV-2 test; increased risk of ischaemic stroke after BNT162b2 mRNA vaccination (1.12, 1.04 to 1.20 at 15–21 days) and after a positive SARS-CoV-2 test; and increased risk of other rare arterial thrombotic events after ChAdOx1 nCoV-19 vaccination (1.21, 1.02 to 1.43 at 8–14 days) and after a positive SARS-CoV-2 test. Conclusion: Increased risks of haematological and vascular events that led to hospital admission or death were observed for short time intervals after first doses of the ChAdOx1 nCoV-19 and BNT162b2 mRNA vaccines. The risks of most of these events were substantially higher and more prolonged after SARS-CoV-2 infection than after vaccination in the same population.”

Fibromyalgia: a new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey: “A final sample of 616 individuals (77.4% women) filled the form 6 ± 3 months after the COVID-19 diagnosis. Of these, 189 (30.7%) satisfied the ACR survey criteria for [fibromyalgia (FM)] (56.6% women). A multivariate logistic regression model including demographic and clinical factors showed that male gender (OR: 9.95, 95% CI 6.02 to 16.43, P < 0.0001) and obesity (OR: 41.20, 95% CI 18.00 to 98.88, P < 0.0001) were the strongest predictors of being classified as having post-COVID-19 FM. Hospital admission rate was significantly higher in men (15.8% vs 9.2%, P = 0.001) and obese (19.2 vs 10.8%, P = 0.016) respondents. Conclusion: Our data suggest that clinical features of FM are common in patients who recovered from COVID-19 and that obesity and male gender affect the risk of developing post-COVID-19 FM.”

Effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe COVID-19 outcomes in Ontario, Canada: “Of 324 033 people with symptoms, 53 270 (16.4%) were positive for SARS-CoV-2 and 21 272 (6.6%) received at least one dose of vaccine. Among participants who tested positive, 2479 (4.7%) were admitted to hospital or died. Vaccine effectiveness against symptomatic infection observed ≥ 14 days after one dose was 60% (95% confidence interval 57% to 64%), increasing from 48% (41% to 54%) at 14–20 days after one dose to 71% (63% to 78%) at 35–41 days. Vaccine effectiveness observed ≥ 7 days after two doses was 91% (89% to 93%). Vaccine effectiveness against hospital admission or death observed ≥14 days after one dose was 70% (60% to 77%), increasing from 62% (44% to 75%) at 14–20 days to 91% (73% to 97%) at ≥ 35 days, whereas vaccine effectiveness observed ≥ 7 days after two doses was 98% (88% to 100%). For adults aged ≥ 70 years, vaccine effectiveness estimates were observed to be lower for intervals shortly after one dose but were comparable to those for younger people for all intervals after 28 days. After two doses, high vaccine effectiveness was observed against variants with the E484K mutation. Conclusions: Two doses of mRNA COVID-19 vaccines were observed to be highly effective against symptomatic infection and severe outcomes. Vaccine effectiveness of one dose was observed to be lower, particularly for older adults shortly after the first dose.”

From the Lancet

Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: “Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8–12 weeks: 267 [83%] of 321; 15–25 weeks: 24 [7%]; or 44–45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8–12 weeks: 115 [44%] of 261; 15–25 weeks: 116 [44%]; and 44–45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44–45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66.00 ELISA units [EUs; 95% CI 47.83–91.08] vs 1.75 EUs [1.60–1.93]). 32 participants received a late second dose of vaccine 44–45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525–1764] with an 8–12 week interval; 1860 EUs [917–4934] with a 15–25 week interval; and 3738 EUs [1824–6625] with a 44–45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047–6420]) than 28 days after a second dose (median 1792 EUs [IQR 899–4634]; Wilcoxon signed rank test P = 0.0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127–389] immediately before the third dose to 399 SFUs per milion PBMCs [314–662] by day 28 after the third dose; Wilcoxon signed rank test P = 0.012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose. Interpretation: An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses.”

Cerebral venous thrombosis after vaccination against COVID-19 in the UK: “Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had [vaccine-induced immune thrombotic thrombocytopenia (VITT)] and 25 did not. The median age of the VITT group (47 years, IQR 32–55) was lower than in the non-VITT group (57 years; 41–62; P = 0.0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2–4) than non-VITT patients (two, 2–3; P = 0.041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; P = 0.0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; P = 0.0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; P = 0.0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; P = 0.022). Interpretation: Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate.”

From JAMA

Surveillance for adverse events after COVID-19 mRNA vaccination: “A total of 11 845 128 doses of mRNA vaccines (57% BNT162b2; 6 175 813 first doses and 5 669 315 second doses) were administered to 6.2 million individuals (mean age, 49 years; 54% female individuals). The incidence of events per 1 000 000 person-years during the risk vs comparison intervals for ischemic stroke was 1612 vs 1781 (RR, 0.97; 95% CI, 0.87–1.08); for appendicitis, 1179 vs 1345 (RR, 0.82; 95% CI, 0.73–0.93); and for acute myocardial infarction, 935 vs 1030 (RR, 1.02; 95% CI, 0.89–1.18). No vaccine-outcome association met the prespecified requirement for a signal. Incidence of confirmed anaphylaxis was 4.8 (95% CI, 3.2–6.9) per million doses of BNT162b2 and 5.1 (95% CI, 3.3–7.6) per million doses of mRNA-1273. Conclusions and relevance: In interim analyses of surveillance of mRNA COVID-19 vaccines, incidence of selected serious outcomes was not significantly higher 1 to 21 days postvaccination compared with 22 to 42 days postvaccination. While CIs were wide for many outcomes, surveillance is ongoing.”

The association between school closures and child mental health during COVID-19: “A total of 2324 adults completed the survey. Overall, 1671 respondents (71.9%) were women, 244 (10.5%) were Black, 372 (16.0%) were Hispanic, and 421 (18.1%) had a high school education or less. Children attending school in-person had higher household incomes (mean difference, $9719; 95% CI, $4327 to $15 111; P < 0.001) and were more likely to be White compared with those attending remotely (366 of 556 [65.8%] vs 597 of 1340 [44.5%]; P < 0.001). Older children in remote schooling had more mental health difficulties than those attending in-person schooling (standardized effect size, 0.23 [95% CI, 0.07 to 0.39] per year older; P = 0.006), corresponding to small effect sizes in favor of in-person schooling for older children and very small effect sizes favoring remote schooling for younger children. Children from families with higher income benefitted more from attending schools in-person compared with their peers from families with lower income (B = −0.20 [95% CI, −0.10 to −0.30] per $10 000-increase in annual income; P < 0.001), although this advantage was not apparent for children attending hybrid school (B = −0.05 [95% CI, −0.16 to 0.06] per $10 000-increase in annual income; P = 0.34), and directionally lower but not significantly different for children attending remote school (B = −0.12 [95% CI, −0.04 to −0.20] per $10 000-increase in annual income; P < 0.001). Learning pods fully buffered the associations of hybrid schooling (d = −0.25; 95% CI, −0.47 to −0.04) but not remote schooling (d = 0.04; 95% CI, −0.10 to 0.18) with negative mental health outcomes. Conclusions and relevance: The findings of this study suggest that older and Black and Hispanic children as well as those from families with lower income who attend school remotely may experience greater impairment to mental health than their younger, White, and higher-income counterparts. Ensuring that all students have access to additional educational and mental health resources must be an important public health priority, met with appropriate funding and workforce augmentation, during and beyond the COVID-19 pandemic.”

Domestic violence police reporting and resources during the 2020 COVID-19 stay-at-home order in Chicago, Illinois: “Of 77 community areas in Chicago, 28 (36.4%) were majority Black, 19 (24.7%) majority Hispanic/Latinx, 18 (23.4%) majority White, and 12 (15.6%) a different or no majority race/ethnicity, representing an estimated population of 2 718 555 individuals. For each community area, the SH order was associated with a decrease in the rate of [domestic violence (DV)] police reports by 21.8 (95% CI, −30.48 to −13.07) crimes per 100 000 persons per month relative to the same months in 2019. Compared with White majority community areas, Black majority areas had a decrease in the rate of DV police reports by 40.8 (95% CI, −62.93 to −18.75) crimes per 100 000 persons per month relative to the same months in 2019. The SH order was also associated with a decrease in DV resource availability at a rate of 5.1 (95% CI, −7.55 to −2.67) resources per 100 000 persons, with the largest decreases for mental health (−4.3 [95% CI, −5.97 to −2.66] resources per 100 000 persons) and personal safety (−2.4 [95% CI, −4.40 to −0.41] resources per 100 000 persons). The Black majority south side of Chicago had a larger decrease in resource availability (−6.7 [95% CI, −12.92 to −0.46] resources per 100 000 persons) than the White majority north side. Conclusions and relevance: In this longitudinal cohort study, the rate of DV police reports decreased after the SH order was implemented in Chicago. This decrease was largely observed in Black majority communities, whereas there was no significant change in White majority communities. These findings may reflect decreased DV incidence but may also reflect an exacerbation of underreporting. In addition, DV resource availability decreased disproportionately on the predominantly Black south side of Chicago.”

Comparison of SARS-CoV-2 antibody response by age among recipients of the BNT162b2 vs the mRNA-1273 vaccine: “The median age of the 167 recipients was 42 (interquartile range, 32-57 years), with 63 recipients (38%) aged 50 years or greater; 120 recipients (72%) were women. There were no differences in age, sex, or race between those who received BNT162b2 (n = 79) or mRNA-1273 (n = 88). Only 6 (4%) of the participants had serologic evidence of prior COVID-19. Levels of IgG to SARS-CoV-2 spike RBD were lower in recipients of BNT162b2 as compared with mRNA-1273 at both the preboost blood draw (5.9 μg/mL [95% CI, 3.7-9.6 μg/mL] vs 19.1 μg/mL [95% CI, 15.8-23.1 μg/mL]) and postboost blood draw (45.9 μg/mL [95% CI, 37.0-57.0 μg/mL] vs 68.5 μg/mL [95% CI 61.9-75.7 μg/mL]). Recipients aged 50 years and older who received BNT162b2 had preboost IgG levels (2.1 μg/mL [95% CI, 1.0-4.3 μg/mL]) that were lower than levels in recipients younger than 50 years who received BNT162b2 (10.2 μg/mL [95% CI, 6.0-17.5 μg/mL]) and also as compared with age-similar peers who received mRNA-1273 (14.7 μg/mL [95% CI, 10.0-21.2 μg/mL]). Recipients aged 50 years and older who received BNT162b2 had postboost IgG levels (31.1 μg/mL [95% CI, 19.9-48.7 μg/mL]) that were lower than the levels in younger recipients of BNT162b2 (59.0 μg/mL [95% CI, 48.8-71.4 μg/mL]) and age-similar peers who received mRNA-1273 (71.8 μg/mL [95% CI, 58.1-88.8 μg/mL]). Discussion: In this cohort study, we used a quantitative assay and found that BNT162b2 elicited relatively lower antibody levels in older adults vs younger adults, which is consistent with emerging reports. By contrast, there was no difference in postboost antibody levels in older adults vs younger adults who received mRNA-1273. One explanation for the difference in immunogenicity observed in older adults could relate to the amount of mRNA used in the respective vaccines, with 30 μg contained in BNT162b2 and 100 μg in mRNA-1273. A limitation of this study is that the neutralizing antibodies were not measured; however, several groups have reported a strong correlation between SARS-CoV-2 binding and neutralizing antibodies. Additional studies are warranted to determine whether binding antibodies to SARS-CoV-2 can be used to predict clinical protection against COVID-19.”