COVID-19 research news in brief

From the New England Journal of Medicine

Homologous and heterologous COVID-19 booster vaccinations: “Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. Conclusions: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.”

Immunogenicity and reactogenicity of vaccine boosters after Ad26.COV2.S priming: “Homologous or heterologous booster vaccination resulted in higher levels of S-specific binding antibodies, neutralizing antibodies, and T-cell responses than a single Ad26.COV2.S vaccination. The increase in binding antibodies was significantly larger with heterologous regimens that included mRNA-based vaccines than with the homologous booster. The mRNA-1273 booster was most immunogenic and was associated with higher reactogenicity than the BNT162b2 and Ad26.COV2.S boosters. Local and systemic reactions were generally mild to moderate in the first 2 days after booster administration. Conclusions: The Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting.”

Evaluation of the BNT162b2 COVID-19 vaccine in children 5 to 11 years of age: “During the phase 1 study, a total of 48 children 5 to 11 years of age received 10 μg, 20 μg, or 30 μg of the BNT162b2 vaccine (16 children at each dose level). On the basis of reactogenicity and immunogenicity, a dose level of 10 μg was selected for further study. In the phase 2–3 trial, a total of 2268 children were randomly assigned to receive the BNT162b2 vaccine (1517 children) or placebo (751 children). At data cutoff, the median follow-up was 2.3 months. In the 5-to-11-year-olds, as in other age groups, the BNT162b2 vaccine had a favorable safety profile. No vaccine-related serious adverse events were noted. One month after the second dose, the geometric mean ratio of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing titers in 5-to-11-year-olds to those in 16-to-25-year-olds was 1.04 (95% confidence interval [CI], 0.93 to 1.18), a ratio meeting the prespecified immunogenicity success criterion (lower bound of two-sided 95% CI, >0.67; geometric mean ratio point estimate, ≥0.8). Covid-19 with onset 7 days or more after the second dose was reported in three recipients of the BNT162b2 vaccine and in 16 placebo recipients (vaccine efficacy, 90.7%; 95% CI, 67.7 to 98.3). Conclusions: A COVID-19 vaccination regimen consisting of two 10-μg doses of BNT162b2 administered 21 days apart was found to be safe, immunogenic, and efficacious in children 5 to 11 years of age.”

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 JAMA network

Association of SARS-CoV-2 infection with serious maternal morbidity and mortality from obstetric complications: “Of the 14 104 included patients (mean age, 29.7 years), 2352 patients had SARS-CoV-2 infection and 11 752 did not have a positive SARS-CoV-2 test result. Compared with those without a positive SARS-CoV-2 test result, SARS-CoV-2 infection was significantly associated with the primary outcome (13.4% vs 9.2%; difference, 4.2% [95% CI, 2.8%-5.6%]; adjusted relative risk [aRR], 1.41 [95% CI, 1.23-1.61]). All 5 maternal deaths were in the SARS-CoV-2 group. SARS-CoV-2 infection was not significantly associated with cesarean birth (34.7% vs 32.4%; aRR, 1.05 [95% CI, 0.99-1.11]). Compared with those without a positive SARS-CoV-2 test result, moderate or higher COVID-19 severity (n = 586) was significantly associated with the primary outcome (26.1% vs 9.2%; difference, 16.9% [95% CI, 13.3%-20.4%]; aRR, 2.06 [95% CI, 1.73-2.46]) and the major secondary outcome of cesarean birth (45.4% vs 32.4%; difference, 12.8% [95% CI, 8.7%-16.8%]; aRR, 1.17 [95% CI, 1.07-1.28]), but mild or asymptomatic infection (n = 1766) was not significantly associated with the primary outcome (9.2% vs 9.2%; difference, 0% [95% CI, −1.4% to 1.4%]; aRR, 1.11 [95% CI, 0.94-1.32]) or cesarean birth (31.2% vs 32.4%; difference, −1.4% [95% CI, −3.6% to 0.8%]; aRR, 1.00 [95% CI, 0.93-1.07]). Conclusions and relevance: Among pregnant and postpartum individuals at 17 US hospitals, SARS-CoV-2 infection was associated with an increased risk for a composite outcome of maternal mortality or serious morbidity from obstetric complications.”

Durability of anti-spike antibodies in infants after maternal COVID-19 vaccination or natural infection: “Seventy-seven vaccinated pregnant mothers and 12 with symptomatic SARS-CoV-2 infection in pregnancy were included. At 2 months, capillary serum samples were collected from 49 infants of vaccinated mothers; at 6 months, serum samples were collected from 28 infants of vaccinated mothers (mean, 170 days after birth) and 12 infants of infected mothers (mean, 207 days after birth). Vaccinated mothers had significantly higher titers at delivery with a mean (SD) of 2.03 (0.47) optical density (OD450-570) compared with mothers after infection with a mean (SD) of 0.65 (0.76) OD450-570 (P < .001). Similarly, the respective mean (SD) cord titers were higher after vaccination vs natural infection: 2.17 (0.50) OD450-570 vs 1.00 (0.83) OD450-570 (P < .001). Among infants of vaccinated mothers at 2 months, 98% (48 of 49) had detectable anti-S IgG. The mean (SD) titer at 2 months was 1.29 (0.53) OD450-570, which was correlated with both maternal (r = 0.55, P < .001) and cord titers (r = 0.43, P = .01) at delivery. Vaccination resulted in significantly greater antibody persistence in infants than infection. At 6 months, 57% (16 of 28) of infants born to vaccinated mothers had detectable antibodies compared with 8% (1 of 12) of infants born to infected mothers (P = .005). Titers were a mean (SD) of 0.33 (0.46) OD450-570 among infants of vaccinated mothers and 0 (0.01) OD450-570 among infants of infected mothers (P = .004). Neither maternal (P = .23) nor cord (P = .05) titers were significantly correlated with infant anti-S titers at 6 months, largely because 43% of infants had no detectable titer at that time.”

SARS-CoV-2 infections in close contacts of positive cases in the Olympic and Paralympic village at the 2021 Tokyo Olympic and Paralympic Games: “At the airport, 54 250 SARS-CoV-2 tests were conducted for arriving participants, with 55 individuals with positive test results confirmed by nasopharyngeal SARS-CoV-2 PCR testing (0.10%) who were moved to quarantine isolation facilities. Among 1 014 170 screening tests conducted during the Olympics and Paralympics, 299 were confirmed to have positive results (0.03%). Approximately 11 000 participants stayed in the Village during the Olympics and 4400 during the Paralympics; 3426 SARS-CoV-2 PCR tests for close contacts were conducted in the Area (0.34% of all screening tests conducted) and 15 results were confirmed positive (0.44%; 7 of 1508 tests during the Olympics [0.46%] and 8 of 1918 tests during the Paralympics [0.42%]). The number of SARS-CoV-2 PCR tests for close contacts increased after the opening of both the Olympics and Paralympics. For the Olympics, the number of SARS-CoV-2 PCR tests increased from 70 on opening day (day 1), reached a peak of 142 on day 5, and then decreased. For the Paralympics, the number of SARS-CoV-2 PCR tests increased from 122 on day 1 to a peak of 166 on day 5, decreasing to 33 on the final day. The 15 positive cases were distributed across the duration of the Olympics and Paralympics, with no major clusters.”

From the Lancet

Risk of infection, hospitalisation, and death up to 9 months after a second dose of COVID-19 vaccine: a retrospective, total population cohort study in Sweden: “Between Dec 28, 2020, and Oct 4, 2021, 842 974 individuals were fully vaccinated (two doses), and were matched (1:1) to an equal number of unvaccinated individuals (total study cohort n=1 685 948). For the outcome SARS-CoV-2 infection of any severity, the vaccine effectiveness of BNT162b2 waned progressively over time, from 92% (95% CI 92 to 93; p<0·001) at 15–30 days, to 47% (39 to 55; p<0·001) at 121–180 days, and to 23% (−2 to 41; p=0·07) from day 211 onwards. Waning was slightly slower for mRNA-1273, with a vaccine effectiveness of 96% (94 to 97; p<0·001) at 15–30 days and 59% (18 to 79; p=0·012) from day 181 onwards. Waning was also slightly slower for heterologous ChAdOx1 nCoV-19 plus an mRNA vaccine, for which vaccine effectiveness was 89% (79 to 94; p<0·001) at 15–30 days and 66% (41 to 80; p<0·001) from day 121 onwards. By contrast, vaccine effectiveness for homologous ChAdOx1 nCoV-19 vaccine was 68% (52 to 79; p<0·001) at 15–30 days, with no detectable effectiveness from day 121 onwards (−19% [–98 to 28]; p=0·49). For the outcome of severe COVID-19, vaccine effectiveness waned from 89% (82 to 93; p<0·001) at 15–30 days to 64% (44 to 77; p<0·001) from day 121 onwards. Overall, there was some evidence for lower vaccine effectiveness in men than in women and in older individuals than in younger individuals. Interpretation: We found progressively waning vaccine effectiveness against SARS-CoV-2 infection of any severity across all subgroups, but the rate of waning differed according to vaccine type. With respect to severe COVID-19, vaccine effectiveness seemed to be better maintained, although some waning became evident after 4 months. The results strengthen the evidence-based rationale for administration of a third vaccine dose as a booster.”

Pandemic preparedness and COVID-19: an exploratory analysis of infection and fatality rates, and contextual factors associated with preparedness in 177 countries, from Jan 1, 2020, to Sept 30, 2021: “The factors that explained the most variation in cumulative rates of SARS-CoV-2 infection between Jan 1, 2020, and Sept 30, 2021, included the proportion of the population living below 100 m (5·4% [4·0–7·9] of variation), GDP per capita (4·2% [1·8–6·6] of variation), and the proportion of infections attributable to seasonality (2·1% [95% uncertainty interval 1·7–2·7] of variation). Most cross-country variation in cumulative infection rates could not be explained. The factors that explained the most variation in COVID-19 IFR over the same period were the age profile of the country (46·7% [18·4–67·6] of variation), GDP per capita (3·1% [0·3–8·6] of variation), and national mean BMI (1·1% [0·2–2·6] of variation). 44·4% (29·2–61·7) of cross-national variation in IFR could not be explained. Pandemic-preparedness indices, which aim to measure health security capacity, were not meaningfully associated with standardised infection rates or IFRs. Measures of trust in the government and interpersonal trust, as well as less government corruption, had larger, statistically significant associations with lower standardised infection rates. High levels of government and interpersonal trust, as well as less government corruption, were also associated with higher COVID-19 vaccine coverage among middle-income and high-income countries where vaccine availability was more widespread, and lower corruption was associated with greater reductions in mobility. If these modelled associations were to be causal, an increase in trust of governments such that all countries had societies that attained at least the amount of trust in government or interpersonal trust measured in Denmark, which is in the 75th percentile across these spectrums, might have reduced global infections by 12·9% (5·7–17·8) for government trust and 40·3% (24·3–51·4) for interpersonal trust. Similarly, if all countries had a national BMI equal to or less than that of the 25th percentile, our analysis suggests global standardised IFR would be reduced by 11·1%. Interpretation: Efforts to improve pandemic preparedness and response for the next pandemic might benefit from greater investment in risk communication and community engagement strategies to boost the confidence that individuals have in public health guidance. Our results suggest that increasing health promotion for key modifiable risks is associated with a reduction of fatalities in such a scenario.”

From the BMJ

Healthcare use in 700 000 children and adolescents for six months after COVID-19: before and after register based cohort study: “A substantial short term relative increase in primary care use was observed for participants during the first month after a positive SARS-CoV-2 test result compared with those who tested negative (age 1-5 years: 339%, 95% confidence interval 308% to 369%; 6-15 years: 471%, 450% to 491%; 16-19 years: 401%, 380% to 422%). Use of primary care for the younger age groups was still increased at two months (1-5 years: 22%, 4% to 40%; 6-15 years: 14%, 2% to 26%) and three months (1-5 years: 26%, 7% to 46%, 6-15 years: 15%, 3% to 28%), but not for the oldest group (16-19 years: 11%, −2% to 24% and 6%, −7% to 19%, respectively). Children aged 1-5 years who tested positive also showed a minor long term (≤6 months) relative increase in primary care use (13%, −0% to 26%) that was not observed for the older age groups, compared with same aged children who tested negative. Results were similar yet the age differences less pronounced compared with untested controls. For all age groups, the increase in primary care visits was due to respiratory and general or unspecified conditions. No increased use of specialist care was observed. Conclusion: COVID-19 among children and adolescents was found to have limited impact on healthcare services in Norway. Preschool aged children might take longer to recover (3-6 months) than primary or secondary school students (1-3 months), usually because of respiratory conditions.”

Indirect effects of the COVID-19 pandemic on childhood infection in England: population based observational study: “After 1 March 2020, substantial and sustained reductions in hospital admissions were found for all but one of the 19 infective conditions studied. Among the respiratory infections, the greatest percentage reductions were for influenza (mean annual number admitted between 1 March 2017 and 29 February 2020 was 5379 and number of children admitted from 1 March 2020 to 28 February 2021 was 304, 94% reduction, 95% confidence interval 89% to 97%), and bronchiolitis (from 51 655 to 9423, 82% reduction, 95% confidence interval 79% to 84%). Among the severe invasive infections, the greatest reduction was for meningitis (50% reduction, 47% to 52%). For the vaccine preventable infections, reductions ranged from 53% (32% to 68%) for mumps to 90% (80% to 95%) for measles. Reductions were seen across all demographic subgroups and in children with underlying comorbidities. Corresponding decreases were also found for the absolute numbers of 60 day case fatalities, although the proportion of children admitted for pneumonia who died within 60 days increased (age-sex adjusted odds ratio 1.71, 95% confidence interval 1.43 to 2.05). More recent data indicate that some respiratory infections increased to higher levels than usual after May 2021. Conclusions: During the COVID-19 pandemic, a range of behavioural changes (adoption of non-pharmacological interventions) and societal strategies (school closures, lockdowns, and restricted travel) were used to reduce transmission of SARS-CoV-2, which also reduced admissions for common and severe childhood infections. Continued monitoring of these infections is required as social restrictions evolve.”

Atorvastatin versus placebo in patients with COVID-19 in intensive care: randomized controlled trial: “Of 605 patients randomized between 29 July 2020 and 4 April 2021 for statin randomization in the INSPIRATION-S trial, 343 were co-randomized to intermediate dose versus standard dose prophylactic anticoagulation with heparin based regimens, whereas 262 were randomized after completion of the anticoagulation study. 587 of the 605 participants were included in the primary analysis of INSPIRATION-S, reported here: 290 were assigned to atorvastatin and 297 to placebo (median age 57 years (interquartile range 45-68 years); 256 (44%) women). The primary outcome occurred in 95 (33%) patients assigned to atorvastatin and 108 (36%) assigned to placebo (odds ratio 0.84, 95% confidence interval 0.58 to 1.21). Death occurred in 90 (31%) patients in the atorvastatin group and 103 (35%) in the placebo group (odds ratio 0.84, 95% confidence interval 0.58 to 1.22). Rates for venous thromboembolism were 2% (n=6) in the atorvastatin group and 3% (n=9) in the placebo group (odds ratio 0.71, 95% confidence interval 0.24 to 2.06). Myopathy was not clinically diagnosed in either group. Liver enzyme levels were increased in five (2%) patients assigned to atorvastatin and six (2%) assigned to placebo (odds ratio 0.85, 95% confidence interval 0.25 to 2.81). Conclusions: In adults with COVID-19 admitted to the ICU, atorvastatin was not associated with a significant reduction in the composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all-cause mortality compared with placebo. Treatment was, however, found to be safe. As the overall event rates were lower than expected, a clinically important treatment effect cannot be excluded.”

GP consultation rates for sequelae after acute COVID-19 in patients managed in the community or hospital in the UK: population based study: “Relative to the negative control and influenza cohorts, patients in the community (n=437 943) had significantly higher GP consultation rates for multiple sequelae, and the most common were loss of smell or taste, or both (adjusted hazard ratio 5.28, 95% confidence interval 3.89 to 7.17, P<0.001); venous thromboembolism (3.35, 2.87 to 3.91, P<0.001); lung fibrosis (2.41, 1.37 to 4.25, P=0.002), and muscle pain (1.89, 1.63 to 2.20, P<0.001); and also for healthcare use after a diagnosis of COVID-19 compared with 12 months before infection. For absolute proportions, the most common outcomes ≥4 weeks after a covid-19 diagnosis in patients in the community were joint pain (2.5%), anxiety (1.2%), and prescriptions for non-steroidal anti-inflammatory drugs (1.2%). Patients admitted to hospital (n=18 059) also had significantly higher GP consultation rates for multiple sequelae, most commonly for venous thromboembolism (16.21, 11.28 to 23.31, P<0.001), nausea (4.64, 2.24 to 9.21, P<0.001), prescriptions for paracetamol (3.68, 2.86 to 4.74, P<0.001), renal failure (3.42, 2.67 to 4.38, P<0.001), and healthcare use after a covid-19 diagnosis compared with 12 months before infection. For absolute proportions, the most common outcomes ≥4 weeks after a covid-19 diagnosis in patients admitted to hospital were venous thromboembolism (3.5%), joint pain (2.7%), and breathlessness (2.8%). In patients in the community, anxiety and depression, abdominal pain, diarrhoea, general pain, nausea, chest tightness, and tinnitus persisted throughout follow-up. GP consultation rates were reduced for all symptoms, prescriptions, and healthcare use, except for neuropathic pain, cognitive impairment, strong opiates, and paracetamol use in patients in the community after the first vaccination dose for COVID-19 relative to before vaccination. GP consultation rates were also reduced for ischaemic heart disease, asthma, and gastro-oesophageal disease. Conclusions: GP consultation rates for sequelae after acute COVID-19 infection differed between patients with COVID-19 who were admitted to hospital and those managed in the community. For individuals in the community, rates of some sequelae decreased over time but those for others, such as anxiety and depression, persisted. Rates of some outcomes decreased after vaccination in this group.”