[Analysis of the treatment of a premature infant with critical coronavirus disease caused by the Omicron variant of SARS-CoV-2].

The patient is a female infant who was born at a gestational age of 30+4 weeks in the breech position and was delivered by assisted vaginal delivery. She was admitted to the neonatal department of Tianjin First Central Hospital for 44 days, during which she had stable respiration, oxygen saturation, and regular weight gain. The patient was discharged home by her family. The infant was readmitted to the hospital due to poor appetite for 15 hours and irregular breathing with weak response for 4 hours at the corrected gestational age of 37+2 weeks at 47 days after birth. The day before admission, the patient's mother experienced throat discomfort, and on the day of admission, the mother had a fever, with the highest temperature of 37.9 centigrade (she later tested positive for SARS-CoV-2 antigen). About 15 hours before admission, the family noticed that the patient had poor milk intake and weakened suction. About 4 hours before admission, the patient developed irregular breathing and weakened responses. After admission, the patient presented frequent apnea, and it was not relieved by adjusting the respiratory mode and parameters of non-invasive assisted ventilation, as well as caffeine citrate to stimulate the respiratory center. The patient was eventually given mechanical ventilation and other symptomatic support treatments. The pharyngeal swab was positive for COVID nucleic acid testing with a Ct value of 20.1 for the N gene. And the chest X-ray showed multiple patchy shadows in both lungs. The patient was diagnosed with critical coronavirus disease (COVID) caused by the Omicron variant in premature infants. After treatment, the child was clinically cured and discharged 8 days after hospitalization. Symptoms of COVID in premature infants may be atypical, and the condition can deteriorate rapidly. During the Omicron variant epidemic, we should pay more attention to premature infants so as to detect severe and critical cases as early as possible, and treat them actively to improve the prognosis.

COVID-19 mRNA vaccine immunogenicity decay and breakthrough illness in adolescents and young adults with childhood-onset rheumatic diseases.

OBJECTIVES: To evaluate the humoral immunogenicity for 6 months after the two-dose COVID-19 mRNA vaccination in adolescents and young adults (AYAs) with childhood-onset rheumatic diseases (cRDs). METHODS: This monocentric observational study was conducted between August 2020 to March 2022. Humoral immunogenicity was assessed at 2-3 weeks after first vaccine dose and 1, 3, and 6 months after the second dose by the cPass™ SARS-CoV-2 Neutralisation Antibody (nAb) Assay. An inhibition signal of ≥ 30% defined seroconversion threshold and the readings calibrated against the World Health Organisation (WHO) International Standard for SARS-CoV-2 antibodies. RESULTS: 169 AYAs with cRDs were recruited (median age 16·8 years (IQR : 14·7-19·5), 52% female, 72% Chinese). Juvenile Idiopathic Arthritis (JIA) (58%) and Systemic Lupus Erythematosus (18%) comprised the major diagnoses. After second vaccine dose, 99% seroconverted with a median nAb titre of 1779·8 IU/ml (IQR : 882·8-2541·9), declining to 935·6 IU/ml (IQR : 261·0-1514·9) and 683·2 IU/ml (IQR : 163·5-1400·5) at the 3- and 6-month timepoints respectively. The diagnosis of JIA (OR 10·1, 95%CI 1·8-58·4, p= 0·010) and treatment with anti-Tumour Necrosis Factor-α (aTNF) (OR 10·1, 95%CI 1·5-70·0, p= 0·019) were independently associated with a > 50% drop of nAb titres at 6 months. Withholding methotrexate or mycophenolate mofetil did not affect the vaccine response or decay rate. The COVID-19 breakthrough infection was estimated at 18·2 cases/1000 patient-months with no clinical risk factors identified. CONCLUSION: Over half of AYAs with cRDs had a significant drop in SARS-CoV-2 nAb at 6-month despite an initial robust humoral response. JIA and aTNF usage are predictors of a faster decay rate.

Ubiquitin specific peptidase 25 alleviates acute lung injury and suppresses the inflammatory response in lung epithelial cells.

As COVID-19 spreads over the world, the treatment of acute lung injury (ALI) has attracted much attention. Considering ubiquitin-specific protease (USP) 25 has been relevant to inflammation, this article focused on its role in ALI and its regulatory mechanism. Lipopolysaccharide (LPS) was applied to separately stimulate mice and human lung epithelial cells to establish in vivo and in vitro ALI models. To discover the effects of USP25 overexpression on mouse, lung pathology, inflammatory factor levels, edema, number of inflammatory cells, and downstream protein levels were evaluated. USP25 overexpression in mice could alleviate LPS-induced lung tissue lesions and edema, and reduce inflammatory factors and inflammatory cells. It also inhibited the levels of downstream TRAF6, MAPK pathway-related proteins, and Fos Proto-Oncogene (FOS) in vivo. Furthermore, BEAS-2B cells were transfected with TNF receptor-associated factor 6 (TRAF6) plasmids to study the role of TRAF6 in the regulatory mechanism of USP25. TRAF6 overexpression was found to reverse the functions of USP25 overexpression on cells. In conclusion, USP25 reduced ALI and inhibited inflammation in lung epithelial cells via regulating TRAF6/MAPK/FOS signaling.

SARS-CoV-2 Omicron variant emerged under immune selection.

The SARS-CoV-2 Omicron variant (B.1.1.529 lineage) escapes antibodies that neutralize the ancestral virus. We tested human serum panels from participants with differing infection and vaccination status using a multiplex surrogate virus neutralization assay targeting 20 sarbecoviruses. We found that bat and pangolin sarbecoviruses showed significantly less neutralization escape than the Omicron variant. We propose that SARS-CoV-2 variants have emerged under immune selection pressure and are evolving differently from animal sarbecoviruses.

Lower vaccine-acquired immunity in the elderly population following two-dose BNT162b2 vaccination is alleviated by a third vaccine dose.

Understanding the impact of age on vaccinations is essential for the design and delivery of vaccines against SARS-CoV-2. Here, we present findings from a comprehensive analysis of multiple compartments of the memory immune response in 312 individuals vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine. Two vaccine doses induce high antibody and T cell responses in most individuals. However, antibody recognition of the Spike protein of the Delta and Omicron variants is less efficient than that of the ancestral Wuhan strain. Age-stratified analyses identify a group of low antibody responders where individuals ≥60 years are overrepresented. Waning of the antibody and cellular responses is observed in 30% of the vaccinees after 6 months. However, age does not influence the waning of these responses. Taken together, while individuals ≥60 years old take longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at 6 months post-vaccination. A third dose strongly boosts the low antibody responses in the older individuals against the ancestral Wuhan strain, Delta and Omicron variants.

Neutralizing Activity and SARS-CoV-2 Vaccine mRNA Persistence in Serum and Breastmilk After BNT162b2 Vaccination in Lactating Women.

Background: There is limited information on the functional neutralizing capabilities of breastmilk SARS-CoV-2-specific antibodies and the potential adulteration of breastmilk with vaccine mRNA after SARS-CoV-2 mRNA vaccination. Methods: We conducted a prospective cohort study of lactating healthcare workers who received the BNT162b2 vaccine and their infants. The presence of SARS-CoV-2 neutralizing antibodies, antibody isotypes (IgG, IgA, IgM) and intact mRNA in serum and breastmilk was evaluated at multiple time points using a surrogate neutralizing assay, ELISA, and PCR, over a 6 week period of the two-dose vaccination given 21 days apart. Results: Thirty-five lactating mothers, median age 34 years (IQR 32-36), were included. All had detectable neutralizing antibodies in the serum immediately before dose 2, with significant increase in neutralizing antibody levels 7 days after this dose [median 168.4 IU/ml (IQR 100.7-288.5) compared to 2753.0 IU/ml (IQR 1627.0-4712.0), p <0.001]. Through the two vaccine doses, all mothers had detectable IgG1, IgA and IgM isotypes in their serum, with a notable increase in all three antibody isotypes after dose 2, especially IgG1 levels. Neutralizing antibodies were detected in majority of breastmilk samples a week after dose 2 [median 13.4 IU/ml (IQR 7.0-28.7)], with persistence of these antibodies up to 3 weeks after. Post the second vaccine dose, all (35/35, 100%) mothers had detectable breastmilk SARS-CoV-2 spike RBD-specific IgG1 and IgA antibody and 32/35 (88.6%) mothers with IgM. Transient, low intact vaccine mRNA levels was detected in 20/74 (27%) serum samples from 21 mothers, and 5/309 (2%) breastmilk samples from 4 mothers within 1 weeks of vaccine dose. Five infants, median age 8 months (IQR 7-16), were also recruited - none had detectable neutralizing antibodies or vaccine mRNA in their serum. Conclusion: Majority of lactating mothers had detectable SARS-CoV-2 antibody isotypes and neutralizing antibodies in serum and breastmilk, especially after dose 2 of BNT162b2 vaccination. Transient, low levels of vaccine mRNA were detected in the serum of vaccinated mothers with occasional transfer to their breastmilk, but we did not detect evidence of infant sensitization. Importantly, the presence of breastmilk neutralising antibodies likely provides a foundation for passive immunisation of the breastmilk-fed infant.

A Randomized, Single-Blind, Group Sequential, Active-Controlled Study to Evaluate the Clinical Efficacy and Safety of α-Lipoic Acid for Critically Ill Patients With Coronavirus Disease 2019 (COVID-19).

OBJECT: To evaluate the clinical efficacy and safety of α-Lipoic acid (ALA) for critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: A randomized, single-blind, group sequential, active-controlled trial was performed at JinYinTan Hospital, Wuhan, China. Between February 2020 and March 2020, 17 patients with critically ill COVID-19 were enrolled in our study. Eligible patients were randomly assigned in a 1:1 ratio to receive either ALA (1200 mg/d, intravenous infusion) once daily plus standard care or standard care plus equal volume saline infusion (placebo) for 7 days. All patients were monitored within the 7 days therapy and followed up to day 30 after therapy. The primary outcome of this study was the Sequential Organ Failure Estimate (SOFA) score, and the secondary outcome was the all-cause mortality within 30 days. RESULT: Nine patients were randomized to placebo group and 8 patients were randomized to ALA group. SOFA score was similar at baseline, increased from 4.3 to 6.0 in the placebo group and increased from 3.8 to 4.0 in the ALA group (P = 0.36) after 7 days. The 30-day all-cause mortality tended to be lower in the ALA group (3/8, 37.5%) compared to that in the placebo group (7/9, 77.8%, P = 0.09). CONCLUSION: In our study, ALA use is associated with lower SOFA score increase and lower 30-day all-cause mortality as compared with the placebo group. Although the mortality rate was two-folds higher in placebo group than in ALA group, only borderline statistical difference was evidenced due to the limited patient number. Future studies with larger patient cohort are warranted to validate the role of ALA in critically ill patients with COVID-19. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn/showproj.aspx?proj=49534.

Neutralizing Activity and SARS-CoV-2 Vaccine mRNA Persistence in Serum and Breastmilk After BNT162b2 Vaccination in Lactating Women

Background There is limited information on the functional neutralizing capabilities of breastmilk SARS-CoV-2-specific antibodies and the potential adulteration of breastmilk with vaccine mRNA after SARS-CoV-2 mRNA vaccination. Methods We conducted a prospective cohort study of lactating healthcare workers who received the BNT162b2 vaccine and their infants. The presence of SARS-CoV-2 neutralizing antibodies, antibody isotypes (IgG, IgA, IgM) and intact mRNA in serum and breastmilk was evaluated at multiple time points using a surrogate neutralizing assay, ELISA, and PCR, over a 6 week period of the two-dose vaccination given 21 days apart. Results Thirty-five lactating mothers, median age 34 years (IQR 32-36), were included. All had detectable neutralizing antibodies in the serum immediately before dose 2, with significant increase in neutralizing antibody levels 7 days after this dose [median 168.4 IU/ml (IQR 100.7-288.5) compared to 2753.0 IU/ml (IQR 1627.0-4712.0), p <0.001]. Through the two vaccine doses, all mothers had detectable IgG1, IgA and IgM isotypes in their serum, with a notable increase in all three antibody isotypes after dose 2, especially IgG1 levels. Neutralizing antibodies were detected in majority of breastmilk samples a week after dose 2 [median 13.4 IU/ml (IQR 7.0-28.7)], with persistence of these antibodies up to 3 weeks after. Post the second vaccine dose, all (35/35, 100%) mothers had detectable breastmilk SARS-CoV-2 spike RBD-specific IgG1 and IgA antibody and 32/35 (88.6%) mothers with IgM. Transient, low intact vaccine mRNA levels was detected in 20/74 (27%) serum samples from 21 mothers, and 5/309 (2%) breastmilk samples from 4 mothers within 1 weeks of vaccine dose. Five infants, median age 8 months (IQR 7-16), were also recruited - none had detectable neutralizing antibodies or vaccine mRNA in their serum. Conclusion Majority of lactating mothers had detectable SARS-CoV-2 antibody isotypes and neutralizing antibodies in serum and breastmilk, especially after dose 2 of BNT162b2 vaccination. Transient, low levels of vaccine mRNA were detected in the serum of vaccinated mothers with occasional transfer to their breastmilk, but we did not detect evidence of infant sensitization. Importantly, the presence of breastmilk neutralising antibodies likely provides a foundation for passive immunisation of the breastmilk-fed infant.

Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study.

BACKGROUND: Studies have found different waning rates of neutralising antibodies compared with binding antibodies against SARS-CoV-2. The impact of neutralising antibody waning rate at the individual patient level on the longevity of immunity remains unknown. We aimed to investigate the peak levels and dynamics of neutralising antibody waning and IgG avidity maturation over time, and correlate this with clinical parameters, cytokines, and T-cell responses. METHODS: We did a longitudinal study of patients who had recovered from COVID-19 up to day 180 post-symptom onset by monitoring changes in neutralising antibody levels using a previously validated surrogate virus neutralisation test. Changes in antibody avidities and other immune markers at different convalescent stages were determined and correlated with clinical features. Using a machine learning algorithm, temporal change in neutralising antibody levels was classified into five groups and used to predict the longevity of neutralising antibody-mediated immunity. FINDINGS: We approached 517 patients for participation in the study, of whom 288 consented for outpatient follow-up and collection of serial blood samples. 164 patients were followed up and had adequate blood samples collected for analysis, with a total of 546 serum samples collected, including 128 blood samples taken up to 180 days post-symptom onset. We identified five distinctive patterns of neutralising antibody dynamics as follows: negative, individuals who did not, at our intervals of sampling, develop neutralising antibodies at the 30% inhibition level (19 [12%] of 164 patients); rapid waning, individuals who had varying levels of neutralising antibodies from around 20 days after symptom onset, but seroreverted in less than 180 days (44 [27%] of 164 patients); slow waning, individuals who remained neutralising antibody-positive at 180 days post-symptom onset (46 [28%] of 164 patients); persistent, although with varying peak neutralising antibody levels, these individuals had minimal neutralising antibody decay (52 [32%] of 164 patients); and delayed response, a small group that showed an unexpected increase of neutralising antibodies during late convalescence (at 90 or 180 days after symptom onset; three [2%] of 164 patients). Persistence of neutralising antibodies was associated with disease severity and sustained level of pro-inflammatory cytokines, chemokines, and growth factors. By contrast, T-cell responses were similar among the different neutralising antibody dynamics groups. On the basis of the different decay dynamics, we established a prediction algorithm that revealed a wide range of neutralising antibody longevity, varying from around 40 days to many decades. INTERPRETATION: Neutralising antibody response dynamics in patients who have recovered from COVID-19 vary greatly, and prediction of immune longevity can only be accurately determined at the individual level. Our findings emphasise the importance of public health and social measures in the ongoing pandemic outbreak response, and might have implications for longevity of immunity after vaccination. FUNDING: National Medical Research Council, Biomedical Research Council, and A*STAR, Singapore.

The pathological autopsy of coronavirus disease 2019 (COVID-2019) in China: a review.

The coronavirus disease 2019 (COVID-2019) that emerged in Wuhan, China, has rapidly spread to many countries across all six WHO regions. However, its pathobiology remains incompletely understood and many efforts are underway to study it worldwide. To clarify its pathogenesis to some extent, it will inevitably require lots of COVID-2019-associated pathological autopsies. Pathologists from all over the world have raised concerns with pathological autopsy relating to COVID-2019. The issue of whether a person died from COVID-2019 infection or not is always an ambiguous problem in some cases, and ongoing epidemiology from China may shed light on it. This review retrospectively summarizes the research status of pathological autopsy for COVID-2019 deaths in China, which will be important for the cause of death, prevention, control and clinical strategies of COVID-2019. Moreover, it points out several challenges at autopsy. We believe pathological studies from China enable to correlate clinical symptoms and pathological features of COVID-2019 for doctors and provide an insight into COVID-2019 disease.