TISSUE-SPECIFIC METABOLOMIC REPROGRAMMING DETERMINES THE DISEASE PATHOPHYSIOLOGY OF SARS-COV-2 VARIANTS IN HAMSTER MODEL (preprint)

Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between organs and specific SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed increased viremia in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection.

Differences in virus and immune dynamics for SARS-CoV-2 Delta and Omicron infections by age and vaccination histories (preprint)

Vaccination against COVID-19 was integral to controlling the pandemic that persisted with the continuous emergence of SARS-CoV-2 variants. Using a mathematical model describing SARS-CoV-2 within-host infection dynamics, we estimate differences in virus and immunity due to factors of infecting variant, age, and vaccination history (vaccination brand, number of doses and time since vaccination). We fit our model in a Bayesian framework to upper respiratory tract viral load measurements obtained from cases of Delta and Omicron infections in Singapore, of whom the majority only had one nasopharyngeal swab measurement. With this dataset, we are able to recreate similar trends in URT virus dynamics observed in past within-host modelling studies fitted to longitudinal patient data. We found that Omicron had greater infection potential than Delta, indicating greater propensity to establish infection. Moreover, heterogeneities in infection dynamics across patient subgroups could be recreated by fitting immunity-related parameters as vaccination history-specific, with or without age modification. Our model results are consistent with the notion of immunosenescence in SARS-CoV-2 pathogenesis in elderly individuals, and the issue of waning immunity with increased time since last vaccination. Lastly, vaccination was not found to subdue virus dynamics in Omicron infections as well as it had for Delta infections. This study provides insight into the influence of vaccine-elicited immunity on SARS-CoV-2 within-host dynamics, and the interplay between age and vaccination history. Furthermore, it demonstrates the need to disentangle host factors and changes in pathogen to discern factors influencing virus dynamics. Finally, this work demonstrates a way forward in the study of within-host virus dynamics, by use of viral load datasets including a large number of patients without repeated measurements.

The role of vitamin D as a preventive strategy in COVID-19 infections: evidence from South Asia (preprint)

Background Regional evidence on prevention of COVID-19 and its sequalae by vitamin D remains inconclusive and sparse.Aim/Objective This study aimed to determine the association between COVID-19 and Vitamin D deficiency among adults in Colombo District, Sri Lanka.Methods A sex-matched case-control study was conducted among 104 RT-PCR-confirmed COVID-19 patients and 104 RT-PCR negative adults recruited from community. Non-fasting blood samples were analysed for serum 25(OH)D using chemiluminescence assay and vitamin D deficiency identified (< 50.0nmol/L).Results Cases (34.2; SD = 15.4nmol/L) had significantly lower 25(OH)D compared to controls (39.8; SD = 17.8nmol/L) (p = 0.02) which persisted after adjustments (p = 0.02), along with Sinhalese ethnicity (p < 0.001). VDD was significantly more prevalent in cases (83.7% vs. 71.2%; crude odds ratio (OR) = 2.1; 95%-CI:1.1,4.1), although not an independent COVID-19 predictor (adjusted OR = 1.9; 95%-CI:0.6,5.7). A significantly lower 25(OH)D level was observed in moderate/severe cases (39.7; SD = 12.3nmol/L) vs mild (32.9; SD = 15.8nmol/L) (p = 0.015). Neither low serum concentrations nor deficiency showed an independent relationship with severity (p > 0.05). Diabetes was the sole predictor of COVID-19 severity (p = 0.022).Conclusions Vitamin D has potential as a cost-effective primary, but not secondary, preventive strategy.

Human coronavirus 229E infection inactivates pyroptosis executioner gasdermin D but ultimately leads to lytic cell death partly mediated by gasdermin E (preprint)

Human coronavirus 229E (HCoV-229E) is associated with upper respiratory tract infections and causes local respiratory symptoms. It has been reported that HCoV-229E can cause cell death in a variety of cells in vitro. However, the molecular pathways that lead to virus-induced cell death remain poorly characterized. Here, we show that the main protease (Mpro) of HCoV-229E can cleave the pyroptosis executioner gasdermin D (GSDMD) within its active N-terminal domain at two different sites (Q29 and Q193) to generate fragments unable to cause pyroptosis. Despite GSDMD cleavage by HCoV-229E Mpro, we show that HCoV-229E infection leads to lytic cell death. We further demonstrate that virus-induced lytic cell death is partially dependent on the activation of caspases-3 and -8. Interestingly, inhibition of caspases does not only reduce lytic cell death upon infection, but also sustains the release of virus particles over time, which suggests that caspase-mediated cell death is a mechanism to limit virus replication and spread. Finally, we show that pyroptosis is partially dependent on another gasdermin family member, gasdermin E (GSDME). During HCoV-229E infection, GSDME is cleaved to yield its N-terminal pore-forming domain (p30). Accordingly, GSDME knockout cells show a significant decrease in lytic cell death upon virus, whereas this is not the case for GSDMD knockout cells, which aligns with the observation that GSDMD is also inactivated by caspase-3 during infection. These results suggest that GSDMD is inactivated during HCoV-229E infection, and point to GSDME as an important player in the execution of virus-induced cell death.

Assessing the impact of Delta and Omicron in German intensive care units: a retrospective multistate analysis based on nationwide inpatient billing data (preprint)

Background The spread of several severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) variants of concern (VOC) repeatedly led to increasing numbers of coronavirus disease 2019 (COVID-19) patients in German intensive care units (ICUs), resulting in capacity shortages and even transfers of COVID-19 intensive care patients between federal states in late 2021. In this respect, there is limited evidence on the impact of predominant VOC in German ICUs on the population level.Methods A retrospective cohort study was conducted from July 01, 2021, to May 31, 2022, using nationwide inpatient billing data from German hospitals on COVID-19 intensive care patients and SARS-COV-2 sequence data from Germany. A multivariable Poisson regression analysis was performed to estimate incidence rate ratios (IRRs) of transfer (to another hospital during inpatient care), discharge and death of COVID-19 intensive care patients associated with Delta or Omicron, adjusted for age group and sex. Furthermore, a multistate model was used for the clinical trajectories of COVID-19 intensive care patients to estimate their competing risk of transfer, discharge or death associated with Delta or Omicron, while further addressing patient age.Results Poisson regression analysis comparing Omicron versus Delta infection yielded an estimated adjusted IRR of 1.23 (95% CI 1.16–1.30) for transfers, 2.27 (95% CI 2.20–2.34) for discharges and 0.98 (95% CI 0.94–1.02) for deaths. For ICU deaths in particular, the estimated adjusted IRR increased from 0.14 (95% CI 0.08–0.22) for the 0–9 age group to 4.09 (95% CI 3.74–4.47) for those aged 90 and older compared to the reference group of 60-69-year olds. Multistate analysis showed that Omicron infection was associated with a higher estimated risk of discharge for COVID-19 intensive care patients across all ages, while Delta infection was associated with a higher estimated risk transfer and death.Conclusions Retrospective, nationwide comparison of transfers, discharges and deaths of COVID-19 intensive care patients during Delta- and Omicron-dominated periods in Germany suggested overall less severe clinical trajectories with Omicron. Age confirmed as an important determinant for fatal clinical outcomes in COVID-19 intensive care patients, necessitating close therapeutic care for the elderly and appropriate public health control measures.

Vitamin D status in hospitalized COVID‑19 patients is associated with disease severity and IL-5 production (preprint)

Background There are many studies on relationship between vitamin D and coronavirus disease 2019 (COVID-19), while the results are matters of debate and the mechanisms remain unknown. The present study to assess the impact of serum 25-hydroxyvitamin D [25(OH)D] levels on the severity of disease in hospitalized COVID-19 patients and identify potential mechanisms.Methods A total of 399 hospitalized COVID-19 patients were recruited from three centers between December 19, 2022, and February 1, 2023.Results Levels of 25(OH)D were significantly lower in the deceased group than other three groups (P < 0.05). The levels of 25(OH)D (odds ratio = 0.986, 95% confidence interval: 0.973–0.998, P = 0.024) and IL-5 (odds ratio = 1.239, 95% confidence interval: 1.104–1.391, P = 0.04) were independent risk factors for the severity of COVID-19 disease upon admission. Serum 25(OH)D levels combined with IL-5 levels and eosinophil (Eos) counts were able to predict the mortality of patients with COVID-19. Circulating 25(OH)D status correlated negatively with the expression of IL-5 (r=-0.262, P < 0.001) and was positively linked with CD8+ T cell counts (r=-0.121, P < 0.05) in patients with COVID-19.Conclusions Most COVID-19 patients have vitamin D deficiency and a severe deficiency is associated with fatal outcomes. This study found that the serum 25(OH)D status in COVID-19 patients correlated negatively with the expression of IL-5. The specific mechanism for this relationship is worth further exploration.Trial registration This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

Evaluation of Waning of SARS-CoV-2 Vaccine-Induced Immunity: A Systematic Review and Meta-analysis.

Importance: Estimates of the rate of waning of vaccine effectiveness (VE) against COVID-19 are key to assess population levels of protection and future needs for booster doses to face the resurgence of epidemic waves. Objective: To quantify the progressive waning of VE associated with the Delta and Omicron variants of SARS-CoV-2 by number of received doses. Data Sources: PubMed and Web of Science were searched from the databases' inception to October 19, 2022, as well as reference lists of eligible articles. Preprints were included. Study Selection: Selected studies for this systematic review and meta-analysis were original articles reporting estimates of VE over time against laboratory-confirmed SARS-CoV-2 infection and symptomatic disease. Data Extraction and Synthesis: Estimates of VE at different time points from vaccination were retrieved from original studies. A secondary data analysis was performed to project VE at any time from last dose administration, improving the comparability across different studies and between the 2 considered variants. Pooled estimates were obtained from random-effects meta-analysis. Main Outcomes and Measures: Outcomes were VE against laboratory-confirmed Omicron or Delta infection and symptomatic disease and half-life and waning rate associated with vaccine-induced protection. Results: A total of 799 original articles and 149 reviews published in peer-reviewed journals and 35 preprints were identified. Of these, 40 studies were included in the analysis. Pooled estimates of VE of a primary vaccination cycle against laboratory-confirmed Omicron infection and symptomatic disease were both lower than 20% at 6 months from last dose administration. Booster doses restored VE to levels comparable to those acquired soon after the administration of the primary cycle. However, 9 months after booster administration, VE against Omicron was lower than 30% against laboratory-confirmed infection and symptomatic disease. The half-life of VE against symptomatic infection was estimated to be 87 days (95% CI, 67-129 days) for Omicron compared with 316 days (95% CI, 240-470 days) for Delta. Similar waning rates of VE were found for different age segments of the population. Conclusions and Relevance: These findings suggest that the effectiveness of COVID-19 vaccines against laboratory-confirmed Omicron or Delta infection and symptomatic disease rapidly wanes over time after the primary vaccination cycle and booster dose. These results can inform the design of appropriate targets and timing for future vaccination programs.

Post COVID-19 condition after delta infection and omicron reinfection in children and adolescents.

BACKGROUND: The burden of COVID-19 in children and adolescents has increased during the delta and omicron waves, necessitating studies of long-term symptoms such as fatigue, dyspnoea and cognitive problems. Furthermore, immune responses in relation to persisting symptoms in younger people have not been well characterised. In this cohort study, we investigated the role of antibodies, vaccination and omicron reinfection upon persisting and long-term symptoms up to 8 months post-delta infection. METHODS: SARS-CoV-2 RT-PCR positive participants (n = 276, aged 10-20 years) were prospectively recruited in August 2021. We recorded the major symptoms of post COVID-19 condition and collected serum samples 3- and 8-months post delta infection. Binding antibodies were measured by spike IgG ELISA, and surrogate neutralising antibodies against Wuhan and delta variants by the hemagglutination test (HAT). FINDINGS: After delta infection, persisting symptoms at 3 months were significantly associated with higher delta antibody titres (OR 2.97, 95% CI 1.57-6.04, p = 0.001). Asymptomatic acute infection compared to symptomatic infection lowered the risk of persisting (OR 0.13, 95% CI 0.02-0.55, p = 0.013) and long-term (OR 0.28 95% CI 0.11-0.66, p = 0.005) symptoms at 3 and 8 months, respectively. Adolescents (16-20 years) were more likely to have long-term symptoms compared to children (10-15 years) (OR 2.44, 95% CI 1.37-4.41, p = 0.003). INTERPRETATION: This clinical and serological study compares long-term symptoms after delta infection between children and adolescents. The association between high antibody titres and persisting symptoms suggest the involvement of an immune mechanism. Similarly to adults, the dominant long-term symptoms in children are fatigue, dyspnoea and cognitive problems. FUNDING: This work was funded by the Ministry of Health and Care Services, Norway, the University of Bergen, Norway and Helse Vest, Norway (F-12621).

Comparison of Symptoms Associated With SARS-CoV-2 Variants Among Children in Canada.

Importance: Clinical manifestations of SARS-CoV-2 variants have not been systematically compared in children. Objective: To compare symptoms, emergency department (ED) chest radiography, treatments, and outcomes among children with different SARS-CoV-2 variants. Design, Setting, and Participants: This multicenter cohort study was performed at 14 Canadian pediatric EDs. Participants included children and adolescents younger than 18 years (hereinafter referred to as children) tested for SARS-CoV-2 infection in an ED between August 4, 2020, and February 22, 2022, with 14 days of follow-up. Exposure(s): SARS-CoV-2 variants detected on a specimen collected from the nasopharynx, nares, or throat. Main Outcomes and Measures: The primary outcome was presence and number of presenting symptoms. The secondary outcomes were presence of core COVID-19 symptoms, chest radiography findings, treatments, and 14-day outcomes. Results: Among 7272 participants presenting to an ED, 1440 (19.8%) had test results positive for SARS-CoV-2 infection. Of these, 801 (55.6%) were boys, with a median age of 2.0 (IQR, 0.6-7.0) years. Children with the Alpha variant reported the fewest core COVID-19 symptoms (195 of 237 [82.3%]), which were most often reported by participants with Omicron variant infection (434 of 468 [92.7%]; difference, 10.5% [95% CI, 5.1%-15.9%]). In a multivariable model with the original type as the referent, the Omicron and Delta variants were associated with fever (odds ratios [ORs], 2.00 [95% CI, 1.43-2.80] and 1.93 [95% CI, 1.33-2.78], respectively) and cough (ORs, 1.42 [95% CI, 1.06-1.91] and 1.57 [95% CI, 1.13-2.17], respectively). Upper respiratory tract symptoms were associated with Delta infection (OR, 1.96 [95% CI, 1.38-2.79]); lower respiratory tract and systemic symptoms were associated with Omicron variant infection (ORs, 1.42 [95% CI, 1.04-1.92] and 1.77 [95% CI, 1.24-2.52], respectively). Children with Omicron infection most often had chest radiography performed and received treatments; compared with those who had Delta infection, they were more likely to have chest radiography performed (difference, 9.7% [95% CI, 4.7%-14.8%]), to receive intravenous fluids (difference, 5.6% [95% CI, 1.0%-10.2%]) and corticosteroids (difference, 7.9% [95% CI, 3.2%-12.7%]), and to have an ED revisit (difference, 8.8% [95% CI, 3.5%-14.1%]). The proportions of children admitted to the hospital and intensive care unit did not differ between variants. Conclusions and Relevance: The findings of this cohort study of SARS-CoV-2 variants suggest that the Omicron and Delta variants were more strongly associated with fever and cough than the original-type virus and the Alpha variant. Children with Omicron variant infection were more likely to report lower respiratory tract symptoms and systemic manifestations, undergo chest radiography, and receive interventions. No differences were found in undesirable outcomes (ie, hospitalization, intensive care unit admission) across variants.

Effectiveness of BNT162b2 vaccine against SARS-CoV-2 Delta and Omicron infection in adolescents, Norway, August 2021 to January 2022.

OBJECTIVES: We estimated the BNT162b2 vaccine effectiveness (VE) against any (symptomatic or not) SARS-CoV-2 Delta and Omicron infection among adolescents (aged 12-17 years) in Norway from August 2021 to January 2022. METHODS: We used Cox proportional hazard models, where vaccine status was included as a time-varying covariate and models were adjusted for age, sex, comorbidities, residence county, birth country, and living conditions. RESULTS: The VE against Delta infection peaked at 68% (95% confidence interval [CI]: 64-71%) and 62% (95% CI: 57-66%) in days 21-48 after the first dose among those aged 12-15 years and 16-17 years, respectively. Among those aged 16-17 years who received two doses, the VE against Delta infection peaked at 93% (95% CI: 90-95%) in days 35-62 and decreased to 84% (95% CI: 76-89%) in ≥63 days after vaccination. We did not observe a protective effect against Omicron infection after receiving one dose. Among those aged 16-17 years, the VE against Omicron infection peaked at 53% (95% CI: 43-62%) in 7-34 days after the second dose and decreased to 23% (95% CI: 3-40%) in ≥63 days after vaccination. CONCLUSION: We found a reduced protection after two BNT162b2 vaccine doses against any Omicron infection compared to Delta. Effectiveness decreased with time from vaccination for both variants. The impact of vaccination among adolescents on reducing infection and thus transmission is limited during the Omicron dominance.

A nationwide multistate analysis estimating the rates and risks of transferring critically ill COVID-19 patients during the Delta and Omicron waves in Germany (preprint)

Background The spread of several SARS-CoV-2 variants of concern (VOC) led to increasing numbers of patients with coronavirus disease 2019 (COVID-19) in German intensive care units (ICU), resulting in capacity shortages and even transfers of COVID-19 ICU patients between federal states in late 2021. Comprehensive evidence on the impact of predominant VOC, in this case Delta and Omicron, on inter-hospital transfers of COVID-19 ICU patients remains scarce. Methods A retrospective cohort study was conducted from July 01, 2021 until May 31, 2022 using nationwide reimbursement inpatient count data of COVID-19 ICU patients and weekly sequence data of VOC in Germany. A multivariable Poisson regression analysis was performed to estimate incidence rates and incidence rate ratios (IRR) for competing events of transfer, discharge and death, adjusted for VOC infection, age group and sex. For corresponding risk estimation, a multistate model for the clinical trajectory in ICU was applied. Results Omicron versus Delta infection yielded estimated adjusted IRR of 1.23 (95% CI, 1.16 - 1.30) for transfer, 2.27 (95% CI, 2.20 - 2.34), for discharge and 0.98 (95% CI, 0.94 - 1.02) for death. For death in ICU, estimated adjusted IRR increased progressively with age up to 4.09 (95% CI, 3.74 - 4.47) for those 90 years and older. COVID-19 ICU patients with Omicron infection were at comparatively higher estimated risk of discharge, whereas the estimated risk of transfer and death were higher for those with Delta infection. Conclusions Inter-hospital transfers and discharges occurred more frequently in COVID-19 ICU patients with Omicron infection than in those with Delta infection, who in turn had a higher estimated risk of death. Age emerges as a relevant determinant for fatal clinical trajectories in COVID-19 ICU patients and imposes close therapeutic care.

Association between calcium and vitamin D in geriatric patients hospitalized for Covid-19: Results from the GERIA-COVID study (preprint)

The deficiency of 25OH vitamin D (25[OH]D) is common in the older population. It physiologically triggers secondary hyperparathyroidism resulting in normal circulating calcium levels. Adjusted calcium (CaA) is estimated by the PAYNE method and several studies report a misclassification of calcium status by corrected calcium compared to ionized calcium (CaI) in older patients. Hypocalcemia is common in older COVID-19 patients. Blunted secondary hyperparathyroidism explain this high prevalence of hypocalcemia in COVID-19. However, no studies have focused on patients older than 75 years despite the high mortality rate in this population. In the present study, the association between the different types of calcium (CaI, CaA, and total calcium [CaT]) and 25(OH)D deficiency (below 50 nmol/L) was investigated. The study of the correlation between each type of calcium was performed secondarily. Observational monocentric study focused on the GERIA-COVID database during the second wave of COVID-19 in France from October 2020 to March 2021. COVID-19 was diagnosed with RT-PCR and/or chest CT-scan. A population of 181 older COVID-19 patients (86.4 years {+/-} 5.7) was analyzed. Sixty-three patients (34.8%) were deficient in 25(OH)D. The prevalence of total and ionized hypocalcemia was 44.1% and 39.2%, respectively. A negative association was reported in linear regression between 25(OH)D deficiency and CaA ({beta} =-0.052 [-0.093; -0.010], p = 0.015) as well as with CaT ({beta} = -0.05 [-0.09; -0.01], p =0.034) in the multivariate model. No association was found between vitamin D deficiency and CaI. In the multivariate models, there was no association between each type of calcium and PTH. CaI was correlated with CaT (r = 0.39, p < 0.001) and with CaA (r = 0.15, p = 0.043). Secondary hyperparathyroidism was not activated in the context of COVID-19 in this study. After reviewing the literature, this appears to be the first study in older patients to expose such results.

Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms.

BACKGROUND & AIMS: Chronic coinfection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. Herein, we aimed to elucidate the molecular mechanisms underlying the widely reported observation that HDV interferes with HBV in most coinfected patients. METHODS: Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-sequencing analyses, as well as RNA synthesis, stability and association assays. RESULTS: Transcriptomic analyses in cell culture and mouse models of coinfection enabled us to define an HDV-induced signature, mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in chronically HDV/HBV-coinfected patients but not in cells that only express HDV antigen (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNA synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNA, and HDAg was associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as HCV or SARS-CoV-2. CONCLUSIONS: Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect the RNA production of its helper virus. Exploiting these findings could pave the way to the development of new therapeutic strategies against HBV. IMPACT AND IMPLICATIONS: Although the molecular mechanisms remained unexplored, it has long been known that despite its dependency, HDV decreases HBV viremia in patients. Herein, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNA metabolism, and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way for the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNA. Additionally, the HDV-induced modulation signature could potentially be correlated with responsiveness to IFN-α treatment, thereby helping to guide management of HBV/HDV-coinfected patients.

Effect of vaccination on the case fatality rate for COVID-19 infections 2020-2021: multivariate modelling of data from the US Department of Veterans Affairs.

OBJECTIVES: To evaluate the benefits of vaccination on the case fatality rate (CFR) for COVID-19 infections. DESIGN, SETTING AND PARTICIPANTS: The US Department of Veterans Affairs has 130 medical centres. We created multivariate models from these data-339 772 patients with COVID-19-as of 30 September 2021. OUTCOME MEASURES: The primary outcome for all models was death within 60 days of the diagnosis. Logistic regression was used to derive adjusted ORs for vaccination and infection with Delta versus earlier variants. Models were adjusted for confounding factors, including demographics, comorbidity indices and novel parameters representing prior diagnoses, vital signs/baseline laboratory tests and outpatient treatments. Patients with a Delta infection were divided into eight cohorts based on the time from vaccination to diagnosis. A common model was used to estimate the odds of death associated with vaccination for each cohort relative to that of unvaccinated patients. RESULTS: 9.1% of subjects were vaccinated. 21.5% had the Delta variant. 18 120 patients (5.33%) died within 60 days of their diagnoses. The adjusted OR for a Delta infection was 1.87±0.05, which corresponds to a relative risk (RR) of 1.78. The overall adjusted OR for prior vaccination was 0.280±0.011 corresponding to an RR of 0.291. Raw CFR rose steadily after 10-14 weeks. The OR for vaccination remained stable for 10-34 weeks. CONCLUSIONS: Our CFR model controls for the severity of confounding factors and priority of vaccination, rather than solely using the presence of comorbidities. Our results confirm that Delta was more lethal than earlier variants and that vaccination is an effective means of preventing death. After adjusting for major selection biases, we found no evidence that the benefits of vaccination on CFR declined over 34 weeks. We suggest that this model can be used to evaluate vaccines designed for emerging variants.

Protection Conferred by Delta and BA.1/BA.2 Infection Against BA.4/BA.5 Infection and Hospitalization: A Retrospective Cohort Study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 immunity has declined with subsequent waves and accrual of viral mutations. In vitro studies raise concern for immune escape by BA.4/BA.5, and a study in Qatar showed moderate protection, but these findings have yet to be reproduced. METHODS: This retrospective cohort study included individuals tested for coronavirus disease 2019 by polymerase chain reaction during Delta or BA.1/BA.2 and retested during BA.4/BA.5. The preventable fraction (PF) was calculated as ratio of the infection to the hospitalization rate for initially positive patients divided by the ratio for initially negative patients, stratified by age and adjusted for age, sex, comorbid conditions, and vaccination using logistic regression. RESULTS: A total of 20 987 patients met inclusion criteria. Prior Delta infection provided no protection against BA.4/BA.5 infection (adjusted PF, 11.9% [95% confidence interval, .8%-21.8%]); P = .04) and minimal protection against hospitalization (10.7% [4.9%-21.7%]; P = .003). In adjusted models, prior BA.1/BA.2 infection provided 45.9% (95% confidence interval, 36.2%-54.1%; P < .001) protection against BA.4/BA.5 reinfection and 18.8% (10.3%-28.3%; (P < .001) protection against hospitalization. Up-to-date vaccination provided modest protection against reinfection with BA.4/BA.5 and hospitalization. CONCLUSIONS: Prior infection with BA.1/BA.2 and up-to-date vaccination provided modest protection against infection with BA.4/BA.5 and hospitalization, while prior Delta infection provided minimal protection against hospitalization and none against infection.

Eastern Mediterranean Health Journal [2022; Vol.28, Issue 11]

Eastern Mediterranean Health Journal is the official health journal published by the Eastern Mediterranean Regional Office of the World Health Organization. It is a forum for the presentation and promotion of new policies and initiatives in health services; and for the exchange of ideas concepts epidemiological data research findings and other information with special reference to the Eastern Mediterranean Region. It addresses all members of the health profession medical and other health educational institutes interested NGOs WHO Collaborating Centres and individuals within and outside the Region.

المجلة الصحية لشرق المتوسط هى المجلة الرسمية التى تصدرعن المكتب الاقليمى لشرق المتوسط بمنظمة الصحة العالمية. وهى منبر لتقديم السياسات والمبادرات الجديدة فى الصحة العامة والخدمات الصحية والترويج لها، و لتبادل الاراء و المفاهيم والمعطيات الوبائية ونتائج الابحاث وغير ذلك من المعلومات، و خاصة ما يتعلق منها باقليم شرق المتوسط. وهى موجهة الى كل اعضاء المهن الصحية، والكليات الطبية وسائر المعاهد التعليمية، و كذا المنظمات غير الحكومية المعنية، والمراكز المتعاونة مع منظمة الصحة العالمية والافراد المهتمين بالصحة فى الاقليم و خارجه

La Revue de Santé de la Méditerranée Orientale est une revue de santé officielle publiée par le Bureau régional de l’Organisation mondiale de la Santé pour la Méditerranée orientale. Elle offre une tribune pour la présentation et la promotion de nouvelles politiques et initiatives dans le domaine de la santé publique et des services de santé ainsi qu’à l’échange d’idées de concepts de données épidémiologiques de résultats de recherches et d’autres informations se rapportant plus particulièrement à la Région de la Méditerranée orientale. Elle s’adresse à tous les professionnels de la santé aux membres des instituts médicaux et autres instituts de formation médico-sanitaire aux ONG Centres collaborateurs de l’OMS et personnes concernés au sein et hors de la Région.

Determinants of protection against SARS-CoV-2 Omicron BA.1 and Delta infections in fully vaccinated outpatients (preprint)

We aimed to evaluate the association between the humoral and cellular immune responses and symptomatic SARS-CoV-2 infection with Delta or Omicron BA.1 variants in fully vaccinated outpatients. Anti-RBD IgG levels and IFN-{gamma} release were evaluated at PCR-diagnosis of SARS-CoV-2 in 636 samples from negative and positive patients during Delta and Omicron BA.1 periods. Median levels of anti-RBD IgG in positive patients were significantly lower than in negative patients for both variants (p < 0.05). The risk of Delta infection was inversely correlated with anti-RBD IgG titres (aOR = 0.63, 95% CI [0.41; 0.95], p = 0.03) and it was lower in the hybrid immunity group compared to the homologous vaccination group (aOR = 0.22, 95% CI [0.05; 0.62], p = 0.01). In contrast, neither the vaccination scheme nor anti-RBD IgG titers were associated with the risk of BA.1 infection in multivariable analysis. IFN-{gamma} release post-SARS-CoV-2 peptide stimulation was not different between samples from patients infected (either with Delta or Omicron BA.1 variant) or not (p = 0.77). Our results show that high circulating levels of anti-RBD IgG and hybrid immunity were independently associated with a lower risk of symptomatic SARS-CoV-2 infection in outpatients with differences according to the infecting variant.

A prospective cross-sectional study on post COVID-19 hair loss at a tertiary care hospital (preprint)

Severe acute respiratory virus syndrome coronavirus 2 (SARS-CoV-2) was responsible for coronavirus disease (COVID-19) pandemic, which resulted in global health care crisis. As patients recovered from COVID-19 infection, hair loss was increasingly observed as a distressing symptom. We conducted a prospective cross-sectional study of patients presenting with post COVID-19 hair loss between July to December 2021 at a tertiary care centre in north India. Detailed history, clinical examination, trichoscopy and biochemical tests were performed and recorded. COVID-19 disease severity was assessed based on the duration of COVID-19 infection and place of management (home or hospitalized). The study included 120 patients with mean age being 39.6 years. There was female preponderance. Majority of the patients (87%) were treated at home and 43.3% had COVID-19 infection for >2 weeks. Mean visual analog scale (VAS) score for stress was 5.25. Vitamin D deficiency was present in 56.7% and low ferritin in 30% of cases. Mean time of onset of hair loss post COVID-19 was 49 days. Patients mainly presented with diffuse (72.4%) and patterned hair loss (31.6%). Trichodynia was present in 15.8% of cases. The degree of hair loss was severe in 55.8% of the subjects, predominantly in older age group and females. Positive hair pull test was seen in 65% of patients. Most common trichoscopic features included single hair follicles’ (81.7%) and vellus hair >10% (60%). Trichoscopy can aid in unmasking co-existing patterned hair loss in patients presenting clinically with diffuse hair loss. Patients with COVID-19 infection for > 2 weeks had significantly more severe hair loss and VAS score. Trichoscopic findings of vellus hair >10% and empty hair follicles were more frequent in patients who were hospitalized for COVID-19 infection.

Identification of differences in the magnitude and specificity of SARS-CoV-2 nucleocapsid antibody responses in naturally infected and vaccinated individuals (preprint)

Background: As there are limited data on B cell epitopes for the nucleocapsid protein in SARS-CoV-2, we sought to identify the immunodominant regions within the N protein, recognized by patients with varying severity of natural infection with the Wuhan strain (WT), delta, omicron and in those who received the Sinopharm vaccines, which is an inactivated, whole virus vaccine. Methods: Using overlapping peptides representing the N protein, with an in-house ELISA, we mapped the immunodominant regions within the N protein, in seronegative (n=30), WT infected (n=30), delta infected (n=30), omicron infected+vaccinated (n=20) and Sinopharm (BBIBP-CorV) vaccinees (n=30). We then investigated the sensitivity and specificity of these immunodominant regions and analysed their conservation with other SARS-CoV-2 variants of concern, seasonal human coronaviruses and bat Sarbecoviruses. We then investigated the kinetics of responses to these regions in those with varying severity of acute COVID-19. Results: We identified four immunodominant regions aa 29-52, aa 155-178, aa 274 to 297 and aa 365 to 388, were highly conserved within SARS-CoV-2 and the bat coronaviruses. The magnitude of responses to these regions varied based on the infecting SARS-CoV-2 variants, with WT infected individuals predominantly recognizing aa155 to 178 regions, delta infected individuals and vaccinated+omicron infected individuals predominantly recognizing regions aa 29 to 52 and aa 274 to 294 regions. Sinopharm vaccinees recognized all four regions, with the magnitude of responses significantly lower than other groups. >80% of individuals gave responses above the positive cut-off threshold to many of the four regions, with some differences with individuals who were infected with different VoCs. These regions were found to be 100% specific, as none of the seronegative individuals gave any responses. Conclusions: N-protein specific responses appear to be detectable in over 90% of those who were naturally infected or vaccinated with a whole virus inactivated vaccine, with responses mainly directed against four regions of the protein, which were highly conserved. As these regions were highly specific with high sensitivity, they have a potential to be used to develop diagnostic assays and to be used in development of vaccines.

A delicate balance between antibody evasion and ACE2 affinity for Omicron BA.2.75.

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused successive global waves of infection. These variants, with multiple mutations in the spike protein, are thought to facilitate escape from natural and vaccine-induced immunity and often increase in affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor-binding domain (RBD). Here, we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared with BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection, which may explain the rapid spread in India, where where there is a high background of Delta infection. ACE2 affinity appears to be prioritized over greater escape.