Conserved longitudinal alterations of anti-S-protein IgG subclasses in disease progression in initial ancestral Wuhan and vaccine breakthrough Delta infections.

Introduction: COVID-19 has a wide disease spectrum ranging from asymptomatic to severe. While humoral immune responses are critical in preventing infection, the immune mechanisms leading to severe disease, and the identification of biomarkers of disease progression and/or resolution of the infection remains to be determined. Methods: Plasma samples were obtained from infections during the initial wave of ancestral wildtype SARS-CoV-2 and from vaccine breakthrough infections during the wave of Delta variant, up to six months post infection. The spike-specific antibody profiles were compared across different severity groups and timepoints. Results: We found an association between spike-specific IgM, IgA and IgG and disease severity in unvaccinated infected individuals. In addition to strong IgG1 and IgG3 response, patients with severe disease develop a robust IgG2 and IgG4 response. A comparison of the ratio of IgG1 and IgG3 to IgG2 and IgG4 showed that disease progression is associated with a smaller ratio in both the initial wave of WT and the vaccine breakthrough Delta infections. Time-course analysis revealed that smaller (IgG1 and IgG3)/(IgG2 and IgG4) ratio is associated with disease progression, while the reverse associates with clinical recovery. Discussion: While each IgG subclass is associated with disease severity, the balance within the four IgG subclasses may affect disease outcome. Acute disease progression or infection resolution is associated with a specific immunological phenotype that is conserved in both the initial wave of WT and the vaccine breakthrough Delta infections.

Prolonged inflammation in patients hospitalized for coronavirus disease 2019 (COVID-19) resolves 2 years after infection.

Long-term complications from coronavirus disease 2019 (COVID-19) are concerning, as survivors can develop subclinical multiorgan dysfunction. It is unknown if such complications are due to prolonged inflammation, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination may reduce sequela. We conducted a prospective longitudinal study on hospitalized patients over 24 months. Clinical symptoms were collected by self-reporting during follow-up, along with blood samples for quantification of inflammatory markers and immune cell frequencies. All patients were given one dose of mRNA vaccine at 12-16 months. Their immune profiles at 12 and 24 months were compared. Approximately 37% and 39% of our patients reported post-COVID-19 symptoms at 12 and 24 months, respectively. The proportion of symptomatic patients with more than one symptom decreased from 69% at 12 months to 56% at 24 months. Longitudinal cytokine profiling revealed a cluster of individuals with persistently high inflammatory cytokine levels 12 months after infection. Patients with prolonged inflammation showed elevated terminally differentiated memory T cells in their blood; 54% had symptoms at 12 months. The majority of inflammatory markers and dysregulated immune cells in vaccinated patients recovered to a healthy baseline at 24 months, even though symptoms persisted. Post-COVID-19 symptoms can linger for 2 years after the initial infection and are associated with prolonged inflammation. Prolonged inflammation in hospitalized patients resolves after 2 years. We define a set of analytes associated with persistent inflammation and presence of symptoms, which could be useful biomarkers for identifying and monitoring high-risk survivors.

Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals.

The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 - 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2.

A living WHO guideline on drugs for covid-19

UPDATES: This is the twelfth version (eleventh update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline. CLINICAL QUESTION: What is the role of drugs in the treatment of patients with covid-19? CONTEXT: The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and under way. The emerging SARS-CoV-2 variants (such as omicron) and subvariants are also changing the role of therapeutics. This update provides updated recommendations for remdesivir, addresses the use of combination therapy with corticosteroids, interleukin-6 (IL-6) receptor blockers, and janus kinase (JAK) inhibitors in patients with severe or critical covid-19, and modifies previous recommendations for the neutralising monoclonal antibodies sotrovimab and casirivimab-imdevimab in patients with non-severe covid-19. NEW OR UPDATED RECOMMENDATIONS: • Remdesivir: a conditional recommendation for its use in patients with severe covid-19; and a conditional recommendation against its use in patients with critical covid-19. • Concomitant use of IL-6 receptor blockers (tocilizumab or sarilumab) and the JAK inhibitor baricitinib: these drugs may now be combined, in addition to corticosteroids, in patients with severe or critical covid-19. • Sotrovimab and casirivimab-imdevimab: strong recommendations against their use in patients with covid-19, replacing the previous conditional recommendations for their use. UNDERSTANDING THE NEW RECOMMENDATIONS: When moving from new evidence to updated recommendations, the Guideline Development Group (GDG) considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. For remdesivir, new trial data were added to a previous subgroup analysis and provided sufficiently trustworthy evidence to demonstrate benefits in patients with severe covid-19, but not critical covid-19. The GDG considered benefits of remdesivir to be modest and of moderate certainty for key outcomes such as mortality and mechanical ventilation, resulting in a conditional recommendation. For baricitinib, the GDG considered clinical trial evidence (RECOVERY) demonstrating reduced risk of death in patients already receiving corticosteroids and IL-6 receptor blockers. The GDG acknowledged that the clinical trials were not representative of the world population and that the risk-benefit balance may be less advantageous, particularly in patients who are immunosuppressed at higher risk of opportunistic infections (such as serious fungal, viral, or bacteria), those already deteriorating where less aggressive or stepwise addition of immunosuppressive medications may be preferred, and in areas where certain pathogens such as HIV or tuberculosis, are of concern. The panel anticipated that there would be situations where clinicians may opt for less aggressive immunosuppressive therapy or to combine medications in a stepwise fashion in patients who are deteriorating. The decision to combine the medications will depend on their availability, and the treating clinician's perception of the risk-benefit balance associated with combination immunosuppressive therapy, particularly in patient populations at risk of opportunistic infections who may have been under-represented in clinical trials. When making a strong recommendation against the use of monoclonal antibodies for patients with covid-19, the GDG considered in vitro neutralisation data demonstrating that sotrovimab and casirivimab-imdevimab evaluated in clinical trials have meaningfully reduced neutralisation activity of the currently circulating variants of SARS-CoV-2 and their subvariants. There was consensus among the panel that the absence of in vitro neutralisation activity strongly suggests absence of clinical effectiveness of these monoclonal antibodies. However, there was also consensus regarding the need for clinical trial evidence in order to confirm clinical efficacy of new monoclonal antibodies that reliably neutralise the circulating strains in vitro. Whether emerging new variants and subvariants might be susceptible to sotrovimab, casirivimab-imdevimab, or other anti-SARS-CoV-2 monoclonal antibodies cannot be predicted. PRIOR RECOMMENDATIONS: • Recommended for patients with severe or critical covid-19­strong recommendations for systemic corticosteroids; IL-6 receptor blockers (tocilizumab or sarilumab) in combination with corticosteroids; and baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids. • Recommended for patients with non-severe covid-19 at highest risk of hospitalisation­a strong recommendation for nirmatrelvir/ritonavir; conditional recommendations for molnupiravir and remdesivir. • Not recommended for patients with non-severe covid-19­a conditional recommendation against systemic corticosteroids; a strong recommendation against convalescent plasma; a recommendation against fluvoxamine, except in the context of a clinical trial; and a strong recommendation against colchicine. • Not recommended for patients with non-severe covid-19 at low risk of hospitalisation­a conditional recommendation against nirmatrelvir/ritonavir. • Not recommended for patients with severe or critical covid-19­a recommendation against convalescent plasma except in the context of a clinical trial; and a conditional recommendation against the JAK inhibitors ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity­a strong recommendations against hydroxychloroquine and against lopinavir/ritonavir; and a recommendation against ivermectin except in the context of a clinical trial. ABOUT THIS GUIDELINE: This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact. Future recommendations: Recommendations on anticoagulation are planned for the next update to this guideline.

Compliance with face mask use during the COVID-19 pandemic: a community observational study in Singapore.

Introduction: Widespread mask use is an important intervention for control of the coronavirus disease 2019 pandemic. However, data on the factors affecting mask use are lacking. In this observational study, we evaluated the proportion of and factors influencing face mask use and related hygiene practices. Methods: We observed randomly selected members from the public in 367 venues across Singapore, and recorded the proportion of individuals with full compliance with mask use and mask hygiene (hand hygiene before and after touching the mask or face). Logistic regression analyses were used to determine variables associated with mask and hand hygiene compliance. Results: We made 3,821 observations - 2,149 (56.2%) females, 3,569 (93.4%) adults (≥21 years), 212 (5.5%) children (6-20 years) and 40 (1.0%) children (2-5 years). The overall full compliance rate (correct mask use), poor compliance rate (incorrect mask use) and absent mask use were 84.5%, 12.9% and 2.6%, respectively. The factors - male gender, fabric mask usage and crowded indoor venues - were associated with lower mask compliance. Face or mask touching behaviour was observed in 10.7% and 13.7% of individuals observed, respectively. Only one individual performed hand hygiene before and after touching the mask. Conclusion: The rate of mask compliance was high, probably due to legislation mandating mask usage. However, specific factors and crowded indoor venues associated with lower mask compliance were identified. We also noted an issue with the absence of hand hygiene before and after face or mask touching. These issues may benefit from targeted public health messaging.

Results from a systematic programme of evaluating COVID-19 reinfection cases in the early phase of the pandemic, Singapore.

OBJECTIVES: The objectives of this study were to describe the coronavirus disease caused by SARS-CoV-2 (COVID-19) reinfection evaluation algorithm used in the early phase of the pandemic in Singapore and analyze the clinical and laboratory characteristics of the cases evaluated. METHODS: We performed a retrospective case-control analysis including all COVID-19 cases evaluated for possible reinfection under the local COVID-19 reinfection evaluation programme between 1 June 2020-30 June 2021. Whole genome sequencing (WGS) was used as confirmatory testing. We compared all reinfection ("RI") cases against those who were evaluated but eventually assessed not to be reinfection ("non-RI"). RESULTS: There were 74 possible reinfection cases evaluated through the programme, of which 32 were subsequently classified as RI. There was strong statistical evidence that RI cases had a longer interval between 1st and 2nd episode (mean 297 days; 95%-confidence interval (CI) 267-327) compared to non-RI cases (mean 186 days; 95%-CI 144-228). The cycle threshold (Ct) value of initial polymerase chain rection (PCR) at 2nd episode was also found to be significantly lower in RI cases (mean 23; 95%-CI 20-26) compared to non-RI cases (mean 34; 95%-CI 32-36). There was no significant difference in the proportion of individuals who had fever, acute respiratory symptoms or asymptomatic in both groups. Delta and beta variants were most commonly identified from WGS and provide indication of re-infection as these were not 'wild-type' and were not circulating during the time period of the index infection. CONCLUSIONS: Using a combination of serologic, microbiologic and genomic criteria to evaluate possible reinfection cases is useful and can provide a framework for evaluation that may be modified for future similar situations.

Real-world effectiveness of sotrovimab and remdesivir for early treatment of high-risk hospitalized COVID-19 patients: A propensity score adjusted retrospective cohort study.

Early treatment of high-risk COVID-19 patients may prevent disease progression. However, there are limited data to support treatment of hospitalized or fully vaccinated patients with mild-to-moderate disease. In this retrospective cohort study, we studied the effect of early use of sotrovimab and remdesivir in high-risk hospitalized COVID-19 patients. We included PCR-confirmed COVID-19 patients admitted to the National Centre for Infectious Diseases who presented within the first 5 days of illness, and who were not requiring oxygen or ICU care at presentation. Sotrovimab- and remdesivir-treated groups were compared with control (no early treatment). A multiple propensity-score adjusted multivariable regression analysis was conducted with a composite primary endpoint of in-hospital deterioration (oxygen requirement, ICU admission, or mortality). Of 1118 patients, 841 were in the control group, 106 in the sotrovimab group and 169 in the remdesivir group. The median age was 63 years (IQR 46-74 years) and 505 (45.2%) were female. In unvaccinated patients, both remdesivir and sotrovimab treatment were protective (adjusted odds ratio [aOR] 0.19, 95% CI 0.064-0.60 and 0.18 [95% CI 0.066-0.47]), respectively. Contrarily, among the vaccinated patients there was no significant treatment effect with early remdesivir treatment (aOR 2.51, 95% CI 0.83-7.57, p = 0.10). Remdesivir and sotrovimab treatment, given early in the disease course to unvaccinated high-risk patients, was effective in reducing the risk of in-hospital deterioration and severe disease. This effect was not seen in fully vaccinated patients, which may be due to a small sample size or residual confounding.

Conserved longitudinal alterations of anti-S-protein IgG subclasses in disease progression in initial ancestral Wuhan and vaccine breakthrough Delta infections

Introduction COVID-19 has a wide disease spectrum ranging from asymptomatic to severe. While humoral immune responses are critical in preventing infection, the immune mechanisms leading to severe disease, and the identification of biomarkers of disease progression and/or resolution of the infection remains to be determined. Methods Plasma samples were obtained from infections during the initial wave of ancestral wildtype SARS-CoV-2 and from vaccine breakthrough infections during the wave of Delta variant, up to six months post infection. The spike-specific antibody profiles were compared across different severity groups and timepoints. Results We found an association between spike-specific IgM, IgA and IgG and disease severity in unvaccinated infected individuals. In addition to strong IgG1 and IgG3 response, patients with severe disease develop a robust IgG2 and IgG4 response. A comparison of the ratio of IgG1 and IgG3 to IgG2 and IgG4 showed that disease progression is associated with a smaller ratio in both the initial wave of WT and the vaccine breakthrough Delta infections. Time-course analysis revealed that smaller (IgG1 and IgG3)/(IgG2 and IgG4) ratio is associated with disease progression, while the reverse associates with clinical recovery. Discussion While each IgG subclass is associated with disease severity, the balance within the four IgG subclasses may affect disease outcome. Acute disease progression or infection resolution is associated with a specific immunological phenotype that is conserved in both the initial wave of WT and the vaccine breakthrough Delta infections.

Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals

The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 – 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2.

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.

Analysis of COVID-19 Incidence and Severity Among Adults Vaccinated With 2-Dose mRNA COVID-19 or Inactivated SARS-CoV-2 Vaccines With and Without Boosters in Singapore.

Importance: Assessing booster effectiveness of COVID-19 mRNA vaccine and inactivated SARS-CoV-2 vaccine over longer time intervals and in response to any further SARS-CoV-2 variants is crucial in determining optimal COVID-19 vaccination strategies. Objective: To determine levels of protection against severe COVID-19 and confirmed SARS-CoV-2 infection by types and combinations of vaccine boosters in Singapore during the Omicron wave. Design, Setting, and Participants: This cohort study included Singapore residents aged 30 years or more vaccinated with either at least 2 doses of mRNA COVID-19 vaccines (ie, Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273) or inactivated SARS-CoV-2 vaccines (Sinovac CoronaVac or Sinopharm BBIBP-CorV) as of March 10, 2022. Individuals with a known SARS-CoV-2 infection prior to December 27, 2021, an infection on or before the date of their second vaccine dose, or with reinfection cases were excluded. Exposures: Two or 3 doses of Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, Sinovac CoronaVac, or Sinopharm BBIBP-CorV. Main Outcomes and Measures: Notified infections from December 27, 2021, to March 10, 2022, adjusted for age, sex, race, housing status, and calendar days. Estimated booster effectiveness, defined as the relative incidence-rate reduction of severe disease (supplemental oxygen, intensive care, or death) or confirmed infection following 3-dose vaccination compared with 5 months after second mRNA dose, was determined using binomial regression. Results: Among 2 441 581 eligible individuals (1 279 047 [52.4%] women, 846 110 (34.7%) aged 60 years and older), there were 319 943 (13.1%) confirmed SARS-CoV-2 infections, of which 1513 (0.4%) were severe COVID-19 cases. mRNA booster effectiveness against confirmed infection 15 to 60 days after boosting was estimated to range from 31.7% to 41.3% for the 4 boosting combinations (homologous BNT162b2, homologous mRNA-1273, 2-dose BNT162b2/mRNA-1273 booster, and 2-dose mRNA-1273/BNT162b2 booster). Five months and more after boosting, estimated booster effectiveness against confirmed infection waned, ranging from -2.8% to 14.6%. Against severe COVID-19, estimated mRNA booster effectiveness was 87.4% (95% CI, 83.3%-90.5%) 15 to 60 days after boosting and 87.2% (95% CI, 84.2%-89.7%) 5 to 6 months after boosting, with no significant difference comparing vaccine combinations. Booster effectiveness against severe COVID-19 15 days to 330 days after 3-dose inactivated COVID-19 vaccination, regardless of combination, was estimated to be 69.6% (95% CI, 48.7%-81.9%). Conclusions and Relevance: Booster mRNA vaccine protection against severe COVID-19 was estimated to be durable over 6 months. Three-dose inactivated SARS-CoV-2 vaccination provided greater protection than 2-dose but weaker protection compared with 3-dose mRNA.

Heterologous booster vaccination with CoronaVac following prime vaccination with mRNA vaccine.

Objective: Despite the high vaccine efficacy of mRNA COVID-19 vaccines, there are individuals who developed excessive reactogenic and/or allergic responses after the first mRNA dose and were considered ineligible for further mRNA doses. CoronaVac, an inactivated SARS-CoV-2 vaccine, is recommended in Singapore as an alternative. Methods: Individuals, ineligible for further mRNA vaccines (BNT162b2 or mRNA-1273) because of excessive reactive responses to prime mRNA vaccination, were recruited and offered two doses of CoronaVac as booster vaccination 38-224 days post their mRNA vaccine dose. Individuals who did not develop any excessive reactive responses after the prime mRNA vaccination were also recruited and given another mRNA vaccine as booster vaccination. Blood samples were collected at days 0, 21 and 90 post first CoronaVac dose and mRNA dose, respectively, for analysis. Results: We showed that two CoronaVac booster doses induced specific immunity in these mRNA vaccine-primed individuals. Although the spike-specific antibody response was lower, their memory B cell response against the receptor-binding domain (RBD) of the spike protein was similar, compared with individuals who received two BNT162b2 injections. The spike-specific memory T cell response also increased following CoronaVac booster doses. However, specific immunity against the Omicron variant was low, similar to individuals with two BNT162b2 doses. Conclusion: Our findings showed that while mRNA vaccine-primed individuals can opt for two subsequent doses of CoronaVac, an additional dose may be necessary to achieve protection, especially against newly emerging immune escape variants such as Omicron.

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia.

Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.

Bracing for impact: operational upshots from the National Centre for Infectious Diseases Screening Centre (Singapore) during the COVID-19 outbreak.

To combat the ongoing COVID-19 pandemic, Singapore has adopted a rigorous screening approach that involves aggressive contact tracing, rapid isolation of confirmed or suspect cases, and immediate ring-fencing of emerging local clusters and hotspots. Our screening centre team has been involved in running Singapore's designated screening centre since the end of January this year. With a well-defined blueprint and substantial pre-outbreak preparatory work, initial operations at our screening centre commenced within a day on activation and full operational status was attained in 3 days. As of 8 April 2020, the screening centre had screened more than 14,000 patients. We have adopted a "whole-of-hospital" approach, enlisting the help from other departments and subspecialties to augment manpower. Meticulous infrastructure planning to facilitate patient flow and strict measures to prevent nosocomial transmission and occupational exposure were instituted to safeguard both the staff and patients. This paper aims to describe our key takeaways in the course of operations and discuss the challenges encountered.

Comparative Effectiveness of mRNA and Inactivated Whole-Virus Vaccines Against Coronavirus Disease 2019 Infection and Severe Disease in Singapore.

Compared with individuals vaccinated with Pfizer-BioNTech/Comirnaty, recipients of Sinovac-CoronaVac and Sinopharm were 2.37 (95% CI, 2.29-2.46) and 1.62 (95% CI, 1.43-1.85) times more likely to be infected with coronavirus disease 19, respectively, while individuals vaccinated with Moderna were 0.42 (95% CI, 0.25-0.70) times less likely to develop severe disease.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination and Pediatric Age on Delta Variant Household Transmission.

BACKGROUND: In Singapore, quarantine of all close contacts with entry and exit polymerase chain reaction testing enabled evaluation of the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and pediatric age on transmission of the Delta variant. METHODS: This retrospective cohort study included all household close contacts between 1 March 2021 and 31 August 2021. RESULTS: Among 8470 Delta variant-exposed contacts linked to 2583 indices, full-vaccination of the index with BNT162b2 or mRNA-1273 was associated with reduction in acquisition by contacts (adjusted odds ratio [aOR], 0.56; 95% robust confidence interval [RCI], .44-.71 and aOR, 0.51; 95% RCI, .27-.96, respectively). Compared with young adults (aged 18-29 years), children (aged 0-11 years) were significantly more likely to transmit (aOR, 2.37; 95% RCI, 1.57-3.60) and acquire (aOR, 1.43; 95% RCI, 1.07-1.93) infection, vaccination considered. Longer duration from vaccination completion among contacts was associated with decline in protection against acquisition (first-month aOR, 0.42; 95% RCI, .33-.55; fifth-month aOR, 0.84; 95% RCI, .55-.98; P < .0001 for trend) and symptomatic disease (first-month aOR, 0.30; 95% RCI, .23-.41; fifth-month aOR, 0.62; 95% RCI, .38-1.02; P < .0001 for trend). Contacts immunized with mRNA-1273 had significant reduction in acquisition (aOR, 0.73; 95% RCI, .58-.91) compared with BNT162b2. CONCLUSIONS: Among household close contacts, vaccination prevented onward SARS-CoV-2 transmission and there was in-creased risk of SARS-CoV-2 acquisition and transmission among children compared with young adults. Time after completion of vaccination and vaccine type affected SARS-CoV-2 acquisition.