BACKGROUND:Recommendations around the use of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13) seldom focus on potential benefits of vaccine on comorbidities. We aimed to investigate whether sequential vaccination with PCV13 and PPSV23 among older adults would provide protection against cardiovascular diseases (CVD) compared with using a single pneumococcal vaccine. METHODS:We conducted a Hong Kong-wide retrospective cohort study between 2012 and 2020. Adults aged ≥65 years were identified as receiving either a single or sequential dual vaccination and followed up until the earliest CVD occurrence, death or study end. To minimize confounding, we matched each person receiving a single vaccination to a person receiving sequential vaccination according to their propensity scores. We estimated the hazard ratio (HR) of CVD risk using Cox regression and applied structural equation modelling to test whether the effect of sequential dual vaccination on CVD was mediated via the reduction in pneumonia. RESULTS:After matching, 69 390 people remained in each group and the median (interquartile range) follow-up time was 1.89 (1.55) years. Compared with those receiving a single vaccine, those receiving sequential dual vaccination had a lower risk of CVD [HR (95% CI): 0.75 (0.71, 0.80), P < 0.001]. Post-hoc mediation analysis showed strong evidence that the decreased CVD risk was mediated by the reduction in all-cause pneumonia. CONCLUSIONS:Sequential dual pneumococcal vaccination was associated with lower risk of CVD compared with single-dose PCV13 or PPSV23 in older adults. Such additional CVD benefits should be considered when making decisions about pneumococcal vaccination.

BACKGROUND AND AIM:We aimed to investigate the effect of metabolic dysfunction-associated steatotic liver disease (MASLD) on three-dose BNT162b2 immunogenicity to the omicron variant. METHODS:Adult recipients of three doses of BNT162b2 were prospectively recruited between May and December 2021. The serology of the neutralizing antibody by live virus microneutralization (vMN) to the omicron variant was measured at baseline, day 180, and day 360 after the first dose. The primary outcome was seroconversion (vMN titer ≥ 10) at day 360. Exposure of interest was MASLD, defined as hepatic steatosis (controlled attenuation parameter ≥ 248 dB/m on transient elastography) plus at least one of five cardiometabolic risk factors. Subjects with prior COVID-19 were excluded. A multivariable logistic regression model was used to derive the adjusted odds ratio of seroconversion with MASLD by adjusting for age, sex, antibiotic use, and proton pump inhibitor use. RESULTS:One hundred forty-eight BNT162b2 recipients (male: 48 [32.4%]; median age: 51.0 years [interquartile range, IQR: 44.5-57.3]) were recruited. The median time from the first dose to the third dose was 8.5 months (IQR: 7.9-8.9). MASLD subjects had a lower seroconversion rate than non-MASLD ones (89.6% vs 99.0%; P = 0.007). MASLD was the only independent risk factor for seroconversion (adjusted odds ratio: 0.051, 95% confidence interval: 0.002-0.440). Subgroup analysis of immunogenicity at 4 months after the third dose shows significantly lower vMN titer (13.06 [IQR: 7.69-22.20] vs 33.49 [IQR: 24.05-46.53]; P = 0.004) and seroconversion rate (76.9% vs 97.4%; P = 0.016) in MASLD than non-MASLD subjects, but not within 4 months from the third dose (vMN titer: 46.87 [IQR: 33.12-66.02] vs 41.86 [IQR: 34.47-50.91], P = 0.240; seroconversion rate: 94.3% vs 100%, P = 0.131). CONCLUSION:Metabolic dysfunction-associated steatotic liver disease was a risk factor for poorer immunogenicity to the omicron variant, with a more pronounced waning effect compared among three-dose BNT162b2 recipients.

Background: Blood pressure (BP) variability is an independent risk factor for cardiovascular disease (CVD). BP variability has been associated with cardiovascular organ damage and is a potential therapeutic target for the prevention of CVD. Recently, the gut microbiome (GM) has been shown to have a pathological role in hypertension, however, the association between GM and BP variability is poorly understood. Methods: 241 community-dwelling individuals free of symptomatic CVD from Hong Kong (113 males and 128 females, mean age 54±6 years) underwent ambulatory BP monitoring and stool microbiota shotgun sequencing. BP variability was determined as systolic/diastolic BP (SBP/DBP) coefficient of variation (CoV), nighttime dipping, and morning BP surge (MBPS). Sleep latency was estimated using 7-day Actigraphy data. Associations of BP variability with GM, and plasma and stool short-chain fatty acids (SCFAs) were analyzed under statistical models adjusting for age, sex, serum glucose and lipids, sodium intake assessed by urine analysis, menopause status, smoking, fatty liver, BP and sleep latency. Results: Women had a significantly higher 24-hour SBP ( p =0.0005) and DBP ( p =0.002) CoV than men. 24-hour SBP CoV had a negative association with GM α-diversity (Shannon and Simpson’s index: all P <0.05) and a positive association with Firmicutes/Bacteroidetes ratio ( P <0.05), suggesting gut dysbiosis in participants with higher systolic BP variability. Several GM species and SCFAs were significantly associated with the indices of BP variability in both men and women. Notably, Parabacteroides merdae had a negative association with both systolic and diastolic BP CoV (all P <0.05-0.01). Bacteroidetes dorei and Bacteroides intestinalis were reduced in women with higher SBP CoV ( P <0.05) and nondipping status ( P< 0.01), respectively. Prewaking and sleepthrough MBPS had a positive association with Faecalibacterium prausnitzii in women (all P <0.001) and plasma acetic acid levels in men ( P <0.05-0.001). Further analysis indicated that Bacteroidetes dorei may mediate SBP CoV via plasma iso-butyric acid in women (bootstrapping 95% CI: -3.6 to -0.19; P <0.05). Conclusions: This cross-sectional study suggests sex-specific associations between GM and BP variability. Most noteworthy, higher systolic BP variability was associated with a significant reduction in potentially beneficial bacterial species, primarily in women which may be explored for therapeutic potential.

Background: Whilst there is emerging evidence that the associations of the gut microbiota (GM) with hypertension differ between sexes, it remains uncertain whether the GM 1) is altered with antihypertensive-use, 2) can predict blood pressure (BP) trajectories, and 3) whether these associations are also sex-dependent. We therefore aimed to determine the sex-dependent associations of the GM with baseline hypertensive state in untreated versus treated participants and BP changes over time. Methods: A total of 451 community-dwelling middle-aged Hong Kong Chinese without symptomatic cardiovascular diseases were recruited (50% men, 14% on antihypertensive agents, mean age, 54.6±6.5 years). Shotgun metagenomic sequencing of stool samples and 24-hour ambulatory blood pressure monitoring (ABPM) were performed. The 24hr-ABPM was repeated on 139 returned subjects after 4 years. Statistical analysis was conducted with 4 covariate models that include age, sex, menopause status, body mass index (BMI), smoking, fasting glucose, triglyceride, cholesterol, sodium intake, and fatty liver status. Results: Amongst the 389/451 subjects not on antihypertensive agents, 167/389 (42.9%) had newly diagnosed hypertension at baseline. Females drove the significantly different b-diversity of the GM composition ( p <0.01) between the normotensives and hypertensives in the baseline study. Multiple GM species were significantly associated with hypertension. In sex stratified analysis, Faecalimonas umbilicate was significantly enriched in hypertensive females while Roseburia sp Am16-25 and Eubacterium ramulus were enriched in hypertensive males (all p <0.05-0.01). When comparing the 62 treated and 167 nontreated hypertensive subjects, the GM abundance, a-, and b-diversity were not significantly different. However, there were significant GM species associated with the use of antihypertensive medication. Notably, Lachnospiraceae bacterium and Flavonifractor plautii were significantly enriched in treated and untreated individuals, respectively (all p <0.05-0.001). During a mean follow up of 51.2±4.5 months, 73.2% of the 71 untreated subjects remained normotensive and were associated with enriched Bacteroides uniformis in their baseline metagenomic data under models adjusted for age, sex, and BMI. Conclusion: The GM displayed sex-dependent associations with hypertension within untreated and treated individuals and can potentially predict BP trajectory changes within a Chinese population.

Background: Nirmatrelvir/ritonavir is mainly used in patients with normal renal function or with only mild renal impairment (eGFR ³ 30 ml/min per 1.73m2). There is limited data regarding its use in advanced kidney disease. We performed a retrospective territory-wide cohort study evaluating the safety and efficacy of nirmatrelvir/ritonavir when compared with molnupiravir.Nirmatrelvir/ritonavir is mainly used in patients with normal renal function or with only mild renal impairment (eGFR ≥ 30 ml/min per 1.73m2). There is limited data regarding its use in advanced kidney disease. We performed a retrospective territory-wide cohort study evaluating the safety and efficacy of nirmatrelvir/ritonavir when compared with molnupiravir.Methods: We performed a retrospective cohort study of hospitalized and non-hospitalized patients with a confirmed diagnosis of COVID-19 in Hong Kong, China, for an observation period from 1 January 2022 to 31 December 2022 (during the omicron BA.2 and BA.5 variant wave). Adult COVID-19 patients (age ≥ 18 years) were selected from medical records held by the Hospital Authority of Hong Kong. We included all patients with COVID-19 regardless of disease severity at baseline having chronic kidney disease (CKD) stage 4 or above (i.e with eGFR < 30 ml/min per 1.73m2) with or without dialysis who receive either nirmatrelvir/ritonavir or molnupiravir. Outcomes at day 90 post-treatment of each treatment arm (nirmatrelvir/ritonavir v.s. molnupiravir) were analyzed and compared. All-cause mortality, respiratory outcomes including mechanical ventilation and non-invasive ventilation, cardiovascular events including myocardial infarction and ischemic stroke, and hepatic complications including elevated liver enzymes were analyzed. Time-to-event analysis was performed for the designated outcomes using univariate and multivariate Cox proportional hazard model regression for unadjusted and adjusted hazard ratios (HR).Findings: We included 454 and 5,880 CKD stage 4 or above patients receiving nirmatrelvir/ritonavir and molnupiravir respectively from public clinics and hospitals managed by the Hospital Authority in Hong Kong during the period. At 90 days, 662 (10.4%) patients of the combined cohort experienced all-cause mortality. Nirmatrelvir/ritonavir group had significant lower all-cause mortality than molnupiravir group (6.82% vs 10.7%) with unadjusted HR of 0.67 (95% CI 0.472 - 0.97, p=0.0337*). After adjusting for sex, age, hypertension, diabetes mellitus, history of myocardial infarction and dialysis in multi-variate analysis, nirmatrelvir/ritonavir group was still associated with superior 90-day survival with adjusted HR of 0.60 (95% CI 0.48 - 0.992, p = 0.0452*). Composites of mechanical and non-invasive ventilation rate were similar in nirmatrelvir/ritonavir and molnupiravir groups (0.96% vs 1.10%, p=0.651). Nirmatrelvir/ritonavir group had higher proportion of patients who received non-invasive ventilation (1.10% vs 0.42%, p = 0.0383*) and trended towards fewer patients requiring mechanical ventilation although statistical significance was not reached (0% vs 0.59%, p = 0.996). There were no significant differences in rate of myocardial infarction (0.88% vs 2.14%, p = 0.0844) and ischemic stroke (0.22% vs 0.61%, p = 0.34) between nirmatrelvir/ritonavir and molnupiravir groups. Hepatic impairment, defined by elevated alanine aminotransferase concentration ≥ 2X upper limit of normal (ULN), was present in 1.45% and 0.94% of patients in nirmatrelvir/ritonavir and molnupiravir groups respectively (p=0.523).Interpretation: Nirmatrelvir/ritonavir is safe and efficacious when compared to molnupiravir in patients with advanced kidney disease.Funding: Health and Medical Research Fund, Health Bureau, The Government of the Hong Kong Special Administrative Region, China and Mr. Lee Won Keung Donation Fund.Declaration of Interest: The authors report no conflict of interest.Ethical Approval: The study was approved by the Institutional Review Board of the University of Hong Kong and Hospital Authority Hong Kong West Cluster. Informed consent from individual patient was waived as the study involved analysis of anonymized data from hospital registry only. The study was performed in compliance with the Declaration of Helsinki.

Background: We aimed to investigate the effect of non-alcoholic fatty liver disease (NAFLD) on BNT162b2 immunogenicity against wild-type SARS-CoV-2 and variants and infection outcome, as data are lacking. Methods: Recipients of two doses of BNT162b2 were prospectively recruited. Outcomes of interest were seroconversion of neutralizing antibody by live virus microneutralization (vMN) to SARS-CoV-2 strains (wild-type, delta and omicron variants) at day 21, 56 and 180 after first dose. Exposure of interest was moderate-to-severe NAFLD (controlled attenuation parameter ≥ 268 dB/M on transient elastography). We calculated adjusted odds ratio (aOR) of infection with NAFLD by adjusting for age, sex, overweight/obesity, diabetes and antibiotic use. Results: Of 259 BNT162b2 recipients (90 (34.7%) male; median age: 50.8 years (IQR: 43.6–57.8)), 68 (26.3%) had NAFLD. For wild type, there was no difference in seroconversion rate between NAFLD and control groups at day 21 (72.1% vs. 77.0%; p = 0.42), day 56 (100% vs. 100%) and day 180 (100% and 97.2%; p = 0.22), respectively. For the delta variant, there was no difference also at day 21 (25.0% vs. 29.5%; p = 0.70), day 56 (100% vs. 98.4%; p = 0.57) and day 180 (89.5% vs. 93.3%; p = 0.58), respectively. For the omicron variant, none achieved seroconversion at day 21 and 180. At day 56, there was no difference in seroconversion rate (15.0% vs. 18.0%; p = 0.76). NAFLD was not an independent risk factor of infection (aOR: 1.50; 95% CI: 0.68–3.24). Conclusions: NAFLD patients receiving two doses of BNT162b2 had good immunogenicity to wild-type SARS-CoV-2 and the delta variant but not the omicron variant, and they were not at higher risk of infection compared with controls.

Monoclonal antibodies (mABs) are safe and effective proteins produced in laboratory that may be used to target a single epitope of a highly conserved protein of a virus or a bacterial pathogen. For this purpose, the epitope is selected among those that play the major role as targets for prevention of infection or tissue damage. In this paper, characteristics of the most important mABs that have been licensed and used or are in advanced stages of development for use in prophylaxis and therapy of infectious diseases are discussed. We showed that a great number of mABs effective against virus or bacterial infections have been developed, although only in a small number of cases these are licensed for use in clinical practice and have reached the market. Although some examples of therapeutic efficacy have been shown, not unlike more traditional antiviral or antibacterial treatments, their efficacy is significantly greater in prophylaxis or early post-exposure treatment. Although in many cases the use of vaccines is more effective and cost-effective than that of mABs, for many infectious diseases no vaccines have yet been developed and licensed. Furthermore, in emergency situations, like in epidemics or pandemics, the availability of mABs can be an attractive adjunct to our armament to reduce the impact. Finally, the availability of mABs against bacteria can be an important alternative, when multidrug-resistant strains are involved.

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant BA.2 sublineage has increased rapidly in Europe and Asia since January 2022. Here, we report the epidemiological and genomic analysis of a large single-source BA.2 outbreak in a housing estate. Methods We analyzed the epidemiological information on a community outbreak of BA.2 (STY outbreak). We performed whole viral genome sequencing using the Oxford Nanopore MinION device. We calculated the doubling time of the outbreak within a housing estate. Results The STY outbreak involved a total of 768 individuals as of 5 February 2022, including 432 residents, visitors, or staff (56.3%) from a single housing estate (KC Estate). The outbreak at the KC Estate had a short doubling time of 1.28 days (95% confidence interval: .560-1.935). The outbreak was promptly controlled with the lockdown of 3 buildings within the housing estate. Whole-genome sequencing was performed for 133 patients in the STY outbreak, including 106 residents of the KC Estate. All 133 sequences from the STY outbreak belonged to the BA.2 sublineage, and phylogenetic analysis showed that these sequences cluster together. All individuals in the STY cluster had the unique mutation C12525T. Conclusions Our study highlights the exceptionally high transmissibility of the Omicron variant BA.2 sublineage in Hong Kong, where stringent measures are implemented as part of the elimination strategy. Continual genomic surveillance is crucial in monitoring the emergence of epidemiologically important Omicron sublineages. Using epidemiological and whole viral genome data, we demonstrated a single-source outbreak of Omicron variant sublineage BA.2 with a short doubling time in Hong Kong. This study highlighted the high transmissibility of BA.2 despite stringent prevention measures.

Acquiring protective immunity through vaccination is essential, especially for patients with type 2 diabetes who are vulnerable for adverse clinical outcomes during coronavirus disease 2019 (COVID-19) infection. Type 2 diabetes (T2D) is associated with immune dysfunction. Here, we evaluated the impact of T2D on the immunological responses induced by mRNA (BNT162b2) and inactivated (CoronaVac) vaccines, the two most commonly used COVID-19 vaccines. The study consisted of two parts. In Part 1, the sera titres of IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) alpha receptor binding domain (RBD), their neutralizing capacity, and antigen-specific CD4+T and CD8+T cell responses at 3-6 months after vaccination were compared between BNT162b2 (n=60) and CoronaVac (n=50) vaccinees with or without T2D. Part 2 was a time-course study investigating the initial B and T cell responses induced by BNT162b2 among vaccinees (n=16) with or without T2D. Our data showed that T2D impaired both cellular and humoral immune responses induced by CoronaVac. For BNT162b2, T2D patients displayed a reduction in CD4+T-helper 1 (Th1) differentiation following their first dose. However, this initial defect was rectified by the second dose of BNT162b2, resulting in comparable levels of memory CD4+ and CD8+T cells, anti-RBD IgG, and neutralizing antibodies with healthy individuals at 3-6 months after vaccination. Hence, T2D influences the effectiveness of COVID-19 vaccines depending on their platform. Our findings provide a potential mechanism for the susceptibility of developing adverse outcomes observed in COVID-19 patients with T2D and received either CoronaVac or just one dose of BNT162b2.

BACKGROUND:Sex differences in the pathogenesis of hypertension exist. While gut microbiota (GM) has been associated with hypertension, it is unclear whether there are sex-linked differences in the association between GM and hypertension.METHODS:We conducted a cross-sectional study to investigate the sex differences in associations between GM characterized by shotgun sequencing, GM-derived short-chain fatty acids, and 24-hour ambulatory blood pressure in 241 Hong Kong Chinese (113 men and 128 women; mean age, 54±6 years).RESULTS:The hypertensive group was associated with GM alterations; however, significant differences in β-diversity and GM composition in hypertensive versus normotensive groups were only observed in women and not in men under various statistical models adjusting for the following covariates: age, sex, body mass index, sodium intake estimated by spot urine analysis, blood glucose, triglycerides, low- and high-density lipoprotein cholesterol, smoking, menopause, and fatty liver status. Specifically, Ruminococcus gnavus, Clostridium bolteae, and Bacteroides ovatus were significantly more abundant in the hypertensive women, whereas Dorea formicigenerans was more abundant in the normotensive women. No bacterial species were found to be significantly associated with hypertension in men. Furthermore, total plasma short-chain fatty acids and propionic acid were independent predictors of systolic and diastolic blood pressure in women but not men.CONCLUSIONS:GM dysregulation was strongly associated with 24-hour ambulatory blood pressure in women but not men, which may be mediated through propionic acid. Our work suggests that sex differences may be an important consideration while assessing the role of GM in the development and treatment of hypertension.

Effective vaccines against SARS-CoV-2 are vital tools for containing the COVID-19 pandemic by increasing population immunity. While currently available vaccines can elicit antibody response against SARS-CoV-2 with high efficacy, the associated side effects may cause vaccine hesitancy.

Abstract Background Patients with COVID‐19 display a broad spectrum of manifestations from asymptomatic to life‐threatening disease with dysregulated immune responses. Mechanisms underlying the detrimental immune responses and disease severity remain elusive. Methods We investigated a total of 137 APs infected with SARS‐CoV‐2. Patients were divided into mild and severe patient groups based on their requirement of oxygen supplementation. All blood samples from APs were collected within three weeks after symptom onset. Freshly isolated PBMCs were investigated for B cell subsets, their homing potential, activation state, mitochondrial functionality and proliferative response. Plasma samples were tested for cytokine concentration, and titer of Nabs, RBD‐, S1‐, SSA/Ro‐ and dsDNA‐specific IgG. Results While critically ill patients displayed predominantly extrafollicular B cell activation with elevated inflammation, mild patients counteracted the disease through the timely induction of mitochondrial dysfunction in B cells within the first week post symptom onset. Rapidly increased mitochondrial dysfunction, which was caused by infection‐induced excessive intracellular calcium accumulation, suppressed excessive extrafollicular responses, leading to increased neutralizing potency index and decreased inflammatory cytokine production. Patients who received prior COVID‐19 vaccines before infection displayed significantly decreased extrafollicular B cell responses and mild disease. Conclusion Our results reveal an immune mechanism that controls SARS‐CoV‐2‐induced detrimental B cell responses and COVID‐19 severity, which may have implications for viral pathogenesis, therapeutic interventions and vaccine development.

By vaccinating SARS-CoV-2 naïve individuals who have already received two doses of COVID-19 vaccines, we aimed to investigate whether a heterologous prime-boost strategy, using vaccines of different platforms as the booster dose, can enhance the immune response against SARS-CoV-2 virus variants. Participants were assigned into four groups, each receiving different combination of vaccinations: two doses of BNT162b2 followed by one dose of BNT162b2 booster (B-B-B); Combination of BNT162b2 (first dose) and CoronaVac (second dose) followed by one dose of BNT162b2 booster (B-C-B); two doses of CoronaVac followed by one dose of CoronaVac booster (C-C-C); two doses of CoronaVac followed by one dose of BNT162b2 booster (C-C-B). The neutralizing antibody in sera against the virus was determined with live virus microneutralization assay (vMN). The B-B-B group and C-C-B group demonstrated significantly higher immunogenicity against SARS-CoV-2 Wild type (WT), Beta variant (BV) and Delta variant (DV). In addition, the B-B-B group and C-C-B group showed reduced but existing protection against Omicron variant (OV). Moreover, A persistent rise in vMN titre against OV was observed 3 days after booster dose. Regarding safety, a heterologous prime-boost vaccine strategy is well tolerated. In this study, it was demonstrated that using vaccines of different platforms as booster dose can enhance protection against SARS-CoV-2 variants, offering potent neutralizing activity against wild-type virus (WT), Beta variant (BV), Delta variant (DV) and some protection against the Omicron variant (OV). In addition, a booster mRNA vaccine results in a more potent immune response than inactivated vaccine regardless of which platform was used for prime doses.

The rapidly emerging SARS-CoV-2 omicron variant is associated with high transmissibility, compromised serum neutralising activity, and reduced vaccine effectiveness.1Lu L Mok BW Chen LL et al.Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients.Clin Infect Dis. 2021; (published online Dec 16.)https://doi.org/10.1093/cid/ciab1041Crossref Scopus (113) Google Scholar, 2Chen LL Chua GT Lu L et al.Omicron variant susceptibility to neutralizing antibodies induced in children by natural SARS-CoV-2 infection or COVID-19 vaccine.Emerg Microbes Infect. 2022; 11: 543-547Crossref PubMed Scopus (23) Google Scholar, 3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar BA.1 is the dominant omicron sublineage, making up more than 97% of omicron variant sequences worldwide in November and December, 2021, whereas BA.2 and BA.3 were rare.3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar Hence, early studies of the omicron variant were mainly based on the BA.1 sublineage. Since early January, 2022, there has been a sudden upsurge of BA.2 in Europe and Asia, accounting for 15·6% of omicron variant sequences detected at the end of January, 2022.3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar In view of the increasing epidemiological importance, there is an urgent need to assess the serum neutralising activity against BA.2, which correlates with vaccine effectiveness.We measured the serum neutralising antibody (NAb) activity against BA.1 and BA.2 with a live virus NAb assay,1Lu L Mok BW Chen LL et al.Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients.Clin Infect Dis. 2021; (published online Dec 16.)https://doi.org/10.1093/cid/ciab1041Crossref Scopus (113) Google Scholar, 2Chen LL Chua GT Lu L et al.Omicron variant susceptibility to neutralizing antibodies induced in children by natural SARS-CoV-2 infection or COVID-19 vaccine.Emerg Microbes Infect. 2022; 11: 543-547Crossref PubMed Scopus (23) Google Scholar and report the results here. We tested serum specimens collected from individuals who had received three doses of COVID-19 vaccine (three-dose vaccinated; n=21; appendix p 4),4Khong K-W Liu D Leung K-Y et al.Antibody response of combination of BNT162b2 and CoronaVac platforms of COVID-19 vaccines against omicron variant.Vaccines (Basel). 2022; 10: 160Crossref PubMed Scopus (19) Google Scholar patients who had COVID-19 in 2020 who received one dose of the Pfizer-BioNTech BNT162b2 vaccine after recovery (pre-variant of concern [VOC] convalescent, one-dose vaccinated; n=15),5Lu L Chen LL Zhang RR et al.Boosting of serum neutralizing activity against the omicron variant among recovered COVID-19 patients by BNT162b2 and Coronavac vaccines.SSRN. 2022; (published online Feb 8.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4029746Google Scholar patients who had COVID-19 in 2020 but had not been vaccinated (pre-VOC convalescent, non-vaccinated; n=9),5Lu L Chen LL Zhang RR et al.Boosting of serum neutralizing activity against the omicron variant among recovered COVID-19 patients by BNT162b2 and Coronavac vaccines.SSRN. 2022; (published online Feb 8.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4029746Google Scholar and patients recently infected by the omicron sublineage BA.2 (omicron BA.2 convalescent; n=10; appendix p 4). Overall (n=55), the geometric mean NAb titre (GMT) against BA.2 was 1·68 (CI 1·63–1·73) times higher than against BA.1 (73·2 against BA.2 vs 43·7 against BA.1; p<0·0001; appendix p 2). Subgroup analysis showed that the GMT against BA.2 was 2·0 times higher (95% CI 1·99–2·01) than the GMT against BA.1 in the pre-VOC convalescent, one-dose vaccinated group (422·2 against BA.2 vs 211·1 against BA.1; p=0·0005), 2·3 times higher (95% CI 2·12-2·56) in the pre-VOC convalescent, non-vaccinated group (29·4 against BA.2 vs 12·6 against BA.1; p=0·0078), and 2·0 times higher (95% CI 1·63–2·50) in the omicron BA.2 convalescent group (32·5 against BA.2 vs 16·3 against BA.1; p=0·031). However, the difference between BA.2 and BA.1 in the three-dose vaccinated group was not statistically significant (p=0·14).To better understand the difference between BA.2 and BA.1, we calculated the ratio of BA.2 NAb titre to BA.1 NAb titre in each individual. All individuals in the pre-VOC convalescent, one-dose vaccinated group; the pre-VOC convalescent, non-vaccinated group; and the omicron BA.2 convalescent group had equal or higher NAb titres for BA.2 than BA.1. However, four (19%) of 21 individuals in the three-dose vaccinated group had a lower NAb titre for BA.2 than BA.1. The BA.2-to-BA.1 NAb titre ratio in the three-dose vaccinated group was numerically lower than in other groups, but was only significantly lower than in the pre-VOC convalescent, non-vaccinated group (p=0·041; appendix p 3).Our data indicate that the immune escape from BA.2 is not as severe as from BA.1, suggesting that other viral or host factors are driving the rapid spread of BA.2. Since NAb titres correlate with vaccine effectiveness, our data suggest that currently available vaccines might be more effective against BA.2 than BA.1. This study was approved by the institutional review board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 13–265 and UW 21–214) and the Hospital Authority Kowloon West Cluster (KW/EX-20–038[144–26]). Written informed consent was obtained from all study participants. The rapidly emerging SARS-CoV-2 omicron variant is associated with high transmissibility, compromised serum neutralising activity, and reduced vaccine effectiveness.1Lu L Mok BW Chen LL et al.Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients.Clin Infect Dis. 2021; (published online Dec 16.)https://doi.org/10.1093/cid/ciab1041Crossref Scopus (113) Google Scholar, 2Chen LL Chua GT Lu L et al.Omicron variant susceptibility to neutralizing antibodies induced in children by natural SARS-CoV-2 infection or COVID-19 vaccine.Emerg Microbes Infect. 2022; 11: 543-547Crossref PubMed Scopus (23) Google Scholar, 3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar BA.1 is the dominant omicron sublineage, making up more than 97% of omicron variant sequences worldwide in November and December, 2021, whereas BA.2 and BA.3 were rare.3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar Hence, early studies of the omicron variant were mainly based on the BA.1 sublineage. Since early January, 2022, there has been a sudden upsurge of BA.2 in Europe and Asia, accounting for 15·6% of omicron variant sequences detected at the end of January, 2022.3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar In view of the increasing epidemiological importance, there is an urgent need to assess the serum neutralising activity against BA.2, which correlates with vaccine effectiveness. We measured the serum neutralising antibody (NAb) activity against BA.1 and BA.2 with a live virus NAb assay,1Lu L Mok BW Chen LL et al.Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients.Clin Infect Dis. 2021; (published online Dec 16.)https://doi.org/10.1093/cid/ciab1041Crossref Scopus (113) Google Scholar, 2Chen LL Chua GT Lu L et al.Omicron variant susceptibility to neutralizing antibodies induced in children by natural SARS-CoV-2 infection or COVID-19 vaccine.Emerg Microbes Infect. 2022; 11: 543-547Crossref PubMed Scopus (23) Google Scholar and report the results here. We tested serum specimens collected from individuals who had received three doses of COVID-19 vaccine (three-dose vaccinated; n=21; appendix p 4),4Khong K-W Liu D Leung K-Y et al.Antibody response of combination of BNT162b2 and CoronaVac platforms of COVID-19 vaccines against omicron variant.Vaccines (Basel). 2022; 10: 160Crossref PubMed Scopus (19) Google Scholar patients who had COVID-19 in 2020 who received one dose of the Pfizer-BioNTech BNT162b2 vaccine after recovery (pre-variant of concern [VOC] convalescent, one-dose vaccinated; n=15),5Lu L Chen LL Zhang RR et al.Boosting of serum neutralizing activity against the omicron variant among recovered COVID-19 patients by BNT162b2 and Coronavac vaccines.SSRN. 2022; (published online Feb 8.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4029746Google Scholar patients who had COVID-19 in 2020 but had not been vaccinated (pre-VOC convalescent, non-vaccinated; n=9),5Lu L Chen LL Zhang RR et al.Boosting of serum neutralizing activity against the omicron variant among recovered COVID-19 patients by BNT162b2 and Coronavac vaccines.SSRN. 2022; (published online Feb 8.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4029746Google Scholar and patients recently infected by the omicron sublineage BA.2 (omicron BA.2 convalescent; n=10; appendix p 4). Overall (n=55), the geometric mean NAb titre (GMT) against BA.2 was 1·68 (CI 1·63–1·73) times higher than against BA.1 (73·2 against BA.2 vs 43·7 against BA.1; p<0·0001; appendix p 2). Subgroup analysis showed that the GMT against BA.2 was 2·0 times higher (95% CI 1·99–2·01) than the GMT against BA.1 in the pre-VOC convalescent, one-dose vaccinated group (422·2 against BA.2 vs 211·1 against BA.1; p=0·0005), 2·3 times higher (95% CI 2·12-2·56) in the pre-VOC convalescent, non-vaccinated group (29·4 against BA.2 vs 12·6 against BA.1; p=0·0078), and 2·0 times higher (95% CI 1·63–2·50) in the omicron BA.2 convalescent group (32·5 against BA.2 vs 16·3 against BA.1; p=0·031). However, the difference between BA.2 and BA.1 in the three-dose vaccinated group was not statistically significant (p=0·14). To better understand the difference between BA.2 and BA.1, we calculated the ratio of BA.2 NAb titre to BA.1 NAb titre in each individual. All individuals in the pre-VOC convalescent, one-dose vaccinated group; the pre-VOC convalescent, non-vaccinated group; and the omicron BA.2 convalescent group had equal or higher NAb titres for BA.2 than BA.1. However, four (19%) of 21 individuals in the three-dose vaccinated group had a lower NAb titre for BA.2 than BA.1. The BA.2-to-BA.1 NAb titre ratio in the three-dose vaccinated group was numerically lower than in other groups, but was only significantly lower than in the pre-VOC convalescent, non-vaccinated group (p=0·041; appendix p 3). Our data indicate that the immune escape from BA.2 is not as severe as from BA.1, suggesting that other viral or host factors are driving the rapid spread of BA.2. Since NAb titres correlate with vaccine effectiveness, our data suggest that currently available vaccines might be more effective against BA.2 than BA.1. This study was approved by the institutional review board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 13–265 and UW 21–214) and the Hospital Authority Kowloon West Cluster (KW/EX-20–038[144–26]). Written informed consent was obtained from all study participants. We declare no competing interests. L-LC and AW-HC contributed equally. This work was supported by Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (ref no. COVID190124 and COVID1903010 [Project 1]), the Emergency Collaborative Project (EKPG22-01) of Guangzhou Laboratory, and donations from Richard Yu and Carol Yu, Shaw Foundation Hong Kong, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Lee Wan Keung Charity Foundation, Hong Kong Sanatorium and Hospital, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, the Jessie and George Ho Charitable Foundation, Kai Chong Tong, Tse Kam Ming Laurence, Foo Oi Foundation, Betty Hing-Chu Lee, and Ping Cham So. The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all data in the study and had final responsibility for the decision to submit for publication. L-LC and KK-WT directly accessed and verified the underlying data. Data are available from the corresponding author upon reasonable request. Supplementary Material Download .pdf (.57 MB) Help with pdf files Supplementary appendix Download .pdf (.57 MB) Help with pdf files Supplementary appendix

Abstract Background Post-vaccination myopericarditis is reported after immunization with coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines. The effect of inadvertent intravenous injection of this vaccine on the heart is unknown. Methods We compared the clinical manifestations, histopathological changes, tissue mRNA expression, and serum levels of cytokine/chemokine and troponin in Balb/c mice at different time points after intravenous (IV) or intramuscular (IM) vaccine injection with normal saline (NS) control. Results Although significant weight loss and higher serum cytokine/chemokine levels were found in IM group at 1–2 days post-injection (dpi), only IV group developed histopathological changes of myopericarditis as evidenced by cardiomyocyte degeneration, apoptosis, and necrosis with adjacent inflammatory cell infiltration and calcific deposits on visceral pericardium, although evidence of coronary artery or other cardiac pathologies was absent. Serum troponin level was significantly higher in IV group. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen expression by immunostaining was occasionally found in infiltrating immune cells of the heart or injection site, in cardiomyocytes and intracardiac vascular endothelial cells, but not skeletal myocytes. The histological changes of myopericarditis after the first IV-priming dose persisted for 2 weeks and were markedly aggravated by a second IM- or IV-booster dose. Cardiac tissue mRNA expression of interleukin (IL)-1β, interferon (IFN)-β, IL-6, and tumor necrosis factor (TNF)-α increased significantly from 1 dpi to 2 dpi in the IV group but not the IM group, compatible with presence of myopericarditis in the IV group. Ballooning degeneration of hepatocytes was consistently found in the IV group. All other organs appeared normal. Conclusions This study provided in vivo evidence that inadvertent intravenous injection of COVID-19 mRNA vaccines may induce myopericarditis. Brief withdrawal of syringe plunger to exclude blood aspiration may be one possible way to reduce such risk.

It has been reported that multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta can reduce neutralization by antibodies, resulting in vaccine breakthrough infections. Virus–antiserum neutralization assays are typically performed to monitor potential vaccine breakthrough strains. However, experiment-based methods took several weeks whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralization titers. Based on this correlation, we obtained a computational model for the receptor-binding domain (RBD) of the spike protein to predict the fold decrease in virus–antiserum neutralization titers with high accuracy (~0.79). Our predicted results were comparable to experimental neutralization titers of variants, including Alpha, Beta, Delta, Gamma, Epsilon, Iota, Kappa, and Lambda, as well as SARS-CoV. Here, we predicted the fold of decrease of Omicron as 17.4-fold less susceptible to neutralization. We visualized all 1,521 SARS-CoV-2 lineages to indicate variants including Mu, B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs Beta, Gamma, Delta, and Omicron. Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed at http://jdlab.online.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection.

Abstract Background: Nosocomial outbreaks leading to healthcare worker (HCW) infection and death have been increasingly reported during the coronavirus disease 2019 (COVID-19) pandemic. Objective: We implemented a strategy to reduce nosocomial acquisition. Methods: We summarized our experience in implementing a multipronged infection control strategy in the first 300 days (December 31, 2019, to October 25, 2020) of the COVID-19 pandemic under the governance of Hospital Authority in Hong Kong. Results: Of 5,296 COVID-19 patients, 4,808 (90.8%) were diagnosed in the first pandemic wave (142 cases), second wave (896 cases), and third wave (3,770 cases) in Hong Kong. With the exception of 1 patient who died before admission, all COVID-19 patients were admitted to the public healthcare system for a total of 78,834 COVID-19 patient days. The median length of stay was 13 days (range, 1–128). Of 81,955 HCWs, 38 HCWs (0.05%; 2 doctors and 11 nurses and 25 nonprofessional staff) acquired COVID-19. With the exception of 5 of 38 HCWs (13.2%) infected by HCW-to-HCW transmission in the nonclinical settings, no HCW had documented transmission from COVID-19 patients in the hospitals. The incidence of COVID-19 among HCWs was significantly lower than that of our general population (0.46 per 1,000 HCWs vs 0.71 per 1,000 population; P = .008). The incidence of COVID-19 among professional staff was significantly lower than that of nonprofessional staff (0.30 vs 0.66 per 1,000 full-time equivalent; P = .022). Conclusions: A hospital-based approach spared our healthcare service from being overloaded. With our multipronged infection control strategy, no nosocomial COVID-19 in was identified among HCWs in the first 300 days of the COVID-19 pandemic in Hong Kong.

Introduction: Renal involvement in COVID-19 is less well characterized in settings with vigilant public health surveillance, including mass screening and early hospitalization. We assessed kidney complications among COVID-19 patients in Hong Kong, including the association with risk factors, length of hospitalization, critical presentation, and mortality. Methods: Linked electronic records of all patients with confirmed COVID-19 from 5 major designated hospitals were extracted. Duplicated records due to interhospital transferal were removed. Primary outcome was the incidence of in-hospital acute kidney injury (AKI). Secondary outcomes were AKI-associated mortality, incident renal replacement therapy (RRT), intensive care admission, prolonged hospitalization and disease course (defined as >90th percentile of hospitalization duration [35 days] and duration from symptom onset to discharge [43 days], respectively), and change of estimated glomerular filtration rate (GFR). Patients were further stratified into being symptomatic or asymptomatic. Results: Patients were characterized by young age (median: 38.4, IQR: 28.4–55.8 years) and short time (median: 5, IQR: 2–9 days) from symptom onset to admission. Among the 591 patients, 22 (3.72%) developed AKI and 4 (0.68%) required RRT. The median time from symptom onset to in-hospital AKI was 15 days. AKI increased the odds of prolonged hospitalization and disease course by 2.0- and 3.5-folds, respectively. Estimated GFR 24 weeks post-discharge reduced by 7.51 and 1.06 mL/min/1.73 m2 versus baseline (upon admission) in the AKI and non-AKI groups, respectively. The incidence of AKI was comparable between asymptomatic (4.8%, n = 3/62) and symptomatic (3.7%, n = 19/519) patients. Conclusion: The overall rate of AKI among COVID-19 patients in Hong Kong is low, which could be attributable to a vigilant screening program and early hospitalization. Among patients who developed in-hospital AKI, the duration of hospitalization is prolonged and kidney function impairment can persist for up to 6 months post-discharge. Mass surveillance for COVID-19 is warranted in identifying asymptomatic subjects for earlier AKI management.

BACKGROUND:Viral genomic surveillance is vital for understanding the transmission of COVID-19. In Hong Kong, breakthrough outbreaks have occurred in July (third wave) and November (fourth wave) 2020. We used whole viral genome analysis to study the characteristics of these waves.METHODS:We analyzed 509 SARS-CoV-2 genomes collected from Hong Kong patients between 22nd January and 29th November, 2020. Phylogenetic and phylodynamic analyses were performed, and were interpreted with epidemiological information.FINDINGS:During the third and fourth waves, diverse SARS-CoV-2 genomes were identified among imported infections. Conversely, local infections were dominated by a single lineage during each wave, with 96.6% (259/268) in the third wave and 100% (73/73) in the fourth wave belonging to B.1.1.63 and B.1.36.27 lineages, respectively. While B.1.1.63 lineage was imported 2 weeks before the beginning of the third wave, B.1.36.27 lineage has circulated in Hong Kong for 2 months prior to the fourth wave. During the fourth wave, 50.7% (37/73) of local infections in November was identical to the viral genome from an imported case in September. Within B.1.1.63 or B.1.36.27 lineage in our cohort, the most common non-synonymous mutations occurred at the helicase (nsp13) gene.INTERPRETATION:Although stringent measures have prevented most imported cases from spreading in Hong Kong, a single lineage with low-level local transmission in October and early November was responsible for the fourth wave. A superspreading event or lower temperature in November may have facilitated the spread of the B.1.36.27 lineage.