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Background: Studies have established the short-term efficacy of nirmatrelvir-ritonavir in managing COVID-19, yet its effect on post-COVID-19 condition, especially in patients admitted to hospital, remains understudied. This study aimed to examine the effect of nirmatrelvir-ritonavir on post-COVID-19 condition among patients admitted to hospital in Hong Kong., Methods: This retrospective cohort study used real-world, territory-wide inpatient records, vaccination records, and confirmed COVID-19 case data from the Hong Kong Hospital Authority and Department of Health, The Government of the Hong Kong Special Administrative Region. Patients aged 18 years and older who tested positive for SARS-CoV-2 between March 11, 2022, and Oct 10, 2023, and who were admitted to hospital with COVID-19 were included. The treatment group included patients prescribed nirmatrelvir-ritonavir within 5 days of symptom onset, excluding those prescribed molnupiravir within 21 days, and the control group had no exposure to either nirmatrelvir-ritonavir or molnupiravir. The outcomes were post-acute inpatient death and 13 sequelae (congestive heart failure, atrial fibrillation, coronary artery disease, deep vein thrombosis, chronic pulmonary disease, acute respiratory distress syndrome, interstitial lung disease, seizure, anxiety, post-traumatic stress disorder, end-stage renal disease, acute kidney injury, and pancreatitis). These outcomes were evaluated starting at 21 days after the positive RT-PCR date in each respective cohort constructed for the outcome. Standardised mortality ratio weights were applied to balance covariates, and Cox proportional hazards regression was used to investigate the relationship between nirmatrelvir-ritonavir and outcomes., Findings: 136 973 patients were screened for inclusion, among whom 50 055 were eligible and included in the analysis (24 873 [49·7%] were female and 25 182 [50·3%] were male). 15 242 patients were prescribed nirmatrelvir-ritonavir during acute COVID-19 and 23 756 patients were included in the control group; 11 057 patients did not meet our definition for the exposed and unexposed groups. Patients were followed up for a median of 393 days (IQR 317-489). In the nirmatrelvir-ritonavir group compared with the control group, there was a significantly lower hazard of post-acute inpatient death (hazard ratio 0·62 [95% CI 0·57-0·68]; p<0·0001), congestive heart failure (0·70 [0·58-0·85]; p=0·0002), atrial fibrillation (0·63 [0·52-0·76]; p<0·0001), coronary artery disease (0·71 [0·59-0·85]; p=0·0002), chronic pulmonary disease (0·68 [0·54-0·86]; p=0·0011), acute respiratory distress syndrome (0·71 [0·58-0·86]; p=0·0007), interstitial lung disease (0·17 [0·04-0·75]; p=0·020), and end-stage renal disease (0·37 [0·18-0·74]; p=0·0049). There was no evidence indicating difference between the groups in deep vein thrombosis, seizure, anxiety, post-traumatic stress disorder, acute kidney injury, and pancreatitis., Interpretation: This study showed extended benefits of nirmatrelvir-ritonavir for reducing the risk of post-acute inpatient death as well as cardiovascular and respiratory complications among patients admitted to hospital with COVID-19. Further research is essential to uncover the underlying mechanisms responsible for these observed negative associations and to devise effective strategies for preventing the onset of post-acute sequelae., Funding: Health and Medical Research Fund, Research Grants Council theme-based research schemes, and Research Grants Council Collaborative Research Fund., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Long COVID occurs in a small but important minority of patients following COVID-19, reducing quality of life and contributing to healthcare burden. Although research into underlying mechanisms is evolving, immunity is understudied. SARS-CoV-2-specific T cell responses are of key importance for viral clearance and COVID-19 recovery. However, in long COVID, the establishment and persistence of SARS-CoV-2-specific T cells are far from clear, especially beyond 12 mo postinfection and postvaccination. We defined ex vivo antigen-specific B cell and T cell responses and their T cell receptors (TCR) repertoires across 2 y postinfection in people with long COVID. Using 13 SARS-CoV-2 peptide-HLA tetramers, spanning 11 HLA allotypes, as well as spike and nucleocapsid probes, we tracked SARS-CoV-2-specific CD8 + and CD4 + T cells and B-cells in individuals from their first SARS-CoV-2 infection through primary vaccination over 24 mo. The frequencies of ORF1a- and nucleocapsid-specific T cells and B cells remained stable over 24 mo. Spike-specific CD8 + and CD4 + T cells and B cells were boosted by SARS-CoV-2 vaccination, indicating immunization, in fully recovered and people with long COVID, altered the immunodominance hierarchy of SARS-CoV-2 T cell epitopes. Meanwhile, influenza-specific CD8 + T cells were stable across 24 mo, suggesting no bystander-activation. Compared to total T cell populations, SARS-CoV-2-specific T cells were enriched for central memory phenotype, although the proportion of central memory T cells decreased following acute illness. Importantly, TCR repertoire composition was maintained throughout long COVID, including postvaccination, to 2 y postinfection. Overall, we defined ex vivo SARS-CoV-2-specific B cells and T cells to understand primary and recall responses, providing key insights into antigen-specific responses in people with long COVID., Competing Interests: Competing interests statement:Hayley McQuilten consults for Ena Respiratory.

Competing Interests: I am supported by the Health and Medical Research Fund Commissioned Research on Influenza (INF-CUHK-2 and HMRF 19180242), Hong Kong Special Administrative Region, and Research Grants Council theme-based research schemes (T11-712/19-N and T11-705/21-N). I declare no competing interests.

This prospective study in Hong Kong aimed at identifying prognostic metabolomic and immunologic biomarkers for Coronavirus Disease 2019 (COVID-19). We examined 327 patients, mean age 55 (19-89) years, in whom 33.6% were infected with Omicron and 66.4% were infected with earlier variants. The effect size of disease severity on metabolome outweighed others including age, gender, peak C-reactive protein (CRP), vitamin D and peak viral levels. Sixty-five metabolites demonstrated strong associations and the majority (54, 83.1%) were downregulated in severe disease (z score: -3.30 to -8.61). Ten cytokines/chemokines demonstrated strong associations ( p < 0.001), and all were upregulated in severe disease. Multiple pairs of metabolomic/immunologic biomarkers showed significant correlations. Fourteen metabolites had the area under the receiver operating characteristic curve (AUC) > 0.8, suggesting a high predictive value. Three metabolites carried high sensitivity for severe disease: triglycerides in medium high-density lipoprotein (MHDL) (sensitivity: 0.94), free cholesterol-to-total lipids ratio in very small very-low-density lipoprotein (VLDL) (0.93), cholesteryl esters-to-total lipids ratio in chylomicrons and extremely large VLDL (0.92);whereas metabolites with the highest specificity were creatinine (specificity: 0.94), phospholipids in large VLDL (0.94) and triglycerides-to-total lipids ratio in large VLDL (0.93). Five cytokines/chemokines, namely, interleukin (IL)-6, IL-18, IL-10, macrophage inflammatory protein (MIP)-1b and tumour necrosis factor (TNF)-a, had AUC > 0.8. In conclusion, we demonstrated a tight interaction and prognostic potential of metabolomic and immunologic biomarkers enabling an outcome-based patient stratification.

Background: The newly emerged SARS-CoV-2 possesses shared antigenic epitopes with other human coronaviruses. We investigated if COVID-19 vaccination or SARS-CoV-2 infection may boost cross-reactive antibodies to other human coronaviruses., Methods: Prevaccination and postvaccination sera from SARS-CoV-2 naïve healthy subjects who received three doses of the mRNA vaccine (BioNTech, BNT) or the inactivated vaccine (CoronaVac, CV) were used to monitor the level of cross-reactive antibodies raised against other human coronaviruses by enzyme-linked immunosorbent assay. In comparison, convalescent sera from COVID-19 patients with or without prior vaccination history were also tested. Pseudoparticle neutralization assay was performed to detect neutralization antibody against MERS-CoV., Results: Among SARS-CoV-2 infection-naïve subjects, BNT or CV significantly increased the anti-S2 antibodies against Betacoronaviruses (OC43 and MERS-CoV) but not Alphacoronaviruses (229E). The prevaccination antibody response to the common cold human coronaviruses did not negatively impact the postvaccination antibody response to SARS-CoV-2. Cross-reactive antibodies that binds to the S2 protein of MERS-CoV were similarly detected from the convalescent sera of COVID-19 patients with or without vaccination history. However, these anti-S2 antibodies do not possess neutralizing activity in MERS-CoV pseudoparticle neutralization tests., Conclusions: Our results suggest that SARS-CoV-2 infection or vaccination may potentially modulate population immune landscape against previously exposed or novel human coronaviruses. The findings have implications for future sero-epidemiological studies on MERS-CoV., (© 2024 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Tuberculosis (TB) remains a leading cause of death worldwide and is estimated to have caused 1.3 million deaths worldwide in 2022. Approximately one quarter of the world's population are infected with Mycobacterium tuberculosis, of whom up to 10% will progress to developing active TB disease. Achieving the World Health Organization End TB Strategy targets of a 95% reduction in TB mortality and a 90% reduction in TB incidence worldwide by 2035 remains a daunting task. The continuing spread of multidrug-resistant TB adds another obstacle to achieving global TB control. Larger funding pledges coupled with technological advances have recently enabled the enhancement of TB vaccine development efforts. These are yielding a pipeline of over 17 products currently in different stages of clinical trials. Emerging promising phase I and II trial results and advancement to phase III trials have necessitated "vaccine preparedness" in parallel so that a smooth transition from any positive clinical trial result to phase IV evaluation and implementation into policy and practice can follow. Promotion of a human rights-based approach, which recognizes and upholds the fundamental rights of all affected by the disease, is essential to ensure universal access to quality TB vaccines, regardless of their background or personal circumstances., Competing Interests: Declarations of competing interest All authors have an academic interest in TB. The authors have no competing interest to declare. The views expressed by the authors are their own and do not reflect those of their individual institutions., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Since the emergence of SARS-CoV-2, different variants and subvariants successively emerged to dominate global virus circulation as a result of immune evasion, replication fitness or both. COVID-19 vaccines continue to be updated in response to the emergence of antigenically divergent viruses, the first being the bivalent RNA vaccines that encodes for both the Wuhan-like and Omicron BA.5 subvariant spike proteins. Repeated infections and vaccine breakthrough infections have led to complex immune landscapes in populations making it increasingly difficult to assess the intrinsic neutralizing antibody responses elicited by the vaccines. Hong Kong's intensive COVID-19 containment policy through 2020-2021 permitted us to identify sera from a small number of infection-naïve individuals who received 3 doses of the RNA BNT162b2 vaccine encoding the Wuhan-like spike (WT) and were boosted with a fourth dose of the WT vaccine or the bivalent WT and BA.4/5 spike (WT + BA.4/5). While neutralizing antibody to wild-type virus was comparable in both vaccine groups, BNT162b2 (WT + BA.4/BA.5) bivalent vaccine elicited significantly higher plaque neutralizing antibodies to Omicron subvariants BA.5, XBB.1.5, XBB.1.16, XBB.1.9.1, XBB.2.3.2, EG.5.1, HK.3, BA.2.86 and JN.1, compared to BNT162b2 monovalent vaccine. The single amino acid substitution that differentiates the spike of JN.1 from BA.2.86 resulted in a profound antigenic change., (© 2024. The Author(s).)

Background: Natural SARS-CoV-2 infection may elicit antibodies to a range of viral proteins including non-structural protein ORF8. RNA, adenovirus vectored and sub-unit vaccines expressing SARS-CoV-2 spike would be only expected to elicit S-antibodies and antibodies to distinct domains of nucleocapsid (N) protein may reliably differentiate infection from vaccine-elicited antibody. However, inactivated whole virus vaccines may potentially elicit antibody to wider range of viral proteins, including N protein. We hypothesized that antibody to ORF8 protein will discriminate natural infection from vaccination irrespective of vaccine type., Methods: We optimized and validated the anti-ORF8 and anti-N C-terminal domain (NCTD) ELISA assays using sera from pre-pandemic, RT-PCR confirmed natural infection sera and BNT162b2 (BNT) or CoronaVac vaccinees. We then applied these optimized assays to a cohort of blood donor sera collected in April-July 2022 with known vaccination and self-reported infection status., Results: We optimized cut-off values for the anti-ORF8 and anti-N-CTD IgG ELISA assays using receiver-operating-characteristic (ROC) curves. The sensitivity of the anti-ORF8 and anti-N-CTD ELISA for detecting past infection was 83.2% and 99.3%, respectively. Specificity of anti-ORF8 ELISA was 96.8 % vs. the pre-pandemic cohort or 93% considering the pre-pandemic and vaccine cohorts together. The anti-N-CTD ELISA specificity of 98.9% in the pre-pandemic cohort, 93% in BNT vaccinated and only 4 % in CoronaVac vaccinated cohorts. Anti-N-CTD antibody was longer-lived than anti-ORF8 antibody after natural infection., Conclusions: Anti-N-CTD antibody assays provide good discrimination between natural infection and vaccination in BNT162b2 vaccinated individuals. Anti-ORF8 antibody can help discriminate infection from vaccination in either type of vaccine and help estimate infection attack rates (IAR) in communities., Competing Interests: Declaration of Competing Interest AH, NK, LLMP, MP and SAV have filed an IDF (US 63/016,898) for the use of ORF8 and ORF3d as diagnostics of SARS-CoV-2 infection. MM produced ORF8 by patent process based on US Patents 8507,220 and 8586,826. Other authors have no declaration of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

We tested seroprevalence of open reading frame 8 antigens to infer the number of unrecognized SARS-CoV-2 Omicron infections in Hong Kong during 2022. We estimate 33.6% of the population was infected, 72.1% asymptomatically. Surveillance and control activities during large-scale outbreaks should account for potentially substantial undercounts.

Objectives: Since the onset of the COVID-19 pandemic in 2020, there has been a significant decline in seasonal influenza infection cases in Hong Kong. However, this decline has also resulted in reduced opportunities for the development of influenza-specific antibodies in the community. The levels of antibodies required for protection against recently circulating influenza A viruses in the post-COVID-19 era remain unclear., Methods: This study involved the analysis of paired plasma samples collected from 479 healthy adults in Hong Kong in 2021 and 2022. The neutralizing titers of plasma against influenza A (H1N1) and (H3N2) viruses circulating before and after the COVID-19 outbreak were determined using a microneutralization assay., Results: The H1N1 and H3N2 vaccine strains selected for the 2022/23 season were found to be closely related to the recently circulating viruses. However, in the samples collected in 2022, only 14.61% and 0.42% showed a neutralization titer (MN50) ≥1:20 against H1N1 A/Wisconsin/588/2019 (H1/Wis19) and H3N2 A/Darwin/6/2021 (H3/Dar21), respectively. Notably, participants who reported receiving annual flu vaccinations exhibited a higher seropositive rate for H1/Wis19 compared to those who had never received the flu vaccine (28.06% vs. 5.30%)., Conclusion: Our results indicate that adults in Hong Kong generally lack neutralizing antibodies against circulating influenza A viruses, particularly H3N2. These findings underscore the importance of promoting flu vaccination in the post-COVID-19 era., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence this work., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The role of gut microbiota in modulating the durability of COVID-19 vaccine immunity is yet to be characterised. In this cohort study, we collected blood and stool samples of 121 BNT162b2 and 40 CoronaVac vaccinees at baseline, 1 month, and 6 months post vaccination (p.v.). Neutralisation antibody, plasma cytokine and chemokines were measured and associated with the gut microbiota and metabolome composition. A significantly higher level of neutralising antibody (at 6 months p.v.) was found in BNT162b2 vaccinees who had higher relative abundances of Bifidobacterium adolescentis, Bifidobacterium bifidum, and Roseburia faecis as well as higher concentrations of nicotinic acid (Vitamin B) and γ-Aminobutyric acid (P < 0.05) at baseline. CoronaVac vaccinees with high neutralising antibodies at 6 months p.v. had an increased relative abundance of Phocaeicola dorei, a lower relative abundance of Faecalibacterium prausnitzii, and a higher concentration of L-tryptophan (P < 0.05) at baseline. A higher antibody level at 6 months p.v. was also associated with a higher relative abundance of Dorea formicigenerans at 1 month p.v. among CoronaVac vaccinees (Rho = 0.62, p = 0.001, FDR = 0.123). Of the species altered following vaccination, 79.4% and 42.0% in the CoronaVac and BNT162b2 groups, respectively, recovered at 6 months. Specific to CoronaVac vaccinees, both bacteriome and virome diversity depleted following vaccination and did not recover to baseline at 6 months p.v. (FDR < 0.1). In conclusion, this study identified potential microbiota-based adjuvants that may extend the durability of immune responses to SARS-CoV-2 vaccines., (© 2023. West China Hospital, Sichuan University.)

Competing Interests: I declare no competing interests.

Objectives: We compared the risk of environmental contamination among patients with COVID-19 who received high-flow nasal cannula (HFNC), noninvasive ventilation (NIV), and conventional oxygen therapy (COT) via nasal cannula for respiratory failure., Methods: Air was sampled from the hospital isolation rooms with 12 air changes/hr where 26 patients with COVID-19 received HFNC (up to 60 l/min, n = 6), NIV (n = 6), or COT (up to 5 l/min of oxygen, n = 14). Surface samples were collected from 16 patients during air sampling., Results: Viral RNA was detected at comparable frequency in air samples collected from patients receiving HFNC (3/54, 5.6%), NIV (1/54, 1.9%), and COT (4/117, 3.4%) (P = 0.579). Similarly, the risk of surface contamination was comparable among patients receiving HFNC (3/46, 6.5%), NIV (14/72, 19.4%), and COT (8/59, 13.6%) (P = 0.143). An increment in the cyclic thresholds of the upper respiratory specimen prior to air sampling was associated with a reduced SARS-CoV-2 detection risk in air (odds ratio 0.83 [95% confidence interval 0.69-0.96], P = 0.027) by univariate logistic regression., Conclusion: No increased risk of environmental contamination in the isolation rooms was observed in the use of HFNC and NIV vs COT among patients with COVID-19 with respiratory failure. Higher viral load in the respiratory samples was associated with positive air samples., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Assess real-world effectiveness of vaccines against COVID-19., Methods: A test-negative study was conducted in January-May 2022 during an Omicron BA.2 wave in Hong Kong. COVID-19 was identified by RT-PCR. 1-1 case-control matching was based on propensity score with vaccine effectiveness adjusted for confounders., Results: Altogether, 1781 cases and 1737 controls aged 3-105 years were analysed. The mean lag time from the last dose of vaccination to testing for SARS-CoV-2 was 133.9 (SD: 84.4) days. Two doses of either vaccine within 180 days offered a low effectiveness against COVID-19 of all severity combined (VE adj [95% CI] for BNT162b2: 27.0% [4.2-44.5], CoronaVac: 22.9% [1.3-39.7]), and further decreased after 180 days. Two doses of CoronaVac were poorly protective 39.5% [4.9-62.5] against severe diseases for age ≥ 60 years, but the effectiveness increased substantially after the third dose (79.1% [25.7-96.7]). Two doses of BNT162b2 protected age ≥ 60 years against severe diseases (79.3% [47.2, 93.9]); however, the uptake was not high enough to assess three doses., Conclusions: The current real-world analysis indicates a high vaccine effectiveness of three doses of inactivated virus (CoronaVac) vaccines against Omicron variant, whereas the effectiveness of two doses is suboptimal., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paul K.S. Chan served as consultant for Moderna Hong Kong Limited on COVID-19 vaccine., (Copyright © 2023 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Longitudinal studies on upper respiratory tract microbiome in coronavirus disease 2019 (COVID-19) without potential confounders such as antimicrobial therapy are limited. The objective of this study is to assess for longitudinal changes in the upper respiratory microbiome, its association with disease severity, and potential confounders in adult hospitalized patients with COVID-19. Serial nasopharyngeal and throat swabs (NPSTSs) were taken for 16S rRNA gene amplicon sequencing from adults hospitalized for COVID-19. Alpha and beta diversity was assessed between different groups. Principal coordinate analysis was used to assess beta diversity between groups. Linear discriminant analysis was used to identify discriminative bacterial taxa in NPSTS taken early during hospitalization on need for intensive care unit (ICU) admission. A total of 314 NPSTS samples from 197 subjects (asymptomatic = 14, mild/moderate = 106, and severe/critical = 51 patients with COVID-19; non-COVID-19 mechanically ventilated ICU patients = 11; and healthy volunteers = 15) were sequenced. Among all covariates, antibiotic treatment had the largest effect on upper airway microbiota. When samples taken after antibiotics were excluded, alpha diversity (Shannon, Simpson, richness, and evenness) was similar across severity of COVID-19, whereas beta diversity (weighted GUniFrac and Bray-Curtis distance) remained different. Thirteen bacterial genera from NPSTS taken within the first week of hospitalization were associated with a need for ICU admission (area under the receiver operating characteristic curve, 0.96; 95% CI, 0.91-0.99). Longitudinal analysis showed that the upper respiratory microbiota alpha and beta diversity was unchanged during hospitalization in the absence of antimicrobial therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ling, Lai, Lui, Yeung, Chan, Cheuk, Cheung, Chang, Chiu, Zhang, Wong, Hui, Wong, Chan and Chen.)

Background: The primary aim of using vaccines in public health responses to SARS-CoV-2 variants of concern is to reduce incidence of severe disease, for which T-cell responses are essential. There is a paucity of data on vaccine-induced T-cell immunity to omicron (B.1.1.529). We aimed to compare SARS-CoV-2 omicron BA.1-specific T-cell responses in adults vaccinated with CoronaVac or BNT162b2., Methods: For this observational cohort, we recruited adults (aged ≥18 years) from three vaccination centres in Hong Kong. We included participants from four cohorts (cohort 1: participants who received two doses of either BNT162b2 or CoronaVac, cohort 2: participants who received two doses and a booster, cohort 3: participants who received two doses and a booster and had a breakthrough omicron infection, and cohort 4: participants who had a previous non-omicron infection and subsequently received one dose of vaccine). People with confirmed history of COVID-19 at recruitment were excluded from cohort 1 and cohort 2. We collected blood samples before vaccination (for cohort 1 and 2), 1-month following vaccination (for all cohorts), and during convalescence for cohort 3 and 4) and determined the proportion of IFNγ + CD4 + and IFNγ + CD8 + T cells in peripheral blood against SARS-CoV-2 using flow cytometry with peptide pools of SARS-CoV-2 wild type or omicron BA.1. The primary outcome was proportion of CD4 + and CD8 + T cells against SARS-CoV-2 1 month after exposure (ie, vaccination or breakthrough infection)., Findings: Overall, between May 21, 2020, and Aug 31, 2021, we recruited 659 participants (231 [35%] men and 428 [65%] women). Of these participants, 428 were included in cohort 1 (214 [50%] received BNT162b2 and 214 [50%] received CoronaVac); 127 in cohort 2 (48 [38%] received all BNT162b2, 40 [31%] received all CoronaVac, and 39 [31%] received two CoronaVac and a booster with BNT162b2); 58 in cohort 3, and 46 in cohort 4 (16 [35%] received CoronaVac and 30 [65%] received BNT162b2). Vaccine-induced T-cell responses to the wild-type and omicron BA.1 variants were generally similar in adults receiving two doses of either CoronaVac (CD4 + cells p=0·33; CD8 + cells p=0·70) or BNT162b2 (CD4 + cells p=0·28; CD8 + cells p=1·0). Using a peptide pool of all structural proteins for stimulation, BNT162b2 induced a higher median frequency of omicron-specific CD4 + T cells in adults younger than 60 years (CD4 + cells 0·012% vs 0·010%, p=0·031; CD8 + cells 0·003% vs 0·000%, p=0·055) and omicron-specific CD8 + T cells in people aged 60 years or older (CD4 + cells 0·015% vs 0·006%, p=0·0070; CD8 + cells 0·007% vs 0·000%, p=0·035). A booster dose of either BNT162b2 or CoronaVac after two doses of CoronaVac boosted waning T-cell responses, but T-cell responses did not exceed those at 1 month after the second dose (CoronaVac CD4 + p=0·41, CD8 + p=0·79; BNT162b2 CD4 + p=0·70 CD8 + p=0·80)., Interpretation: The evidence that mRNA and inactivated vaccines based on the ancestral SARS-CoV-2 virus elicited T-cell responses to SARS-CoV-2 omicron variants might explain the high observed vaccine effectiveness against severe COVID-19 shown by both types of vaccine, despite great differences in neutralising antibody responses. The use of either vaccine can be considered if the primary aim is to reduce severity and death caused by the new omicron subvariants; however, BNT162b2 is preferable for adults older than 60 years., Funding: The Health and Medical Research Fund Commissioned Research on the Novel Coronavirus Disease and S H Ho Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The World Health Organization priority zoonotic pathogen Middle East respiratory syndrome (MERS) coronavirus (CoV) has a high case fatality rate in humans and circulates in camels worldwide., Methods: We performed a global analysis of human and camel MERS-CoV infections, epidemiology, genomic sequences, clades, lineages, and geographical origins for the period January 1, 2012 to August 3, 2022. MERS-CoV Surface gene sequences (4061 bp) were extracted from GenBank, and a phylogenetic maximum likelihood tree was constructed., Results: As of August 2022, 2591 human MERS cases from 26 countries were reported to the World Health Organization (Saudi Arabia, 2184 cases, including 813 deaths [case fatality rate: 37.2%]) Although declining in numbers, MERS cases continue to be reported from the Middle East. A total of 728 MERS-CoV genomes were identified (the largest numbers were from Saudi Arabia [222: human = 146, camels = 76] and the United Arab Emirates [176: human = 21, camels = 155]). A total of 501 'S'-gene sequences were used for phylogenetic tree construction (camels [n = 264], humans [n = 226], bats [n = 8], other [n=3]). Three MERS-CoV clades were identified: clade B, which is the largest, followed by clade A and clade C. Of the 462 clade B lineages, lineage 5 was predominant (n = 177)., Conclusion: MERS-CoV remains a threat to global health security. MERS-CoV variants continue circulating in humans and camels. The recombination rates indicate co-infections with different MERS-CoV lineages. Proactive surveillance of MERS-CoV infections and variants of concern in camels and humans worldwide, and development of a MERS vaccine, are essential for epidemic preparedness., Competing Interests: Declaration of competing interests The authors have no competing interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose of Review: This article reviews the epidemiology and transmission of respiratory tract infections (RTIs) during mass gathering events (MGEs) before and during the COVID-19 pandemic., Recent Findings: RTIs of viral cause such as influenza, rhinovirus and coronaviruses (229E, HKU1, OC43) are common in MGEs. No cases of MERS-CoV have yet been identified in pilgrims during Hajj, despite the fact that MERS-CoV continues to circulate in the Middle East. Due to the COVID-19 pandemic, organizers of mass gathering religious and sporting events have implemented risk-based infection control measures and lockdowns that limited transmission of RTIs., Summary: Large-scale RTI outbreaks at MGEs are uncommon due to more robust public health planning, prevention, risk assessment and improved health infrastructures in host countries during the COVID-19 pandemic., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The heavily suppressed global influenza activity during the coronavirus disease 2019 (COVID-19) pandemic is expected to return upon relaxation of travel restriction and nonpharmaceutical interventions (NPI). We reviewed the four marketed neuraminidase inhibitors (NAI e.g., oseltamivir, zanamivir, peramivir, laninamivir) and the only endonuclease inhibitor (baloxavir) on their clinical therapeutic effects and the ability of viral suppression in various groups of patients of different clinical settings based on the latest evidence., Recent Findings: Early initiation, preferably within 48 h of symptom onsets, of antiviral treatments with NAI and baloxavir, is crucial to produce favourable outcomes in patients with influenza infection. Updated evidence does not suggest routine use of combined antiviral agents in patients with influenza infection. Treatment-emergent resistant influenza variants may occur during NAI and baloxavir use, but it has no major impact on subsequent recovery. Early treatment of index patients with influenza infection and post-exposure prophylaxis in specific populations is crucial in preventing influenza transmission., Summary: Antiviral therapy is the major defence therapeutically in the community and hospital settings to expedite early recovery and reduce influenza-related complications. Early treatment of index patients and post-exposure prophylaxis in susceptible close contacts may mitigate the spread of infection., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The SARS-CoV-2 Omicron variant has demonstrated enhanced transmissibility and escape of vaccine-derived immunity. Although first-generation vaccines remain effective against severe disease and death, robust evidence on vaccine effectiveness (VE) against all Omicron infections, irrespective of symptoms, remains sparse. We used a community-wide serosurvey with 5,310 subjects to estimate how vaccination histories modulated risk of infection in infection-naive Hong Kong during a large wave of Omicron BA.2 epidemic in January-July 2022. We estimated that Omicron infected 45% (41-48%) of the local population. Three and four doses of BNT162b2 or CoronaVac were effective against Omicron infection 7 days after vaccination (VE of 48% (95% credible interval 34-64%) and 69% (46-98%) for three and four doses of BNT162b2, respectively; VE of 30% (1-66%) and 56% (6-97%) for three and four doses of CoronaVac, respectively). At 100 days after immunization, VE waned to 26% (7-41%) and 35% (10-71%) for three and four doses of BNT162b2, and to 6% (0-29%) and 11% (0-54%) for three and four doses of CoronaVac. The rapid waning of VE against infection conferred by first-generation vaccines and an increasingly complex viral evolutionary landscape highlight the necessity for rapidly deploying updated vaccines followed by vigilant monitoring of VE., (© 2023. The Author(s).)

Background: Patients with severe asthma have higher total- and asthma-related health burden than those whose disease is not severe. Recent medical advances in biologic therapies allow better control of asthma characterized by type 2 inflammation., Objective: To study the prevalence of eosinophilic phenotype and IgE levels in Chinese with severe asthma, and the relationship of these type 2 characteristics with asthma control, exacerbations and lung function., Methods: This was a multicenter cross-sectional observational study in Hong Kong, in Chinese adults with asthma on Step 4 or 5 of GINA treatment. Their blood eosinophil counts and total IgE levels were measured, and the relationship of these phenotypic parameters to the number of exacerbations in the past 12 months, and to symptom control in the past 4 weeks, were investigated., Results: A total of 232 subjects were recruited from 6 centers. The mean age was 53.9±12.9 years, with 86 (37.1%) male, and the duration of diagnosed asthma was 26.2±15.7 years. A T-helper 2 (Th2) phenotype indicated by elevated eosinophils and/or IgE was present in 169 (72.8%) of patients. Of 232 patients, 43% had an eosinophilic phenotype (blood eosinophil count ≥300 cell/mm 3 ), while 59% had high total IgE levels of >100 IU/mL (overlap with eosinophilic phenotype in 30%) and 44% had IgE levels of >150 IU/mL (overlap with eosinophilic phenotype in 22%). Subjects with eosinophilic phenotype and IgE >150 IU/mL had a higher rate (1.8 times) of uncontrolled asthma compared with those without such a combination., Conclusion: In Chinese adults with severe asthma defined by the use of conventional maintenance medication regimens, the prevalence of Th2 inflammation is comparable to that reported from other ethnic populations. Those with both eosinophil count ≥300 cell/mm 3 and high IgE levels >150 IU/mL had a higher rate of uncontrolled asthma compared with those without a combination of these features., Competing Interests: MSM Ip has received honouraria for participating in advisory board meetings or expert panel meetings regarding asthma management for Astra Zeneca and Glaxo-Smith-Kline, and has received grants for clinical studies on asthma and COPD from Sanofi, Astra Zeneca, and Boerhinger Ingelheim. Other authors have no conflict of interest to declare in relation to this manuscript., (© 2023 Ko et al.)

Competing Interests: I declare no competing interests.

Our knowledge of the role of the gut microbiome in acute coronavirus disease 2019 (COVID-19) and post-acute COVID-19 is rapidly increasing, whereas little is known regarding the contribution of multi-kingdom microbiota and host-microbial interactions to COVID-19 severity and consequences. Herein, we perform an integrated analysis using 296 fecal metagenomes, 79 fecal metabolomics, viral load in 1378 respiratory tract samples, and clinical features of 133 COVID-19 patients prospectively followed for up to 6 months. Metagenomic-based clustering identifies two robust ecological clusters (hereafter referred to as Clusters 1 and 2), of which Cluster 1 is significantly associated with severe COVID-19 and the development of post-acute COVID-19 syndrome. Significant differences between clusters could be explained by both multi-kingdom ecological drivers (bacteria, fungi, and viruses) and host factors with a good predictive value and an area under the curve (AUC) of 0.98. A model combining host and microbial factors could predict the duration of respiratory viral shedding with 82.1% accuracy (error ± 3 days). These results highlight the potential utility of host phenotype and multi-kingdom microbiota profiling as a prognostic tool for patients with COVID-19., (© 2022. The Author(s).)

Vaccines that are broadly cross-protective against current and future SARS-CoV-2 variants of concern (VoC) or across the sarbecoviruses subgenus remain a priority for public health. Virus neutralization is the best available correlate of protection. To define the magnitude and breadth of cross-neutralization in individuals with different exposure to SARS-CoV-2 infection and vaccination, we here use a multiplex surrogate neutralization assay based on virus spike receptor binding domains of multiple SARS-CoV-2 VoC, as well as related bat and pangolin viruses. We include sera from cohorts of individuals vaccinated with two or three doses of mRNA (BNT162b2) or inactivated SARS-CoV-2 (Coronavac or Sinopharm) vaccines with or without a history of previous SARS-CoV-2 or SARS-CoV-1 infection. SARS-CoV-2 or SARS-CoV-1 infection followed by BNT162b2 vaccine, Omicron BA.2 breakthrough infection following BNT162b2 vaccine or a third dose of BNT162b2 following two doses of BNT162b2 or Coronavac elicit the highest and broadest neutralization across VoCs. For both breadth and magnitude of neutralization across all sarbecoviruses, those infected with SARS-CoV-1 immunized with BNT162b2 outperform all other combinations of infection and/or vaccination. These data may inform vaccine design strategies for generating broadly neutralizing antibodies to SARS-CoV-2 variants or across the sarbecovirus subgenus., (© 2022. The Author(s).)

Background: The burden of chronic obstructive pulmonary disease (COPD) in the Asia-Pacific region is projected to increase. Data from other regions show bacterial and viral infections can trigger acute exacerbations of COPD (AECOPD)., Methods: This 1-year prospective epidemiological study (ClinicalTrials.gov identifier: NCT03151395) of patients with moderate to very severe COPD in Hong Kong, the Philippines, South Korea and Taiwan assessed the prevalence in sputum samples (by culture and PCR) of bacterial and viral pathogens during stable COPD and AECOPD. The odds of experiencing an exacerbation was evaluated for pathogen presence, acquisition and apparition. Health-related quality of life (HRQOL) was assessed., Results: 197 patients provided 983 sputum samples, with 226 provided during exacerbation episodes. The mean yearly AECOPD incidence rate was 1.27 per patient. The most prevalent bacteria by PCR at exacerbation were Haemophilus influenzae (Hi) and Moraxella catarrhalis (Mcat); Mcat prevalence was higher at exacerbation than at stable state. Virus prevalence was low, other than for human rhinovirus (HRV) (8.1%, stable state; 16.6%, exacerbation). The odds ratio (95% CI) for an exacerbation ( versus stable state) was statistically significant for the presence, acquisition and apparition of Hi (2.20, 1.26-3.89; 2.43, 1.11-5.35; 2.32, 1.20-4.46, respectively), Mcat (2.24, 1.30-3.88; 5.47, 2.16-13.86; 3.45, 1.71-6.98, respectively) and HRV (2.12, 1.15-3.91; 2.22, 1.09-4.54; 2.09, 1.11-3.91, respectively). HRQOL deteriorated according to the number of exacerbations experienced., Conclusion: In patients with COPD in the Asia-Pacific region, the presence of Hi, Mcat or HRV in sputum samples significantly increased the odds of an exacerbation, providing further evidence of potential roles in triggering AECOPD., Competing Interests: Conflict of interest: L. Taddei, L. Malvaux and A.K. Arora are employed by GSK. L. Taddei and L. Malvaux hold shares in GSK. L. Malvisi was employed by GSK at the time the study was conducted. L. Taddei, L. Malvaux, A.K. Arora and L. Malvisi declare no other financial and non-financial relationships and activities. D. Hui, R.Z. Samoro, S.H. Lee, Y.C. Yeung and Y-C. Liu declare no financial or non-financial relationships or activities and no conflicts of interest., (Copyright ©The authors or their employers 2022.)

Annual seasonal influenza epidemics of variable severity caused by influenza A and B virus infections result in substantial disease burden worldwide. Seasonal influenza virus circulation declined markedly in 2020-21 after SARS-CoV-2 emerged but increased in 2021-22. Most people with influenza have abrupt onset of respiratory symptoms and myalgia with or without fever and recover within 1 week, but some can experience severe or fatal complications. Prevention is primarily by annual influenza vaccination, with efforts underway to develop new vaccines with improved effectiveness. Sporadic zoonotic infections with novel influenza A viruses of avian or swine origin continue to pose pandemic threats. In this Seminar, we discuss updates of key influenza issues for clinicians, in particular epidemiology, virology, and pathogenesis, diagnostic testing including multiplex assays that detect influenza viruses and SARS-CoV-2, complications, antiviral treatment, influenza vaccines, infection prevention, and non-pharmaceutical interventions, and highlight gaps in clinical management and priorities for clinical research., Competing Interests: Declaration of interests DSH reports grant support unrelated to contributions to the Clinical spectrum and clinical complications, Clinical management, and Prevention and control interventions health-care settings sections, and, outside the submitted work support, from F Hoffmann-La Roche for a research nurse to enrol participants in a phase 3, randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of baloxavir marboxil in combination with standard-of-care neuraminidase inhibitor in hospitalised patients with severe influenza. DEW reports research unit support (CRADA) from Seqirus for evaluation of virus isolation and propagation of viruses for the implementation of cell-based vaccines (US$200 000 per year) unrelated to contributions to the virology and pathogenesis sections and outside the submitted work. MZ reports being a member of the WHO Strategic Advisory Group of Experts on Immunization, the J Craig Venter Institute, and the UK New and Emerging Respiratory Virus Threats Advisory Group, and is Chair of the International Society of Influenza and Respiratory Viruses, unrelated to contributions to the influenza surveillance and diagnosis sections and outside the submitted work. ASM reports serving on a Roche advisory board unrelated to the contributions to the Influenza vaccines and vaccine effectiveness sections and outside the submitted work. TMU declares no competing interests. The views expressed are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the UK Health Security Agency., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Bats are likely the primary source of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Minks are highly susceptible to infection by SARS-CoV-2. Transmission from asymptomatic individuals was estimated to account for over 50% of all transmissions of coronavirus disease 2019 (COVID-19) cases. SARS-CoV-2 is evolving towards more efficient aerosol transmission. Remdesivir, baricitinib, tocilizumab and dexamethasone are frequently used for the treatment of patients with respiratory failure due to COVID-19. There is a rising incidence of non-tuberculous Mycobacterium pulmonary disease globally, with a higher prevalence in Asian countries than in the Western world. Protracted bacterial bronchitis is a common cause of chronic productive cough in childhood. Re-emergence of respiratory syncytial virus may occur after the relaxation of infection control measures and the reopening of borders during COVID-19 pandemic., (© 2022 Asian Pacific Society of Respirology.)

Objective: People with HIV (PWH) co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at higher odds of severe diseases. Whereas the immunogenicity of mRNA vaccine and adenovirus-vectored vaccine was similar between PWH in stable condition and healthy adults, the effects of inactivated vaccines are not known., Design: Prospective longitudinal observational study in real-world setting., Methods: Adult PWH in care and planning to receive either inactivated (day 0 and day 28) or mRNA-based (day 0 and day 21) vaccine against SARS-CoV-2 were recruited, with blood samples collected over 6 months for surrogate virus neutralization test (sVNT). Demographic and clinical data including age, sex, CD4 + cell count, and suppressed viral load (SVL) status were transcribed for analyses, by simple and multivariable linear regression models, and multivariable linear generalized estimating equations (GEE)., Results: A total of 611 HIV patients, 91% male patients, were recruited, of whom 423 and 184 have received mRNA-based and inactivated vaccine, respectively. The seroconversion rate was 99% for mRNA-based vs, 86% for inactivated vaccine [odds ratio (OR) = 21.56, P  = 0.004]. At 6 months, mRNA-based vaccine continued to give a higher response (94 vs. 57%, P  < 0.001). The temporal pattern varied between the two vaccines. By GEE, mRNA-based vaccine ( B  = 40.59, P  < 0.001) and latest SVL status ( B  = 10.76, P  = 0.01) were positively associated with sVNT level, but not latest CD4 + cell count., Conclusion: In HIV patients, inactivated vaccine gave a lower peak and shorter duration of sVNT responses compared with mRNA vaccine. The results suggested that different strategies may be needed in boosting the immunity in anticipation of the emergence of variants in the community., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

The antibody response magnitude and kinetics may impact clinical severity, serological diagnosis and long-term protection of COVID-19, which may play a role in why children experience lower morbidity. We therefore tested samples from 122 children in Hong Kong with symptomatic (n = 78) and asymptomatic (n = 44) SARS-CoV-2 infections up to 200 days post infection, relative to 71 infected adults (symptomatic n = 61, and asymptomatic n = 10), and negative controls (n = 48). We assessed serum IgG antibodies to a 14-wide antigen panel of structural and accessory proteins by Luciferase Immuno-Precipitation System (LIPS) assay and circulating cytokines. Infected children have lower levels of Spike, Membrane, ORF3a, ORF7a, ORF7b antibodies, comparable ORF8 and elevated E-specific antibodies than adults. Combination of two unique antibody targets, ORF3d and ORF8, can accurately discriminate SARS-CoV-2 infection in children. Principal component analysis reveals distinct pediatric serological signatures, and the highest contribution to variance from adults are antibody responses to non-structural proteins ORF3d, NSP1, ORF3a and ORF8. From a diverse panel of cytokines that can modulate immune priming and relative inflammation, IL-8, MCP-1 and IL-6 correlate with the magnitude of pediatric antibody specificity and severity. Antibodies to SARS-CoV-2 internal proteins may become an important sero surveillance tool of infection with the roll-out of vaccines in the pediatric population., (© 2022. The Author(s).)

Background: The adaptive immune responses of COVID-19 patients contributes to virus clearance, restoration of health and protection from re-infection. The patterns of and the associated characteristics with longitudinal neutralising antibody (NAb) response following SARS-CoV-2 infection are important in their potential association with the population risks of re-infection., Methods: This is a longitudinal study with blood samples and clinical data collected in adults aged 18 or above following diagnosis of SARS-CoV-2 infection. NAb levels were measured by the SARS-CoV-2 surrogate virus neutralisation test (sVNT). Anonymous clinical and laboratory data were matched with surveillance data for each subject for enabling analyses and applying latent class mixed models for trajectory delineation. Logistic regression models were performed to compare the characteristics between the identified classes., Results: In 2020-2021, 368 convalescent patients in Hong Kong are tested for NAb. Their seroconversion occur within 3 months in 97% symptomatic patients, the level of which are maintained at 97% after 9 months. The NAb trajectories of 200 symptomatic patients are classified by the initial response and subsequent trend into high-persistent and waning classes in latent class mixed models. High-persistent (15.5%) class patients are older and most have chronic illnesses. Waning class patients (84.5%) are largely young adults who are mildly symptomatic including 2 who serorevert after 10 months., Conclusions: Characteristic sub-class variabilities in clinical pattern are noted especially among patients with waning NAb. The heterogeneity of the NAb trajectory patterns and their clinical association can be important for informing vaccination strategy to prevent re-infection., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Purpose of Review: The current article reviews the latest information on the epidemiology, clinical features, diagnostics, clinical management and prevention of coronavirus disease 2019 (COVID-19)., Recent Findings: Atypical pneumonia due to severe acute respiratory syndrome coronavirus-2 emerged in December 2019 in a market in Wuhan, China and rapidly evolved into a pandemic in March 2020. Viral loads of patients with COVID-19 peak in the first week of illness around day 2-4 and hence there is very high-transmission potential causing community outbreaks. Asymptomatic and presymptomatic transmission is a hallmark of COVID-19. Several variants of concern (VOC) have emerged over the last 2 years and Omicron is the predominant variant in many countries. PCR is the standard diagnostic test while rapid antigen test is a useful supplementary test. Serology tests provide indirect evidence of infection 1 -2 weeks after the onset of symptoms. Molnupiravir and nirmatrelvir are oral antiviral agents that may reduce the risk of hospitalization and deaths if administered early to high-risk subjects. Remdesivir, baricitinib, anti-IL-6 tocilizumab and dexamethasone are frequently used for treatment of patients with respiratory failure., Summary: COVID-19 pandemic progresses relentlessly with substantial morbidity and mortality especially in unvaccinated subjects. Mass COVID-19 vaccinations are the most important measure for control of the COVID-19 pandemic., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We investigated the ocular surface disturbances in COVID-19 patients discharged from the hospital., Methods: One hundred and seventy-nine eyes of 109 healthy participants and 456 eyes of 228 post-COVID-19 patients received comprehensive eye examinations; the latter were interviewed with questionnaires on ocular symptoms before and after COVID-19 diagnosis. Associations of ocular surface manifestations with virological and ophthalmic parameters were evaluated by multivariable mixed linear or logistic regression models., Results: Mean interval between COVID-19 diagnosis and ophthalmic evaluation was 52.23 ± 16.12 days. The severity of meibomian gland dysfunction (MGD) based on clinical staging was higher in post-COVID-19 than healthy eyes (1.14 ± 0.67 vs. 0.92 ± 0.68, p = 0.002) and so was ocular surface staining score (0.60 ± 0.69 vs. 0.49 ± 0.68, p = 0.044). Patients requiring supplementary oxygen during hospitalisation had shorter tear break-up time (β -1.63, 95% CI -2.61 to -0.65). Cycle threshold (Ct) value from upper respiratory samples (inversely correlated with viral load) at diagnosis had an OR = 0.91 (95% CI 0.84-0.98) with new ocular surface symptoms 4 weeks after diagnosis. The presence of ocular surface symptoms 1 week prior to COVID-19 diagnosis showed an OR of 20.89 (95% CI 6.35-68.66) of persistent or new ocular symptoms 4 weeks afterward., Conclusions: MGD and ocular surface staining are more common and severe in post-COVID-19 patients. Patients with higher viral loads have greater risks of ocular surface symptoms. Patients requiring supplementary oxygen are more likely to show tear film instability. Ocular surface evaluation should be considered 1-3 months following hospital discharge for any COVID-19 patient., (© 2022 Royal Australian and New Zealand College of Ophthalmologists.)

Background: Neuraminidase inhibitors (NAIs) are considered the standard of care for hospitalised patients with influenza. We aimed to test whether combining the cap-dependent endonuclease inhibitor baloxavir marboxil (hereafter baloxavir) with standard-of-care NAIs would result in improved clinical outcomes compared with NAI monotherapy in hospitalised patients with severe influenza., Methods: We did a randomised, parallel-group, double-blind, placebo-controlled, superiority trial. Patients aged 12 years or older who were hospitalised with laboratory-confirmed influenza (by RT-PCR or a rapid test) and had a National Early Warning Score 2 (NEWS2) of 4 or greater were included. Recruitment took place in 124 centres across 25 countries. Using a permuted-block method and an interactive response system, patients were randomly assigned (2:1) to receive either baloxavir plus NAIs (hereafter the baloxavir group) or placebo plus NAIs (hereafter the control group). Participants, investigators, and those assessing outcomes were masked to group assignment. Baloxavir was administered orally on day 1 and day 4 (40 mg for bodyweight <80 kg, or 80 mg for ≥80 kg), and on day 7 if no clinical improvement had occurred by day 5. The NAIs included in this study were oseltamivir, zanamivir, and peramivir, which were selected and administered according to local standard practice. The primary endpoint was time to clinical improvement, defined as time to a NEWS2 of 2 or lower for 24 h or hospital discharge, whichever came first, based on daily assessments over the study duration of 35 days. Secondary endpoints included safety analyses. The modified intention-to-treat infected (mITTI) population (ie, all patients who were randomly assigned to treatment, received a dose of study drug, and were RT-PCR-positive for influenza at any timepoint according to the treatment assigned at randomisation) was used in all efficacy analyses. The safety population (ie, all patients who received at least one dose of study treatment, according to the treatment received) was used in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03684044., Findings: Overall, 366 patients were enrolled between Jan 8, 2019, and March 16, 2020, of whom 241 were assigned to the baloxavir group and 125 to the control group. The mITTI population comprised 322 patients, 208 in the baloxivir group and 114 in the control group. In total, 280 (87%) of these patients had influenza A infections. Median time to clinical improvement was 97·5 h (95% CI 75·9 to 117·2) in the baloxavir group and 100·2 h (75·9 to 144·4) in the control group (median difference -2·7 h [95% CI -53·4 to 25·9], p=0·467). Baloxavir plus NAI was well tolerated, and no new safety signals were observed; serious adverse events occurred in 29 (12%) of 239 patients in the baloxavir group versus 19 (15%) of 124 patients in the control group, of which one was considered related to treatment (orthostatic hypotension in a patient in the control group). Overall, four deaths (2%) occurred in the baloxavir group and seven (6%) in the control group; none were considered related to treatment., Interpretation: Combining baloxavir with NAIs did not result in superior clinical outcomes compared with NAIs alone. The combination of baloxavir plus NAI was well tolerated. The findings suggest that combination antivirals would not be routinely indicated in clinical practice for hospitalised patients with severe influenza., Funding: F Hoffmann-La Roche and the Biomedical Advanced Research and Development Authority., Competing Interests: Declaration of interests DK has received advisory fees from F Hoffmann-La Roche, Sanofi Pasteur, and GlaxoSmithKline, and a clinical trials grant from F Hoffmann-La Roche and GlaxoSmithKline. MGI received research support, paid to Northwestern University, from AiCuris, Janssen, and Shire; he is a paid consultant for Adagio, AlloVir, Celltrion, Cidara, Genentech, F Hoffmann-La Roche, Janssen, Shionogi, and Viracor Eurofins, and he is a paid member of data monitoring and safety boards for Janssen, Merck, SAB Biotherapeutics, Sequiris, Takeda, and Vitaeris. J-PM has received advisory fees from F Hoffmann-La Roche, AM-Pharma, and AKPA; lecture fees from Fresenius, MSD, Astellas, and Estor; and clinical trial grants from AKPA and Biomérieux. NL has previously received honoraria for consultancy work and speaking in educational programmes from Shionogi, Janssen, Sanofi Pasteur, Gilead Sciences Canada, F Hoffmann-La Roche, Genentech, and CIDARA Therapeutics, and travel support from Shionogi, Sanofi Pasteur, F Hoffmann-La Roche, and Genentech. LK, NC, AA, BC, and SWill are employees of Roche Products. SWild is an employee of F Hoffmann-La Roche. TW has received honoraria for consultancy work and speaking in educational programmes from AstraZeneca, Basilea, Biotest, Bayer, Boehringer Ingelheim, Berlin Chemie, GlaxoSmithKline, Infectopharm, Johnson & Johnson, MSD, Novartis, Pfizer, F Hoffmann-La Roche, and Sanofi Aventis. TS has received lecture fees from AstraZeneca, Boehringer Ingelheim, Sanofi Pasteur, Novartis, KYORIN Pharmaceutical, and Daiichi Sankyo. DSH, NZ, and JHH have nothing to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Objective: Few head-to-head evaluations of immune responses to different vaccines have been reported., Methods: Surrogate virus neutralization test (sVNT) antibody levels of adults receiving either two doses of BNT162b2 (n = 366) or CoronaVac (n = 360) vaccines in Hong Kong were determined. An age-matched subgroup (BNT162b2 [n = 49] vs. CoronaVac [n = 49]) was tested for plaque reduction neutralization (PRNT) and spike-binding antibody and T-cell reactivity in peripheral blood mononuclear cells., Results: One month after the second dose of vaccine, BNT162b2 elicited significantly higher PRNT 50 , PRNT 90 , sVNT, spike receptor binding, spike N-terminal domain binding, spike S2 domain binding, spike FcR binding and antibody avidity levels than CoronaVac. The geometric mean PRNT 50 titres in those vaccinated with BNT162b2 and CoronaVac vaccines were 251.6 and 69.45, while PRNT 90 titres were 98.91 and 16.57, respectively. All of those vaccinated with BNT162b2 and 45 (91.8%) of 49 vaccinated with CoronaVac achieved the 50% protection threshold for PRNT 90. Allowing for an expected seven-fold waning of antibody titres over 6 months for those receiving CoronaVac, only 16.3% would meet the 50% protection threshold versus 79.6% of BNT162b2 vaccinees. Age was negatively correlated with PRNT 90 antibody titres. Both vaccines induced SARS-CoV-2-specific CD4 + and CD8 + T-cell responses at 1 month post-vaccination but CoronaVac elicited significantly higher structural protein-specific CD4 + and CD8 + T-cell responses., Conclusion: Vaccination with BNT162b2 induces stronger humoral responses than CoronaVac. CoronaVac induces higher CD4 + and CD8 + T-cell responses to the structural protein than BNT162b2., (© 2021 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)