Association of nirmatrelvir-ritonavir with post-acute sequelae and mortality in patients admitted to hospital with COVID-19: a retrospective cohort study.

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.

Cross-Reactive Antibody Responses to Coronaviruses Elicited by SARS-CoV-2 Infection or Vaccination.

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.

Cross-neutralizing antibody against emerging Omicron subvariants of SARS-CoV-2 in infection-naïve individuals with homologous BNT162b2 or BNT162b2(WT + BA.4/5) bivalent booster vaccination.

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.

Perspectives on development and advancement of new tuberculosis vaccines.

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.

Inferring Incidence of Unreported SARS-CoV-2 Infections Using Seroprevalence of Open Reading Frame 8 Antigen, Hong Kong.

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.

Serological assays for differentiating natural COVID-19 infection from vaccine induced immunity.

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.

Baseline gut microbiota and metabolome predict durable immunogenicity to SARS-CoV-2 vaccines.

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.

Characterization of upper airway microbiome across severity of COVID-19 during hospitalization and treatment.

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.

Lack of neutralizing antibodies against influenza A viruses in adults during the 2022/2023 winter season - a serological study using retrospective samples collected in Hong Kong.

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.

Risk of air and surface contamination during application of different noninvasive respiratory support for patients with COVID-19.

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.

Effectiveness of mRNA and inactivated COVID-19 vaccines: A test-negative study in an infection-naïve Hong Kong population.

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 (VEadj [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.