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The emergence of various SARS-CoV-2 variants presents challenges for antibody therapeutics, emphasizing the need for more potent and broadly neutralizing antibodies. Here, we employed an unbiased screening approach and successfully isolated two antibodies from individuals with only exposure to ancestral SARS-CoV-2. One of these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum of SARS-CoV-2 variants, including the latest KP.2, KP.3 and XEC, with consistent IC 50 values ranging from ~1 to 5 ng/mL. It also displayed broad neutralization activity against SARS-CoV and related sarbecoviruses. Structural analysis revealed that these antibodies target shared hotspot but mutation-resistant epitopes, with their Fabs locking receptor binding domains (RBDs) in the "down" conformation through interactions with adjacent Fabs and RBDs, and cross-linking Spike trimers into di-trimers. In vivo studies conducted in a JN.1-infected hamster model validated the protective efficacy of CYFN1006-1. These findings suggest that antibodies with cross-neutralization activities can be identified from individuals with exclusively ancestral virus exposure., Competing Interests: Competing interests: Y.G. is a co-founder and shareholder of Antibody BioPharm, Inc. and ChangYuan FuNeng (Shanghai) Life Technology Co., Ltd. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Background: This study updates the COVID-19 pandemic surveillance in East Asia and the Pacific region that we first conducted in 2020 with 2 additional years of data for the region., Objective: First, we aimed to measure whether there was an expansion or contraction of the pandemic in East Asia and the Pacific region when the World Health Organization (WHO) declared the end of the COVID-19 public health emergency of international concern on May 5, 2023. Second, we used dynamic and genomic surveillance methods to describe the dynamic history of the pandemic in the region and situate the window of the WHO declaration within the broader history. Finally, we aimed to provide historical context for the course of the pandemic in East Asia and the Pacific region., Methods: In addition to updates of traditional surveillance data and dynamic panel estimates from the original study, this study used data on sequenced SARS-CoV-2 variants from the Global Initiative on Sharing All Influenza Data to identify the appearance and duration of variants of concern. We used Nextclade nomenclature to collect clade designations from sequences and Pangolin nomenclature for lineage designations of SARS-CoV-2. Finally, we conducted a 1-sided t test to determine whether the regional weekly speed was greater than an outbreak threshold of 10. We ran the test iteratively with 6 months of data across the sample period., Results: Several countries in East Asia and the Pacific region had COVID-19 transmission rates above an outbreak threshold at the point of the WHO declaration (Brunei, New Zealand, Australia, and South Korea). However, the regional transmission rate had remained below the outbreak threshold for 4 months. In the rolling 6-month window t test for regional outbreak status, the final P value ≤.10 implies a rejection of the null hypothesis (at the α=.10 level) that the region as a whole was not in an outbreak for the period from November 5, 2022, to May 5, 2023. From January 2022 onward, nearly every sequenced SARS-CoV-2 specimen in the region was identified as the Omicron variant., Conclusions: While COVID-19 continued to circulate in East Asia and the Pacific region, transmission rates had fallen below outbreak status by the time of the WHO declaration. Compared to other global regions, East Asia and the Pacific region had the latest outbreaks driven by the Omicron variant. COVID-19 appears to be endemic in the region, no longer reaching the threshold for a pandemic definition. However, the late outbreaks raise uncertainty about whether the pandemic was truly over in the region at the time of the WHO declaration., (©Alexander L Lundberg, Alan G Soetikno, Scott A Wu, Egon Ozer, Sarah B Welch, Yingxuan Liu, Claudia Hawkins, Maryann Mason, Robert Murphy, Robert J Havey, Charles B Moss, Chad J Achenbach, Lori Ann Post. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 21.02.2025.)

Background: The emergence of new SARS-CoV-2 variants, the resulting reinfections, and post-COVID-19 condition continue to impact many people's lives. Tracking websites like the one at Johns Hopkins University no longer report the daily confirmed cases, posing challenges to accurately determine the true extent of infections. Many COVID-19 cases with mild symptoms are self-assessed at home and reported on social media, which provides an opportunity to monitor and understand the progression and evolving trends of the disease., Objective: We aim to build a publicly available database of COVID-19-related tweets and extracted information about symptoms and recovery cycles from self-reported tweets. We have presented the results of our analysis of infection, reinfection, recovery, and long-term effects of COVID-19 on a visualization website that refreshes data on a weekly basis., Methods: We used Twitter (subsequently rebranded as X) to collect COVID-19-related data, from which 9 native English-speaking annotators annotated a training dataset of COVID-19-positive self-reporters. We then used large language models to identify positive self-reporters from other unannotated tweets. We used the Hibert transform to calculate the lead of the prediction curve ahead of the reported curve. Finally, we presented our findings on symptoms, recovery, reinfections, and long-term effects of COVID-19 on the Covlab website., Results: We collected 7.3 million tweets related to COVID-19 between January 1, 2020, and April 1, 2024, including 262,278 self-reported cases. The predicted number of infection cases by our model is 7.63 days ahead of the official report. In addition to common symptoms, we identified some symptoms that were not included in the list from the US Centers for Disease Control and Prevention, such as lethargy and hallucinations. Repeat infections were commonly occurring, with rates of second and third infections at 7.49% (19,644/262,278) and 1.37% (3593/262,278), respectively, whereas 0.45% (1180/262,278) also reported that they had been infected >5 times. We identified 723 individuals who shared detailed recovery experiences through tweets, indicating a substantially reduction in recovery time over the years. Specifically, the average recovery period decreased from around 30 days in 2020 to approximately 12 days in 2023. In addition, geographic information collected from confirmed individuals indicates that the temporal patterns of confirmed cases in states such as California and Texas closely mirror the overall trajectory observed across the United States., Conclusions: Although with some biases and limitations, self-reported tweet data serves as a valuable complement to clinical data, especially in the postpandemic era dominated by mild cases. Our web-based analytic platform can play a significant role in continuously tracking COVID-19, finding new uncommon symptoms, detecting and monitoring the manifestation of long-term effects, and providing necessary insights to the public and decision-makers., (©Jiacheng Xie, Ziyang Zhang, Shuai Zeng, Joel Hilliard, Guanghui An, Xiaoting Tang, Lei Jiang, Yang Yu, Xiufeng Wan, Dong Xu. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 20.02.2025.)

Antibody assays of IgM, IgG and surrogate isotype independent virus neutralizing antibody (sVNT) targeting receptor binding domain of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were employed in 97 real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR) confirmed Coronavirus Disease 2019 (COVID-19) patients with varying severity admitted to King Chulalongkorn Memorial Hospital. Concordance rate was 100% regardless of severity, onset of symptoms and magnitude of viral load. Per available samples, antibodies appeared on the same day of symptom onset in one patient; one day after in 18 patients and two days after in 19 patients. In two patients, antibodies appeared as early as 4 days after infection (exposure). IgM and IgG were evident in all patients' first assay (within two days of admission). sVNT was also evident within two days of admission in all but 3 patients. IgM usually remained positive during the entire course of hospital stay, where the longest in this study was 32 days. Antibody assays were also applied to samples collected at a State Quarantine premise from 77 asymptomatic Thais returning from Sudan in October. Virus was detected by real-time RT-PCR in 15 cases (day 0 = 6, day 3 = 4, day 5 = 4 and day 9 = 1). Twenty-nine (including 11 RT-PCR positive cases) were antibody positive on day 0, while 4 PCR positive with antibody negative on day 0 became antibody positive on day 14. Evaluation on antibody response at days 7 or 10 is needed to help build a case to shorten length of quarantine among negative cases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Ruchisrisarod et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We constructed a rapid infection risk assessment model for contacts of COVID-19. The improved Wells-Riley model was used to estimate the probability of infection for contacts of COVID-19 in the same place and evaluate their risk grades. We used COVID-19 outbreaks that were documented to validate the accuracy of the model. We analyzed the relationship between controllable factors and infection probability and constructed common scenarios to analyze the infection risk of contacts in different scenarios. The model showed the robustness of the fitting (mean relative error = 5.89%, mean absolute error = 2.03%, root mean squared error = 2.03%, R 2 = 0.991). We found that improving ventilation from poorly ventilated to naturally ventilated and wearing masks can reduce the probability of infection by about two times. Contacts in places of light activity, loud talking or singing, and heavy exercise, oral breathing (e.g., gyms, KTV, choirs) were at higher risk of infection. The model constructed in this study can quickly and accurately assess the infection risk grades of COVID-19 contacts. Simply opening doors and windows for ventilation can significantly reduce the risk of infection in certain places. The places of light activity, loud talking or singing, and heavy exercise, oral breathing, should pay more attention to prevent and control transmission of the epidemic., (© 2024 The Author(s). Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis.)

Problem: Despite being at increased risk for severe COVID-19, pregnant women were initially excluded from vaccine clinical trials, which limited data regarding vaccine effectiveness and protection in this group. Aiming to better understand the immune response to vaccination during pregnancy, we compared the kinetics and titers of neutralizing and IgG antibodies generated against SARS-CoV-2 during vaccination with BNT162b2 (Pfizer-BioNTech) or CoronaVac (Sinovac Biotech) in a cohort of pregnant women., Methods of Study: We evaluated participants before vaccination and 30 days after each vaccine dose, using a multiplex bead assay to measure IgG antibodies against SARS-CoV-2 antigens (total spike, spike-1, spike-2, receptor binding domain, and nucleocapsid) and a live virus fluorescence reduction neutralization assay (FRNA) to quantify neutralizing antibodies., Results: Our data showed that vaccination resulted in a robust humoral response, with a considerable increase in the levels of IgG and neutralizing antibodies after the first vaccine dose and a sustained neutralizing response after the vaccine boost. In addition, antispike IgG assays presented a slight decrease after the second dose, while the neutralization rate remained stable., Conclusions: Immune response to the SARS-CoV-2 vaccine in pregnant women demonstrated an important increase in neutralizing antibodies., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Long COVID or Post-acute sequelae of COVID-19 is an emerging syndrome, recognized in COVID-19 patients who suffer from mild to severe illness and do not recover completely. Most studies define Long COVID, through symptoms like fatigue, brain fog, joint pain, and headache prevailing four or more weeks post-initial infection. Global variations in Long COVID presentation and symptoms make it challenging to standardize features of Long COVID. Long COVID appears to be accompanied by an auto-immune multi-faceted syndrome where the virus or viral antigen persistence causes continuous stimulation of the immune response, resulting in multi-organ immune dysregulation., Main Text: This review is focused on understanding the risk factors of Long COVID with a special emphasis on the dysregulation of the gut-brain axis. Two proposed mechanisms are discussed here. The first mechanism is related to the dysfunction of angiotensin-converting enzyme 2 receptor due to Severe Acute Respiratory Syndrome Corona Virus 2 infection, leading to impaired mTOR pathway activation, reduced AMP secretion, and causing dysbiotic changes in the gut. Secondly, gut-brain axis dysregulation accompanied by decreased production of short-chain fatty acids, impaired enteroendocrine cell function, and increased leakiness of the gut, which favors translocation of pathogens or lipopolysaccharide in circulation causing the release of pro-inflammatory cytokines. The altered Hypothalamic-Pituitary-Adrenal axis is accompanied by the reduced level of neurotransmitter, and decreased stimulation of the vagus nerve, which may cause neuroinflammation and dysregulation of serum cortisol levels. The dysbiotic microbiome in Long COVID patients is characterized by a decrease in beneficial short chain fatty acid-producing bacteria (Faecalibacterium, Ruminococcus, Dorea, and Bifidobacterium) and an increase in opportunistic bacteria (Corynebacterium, Streptococcus, Enterococcus). This dysbiosis is transient and may be impacted by interventions including probiotics, and dietary supplements., Conclusions: Further studies are required to understand the geographic variation, racial and ethnic differences in phenotypes of Long COVID, the influence of viral strains on existing and emerging phenotypes, to explore long-term effects of gut dysbiosis, and gut-brain axis dysregulation, as well as the potential role of diet and probiotics in alleviating those symptoms., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: The emergence of SARS-CoV-2 variants necessitates ongoing evaluation of vaccine performance. This study evaluates and compares the safety and immunogenicity of the Comirnaty and Spikevax monovalent XBB.1.5 COVID-19 vaccines in an elderly population., Methods: Altogether, 129 elderly individuals were recruited between 2 January and 3 February 2024, and received a booster dose of either Comirnaty (n=59) or Spikevax (n=70) monovalent XBB.1.5 COVID-19 vaccine. Blood samples were collected at before and one month after vaccination. Immunogenicity was assessed by measuring the percentage of IFNγ + CD4 + and IFNγ + CD8 + T cells, and neutralizing antibody titers (NT50) using a surrogate virus neutralization test (sVNT). Adverse reactions were recorded and analyzed., Findings: Both vaccines significantly increased the percentage of IFNγ + CD8 + T cells against XBB.1.5 and wild-type (WT) SARS-CoV-2 at one-month post-vaccination. Spikevax induced a significantly higher percentages of IFNγ + CD8 + and CD4 + T cells against XBB.1.5 than Comirnaty (p<0.001). The proportion of participants showing a positive T cell response to XBB1.5 after vaccination was higher in the Spikevax group (64.3% CD8, 71.4% CD4) than in the Comirnaty group (42.4% CD8, 57.6% CD4). Spikevax also elicited higher NT50 levels against XBB1.5, JN.1 and the latest variant KP.2 than Comirnaty (XBB1.5: p<0.01; KP.2: p<0.05). Fever was more common in the Spikevax group (fever: p=0.006). However, all side effects were short-term and resolved on their own., Interpretation: Both vaccines induce neutralizing antibody to XBB1.5, JN.1 and KP.2. Specifically, Spikevax induces higher cellular and humoral immune responses than Comirnaty in the elderly, but it is also associated with a higher incidence of fever. These findings can guide public health strategies for vaccinating the elderly population., 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 the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The COVID-19 pandemic has revealed the need for nations to prepare more effectively for emerging infectious diseases. Preparing for these threats requires a multifaceted approach that includes assessing pathogen threat, building flexible capabilities for rapid medical countermeasure (MCM) development, and exercising, maintaining, and improving those response capabilities. The Biomedical Advanced Research and Development Authority (BARDA) promotes the advanced development of MCMs in response to natural and manmade threats. In this article, the authors describe a BARDA threat assessment tool that, in conjunction with other factors, facilitates portfolio management and decisionmaking related to the advanced development of MCMs for emerging infectious diseases. The tool was designed to use readily accessible public data and information related to the threat posed by pathogens. It can be adjusted to modify the specific areas of interest (eg, removal/addition of parameters) to facilitate cross-pathogen analysis and can be updated to reflect changes (eg, new outbreak) that may impact the overall threat assessment. Finally, assessment of certain pathogens is included.

Background: Liver involvement is a common complication of coronavirus disease 2019 (COVID-19), especially in hospitalized patients. However, the underlying mechanisms involved are not fully understood., Methods: Immunohistochemistry (IHC) staining of SARS-CoV-2 spike (S) and nucleocapsid (N) proteins was conducted on liver tissues from six patients with COVID-19. The 10x Genomics Visium CytAssist Spatial Gene Assay was designed to analyze liver transcriptomics. TCR CDR3 sequences were analyzed in DNA from liver tissues. Liver function indicators were retrospectively studied in 650 hospitalized patients with COVID-19., Findings: SARS-CoV-2 proteins were initially detected in the livers of naturally infected golden (Syrian) hamsters, prompting us to investigate the situation in clinical cases. Thus, we collected liver tissues from patients with abnormal liver biochemical values. Viral S and N proteins were detected in the livers of severe and deceased patients but not in those of moderate patients. We further demonstrated that hepatocytes and erythroid cells in hepatic sinusoids are major cells targeted by SARS-CoV-2. Immune cells, especially T cells, were enriched in surviving severe patients, characterized by enhanced CDR3α clonality and novel CDR3β recombination of the T-cell receptor. In contrast, hepatocyte apoptosis was triggered, and the transcription of albumin (ALB) was obviously impaired in the deceased patients. We then performed a retrospective study including patients with COVID-19. Serum aspartate aminotransferase (AST) and ALB levels at baseline significantly differed in the deceased cohort. However, AST regression did not decrease the risk of death. ALB recovery indicated clinical improvement, and declining or low serum ALB concentrations were associated with death., Interpretation: This study provides clinical evidence for liver infection with SARS-CoV-2, insight into the impact of SARS-CoV-2 on the liver, and a potential way to evaluate the risk of death via assessing serum ALB concentration fluctuations in patients with COVID-19., Funding: National Key R&D Program of China (2021YFC2300602), National Natural Science Foundation of China (92369110), National Natural Science Foundation of China (U23A20474), Shanghai Municipal Science and Technology Major Project (ZD2021CY001), Shanghai Jinshan District Medical and Health Technology Innovation Fund Project (2023-WS-31)., Competing Interests: Declaration of interests The authors declared no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Dynamic pathogen exposure may impact the immunological response to SARS-CoV-2 (SCV2). One potential explanation for the lack of severe SCV2-related morbidity and mortality in Southeast Asia is prior exposure to related betacoronaviruses. Recent discoveries of SCV2-related betacoronaviruses from horseshoe bats (Rhinolophus sinicus) in Thailand, Laos, and Cambodia suggest the potential for bat-to-human spillover exposures in the region. In this work, serum antibodies to protein constructs from SCV2 and a representative bat coronavirus isolated in Cambodia (RshSTT182) are measured in pre-pandemic Cambodian human sera using ELISA assays. Of 293 Cambodian samples tested (N = 131 with acute malaria, n = 162 with acute undifferentiated febrile illness), 32 (10.9%) are seropositive for SCV2 based on established Spike and receptor-binding domain (RBD) cutoffs. Within SCV2 seropositive samples, 16 (50%) have higher antibody levels to antigens from the representative virus RshSTT182 versus SCV2 antigens; competitive binding ELISA assays demonstrate inhibition of reactivity to SCV2 Spike after pre-incubation with RshSTT182 Spike. Surrogate virus neutralization tests demonstrate that 8/30 (26.7%) SCV2 ELISA positive pre-pandemic Cambodian samples have neutralizing activity against SCV2, while 14/30 (46.7%) have activity against other SCV2-related betacoronaviruses. These data suggest that exposure to related betacoronaviruses may elicit cross-reactive immunity to SCV2 prior to the global pandemic., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Advanced Science published by Wiley‐VCH GmbH.)

Mathematical models of viral dynamics are crucial in understanding infection trajectories. However, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load data often includes limited sparse observations with significant heterogeneity. This study aims to: (1) understand the impact of patient characteristics in shaping the temporal viral load trajectory and (2) establish a data collection protocol (DCP) to reliably reconstruct individual viral load trajectories. We collected longitudinal viral load data for SARS-CoV-2 Delta and Omicron variants from 243 patients in Singapore (2021-2022). A viral dynamics model was calibrated using patients' age, symptom presence, and vaccination status. We accessed associations between these patient characteristics and aspects of viral dynamics using linear regression models. We evaluated the accuracy of viral load trajectory estimation under different simulated DCPs by varying patient numbers, test frequencies, and test intervals. Older unvaccinated individuals had a longer viral shedding duration due to lower infection and cell death rates. Higher peak viral loads were found in older, symptomatic, and vaccinated individuals, with earlier peaks in younger vaccinated individuals. Symptom presence and vaccination resulted in a shorter time from infection to diagnosis. To accurately estimate viral dynamics, more frequent tests, longer test intervals, and larger patient samples are required. For 500 patients, a 21-day follow-up with measurements every 3 days and an 8-day follow-up with daily measurements was optimal for the Delta and Omicron variants, respectively. Patient characteristics significantly impacted viral dynamics. Our analytic approach and recommended DCPs can enhance preparedness and response to emerging pathogens beyond SARS-CoV-2., (© 2025 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

The Paneth cell, a secretory cell of the small intestine, expresses numerous host defense proteins, and is hypothesized to play an important role in host defense against infection. However, studying gene expression in this cell requires invasive procedures. To test the hypothesis that we could observe Paneth cell-specific gene regulation from exfoliated cells in infectious conditions, we obtained stool samples from patients with COVID-19 and uninfected controls. Total mRNA was isolated, and Paneth cell-specific and non-specific gene expression was quantified by RT-PCR. Results revealed a significant decrease in mRNA levels from Paneth cell-specific genes, including DEFA5, DEFA6, PLA2G2A, PRSS2 and ITLN2 in SARS-CoV-2 positive patients compared with controls. Other gut markers, not specific to Paneth cells were unchanged. To validate this experimentally, we infected mice with SARS-CoV-2 and collected fecal pellets over the course of 7 days. We observed a similar time-dependent reduction in Paneth cell-specific transcripts, which correlates with histological changes in the gut. This is the first demonstration of quantification of Paneth cell-specific transcripts without invasive sampling. It also shows the coordinate regulation of these genes as a response to infection with SARS-CoV-2, possibly through viral pathogenesis, to increase infectivity in the gut., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: In endemic COVID-19, immunocompromised children are vulnerable until vaccinated but the optimal primary vaccination regime and need for booster doses remains uncertain., Methods: We recruited 19 immunocompromised children (post-solid organ transplantation, have autoimmune disease or were on current or recent chemotherapy for acute lymphoblastic leukemia), and followed them from the start of primary vaccination with BNT162b2 mRNA SARS-CoV-2 until 1-year post-vaccination. We investigated the quality of vaccine immunogenicity, and longevity of hybrid immunity, in comparison to healthy children., Results: Immunocompromised children failed to produce T cell and memory B cell (MBC) responses reaching thresholds of protection after 2 doses; a third dose however improved both responses. Initially robust hybrid immunity demonstrated significantly more decline in T cell and MBC responses in immunocompromised compared to healthy children, to levels below the protective threshold by month 12., Discussion: Immunocompromised children may benefit from a 3-dose primary vaccination regime, with yearly or twice-yearly booster doses for sustained immunity., 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 © 2024 Zhong, Kottaiswamy, Ang, Li, Yap, Tay, Osman, Roslan, Tan, Yap, Ang, Chan Ng, Yap, Lu, Aw, Karthik, Quak, Quah, Tham, Shek and Ooi.)

Background: This study provides an update on the status of the COVID-19 pandemic in Canada, building upon our initial analysis conducted in 2020 by incorporating an additional 2 years of data., Objective: This study aims to (1) summarize the status of the pandemic in Canada when the World Health Organization (WHO) declared the end of the public health emergency for the COVID-19 pandemic on May 5, 2023; (2) use dynamic and genomic surveillance methods to describe the history of the pandemic in Canada and situate the window of the WHO declaration within the broader history; and (3) provide historical context for the course of the pandemic in Canada., Methods: This longitudinal study analyzed trends in traditional surveillance data and dynamic panel estimates for COVID-19 transmissions and deaths in Canada from June 2020 to May 2023. We also used sequenced SARS-CoV-2 variants from the Global Initiative on Sharing All Influenza Data (GISAID) to identify the appearance and duration of variants of concern. For these sequences, we used Nextclade nomenclature to collect clade designations and Pangolin nomenclature for lineage designations of SARS-CoV-2. We used 1-sided t tests of dynamic panel regression coefficients to measure the persistence of COVID-19 transmissions around the WHO declaration. Finally, we conducted a 1-sided t test for whether provincial and territorial weekly speed was greater than an outbreak threshold of 10. We ran the test iteratively with 6 months of data across the sample period., Results: Canada's speed remained below the outbreak threshold for 8 months by the time of the WHO declaration ending the COVID-19 emergency of international concern. Acceleration and jerk were also low and stable. While the 1-day persistence coefficient remained statistically significant and positive (1.074; P<.001), the 7-day coefficient was negative and small in magnitude (-0.080; P=.02). Furthermore, shift parameters for either of the 2 most recent weeks around May 5, 2023, were negligible (0.003 and 0.018, respectively, with P values of .75 and .31), meaning the clustering effect of new COVID-19 cases had remained stable in the 2 weeks around the WHO declaration. From December 2021 onward, Omicron was the predominant variant of concern in sequenced viral samples. The rolling 1-sided t test of speed equal to 10 became entirely insignificant from mid-October 2022 onward., Conclusions: While COVID-19 continues to circulate in Canada, the rate of transmission remained well below the threshold of an outbreak for 8 months ahead of the WHO declaration. Both standard and enhanced surveillance metrics confirm that the pandemic had largely ended in Canada by the time of the WHO declaration. These results can inform future public health interventions and strategies in Canada, as well as contribute to the global understanding of the trajectory of the COVID-19 pandemic., (©Scott A Wu, Alan G Soetikno, Egon A Ozer, Sarah B Welch, Yingxuan Liu, Robert J Havey, Robert L Murphy, Claudia Hawkins, Maryann Mason, Lori A Post, Chad J Achenbach, Alexander L Lundberg. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 05.12.2024.)

Patients with type 2 diabetes (T2D) are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that patients with T2D and coronavirus disease 2019 (COVID-19) infections, and influenza-infected T2D mice, exhibit defective T helper 1 (Th1) responses, which are an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4 + T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4 + T cells. These abnormalities promote lipid peroxidation (LPO), which drives carbonylation of signal transducer and activator of transcription 4 (STAT4), a crucial Th1-lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates Th1 defects in patients with T2D who have poor glycemic control and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Up to seven doses of coronavirus disease 2019 (COVID-19) mRNA vaccines (BNT162b2) were administered to Japanese healthcare workers, until February 2024. The monovalent Omicron XBB.1.5 vaccine (hereafter called XBB.1.5 vaccine) was used for dose 7., Objective: Although the XBB.1.5 vaccine has been reported to induce a robust increase in neutralizing antibodies against the currently circulating Omicron variant BA.2.86, little is known about its serological effects in Japan, where the BNT162b2 mRNA vaccine is the most frequently administered in the world., Study Design: Twenty-five recipients of the XBB.1.5 vaccine, categorized as seronegative (n = 18) or seropositive (n = 7) based on their recent history of COVID-19, were analyzed. Neutralizing antibody titers against Omicron subvariants, receptor binding domain (RBD) IgG levels, IgG subclass distribution, and T-cell responses were assessed., Results: We found a significant increase in neutralizing antibody titers against XBB.1.5 and BA.2.86 variants following XBB.1.5 vaccination, particularly in seropositive individuals. No significant change in total RBD IgG levels was observed, indicating efficient induction of antibodies targeting regions outside the RBD by XBB.1.5 vaccination. IgG subclass analysis demonstrated no significant subclass switching after vaccination. T-cell responses against the virus were comparable between seropositive and seronegative groups., Conclusions: The study suggests that XBB.1.5 vaccination enhances humoral immunity against Omicron variants without significant IgG subclass switching. However, some individuals with low pre-vaccination IgG titers did not exhibit increased antibody levels post-vaccination, raising concerns about potential immune tolerance., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Tuberculosis (TB) poses a significant risk to people with HIV (PWH), with heightened incidence and prevalence rates, especially in countries with a high TB burden. This study assesses the prevalence and incidence rates of TB among PWH during the COVID-19 pandemic, and on treatment outcomes in TB-HIV co-infections., Methods: A retrospective study was conducted at Suddhavej Hospital, Faculty of Medicine, Mahasarakham University, Maha Sarakham, Thailand, from January 2020 to September 2023, involving newly diagnosed adult PWH. Data were collected on TB prevalence and incidence rates, with TB cases categorized as definite or possible. The primary outcomes were TB prevalence and incidence rates per 100,000 person-years of follow-up., Results: Among 171 newly diagnosed PWH, the prevalence of TB was 5.85%, with an incidence rate of 4,568.71 per 100,000 person-years. All but one TB cases were diagnosed before antiretroviral therapy (ART) initiation. There was no incident TB during the follow-up period during ART. Nearly half of the TB cases required therapeutic trials without microbiological confirmation., Conclusions: The study revealed a high prevalence and incidence rate of TB among PWH during the COVID-19 pandemic, comparable to pre-pandemic rates in Thailand. The findings highlight the necessity of comprehensive TB screening prior to ART initiation and the cautious implementation of universal TB preventive therapy. The use of molecular diagnostics, in addition to symptom screening, can enhance TB diagnosis among PWH, though accessibility remains an issue in many regions.

SARS-CoV-2 has caused over 6.9 million deaths and continues to produce lasting health consequences. COVID-19 manifests broadly from no symptoms to death. In a retrospective cross-sectional study, we developed personalized risk assessment models that predict clinical outcomes for individuals with COVID-19 and inform targeted interventions. We sequenced viruses from SARS-CoV-2-positive nasopharyngeal swab samples between July 2020 and July 2022 from 4450 individuals in Missouri and retrieved associated disease courses, clinical history, and urban-rural classification. We integrated this data to develop machine learning-based predictive models to predict hospitalization, ICU admission, and long COVID.The mean age was 38.3 years (standard deviation = 21.4) with 55.2% ( N  = 2453) females and 44.8% ( N  = 1994) males (not reported, N  = 4). Our analyses revealed a comprehensive set of predictors for each outcome, encompassing human, environment, and virus genome-wide genetic markers. Immunosuppression, cardiovascular disease, older age, cardiac, gastrointestinal, and constitutional symptoms, rural residence, and specific amino acid substitutions were associated with hospitalization. ICU admission was associated with acute respiratory distress syndrome, ventilation, bacterial co-infection, rural residence, and non-wild type SARS-CoV-2 variants. Finally, long COVID was associated with hospital admission, ventilation, and female sex.Overall, we developed risk assessment models that offer the capability to identify patients with COVID-19 necessitating enhanced monitoring or early interventions. Of importance, we demonstrate the value of including key elements of virus, host, and environmental factors to predict patient outcomes, serving as a valuable platform in the field of personalized medicine with the potential for adaptation to other infectious diseases.

As COVID-19 has become endemic, SARS-CoV-2 variants are becoming increasingly diverse, underscoring the escalating importance of global genomic surveillance. This study analyzed 86,762 COVID-19 samples identified in the Republic of Korea from September 2022 to November 2023. The results revealed a consistent increase in the prevalence of the XBB variants following the dominance of BN.1, with various XBB sub-lineages co-circulating in the Republic of Korea. The overall nucleotide diversity (π) among the SARS-CoV-2 genomes was 0.00155. Evolutionary analysis revealed that the average time interval between the first detection and estimated date of the most recent common ancestor of Korean XBB sub-lineages was 47 d, suggesting that the novel variants were efficiently identified in the Korean surveillance system. The mutation rate was determined to be in the range of 5.6 × 10 -4 to 9.1 × 10 -4 substitutions/site/year. In conclusion, this study provides insights into the genetic diversity and evolutionary interpretation of the XBB sub-lineages during the XBB wave in the Republic of Korea, highlighting the importance of continued genomic surveillance for emerging variants., 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 the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: As the SARS-CoV-2 virus evolves more rapidly than vaccines are updated, T cell immunity potentially confers protection against disease progression and death from new variants. In this study, we aimed to assess whether the current boosting vaccination schemes offer sufficient T cell protection against new SARS-CoV-2 variants., Methods: A total of 292 adults who had received the second booster of either monovalent wild-type (WT) vaccines (inactivated virus or mRNA) (Cohort 1) or the second/third booster of bivalent WT/BA.4-5 mRNA vaccine (Cohort 2) were recruited in Hong Kong. All participants showed no serological evidence of recent infection of SARS-CoV-2. Blood samples of each participant were collected before and 1 month after receiving the booster. T cell and antibody responses were determined by flow cytometry and neutralization test, respectively., Results: Among all vaccination strategies, only the adults who had received the bivalent vaccine as the third booster dose significantly elicited T cell responses to the XBB variant. Either monovalent or bivalent mRNA but not inactivated virus vaccine as the second/third booster induced antibody against different XBB variants., Conclusion: Receiving bivalent mRNA vaccine as the third booster is preferable to induce both T cell and antibody responses against XBB., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cellular nanoparticles (CNPs), which refer to nanoparticles coated with natural cell membranes, are promising for neutralizing pathological agents. Here, we use CNPs as a medical countermeasure against the infection of SARS-CoV-2 variants in an animal model. CNPs comprise polymeric cores coated with the plasma membranes of human macrophages. The resulting nanoparticles (MΦ-NPs) act as host cell decoys to intercept SARS-CoV-2 and block its cellular entry, thus inhibiting subsequent viral infection. Our findings indicate that MΦ-NPs bind to the spike proteins of SARS-CoV-2 variants in a dose-dependent manner and inhibit the infectivity of live viruses. In hamsters infected with SARS-CoV-2 variants, MΦ-NPs significantly reduce the viral burden in the lungs, demonstrating their effectiveness in inhibiting viral infectivity in vivo . Furthermore, MΦ-NPs are primarily taken up by alveolar macrophages without inducing noticeable adverse effects. Given the crucial role of macrophages in viral infections, MΦ-NPs present a promising approach to combating emerging viral threats.

Elucidating the detailed features of emerging SARS-CoV-2 strains both in vitro and in vivo is indispensable for the development of effective vaccines or drugs against viral infection. We thoroughly characterized the virological and pathogenic features of eight different pandemic SARS-CoV-2 strains, from the WT strain to current circulating sublineage EG.5.1, both in vitro and in vivo. Besides detailed virological features observed in Vero E6 cells, the Omicron variants, from BA.1 to EG.5.1, exhibited enhanced infectious effects to upper respiratory tract in K18 human angiotensin-converting enzyme (ACE2) (K18 hACE2) transgenic mice. Both XBB.1.9.1 and EG.5.1 presented stronger tropism to brain, which could be the main reason for the increased lethal effects on mice. In addition, the pathogenesis comparisons among all these viruses in C57BL/6JGpt mice indicated that Omicron variant BA.1 and two new sublineages XBB.1.9.1 and EG.5.1 possessed dual tropisms to both human and mice, which were further confirmed by subsequent bioinformatic analyses and actual affinity comparison between viral RBDs and mouse or human receptor ACE2. Furthermore, the immunocompromised BKS-db mice were found to be more susceptible to Omicron strains compared to C57BL/6JGpt mice, which revealed that viral infectivity was determined by both its affinity to the host receptor and host immunocompetence. Thus, this study not only contributes to a systematic understanding of the pathogenic features of SARS-CoV-2 in mice, but also provides new insights to combat potential future surges of new SARS-CoV-2 variants., (© 2024 Wiley Periodicals LLC.)

The adenovirus detection rate is <10% throughout the year in South Korea; however, during the summer of 2023, it showed an unusual increase. We analyzed the adenovirus detection rate using data from the Korea Respiratory Integrated Surveillance System before and after coronavirus disease (COVID-19) collected from 2019 to week 36 of 2023. Before the COVID-19 outbreak in 2019, the mean detection rate was 8.2%, which decreased to 6.1% during the COVID-19 pandemic from 2020 to 2022. In 2023, the mean detection rate was 14.3% in week 36 and the highest in week 34, at 42.2%, and adenovirus was predominantly detected in the summer. The detection rate by age group showed substantially high activity among 0-12-yr-olds after the pandemic. This age group had a steady mean rate of 9.5% during the pandemic, without seasonality. In 2023, the detection rate surged in the 0-6-yr and 7-12-yr age groups, peaking at 61.6% and 57.1%, respectively. The dominant epidemic serotypes were HAdV-1 and HAdV-2 during and HAdV-3 after the pandemic. The multifaceted non-pharmaceutical interventions during the COVID-19 pandemic considerably impacted the prevalence of common respiratory viruses and complicated respiratory virus patterns after the pandemic. Constant surveillance is crucial for epidemic preparedness to monitor the possible surge of certain respiratory viruses.

Increasing evidence suggests bats are the ancestral hosts of the majority of coronaviruses. In general, coronaviruses primarily target the gastrointestinal system, while some strains, especially Betacoronaviruses with the most relevant representatives SARS-CoV, MERS-CoV, and SARS-CoV-2, also cause severe respiratory disease in humans and other mammals. We previously reported the susceptibility of Rousettus aegyptiacus (Egyptian fruit bats) to intranasal SARS-CoV-2 infection. Here, we compared their permissiveness to an oral infection versus respiratory challenge (intranasal or orotracheal) by assessing virus shedding, host immune responses, tissue-specific pathology, and physiological parameters. While respiratory challenge with a moderate infection dose of 1 × 10 4 TCID 50 caused a systemic infection with oral and nasal shedding of replication-competent virus, the oral challenge only induced nasal shedding of low levels of viral RNA. Even after a challenge with a higher infection dose of 1 × 10 6 TCID 50 , no replication-competent virus was detectable in any of the samples of the orally challenged bats. We postulate that SARS-CoV-2 is inactivated by HCl and digested by pepsin in the stomach of R. aegyptiacus , thereby decreasing the efficiency of an oral infection. Therefore, fecal shedding of RNA seems to depend on systemic dissemination upon respiratory infection. These findings may influence our general understanding of the pathophysiology of coronavirus infections in bats.

The SARS-CoV-2 pandemic has highlighted the challenges posed by the emergence and rapid global spread of previously unknown viruses. Early investigations on the pathogenesis of newly identified viruses are often hampered by a lack of appropriate sample material and conventional detection methods. In this study, viral replication within the lungs of SARS-CoV-2-infected Syrian golden hamsters was assessed by immunolabeling dsRNA intermediates with three different monoclonal antibodies in formalin-fixed, paraffin-embedded tissue samples. The presence of dsRNA was compared to viral antigen levels, viral titers, and genomic RNA replicates using three different variants of concern and an ancestral virus strain at a single time point and during the course of infection with an ancestral variant, and then validated using fluorescent 2-plex in situ hybridization. The results indicate that the detection of viral infection using anti-dsRNA antibodies is restricted to an early phase of infection with high viral replication activity. Additionally, the combined detection of dsRNA intermediates and viral antigens may help to bridge the interpretation gaps between viral antigen levels and viral titers at a single time point. Further testing in other viral infections or species is needed to assess the potential of dsRNA as an early marker for viral infections.

Background: This study updates the initial COVID-19 pandemic surveillance in sub-Saharan Africa (SSA) from 2020 by providing 2 additional years of data for the region., Objective: First, we aimed to measure whether there was an expansion or contraction in the pandemic in SSA when the World Health Organization (WHO) declared an end to the public health emergency for the COVID-19 pandemic on May 5, 2023. Second, we used dynamic and genomic surveillance methods to describe the history of the pandemic in the region and situate the window of the WHO declaration within the broader history. Third, we aimed to provide historical context for the course of the pandemic in SSA., Methods: In addition to updates of traditional surveillance data and dynamic panel estimates from the original study by Post et al (2021), this study used data on sequenced SARS-CoV-2 variants from the Global Initiative on Sharing All Influenza Data (GISAID) to identify the appearance and duration of variants of concern. We used Nextclade nomenclature to collect clade designations from sequences and used Pangolin nomenclature for lineage designations of SARS-CoV-2. Finally, we conducted a 1-sided t-test to assess whether regional weekly speed was greater than an outbreak threshold of 10. We ran the test iteratively with a rolling 6-month window of data across the sample period., Results: Speed for the region remained well below the outbreak threshold before and after the WHO declaration. Acceleration and jerk were also low and stable. The 7-day persistence coefficient remained somewhat large (1.11) and statistically significant. However, both shift parameters for the weeks around the WHO declaration were negative, meaning the clustering effect of new COVID-19 cases had become recently smaller. From November 2021 onward, Omicron was the predominant variant of concern in sequenced viral samples. The rolling t-test of speed equal to 10 was insignificant for the entire sample period., Conclusions: While COVID-19 continues to circulate in SSA, the region never reached outbreak status, and the weekly transmission rate remained below 1 case per 100,000 population for well over 1 year ahead of the WHO declaration. COVID-19 is endemic in the region and no longer reaches the threshold for its classification as a pandemic. Both standard and enhanced surveillance metrics confirm that the pandemic ended in SSA by the time the WHO made its declaration., (©Alexander L Lundberg, Alan G Soetikno, Scott A Wu, Egon A Ozer, Sarah B Welch, Maryann Mason, Robert L Murphy, Claudia Hawkins, Yingxuan Liu, Charles B Moss, Robert J Havey, Chad J Achenbach, Lori A Post. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 23.10.2024.)

Inflammasome is linked to many inflammatory diseases, including COVID-19 and autoimmune liver diseases. While severe COVID-19 was reported to exacerbate liver failure, we report a fatal acute-on-chronic liver failure (ACLF) in a stable primary biliary cholangitis-autoimmune hepatitis overlap syndrome patient triggered by a mild COVID-19 infection. Postmortem liver biopsy showed sparse SARS-CoV-2-infected macrophages with extensive ASC (apoptosis-associated speck-like protein containing a CARD) speck-positive hepatocytes, correlating with elevated circulating ASC specks and inflammatory cytokines, and depleted blood monocyte subsets, indicating widespread liver inflammasome activation. This first report of a fatal inflammatory cascade in an autoimmune liver disease triggered by a mild remote viral infection hopes to elucidate a less-described pathophysiology of ACLF that could prompt consideration of new diagnostic and therapeutic options.

Corticosteroids can reduce the mortality rate among patients with severe COVID-19 pneumonia. However, opportunistic infections such as Mycobacterium tuberculosis are of concern, especially among those on high doses of corticosteroids. It is unknown whether the risk of developing subsequent TB infection is high or not among COVID-19 patients on high doses of corticosteroids. Hence, this study was conducted to address this gap of knowledge. We conducted a retrospective, cross-sectional study at the King Chulalongkorn Memorial Hospital from October 12, 2022 to June 30, 2023. Two hundred forty-three participants with documented COVID-19 diagnosis on high dose corticosteroids were enrolled into the study. Baseline characteristics and risk factors of developing TB were collected. The prevalence of TB was significantly different among participants with chronic kidney disease (CKD) stages 2-4 and chronic lung diseases. The incidence of TB post 1-year diagnosis of COVID-19 was 4 out of 243 patients (1.6%) or 1,646 cases per 100,000 person-year. The mortality rate among subsequent TB group was significantly much higher than the non-TB group (50% vs 0.4%; p-value = 0.001). COVID-19 participants on high doses of corticosteroids also were co-infected with other infections such as bacteria (37.1%), fungi (5.3%), and Pneumocystis jirovecii (PJP) (1.2%). We found that the incidence of TB in participants with COVID-19 on high doses of corticosteroids was 11 times higher than the general population. Therefore, we recommend screening for latent TB among these patients to prevent/early diagnose TB disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Praphakornmano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The effect of the COVID-19 pandemic on healthcare systems emphasized the need for rapid and effective triage tools to identify patients at risk of severe or fatal infection. Measuring host response markers of inflammation and endothelial activation at clinical presentation may help to inform appropriate triage and care practices in patients with SARS-CoV-2 infection., Methods: We enrolled patients with COVID-19 across five GeoSentinel clinical sites (in Italy, Belgium, Canada, and the United States) from September 2020 to December 2021, and analyzed the association of plasma markers, including soluble urokinase-type plasminogen activator receptor (suPAR), soluble tumor necrosis factor receptor-1 (sTREM-1), interleukin-6 (IL-6), interleukin-8 (IL-8), complement component C5a (C5a), von Willebrand factor (VWF-a2), and interleukin-1 receptor antagonist (IL-1Ra), with 28-day (D28) mortality and 7-day (D7) severity (discharged, hospitalized on ward, or died/admitted to the ICU)., Results: Of 193 patients, 8.9% (16 of 180) died by D28. Higher concentrations of suPAR were associated with increased odds of mortality at D28 and severity at D7 in univariable and multivariable regression models. The biomarkers sTREM-1 and IL-1Ra showed bivariate associations with mortality at D28 and severity at D7. IL-6, VWF, C5a, and IL-8 were not as indicative of progression to severe disease or death. Conclusions : Our findings confirm previous studies' assertions that point-of-care tests for suPAR and sTREM-1 could facilitate the triage of patients with SARS-CoV-2 infection, which may help guide hospital resource allocation.

SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared with its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated the immune resistance of SARS-CoV-2 JN.1 but additional factors are speculated to contribute to its global dominance, which remain elusive until today. Here, we find that SARS-CoV-2 JN.1 has a higher infectivity than BA.2.86 in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, we demonstrate that the gained infectivity of SARS-CoV-2 JN.1 over BA.2.86 associates with increased entry efficiency conferred by L455S and better spike cleavage in hNECs. Structurally, S455 altered the mode of binding of JN.1 spike protein to ACE2 when compared to BA.2.86 spike at ACE2 H34 , and modified the internal structure of JN.1 spike protein by increasing the number of hydrogen bonds with neighboring residues. These findings indicate that a single mutation (L455S) enhances virus entry in hNECs and increases immune evasiveness, which contribute to the robust transmissibility of SARS-CoV-2 JN.1. We further evaluate the in vitro and in vivo virological characteristics between SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3, and identify key lineage-specific features of the two Omicron sublineages that contribute to our understanding on Omicron antigenicity, transmissibility, and pathogenicity., (© 2024. The Author(s).)

Golden Syrian hamsters (Mesocricetus auratus) are a well-established animal model for human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to their susceptibility to SARS-CoV-2 infection, robust virus replication and pathological manifestations similar to human COVID-19 pneumonia. To investigate the physiological changes upon infection in this animal model, we explored the alterations in daily energy expenditure (DEE), water turnover, body mass, body temperature, and locomotor activity in non-infected and SARS-CoV-2 infected Golden Syrian hamsters for four days post SARS-CoV-2. DEE was measured using the doubly labelled water method, which allows for the accurate estimation of carbon dioxide production and, consequently, energy expenditure in animals. Additionally, we investigated total water intake (TWI), which comprises drinking water, preformed water in food, and metabolic water. Using intraperitoneally implanted data loggers, we also monitored body core temperature and locomotor activity in some of the animals. Here we provide evidence for infected hamsters exhibiting significantly lower DEE and TWI compared to non-infected animals. We also observed an increase in body weight in the non-infected animals, while infected animals experienced weight loss. Further, infected animals showed a significantly decreased body temperature, indicating a generally lowered metabolic rate., (© 2024. The Author(s).)

Introduction: The frequent occurrence of mutations in the SARS-CoV-2 Spike (S) protein, with up to dozens of mutations, poses a severe threat to the current efficacy of authorized COVID-19 vaccines. Membrane (M) protein, which is the most abundant viral structural protein, exhibits a high level of amino acid sequence conservation. M protein ectodomain could be recognized by specific antibodies; however, the extent to which it is immunogenic and provides protection remains unclear., Methods: We designed and synthesized multiple peptides derived from coronavirus M protein ectodomains, and determined the secondary structure of specific peptides using circular dichroism (CD) spectroscopy. Enzyme-linked immunosorbent assay (ELISA) was utilized to detect IgG responses against the synthesized peptides in clinical samples. To evaluate the immunogenicity of peptide vaccines, BALB/c mice were intraperitoneally immunized with peptide-keyhole limpet hemocyanin (KLH) conjugates adjuvanted with incomplete Freund's adjuvant (IFA). The humoral and T-cell immune responses induced by peptide-KLH conjugates were assessed using ELISA and ELISpot assays, respectively. The efficacy of the S2M2-30-KLH vaccine against SARS-CoV-2 variants was evaluated in vivo using the K18-hACE2 transgenic mouse model. The inhibitory effect of mouse immune serum on SARS-CoV-2 virus replication in vitro was evaluated using microneutralization assays. The subcellular localization of the M protein was evaluated using an immunofluorescent staining method, and the Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) activity of the S2M2-30-specific monoclonal antibody (mAb) was measured using an ADCC reporter assay., Results: Seroconversion rates for ectodomain-specific IgG were observed to be high in both SARS-CoV-2 convalescent patients and individuals immunized with inactivated vaccines. To assess the protective efficacy of the M protein ectodomain-based vaccine, we initially identified a highly immunogenic peptide derived from this ectodomain, named S2M2-30. The mouse serum specific to S2M2-30 showed inhibitory effects on the replication of SARS-CoV-2 variants in vitro . Immunizations of K18-hACE2-transgenic mice with the S2M2-30-keyhole limpet hemocyanin (KLH) vaccine significantly reduced the lung viral load caused by B.1.1.7/Alpha (UK) infection. Further mechanism investigations reveal that serum neutralizing activity, specific T-cell response and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) correlate with the specific immuno-protection conferred by S2M2-30., Discussion: The findings of this study suggest that the antibody responses against M protein ectodomain in the population most likely exert a beneficial effect on preventing various SARS-CoV-2 infections., Competing Interests: Author LD was employed by company Beijing Weimiao Biotechnology Co. Ltd. Authors LD, YT, SY, YC, CL, Z-WY, YH, and DL are inventors of the patent application related to this study Patent applicant: Hunan University; Application No.: CN202210366334.5. The remaining 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 © 2024 Tang, Tang, Hu, Ye, Luo, Luo, Cao, Wang, Yue, Liu, Liu, Ge, Liu, Chen, Yuan and Deng.)

Competing Interests: Declaration of interests The authors declare no competing interests.

Objective: To investigate the effects of repeated vaccination with ancestral SARS-CoV-2 (Wuhan-hu-1)-based inactivated, recombinant protein subunit or vector-based vaccines on the neutralizing antibody response to Omicron subvariants., Methods: Individuals who received four-dose vaccinations with the Wuhan-hu-1 strain, individuals who were infected with the BA.5 variant alone without prior vaccination, and individuals who experienced a BA.5 breakthrough infection (BTI) following receiving 2-4 doses of the Wuhan-hu-1 vaccine were enrolled. Neutralizing antibodies against D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 were detected using a pseudovirus-based neutralization assay. Antigenic cartography was used to analyze cross-reactivity patterns among D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 and sera from individuals., Results: The highest neutralizing antibody titers against D614G were observed in individuals who only received four-dose vaccination and those who experienced BA.5 BTI, which was also significantly higher than the antibody titers against XBB.1.5, EG.5.1, and BA.2.86. In contrast, only BA.5 infection elicited comparable neutralizing antibody titers against the tested variants. While neutralizing antibody titers against D614G or BA.5 were similar across the cohorts, the neutralizing capacity of antibodies against XBB.1.5, EG.5.1, and BA.2.86 was significantly reduced. BA.5 BTI following heterologous booster induced significantly higher neutralizing antibody titers against the variants, particularly against XBB.1.5 and EG.5.1, than uninfected vaccinated individuals, only BA.5 infected individuals, or those with BA.5 BTI after primary vaccination., Conclusions: Our findings suggest that repeated vaccination with the Wuhan-hu-1 strain imprinted a neutralizing antibody response toward the Wuhan-hu-1 strain with limited effects on the antibody response to the Omicron subvariants., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The COVID-19 pandemic had a significant impact on the global influenza vaccination and the epidemics of seasonal influenza. To further explore the molecular epidemiology of influenza viruses and assess vaccine effectiveness, we collected influenza cases in Wuhan during the 2022-2023 influenza season. Among 1312 clinical samples, 312 samples tested positive for influenza viruses using reverse transcription polymerase chain reaction. These positive samples included 146A/H1N1 subtypes (46.8%), 164A/H3N2 subtypes (52.6%) and 2 influenza B virus types (0.6%). Based on the whole genome sequence information of hemagglutinin (HA) and neuraminidase (NA) from 27A/H1N1 influenza virus strains and 26A/H3N2 influenza virus strains obtained in this study, a phylogenetic analysis was conducted. The analysis revealed that all A/H1N1 strains belonged to the evolutionary branch 6B.1A.5a.2a, and they exhibited specific substitutions at positions K71Q, Q206E, E241A, and R276K. Similarly, all A/H3N2 strains were classified into the 3C.2a1b.2a.1a subclade and displayed amino acid substitutions at positions S172H, N175Y, I176T, K187N, and S214P. Notably, the A/H3N2 strains also acquired a new potential glycosylation site at position N174. Using an epitope model, the predicted vaccine effectiveness was assessed for the A/H1N1 and A/H3N2 strains. The predicted vaccine effectiveness against the Wuhan influenza epidemic strain was over 85% for the A/H1N1 vaccine strain. However, the effectiveness against the A/H3N2 vaccine strain was only 48.7%. To further verify the protection of influenza vaccine against circulating influenza viruses in the region, we conducted in vivo and in vitro animal studies. The results of in vitro neutralization experiment showed that rabbit serum antibodies inoculated with quadrivalent isolated influenza vaccine had neutralization ability against all 24 isolated influenza viruses. In vivo experiments showed that vaccinated mice had fewer lung lesions when infected with the influenza strain circulating in Wuhan, suggesting that vaccination can effectively reduce the occurrence of severe lung damage. These findings emphasize the importance of accurately predicting seasonal influenza strains for effective influenza prevention and control, especially during the co-circulation of SARS-CoV-2 and influenza viruses. This study provides valuable information on the seasonal influenza virus in Wuhan during the COVID-19 pandemic and serves as a basis for vaccine prediction and updates., (© 2024 Wiley Periodicals LLC.)

Objectives: We studied the immunogenicity after primary and booster vaccinations of the Abdala COVID-19 vaccine, a receptor-binding domain protein subunit vaccine, in Vietnamese people by determining the level of neutralization and cross-neutralization activities against the ancestral SARS-CoV-2 and its variants and SARS-CoV-1., Methods: We performed a prospective observational study, enrolling adults aged 19-59 years in Dong Thap province, southern Vietnam, and collected blood samples from baseline until 4 weeks after the booster dose. We measured anti-nucleocapsid, anti-spike, and neutralizing antibodies against SARS-CoV-2 and assessed the cross-neutralization against 14 SARS-CoV-2 variants and SARS-CoV-1. Complementary antibody data came from Vietnamese health care workers fully vaccinated with ChAdOx1-S., Results: After primary vaccination, anti-spike antibody and neutralizing antibodies were detectable in 98.4% and 87% of 251 study participants, respectively, with neutralizing antibody titers similar to that induced by ChAdOx1-S vaccine. Antibody responses after a homologous (Abdala COVID-19) or heterologous (messenger RNA BNT162b2) booster could neutralize 14 SARS-CoV-2 variants (including Omicron) and SARS-CoV-1., Conclusions: Abdala COVID-19 vaccine is immunogenic in Vietnamese people. Enhanced antibody response after a booster dose could cross-neutralize 14 SARS-CoV-2 variants and SARS-CoV-1. Our results have added to the growing body of knowledge about the contribution of protein subunit vaccine platforms to pandemic control., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Joint pain and osteoarthritis can occur as coronavirus disease 2019 (COVID-19) sequelae after infection. However, little is known about the damage to articular cartilage. Here we illustrate knee joint damage after wild-type, Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vivo. Rapid joint injury with cystic lesions at the osteochondral junction was observed in two patients with post-COVID osteoarthritis and recapitulated in a golden Syrian hamster model. SARS-CoV-2-activated endothelin-1 signalling increased vascular permeability and caused viral spike proteins leakage into the subchondral bone. Osteoclast activation, chondrocyte dropout and cyst formation were confirmed histologically. The US Food and Drug Administration-approved endothelin receptor antagonist, macitentan, mitigated cystic lesions and preserved chondrocyte number in the acute phase of viral infection in hamsters. Delayed macitentan treatment at post-acute infection phase alleviated chondrocyte senescence and restored subchondral bone loss. It is worth noting that it could also attenuate viral spike-induced joint pain. Our work suggests endothelin receptor blockade as a novel therapeutic strategy for post-COVID arthritis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Post-acute sequalae of COVID-19 defines a wide range of ongoing symptoms and conditions long after SARS-CoV-2 infection including respiratory diseases. The histopathological changes in the lung and underlying mechanism remain elusive., Methods: We investigated lung histopathological and transcriptional changes in SARS-CoV-2-infected male hamsters at 7, 14, 42, 84 and 120dpi, and compared with A (H1N1)pdm09 infection., Findings: We demonstrated viral residue, inflammatory and fibrotic changes in lung after SARS-CoV-2 but not H1N1 infection. The most prominent histopathological lesion was multifocal alveolar-bronchiolization observed in every SARS-CoV-2 infected hamster (31/31), from 42dpi to 120dpi. Proliferating (Ki67+) CK14+ basal cells accumulated in alveoli adjacent to bronchioles at 7dpi, where they proliferated and differentiated into SCGB1A+ club cell or Tubulin+ ciliated cells forming alveolar-bronchiolization foci. Molecularly, Notch pathway significantly upregulated with intensive Notch3 and Hes1 protein expression in alveolar-bronchiolization foci at 42 and 120dpi, suggesting Notch signaling involving the persistence of alveolar-bronchiolization. This is further demonstrated by spatial transcriptomic analysis. Intriguingly, significant upregulation of some cell-growth promoting pathways and genes such as Tubb4b, Stxbp4, Grb14 and Mlf1 were spatially overlapping with bronchiolization lesion., Interpretation: Incomplete resolution of SARS-CoV-2 infection in lung with viral residue, chronic inflammatory and fibrotic damage and alveolar-bronchiolization impaired respiratory function. Aberrant activation of CK14+ basal cells during tissue regeneration led to persistent alveolar-bronchiolization due to sustained Notch signaling. This study advances our understanding of respiratory PASC, sheds light on disease management and highlights the necessity for monitoring disease progression in people with respiratory PASC., Funding: Funding is listed in the Acknowledgements section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The spread of emerging SARS-CoV-2 immune escape sublineages, especially JN.1 and KP.2, has resulted in new waves of COVID-19 globally. The evolving memory B cell responses elicited by the parental Omicron variants to subvariants with substantial antigenic drift remain incompletely investigated., Methods: Using the single B cell antibody cloning technology, we isolated single memory B cells, delineated the B cell receptor repertoire and conducted the pseudovirus-based assay for recovered neutralizing antibodies (NAb) screening. We analyzed the cryo-EM structures of top broadly NAbs (bnAbs) and evaluated their in vivo efficacy (golden Syrian hamster model)., Findings: By investigating the evolution of human B cell immunity, we discovered a new panel of bnAbs arising from vaccinees after Omicron BA.2/BA.5 breakthrough infections. Two lead bnAbs neutralized major Omicron subvariants including JN.1 and KP.2 with IC 50 values less than 10 ng/mL, representing ultrapotent receptor binding domain (RBD)-specific class I bnAbs. They belonged to the IGHV3-53/3-66 clonotypes instead of evolving from the pre-existing vaccine-induced IGHV1-58/IGKV3-20 bnAb ZCB11. Despite sequence diversity, they targeted previously unrecognized, highly conserved conformational epitopes in the receptor binding motif (RBM) for ultrapotent ACE2 blockade. The lead bnAb ZCP3B4 not only protected the lungs of hamsters intranasally challenged with BA.5.2, BQ.1.1 and XBB.1.5 but also prevented their contact transmission., Interpretation: Our findings demonstrated that class I bnAbs have evolved an ultrapotent mode of action protecting against highly transmissible and broad Omicron escape variants, and their epitopes are potential targets for novel bnAbs and vaccine development., Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section., Competing Interests: Declaration of interests The other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Rationale: The epidemiology and clinical impact of COVID-19-associated candidemia (CAC) remained uncertain, leaving gaps in understanding its prevalence, risk factors and outcomes., Methods: A systematic review and meta-analysis were conducted by searching PubMed, Embase and Scopus for reports of CAC prevalence, risk factors and clinical outcomes up to June 18, 2024. The generalised linear mixed model was employed to determine the prevalence and 95% confidence intervals (CIs). The risk factors and clinical outcomes were compared between patients with and without CAC using the inverse variance method., Results: From 81 studies encompassing 29 countries and involving 351,268 patients, the global prevalence of CAC was 4.33% (95% Cl, 3.16%-5.90%) in intensive care unit (ICU) patients. In ICUs, the pooled prevalence of CAC in high-income countries was significantly higher than that of lower-middle-income countries (5.99% [95% Cl, 4.24%-8.40%] vs. 2.23% [95% Cl, 1.06%-4.61%], p = 0.02). Resistant Candida species, including C. auris, C. glabrata (Nakaseomyces glabratus) and C. krusei (Pichia kudriavzveii), constituted 2% of ICU cases. The mortality rate for CAC was 68.40% (95% Cl, 61.86%-74.28%) among ICU patients. Several risk factors were associated with CAC, including antibiotic use, central venous catheter placement, dialysis, mechanical ventilation, tocilizumab, extracorporeal membrane oxygenation and total parenteral nutrition. Notably, the pooled odds ratio of tocilizumab was 2.59 (95% CI, 1.44-4.65)., Conclusions: The prevalence of CAC is substantial in the ICU setting, particularly in high-income countries. Several risk factors associated with CAC were identified, including several that are modifiable, offering the opportunity to mitigate the risk of CAC., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Gold standard detection of SARS-CoV-2 by reverse transcription quantitative PCR (RT-qPCR) can achieve ultrasensitive viral detection down to a few RNA copies per sample. Yet, the lengthy detection and labor-intensive protocol limit its effectiveness in community screening. In view of this, a structural switching electrochemical aptamer-based biosensor (E-AB) targeting the SARS-CoV-2 nucleocapsid (N) protein was developed. Four N protein-targeting aptamers were characterized on an electrochemical cell configuration using square wave voltammetry (SWV). The sensor was investigated in an artificial saliva matrix optimizing the aptamer anchoring orientation, SWV interrogation frequency, and target incubation time. Rapid detection of the N protein was achieved within 5 min at a low nanomolar limit of detection (LOD) with high specificity. Specific N protein detection was also achieved in simulated positive saliva samples, demonstrating its feasibility for saliva-based rapid diagnosis. Further research will incorporate novel signal amplification strategies to improve sensitivity for early diagnosis.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant exhibits high transmissibility with a strong immune escape ability and causes frequent large-scale global infections by producing predominant subvariants. Here, using human upper/lower airway and intestinal cells, we examined the previously dominant BA.1-BA.5 and BA.2.75 subvariants, together with the recently emerged XBB/BQ lineages, in comparison to the former Delta variant. We observed a tendency for each virus to demonstrate higher growth capability than the previously dominant subvariants. Unlike human bronchial and intestinal cells, nasal epithelial cells accommodated the efficient entry of certain Omicron subvariants, similar to the Delta variant. In contrast to the Delta's reliance on cell-surface transmembrane protease serine 2, all tested Omicron variants depended on endosomal cathepsin L. Moreover, S1/S2 cleavage of early Omicron spikes was less efficient, whereas recent viruses exhibit improved cleavage efficacy. Our results show that the Omicron variant progressively adapts to human cells through continuous endosome-mediated host cell entry.IMPORTANCESARS-CoV-2, the causative agent of coronavirus disease 2019, has evolved into a number of variants/subvariants, which have generated multiple global waves of infection. In order to monitor/predict virological features of emerging variants and determine appropriate strategies for anti-viral development, understanding conserved or altered features of evolving SARS-CoV-2 is important. In this study, we addressed previously or recently predominant Omicron subvariants and demonstrated the gradual adaptation to human cells. The host cell entry route, which was altered from the former Delta variant, was conserved among all tested Omicron subvariants. Collectively, this study revealed both changing and maintained features of SARS-CoV-2 during the Omicron variant evolution., Competing Interests: The authors declare no conflict of interest.

Influenza and coronavirus disease 2019 (COVID-19) represent two respiratory diseases that have significantly impacted global health, resulting in substantial disease burden and mortality. An optimal solution would be a combined vaccine capable of addressing both diseases, thereby obviating the need for multiple vaccinations. Previously, we conceived a chimeric protein subunit vaccine targeting both influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), utilizing the receptor binding domain of spike protein (S-RBD) and the stalk region of hemagglutinin protein (HA-stalk) components. By integrating the S-RBD from the SARS-CoV-2 Delta variant with the headless hemagglutinin (HA) from H1N1 influenza virus, we constructed stable trimeric structures that remain accessible to neutralizing antibodies. This vaccine has demonstrated its potential by conferring protection against a spectrum of strains in mouse models. In this study, we designed an mRNA vaccine candidate encoding the chimeric antigen. The resultant humoral and cellular immune responses were meticulously evaluated in mouse models. Furthermore, the protective efficacy of the vaccine was rigorously examined through challenges with either homologous or heterologous influenza viruses or SARS-CoV-2 strains. Our findings reveal that the mRNA vaccine exhibited robust immunogenicity, engendering high and sustained levels of neutralizing antibodies accompanied by robust and persistent cellular immunity. Notably, this vaccine effectively afforded complete protection to mice against H1N1 or heterosubtypic H5N8 subtypes, as well as the SARS-CoV-2 Delta and Omicron BA.2 variants. Additionally, our mRNA vaccine design can be easily adapted from Delta RBD to Omicron RBD antigens, providing protection against emerging variants. The development of two-in-one vaccine targeting both influenza and COVID-19, incorporating the mRNA platform, may provide a versatile approach to combating future pandemics., Competing Interests: Y.L.L., T.H., Y.B., B.Z., H.S. and G.F.G. are listed in the patent as the inventors of the influenza-COVID-19 chimeric protective vaccine. All other authors declare no competing interests., (Copyright: © 2024 Hao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The inactivated COVID-19 vaccine has demonstrated high efficacy in the general population through extensive clinical and real-world studies. However, its effectiveness in immunocompromised individuals, particularly those living with HIV (PLWH), remains limited. In this study, 20 PLWH and 15 HIV-seronegative individuals were recruited to evaluate the immunogenicity of an inactivated COVID-19 vaccine in PLWH through a prospective cohort study. The median age of the 20 PLWH and 15 HIV-seronegative individuals was 42 years and 31 years, respectively. Of the PLWH, nine had been on ART for over five years. The median anti-SARS-CoV-2 S-RBD IgG antibody level on d 224 was higher than that on d 42 (8188.7 ng/mL vs. 3200.9 ng/mL, P < 0.05). Following COVID-19 infection, the antibody level increased to 29,872.5 ng/mL on d re+90 , 12.19 times higher than that on d 300 . Compared with HIV-seronegative individuals, the antibody level in PLWH was lower on d 210 (183.3 ng/mL vs. 509.3 ng/mL, P < 0.01), while there was no difference after d 224 . The symptoms of COVID-19 infection in PLWH were comparable to those in HIV-seronegative individuals. In this study, the inactivated COVID-19 vaccine demonstrated good immunogenicity in PLWH. The protective benefit of booster vaccinations for PLWH cannot be ignored. Implementing a booster vaccination policy for PLWH is an effective approach to providing better protection against the COVID-19 pandemic.

Objective: Obesity and type 2 diabetes (DM) are risk factors for severe coronavirus disease 2019 (COVID-19) outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with overweight/obesity (Ov/Ob, BMI ≥ 23 kg/m2) and DM in Bangladesh., Methods: In this cross-sectional study, SARS-CoV-2-specific antibody and T-cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020., Results: In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T-cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, Ov/Ob was associated with decreased neutralizing antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8 + T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T-cell responses after adjustment for obesity and other confounders., Conclusion: Ov/Ob is associated with lower neutralizing antibody levels and higher T-cell responses to SARS-CoV-2 post-COVID-19 recovery, while antibody or T-cell responses remain unaltered in DM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

The evidence shows that COVID-19 vaccines can reduce the risks of poor pregnancy outcomes. Yet, reluctance to vaccinate remains high in pregnant populations. In this paper, we take a precision health and patient-centered approach to vaccine hesitancy. We adopted the society-to-cells vaccine hesitancy framework to identify society, community, family, individual, and physiologic factors contributing to COVID-19 vaccine hesitancy in pregnancy. Nurses are particularly well-suited to impact the factors associated with vaccine hesitancy. Because of their proximity to the patient, nurses are positioned to provide individualized, timely health information, and clinical guidelines to assist patients with decision-making related to vaccinations. Recommendations are provided to bolster nurses' engagement in precision health and patient-centered models of care to mitigate COVID-19 vaccine hesitancy in pregnancy., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The rapid expansion of the biomedical literature challenges traditional review methods, especially during outbreaks of emerging infectious diseases when quick action is critical. Our study aims to explore the potential of ChatGPT to automate the biomedical literature review for rapid drug discovery., Materials and Methods: We introduce a novel automated pipeline helping to identify drugs for a given virus in response to a potential future global health threat. Our approach can be used to select PubMed articles identifying a drug target for the given virus. We tested our approach on two known pathogens: SARS-CoV-2, where the literature is vast, and Nipah, where the literature is sparse. Specifically, a panel of three experts reviewed a set of PubMed articles and labeled them as either describing a drug target for the given virus or not. The same task was given to the automated pipeline and its performance was based on whether it labeled the articles similarly to the human experts. We applied a number of prompt engineering techniques to improve the performance of ChatGPT., Results: Our best configuration used GPT-4 by OpenAI and achieved an out-of-sample validation performance with accuracy/F1-score/sensitivity/specificity of 92.87%/88.43%/83.38%/97.82% for SARS-CoV-2 and 87.40%/73.90%/74.72%/91.36% for Nipah., Conclusion: These results highlight the utility of ChatGPT in drug discovery and development and reveal their potential to enable rapid drug target identification during a pandemic-level health emergency., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Understanding how SARS-CoV-2 breakthrough infections impacts the breadth of immune responses against existing and pre-emergent SARS-CoV-2 strains is needed to develop an evidence-based long-term immunisation strategy., Methods: We performed a randomised, controlled trial to assess the immunogenicity of homologous (BNT162b2) versus heterologous (mRNA-1273) booster vaccination in 100 BNT162b2-vaccinated infection-naïve individuals enrolled from October 2021. Post hoc analysis was performed to assess the impact of SARS-CoV-2 infection on humoral and cellular immune responses against wild-type SARS-CoV-2 and/or Omicron subvariants., Findings: 93 participants completed the study at day 360. 71% (66/93) of participants reported first SARS-CoV-2 Omicron infection by the end of the study with similar proportions of infections between homologous and heterologous booster groups (72.3% [34/47] vs 69.6% [32/46]; p = 0.82). Mean wildtype SARS-CoV-2 anti-S-RBD antibody level was significantly higher in heterologous booster group compared with homologous group at day 180 (14,588 IU/mL; 95% CI, 10,186-20,893 vs 7447 IU/mL; 4646-11,912; p = 0.025). Participants who experienced breakthrough infections during the Omicron BA.1/2 wave had significantly higher anti-S-RBD antibody levels against wildtype SARS-CoV-2 and antibody neutralisation against BA.1 and pre-emergent BA.5 compared with infection-naïve participants. Regardless of hybrid immunity status, wildtype SARS-CoV-2 anti-S-RBD antibody level declined significantly after six months post-booster or post-SARS-CoV-2 infection., Interpretation: Booster vaccination with mRNA-1273 was associated with significantly higher antibody levels compared with BNT162b2. Antibody responses are narrower and decline faster among uninfected, vaccinated individuals. Boosters may be more effective if administered shortly before infection outbreaks and at least six months after last infection or booster., Funding: Singapore NMRC, USFDA, MRC., Competing Interests: Declaration of interests Young reports personal fees from Astra-Zeneca, Gilead, Moderna, Pfizer and Sanofi outside the submitted work. Chia and Wang disclose that a patent (Patent No.: US 11,054,429 B1) was issued for the surrogate virus neutralisation test platform (cPass kit) used in this study, and declare royalty payment from GenScript for inventing the technology. All other authors no potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To develop an Artificial Intelligence (AI)-based anomaly detection model as a complement of an "astute physician" in detecting novel disease cases in a hospital and preventing emerging outbreaks., Methods: Data included hospitalized patients (n = 120,714) at a safety-net hospital in Massachusetts. A novel Generative Pre-trained Transformer (GPT)-based clinical anomaly detection system was designed and further trained using Empirical Risk Minimization (ERM), which can model a hospitalized patient's Electronic Health Records (EHR) and detect atypical patients. Methods and performance metrics, similar to the ones behind the recent Large Language Models (LLMs), were leveraged to capture the dynamic evolution of the patient's clinical variables and compute an Out-Of-Distribution (OOD) anomaly score., Results: In a completely unsupervised setting, hospitalizations for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection could have been predicted by our GPT model at the beginning of the COVID-19 pandemic, with an Area Under the Receiver Operating Characteristic Curve (AUC) of 92.2 %, using 31 extracted clinical variables and a 3-day detection window. Our GPT achieves individual patient-level anomaly detection and mortality prediction AUC of 78.3 % and 94.7 %, outperforming traditional linear models by 6.6 % and 9 %, respectively. Different types of clinical trajectories of a SARS-CoV-2 infection are captured by our model to make interpretable detections, while a trend of over-pessimistic outcome prediction yields a more effective detection pathway. Furthermore, our comprehensive GPT model can potentially assist clinicians with forecasting patient clinical variables and developing personalized treatment plans., Conclusion: This study demonstrates that an emerging outbreak can be accurately detected within a hospital, by using a GPT to model patient EHR time sequences and labeling them as anomalous when actual outcomes are not supported by the model. Such a GPT is also a comprehensive model with the functionality of generating future patient clinical variables, which can potentially assist clinicians in developing personalized treatment plans., 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 the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)