Potent and broadly neutralizing antibodies against sarbecoviruses induced by sequential COVID-19 vaccination (preprint)

The current SARS-CoV-2 variants strikingly evade all authorized monoclonal antibodies and threaten the efficacy of serum-neutralizing activity elicited by vaccination or prior infection, urging the need to develop antivirals against SARS-CoV-2 and related sarbecoviruses. Here, we identified both potent and broadly neutralizing antibodies from a five-dose vaccinated donor who exhibited cross-reactive serum neutralizing activity against diverse coronaviruses. Through single B cell sorting and sequencing followed by a tailor-made computational pipeline, we successfully selected 86 antibodies with potential cross-neutralizing ability from 684 antibody sequences. Among them, one potently neutralized all SARS-CoV-2 variants that arose prior to Omicron BA.5, and the other three could broadly neutralize all current SARS-CoV-2 variants of concern, SARS-CoV and their related sarbecoviruses (Pangolin-GD, RaTG13, WIV-1, and SHC014). Cryo-EM analysis demonstrates that these antibodies have diverse neutralization mechanisms, such as disassembling spike trimers, or binding to RBM or SD1 to affect ACE2 binding. In addition, prophylactic administration of these antibodies significantly protects nasal turbinate and lung infections against BA.1, XBB.1 and SARS-CoV viral challenge in golden Syrian hamsters, respectively. This study reveals the potential utility of computational process to assist screening cross-reactive antibodies, as well as the potency of vaccine-induced broadly neutralizing antibodies against current SARS-CoV-2 variants and related sarbecoviruses, offering promising avenues for the development of broad therapeutic antibody drugs.

Streamlining Social Media Information Retrieval for COVID-19 Research with Deep Learning (preprint)

Objective: Social media-based public health research is crucial for epidemic surveillance, but most studies identify relevant corpora with keyword-matching. This study develops a system to streamline the process of curating colloquial medical dictionaries. We demonstrate the pipeline by curating a UMLS-colloquial symptom dictionary from COVID-19-related tweets as proof of concept. Methods: COVID-19-related tweets from February 1, 2020, to April 30, 2022 were used. The pipeline includes three modules: a named entity recognition module to detect symptoms in tweets; an entity normalization module to aggregate detected entities; and a mapping module that iteratively maps entities to Unified Medical Language System concepts. A random 500 entity sample were drawn from the final dictionary for accuracy validation. Additionally, we conducted a symptom frequency distribution analysis to compare our dictionary to a pre-defined lexicon from previous research. Results: We identified 498,480 unique symptom entity expressions from the tweets. Pre-processing reduces the number to 18,226. The final dictionary contains 38,175 unique expressions of symptoms that can be mapped to 966 UMLS concepts (accuracy = 95%). Symptom distribution analysis found that our dictionary detects more symptoms and is effective at identifying psychiatric disorders like anxiety and depression, often missed by pre-defined lexicons. Conclusions: This study advances public health research by implementing a novel, systematic pipeline for curating symptom lexicons from social media data. The final lexicon's high accuracy, validated by medical professionals, underscores the potential of this methodology to reliably interpret and categorize vast amounts of unstructured social media data into actionable medical insights across diverse linguistic and regional landscapes.

Neutralization of SARS-CoV-2 BQ.1.1 and XBB.1.5 by Breakthrough Infection Sera from Previous and Current Waves in China (preprint)

SARS-CoV-2 is continuing to evolve and diversify, with an array of various Omicron sub-lineages, including BA.5, BA.2.75, BN.1, BF.7, BQ.1, BQ.1.1, XBB and XBB.1.5, now circulating globally at recent time. In this study, we evaluated the neutralization sensitivity of a comprehensive panel of Omicron subvariants to sera from different clinical cohorts, including individuals who received homologous or heterologous booster vaccinations, vaccinated people who had Delta or BA.2 breakthrough infection in previous waves, and patients who had BA.5 or BF.7 breakthrough infection in the current wave in China. All the Omicron subvariants exhibited substantial neutralization evasion, with BQ.1, BQ.1.1, XBB.1, and XBB.1.5 being the strongest escaped subvariants. Sera from Omicron breakthrough infection, especially the recent BA.5 or BF.7 breakthrough infection, exhibited higher neutralizing activity against all Omicron sub-lineages, indicating the chance of BA.5 and BF.7 being entirely replaced by BQ or XBB subvariants in China in a short-term might be low. We also demonstrated that the BQ and XBB subvariants were the most resistant viruses to monoclonal antibodies. Continuing to monitor the immune escape of SARS-CoV-2 emerging variants and developing novel broad-spectrum vaccines and antibodies are still crucial.

Trend and co-occurrence network study of symptoms through social media: an example of COVID-19 (preprint)

ImportanceCOVID-19 is a multi-organ disease with broad-spectrum manifestations. Clinical data-driven research can be difficult because many patients do not receive prompt diagnoses, treatment, and follow-up studies. Social medias accessibility, promptness, and rich information provide an opportunity for large-scale and long-term analyses, enabling a comprehensive symptom investigation to complement clinical studies. ObjectivePresent an efficient workflow to identify and study the characteristics and co-occurrences of COVID-19 symptoms using social media. Design, Setting, and ParticipantsThis retrospective cohort study analyzed 471,553,966 COVID-19-related tweets from February 1, 2020, to April 30, 2022. A comprehensive lexicon of symptoms was used to filter tweets through rule-based methods. 948,478 tweets with self-reported symptoms from 689,551 Twitter users were identified for analysis. Main Outcomes and MeasuresThe overall trends of COVID-19 symptoms reported on Twitter were analyzed (separately by the Delta strain and the Omicron strain) using weekly new numbers, overall frequency, and temporal distribution of reported symptoms. A co-occurrence network was developed to investigate relationships between symptoms and affected organ systems. ResultsThe weekly quantity of self-reported symptoms has a high consistency (0.8528, P<0.0001) and one-week leading trend (0. 8802, P<0.0001) with new infections in four countries. We grouped 201 common symptoms (mentioned [≥] 10 times) into 10 affected systems. The frequency of symptoms showed dynamic changes as the pandemic progressed, from typical respiratory symptoms in the early stage to more musculoskeletal and nervous symptoms at later stages. When comparing symptoms reported during the Delta strain versus the Omicron variant, significant changes were observed, with dropped odd ratios of coma (95%CI 0.55-0.49, P<0.01) and anosmia (95%CI, 0.6-0.56), and more pain in the throat (95%CI, 1.86-1.96) and concentration problems (95%CI, 1.58-1.70). The co-occurrence network characterizes relationships among symptoms and affected systems, both intra-systemic, such as cough and sneezing (respiratory), and inter-systemic, such as alopecia (integumentary) and impotence (reproductive). Conclusions and RelevanceWe found dynamic COVID-19 symptom evolution through self-reporting on social media and identified 201 symptoms from 10 affected systems. This demonstrates that social medias prevalence trends and co-occurrence networks can efficiently identify and study public health problems, such as common symptoms during pandemics. Key pointsO_ST_ABSQuestionsC_ST_ABSWhat are the epidemic characteristics and relationships of COVID-19 symptoms that have been extensively reported on social media? FindingsThis retrospective cohort study of 948,478 related tweets (February 2020 to April 2022) from 689,551 users identified 201 self-reported COVID-19 symptoms from 10 affected systems, mitigating the potential missing information in hospital-based epidemiologic studies due to many patients not being timely diagnosed and treated. Coma, anosmia, taste sense altered, and dyspnea were less common in participants infected during Omicron prevalence than in Delta. Symptoms that affect the same system have high co-occurrence. Frequent co-occurrences occurred between symptoms and systems corresponding to specific disease progressions, such as palpitations and dyspnea, alopecia and impotence. MeaningTrend and network analysis in social media can mine dynamic epidemic characteristics and relationships between symptoms in emergent pandemics.

Neutralization of Omicron BA.4/BA.5 and BA.2.75 by Booster Vaccination or BA.2 Breakthrough Infection Sera (preprint)

Many new Omicron sub-lineages have been reported to evade neutralizing antibody response, including BA.2, BA.2.12.1, BA.4 and BA.5. Most recently, another emerging sub-lineage BA.2.75 has been reported in multiple countries. In this study, we constructed a comprehensive panel of pseudoviruses (PsVs), including wild-type, Delta, BA.1, BA.1.1, BA.2, BA.3, BA.2.3.1, BA.2.10.1, BA.2.12.1, BA.2.13, BA.2.75 and BA.4/BA.5, with accumulate coverage reached 91% according to the proportion of sequences deposited in GISAID database since Jan 1st, 2022. We collected serum samples from healthy adults at day14 post homologous booster with BBIBP-CorV, or heterologous booster with ZF2001, primed with two doses of BBIBP-CorV, or from convalescents immunized with three-dose inactivated vaccines prior to infection with Omicron BA.2, and tested their neutralization activity on this panel of PsVs. Our results demonstrated that all Omicron sub-lineages showed substantial evasion of neutralizing antibodies induced by vaccination and infection, although BA.2.75 accumulated the largest number of mutations in its spike, BA.4 and BA.5 showed the strongest serum escape. However, BA.2 breakthrough infection could remarkably elevated neutralization titers against all different variants, especially titers against BA.2 and its derivative sub-lineages.

Antibody Resistance of SARS-CoV-2 Omicron BA.1, BA.1.1, BA.2 and BA.3 Sub-lineages (preprint)

The SARS-CoV-2 Omicron variant has been partitioned into four sub-lineages designated BA.1, BA.1.1, BA.2 and BA.3, with BA.2 becoming dominant worldwide recently by outcompeting BA.1 and BA.1.1. We and others have reported the striking antibody evasion of BA.1 and BA.2, but side-by-side comparison of susceptibility of all the major Omicron sub-lineages to vaccine-elicited or monoclonal antibody (mAb)-mediated neutralization are urgently needed. Using VSV-based pseudovirus, we found that sera from individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV) showed very weak to no neutralization activity, while a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) markedly improved the neutralization titers against all Omicron variants. The comparison between sub-lineages indicated that BA.1.1, BA.2 and BA.3 had comparable or even greater antibody resistance than BA.1. We further evaluated the neutralization profile of a panel of 20 mAbs, including 10 already authorized or approved, against these Omicron sub-lineages as well as viruses with different Omicron spike single or combined mutations. Most mAbs lost their neutralizing activity completely or substantially, while some demonstrated distinct neutralization patterns among Omicron sub-lineages, reflecting their antigenic difference. Taken together, our results suggest all four Omicron sub-lineages threaten the efficacies of current vaccines and antibody therapeutics, highlighting the importance of vaccine boosters to combat the emerging SARS-CoV-2 variants.

Tracking the impact of COVID-19 and lockdown policy on public mental health using social media (preprint)

The COVID-19 pandemic and its corresponding preventive and control measures have increased the mental burden on the public. Social media serve as important platforms to timely track public mental status. In this study, we conducted social-media-based analyses on temporal, geographical and occupational distributions of public mental health status during the pandemic, and how the public reacted to the lock-down policy from the perspective of mental health. We extracted 2,973,319 mental health-related tweets of 1,778,140 users from February 1, 2020 to September 30, 2021. We found that, compared to the general public, healthcare workers had higher concerns on three types of mental health problems (depression, insomnia, addiction) (P<0.001) and focused more on clinical topics while the public worried more about daily life issues. The lockdown policy in New York was correlated with a proportional decrease of mental health-related tweets, while Florida had an opposite correlation (both P<0.05). Our findings indicated that the mental burden brought by the pandemic varied across occupations and locations and changed over time.

Homologous or Heterologous Booster of Inactivated Vaccine Reduces SARS-CoV-2 Omicron Variant Escape from Neutralizing Antibodies (preprint)

The massive and rapid transmission of SARS-CoV-2 has led to the emergence of several viral variants of concern (VOCs), with the most recent one, B.1.1.529 (Omicron), which accumulated a large number of spike mutations, raising the specter that this newly identified variant may escape from the currently available vaccines and therapeutic antibodies. Using VSV-based pseudovirus, we found that Omicron variant is markedly resistant to neutralization of sera form convalescents or individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV). However, a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) significantly increased neutralization titers to both WT and Omicron variant. Moreover, at day 14 post the third dose, neutralizing antibody titer reduction for Omicron was less than that for convalescents or individuals who had only two doses of the vaccine, indicating that a homologous or heterologous booster can reduce the Omicron escape from neutralizing. In addition, we tested a panel of 17 SARS-CoV-2 monoclonal antibodies (mAbs). Omicron resists 7 of 8 authorized/approved mAbs, as well as most of the other mAbs targeting distinct epitopes on RBD and NTD. Taken together, our results suggest the urgency to push forward the booster vaccination to combat the emerging SARS-CoV-2 variants.

Inhibitor screening of Spike variants reveals the heterogeneity of neutralizing antibodies to COVID-19 infection and vaccination (preprint)

Mutations of the coronavirus responsible for coronavirus disease 2019 (COVID-19) could impede drug development and reduce the efficacy of COVID-19 vaccines. Here, we developed a multiplexed Spike-ACE2 Inhibitor Screening (mSAIS) assay that can measure the neutralizing effect of antibodies across numerous variants of the coronavirus's Spike (S) protein simultaneously. By screening purified antibodies and serum from convalescent COVID-19 patients and vaccinees against 72 S variants with the mSAIS assay, we identified new S mutations that are sensitive and resistant to neutralization. Serum from both infected and vaccinated groups with a high titer of neutralizing antibodies (NAbs) displayed a broader capacity to neutralize S variants than serum with low titer NAbs. These data were validated using serum from a large vaccinated cohort (n=104) with a tiled S peptide microarray. In addition, similar results were obtained using a SARS-CoV-2 pseudovirus neutralization assay specific for wild-type S and four prevalent S variants (D614G, B.1.1.7, B.1.351, P.1), thus demonstrating that high antibody diversity is associated with high NAb titers. Our results demonstrate the utility of the mSAIS platform in screening NAbs. Moreover, we show that heterogeneous antibody populations provide a more protective effect against S variants, which may help direct COVID-19 vaccine and drug development.

A survey on the COVID-19-related prevention behaviors and psychological status among Macao residents

Objectives: To explore the Macao residents' perceived risk of being infected by Coronavirus Disease 2019 (COVID-19), their preventing behaviors, and their psychological health status during the epidemic. Method: An online survey was conducted with 3,236 Macao residents from February 6 to 14, 2020. Results: The respondents were worried about being infected but had confidence in the outbreak control in Macao. Most of them were aware of the importance in taking prevention measures and actively followed the prevention guide suggested by the government. Such psychological symptoms as "sad" and "anxious" were relatively common among the respondents, but few of them felt "helpless". Those respondents who were more worried about the risk of being infected than others were more likely to have the prevention behaviors. Meanwhile, the more worried they were, the more likely they were to show psychological symptoms. Those who had "irrational panic-buying" behaviors were most likely to have psychological symptoms. Conclusion: Macao residents' psychological symptoms are associated with their prevention behaviors. Excessive worry and irrational behaviors affect residents' psychological health and their daily life. The worrying residents need to relax and adjust properly to maintain physical and psychological health.

Eleven Routine Clinical Features Predict COVID-19 Severity (preprint)

Severity prediction of COVID-19 remains one of the major clinical challenges for the ongoing pandemic. Here, we have recruited a 144 COVID-19 patient cohort consisting of training, validation, and internal test sets, longitudinally recorded 124 routine clinical and laboratory parameters, and built a machine learning model to predict the disease progression based on measurements from the first 12 days since the disease onset when no patient became severe. A panel of 11 routine clinical factors, including oxygenation index, basophil counts, aspartate aminotransferase, gender, magnesium, gamma glutamyl transpeptidase, platelet counts, activated partial thromboplastin time, oxygen saturation, body temperature and days after symptom onset, constructed a classifier for COVID-19 severity prediction, achieving accuracy of over 94%. Validation of the model in an independent cohort containing 25 patients achieved accuracy of 80%. The overall sensitivity, specificity, PPV and NPV were 0.70, 0.99, 0.93 and 0.93, respectively. Our model captured predictive dynamics of LDH and CK while their levels were in the normal range. This study presents a practical model for timely severity prediction and surveillance for COVID-19, which is freely available at webserver https://guomics.shinyapps.io/covidAI/.

Afebrile patients with severe acute respiratory syndrome coronavirus 2 infection have a longer viral positivity duration: a retrospective analysis of 143 patients (preprint)

Background A pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is on-going. Clinical characters of afebrile cases infected with SARS-CoV-2 remain poorly understood and informations are limited on the duration of SARS-CoV-2 viral positivity.Methods We performed a single-center retrospective study of 143 patients with SARS-CoV-2 infection in Beijing Ditan Hospital, Capital Medical University from January 26 to April 15, 2020. Differences were compared among patients with/without fever. Risk factors for the duration of SARS-CoV-2 viral positivity were evaluated.Results A total of 143 patients with positive SARS-CoV-2 test were enrolled, including 38 afebrile patients and 105 febrile patients. On admission, a total of 40 (28%) patients had leukopenia, 44 (30.8%) had lymphopenia and 8 (5.6%) had thrombocytopenia. 78 patients (54.5%) had decreased T lymphocytes and 105 patients (73.4%) had decreased CD4+T lymphocytes. Compared with febrile cases, afebrile patients had a significantly higher white blood cell count (P = 0.02), total lymphocytes (P < 0.01), platelet count (P < 0.01), T lymphocytes (P < 0.01) and CD8+ T lymphocytes (P = 0.02). The median SARS-CoV-2 viral positivity duration of these 143 patients was 14 days (IQR, 10-30 days) and for febrile and afebrile group were 13 days (IQR, 10-29 days) and 20 days (IQR, 11-31 days) respectively. Multivariate Cox regression results showed that the fever [hazard ratio (HR) = 0.49, P < 0.01]and higher count of platelet (HR = 5.47, P = 0.02) were the predominant risk factor for the SARS-CoV-2 viral positivity duration.Conclusion The SARS-CoV-2 virial positivity duration of the afebrile group was significantly longer than that in the febrile group. Fever and a higher count of platelet were the independent protective factors for a shorter SARS-CoV-2 RNA positivity duration.

Early antiviral therapy of abidor combined with lopinavir/ritonavir and re-combinant interferonα-2b in patients with novel coronavirus pneumonia in Zhejiang: A multicenter and prospective study / 中华临床感染病杂志

Objective@#Comparing the benefit of Abidor, lopinavir/ritonavir and recombinant interferon α-2b triple combination antiviral therapy and lopinavir/ritonavir and interferon dual combination antiviral therapy to hospitalized novel coronavirus pneumonia 2019 in Zhejiang province.@*Methods@#A multi-center prospective study was carried out to compare the effect of triple combination antiviral therapy with dual combination antiviral therapy in 15 medical institutions of Zhejiang Province. All patients were treated with recombinant interferon α-2b (5 million U, 2 times/d) aerosol inhalation. 196 patients were treated with abidol (200 mg, 3 times/d) + lopinavir / ritonavir (2 tablets, 1 time/12 h) as the triple combination antiviral treatment group. 41 patients were treated with lopinavir / ritonavir (2 tablets, 1 time/12 h) as the dual combination antiviral treatment group. The patients who received triple combination antiviral therapy were divided into three groups: within 48 hours, 3-5 days and > 5 days after the symptom onset. To explore the therapeutic effects of triple combination antiviral drugs and dual combination antiviral drugs, as well as triple combination antiviral drugs with different antiviral initiate time. SPSS17.0 software was used to analyze the data.@*Results@#The time of virus nucleic acid turning negative was (12.2 ± 4.7) days in the triple combination antiviral drug group, which was shorter than that in the dual combination antiviral drug group [(15.0 ± 5.0) days] (t = 6.159, P < 0.01 ). The length of hospital stay [12 (9, 17) d] in the triple combination antiviral drug group was also shorter than that in the dual combination antiviral drug group [15 (10, 18) d] (H = 2.073, P < 0.05). Comparing the antiviral treatment which was started within 48 hours, 3-5 days and > 5 days after the symptom onset of triple combination antiviral drug group, the time from the symptom onset to the negative of viral shedding was 13 (10,16.8), 17 (13,22) and 21 (18-24) days respectively (Z = 32.983, P < 0.01), and the time from antiviral therapy to the negative of viral shedding was (11.8±3.9) , (13.5±5.1) and (11.2±4.3) d. The differences among the three groups were statistically significant (Z=32.983 and 6.722, P<0.01 or<0.05).@*Conclusions@#The triple combination antiviral therapy of Abidor, Lopinavir/Litonavir and recombinant interferon α-2b showed shorter viral shedding time and hospitalization time compared with the dual combination antiviral therapy. The earlier the time to initiate triple antiviral treatment, the shorter the time of virus shedding.

Pattern of liver injury in adult patients with COVID-19: a retrospective analysis of 105 patients (preprint)

【Background】Recent studies reported that patients with coronavirus disease-2019 (COVID-19) might have liver injury. However, few data on the combined analysis and change patterns of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) have been shown.【Methods】 This is a single-center retrospective study. A total of 105 adult patients hospitalized for confirmed COVID-19 in Beijing Ditan Hospital between January 12, and March 17, 2020 were included, and divided into mild and severe groups. We compared liver functional test results between the two groups. Category of ALT change during the disease course was also examined.【Results】 56.2% of the patients had unnormal ALT, AST, or total TBil throughout the course of the disease, but in 91.4% cases the level of ALT, AST or TBil ≤ 3 fold of the upper normal range. The overall distribution of ALT, AST, and TBil were all significantly difference between mild and severe group (p<0.05).The percentage of the patients with both elevated ALT and AST was 12.7% in mild cases vs. 46.2% in severe cases (p = 0.001). 34.6% severe group patients started to have abnormal ALT after admission，and 73.4% of all patients had normal ALT before discharge.【Conclusion】Elevated liver function index is very common in patients with COVID-19 infection, and the level were less than 3 × ULN，but most are reversible. The abnormality of 2 or more indexes is low in the patients with COVID-19, but it is more likely to occur in the severe group.